Colorectal cancer， a leading malignant gastrointestinal tumor globally in terms of incidence and mortality， has seen a consistent annual rise in newly diagnosed cases. While conventional therapies like radiotherapy， chemotherapy， and surgery are available， problems such as lack of early diagnosis， poor prognosis， and drug resistance remain significant burdens for patients. Given the complex and diverse pathogenesis of colorectal cancer， there is an urgent clinical need for safe， effective， reliable， and multi-targeted therapeutic strategies. The Hippo signaling pathway， closely linked to mechanisms like tumorigenesis， cancer cell invasion， migration， and drug resistance， extensively participates in the occurrence and development of colorectal cancer， so targeting the signaling pathway for cancer prevention and treatment has become a crucial research direction in recent years. Traditional Chinese medicine （TCM） offers multi-faceted， multi-pathway， and multi-target advantages and becomes an important therapy for colorectal cancer by enhancing patients' immunity， improving the life quality， and prolonging survival. Studies show that the active components of TCM， including flavonoids， terpenoids， phenols， alkaloids， quinones， lignans， and saponins， as well as TCM compounds such as modified Sijunzi decoction， Jiedu Sangen decoction， Jianpi Jiedu compound， and Quyu Jiedu decoction， exhibit significant targeting effects on the Hippo signaling pathway. These TCMs can exert an anti-colorectal cancer effect through various mechanisms， such as inducing cancer cell autophagy and apoptosis， inhibiting epithelial-mesenchymal transition， reversing drug resistance of the tumor， and blocking the cancer cell cycle. This paper reviewed and analyzed Chinese and international research on the action mechanisms of TCM in regulating the Hippo signaling pathway for the prevention and treatment of colorectal cancer with a comprehensive overview presentation， aiming to provide new references and ideas for the clinical application of TCM and the development of new pharmacological agents in the prevention and treatment of colorectal cancer.

Colorectal cancer， a leading malignant gastrointestinal tumor globally in terms of incidence and mortality， has seen a consistent annual rise in newly diagnosed cases. While conventional therapies like radiotherapy， chemotherapy， and surgery are available， problems such as lack of early diagnosis， poor prognosis， and drug resistance remain significant burdens for patients. Given the complex and diverse pathogenesis of colorectal cancer， there is an urgent clinical need for safe， effective， reliable， and multi-targeted therapeutic strategies. The Hippo signaling pathway， closely linked to mechanisms like tumorigenesis， cancer cell invasion， migration， and drug resistance， extensively participates in the occurrence and development of colorectal cancer， so targeting the signaling pathway for cancer prevention and treatment has become a crucial research direction in recent years. Traditional Chinese medicine （TCM） offers multi-faceted， multi-pathway， and multi-target advantages and becomes an important therapy for colorectal cancer by enhancing patients' immunity， improving the life quality， and prolonging survival. Studies show that the active components of TCM， including flavonoids， terpenoids， phenols， alkaloids， quinones， lignans， and saponins， as well as TCM compounds such as modified Sijunzi decoction， Jiedu Sangen decoction， Jianpi Jiedu compound， and Quyu Jiedu decoction， exhibit significant targeting effects on the Hippo signaling pathway. These TCMs can exert an anti-colorectal cancer effect through various mechanisms， such as inducing cancer cell autophagy and apoptosis， inhibiting epithelial-mesenchymal transition， reversing drug resistance of the tumor， and blocking the cancer cell cycle. This paper reviewed and analyzed Chinese and international research on the action mechanisms of TCM in regulating the Hippo signaling pathway for the prevention and treatment of colorectal cancer with a comprehensive overview presentation， aiming to provide new references and ideas for the clinical application of TCM and the development of new pharmacological agents in the prevention and treatment of colorectal cancer.

Colorectal cancer is a common malignant tumor of the digestive system. In recent years， its incidence rate and mortality are increasing year by year. Due to the complex pathogenesis and poor prognosis of patients， colorectal cancer poses a serious threat to human physical and mental health. Currently， although Western medicine treatment methods can to some extent inhibit tumor growth and alleviate patient symptoms， postoperative recurrence， metastasis， multiple adverse reactions， and susceptibility to drug resistance are prominent issues， resulting in unsatisfactory overall treatment outcomes. Therefore， exploring more efficient and safe treatment methods has become an urgent task. The adenosine monophosphate-activated protein kinase （AMPK） signaling pathway plays a regulatory role in the growth， differentiation， apoptosis， and autophagy of colorectal cancer cells， and is widely involved in the occurrence and development of colorectal cancer. It is considered an important target for colorectal cancer treatment. Traditional Chinese medicine has unique advantages in the treatment of colorectal cancer， as it can exert its effects through multiple mechanisms and pathways. It can prevent postoperative recurrence and metastasis， reduce adverse reactions to radiotherapy and chemotherapy， and improve patients' quality of life. It has become a key means of treating colorectal cancer. Research has shown that active ingredients in traditional Chinese medicine such as flavonoids， polyphenols， terpenes， and esters， as well as traditional Chinese medicine compounds such as Qingjie Fuzheng Granules and some traditional Chinese medicine extracts， have significant regulatory effects on AMPK and its interaction signaling pathways. They exert their anti-colorectal cancer effects by inducing autophagy and apoptosis in colorectal cancer cells， promoting ferroptosis， inhibiting epithelial-mesenchymal transition， reversing drug resistance， and arresting the cell cycle. This article reviewed and summarized the relevant research on traditional Chinese medicine in the treatment of colorectal cancer in recent years， with a focus on the mechanism of traditional Chinese medicine in regulating the AMPK signaling pathway for the treatment of colorectal cancer. It is expected to provide ideas and references for the development of new drugs for clinical anti-colorectal cancer treatment.

ObjectiveTo investigate the processing technology of calcined Haematitum based on the concept of quality by design（QbD） and to assess its health risk. MethodsTaking whole iron content， Fe²⁺ dissolution content and looseness as critical quality attributes（CQAs）， and calcination temperature， calcination time， spreading thickness and particle size as critical process parameters（CPPs） determined by the failure mode and effect analysis（FMEA）， the processing technology of calcined Haematitum was optimized by orthogonal test combined with analytic hierarchy process-criteria importance through intercriteria correlation（AHP-CRITIC） hybrid weighting method. The contents of heavy metals and harmful elements were determined by inductively coupled plasma mass spectrometry， and the health risk assessment was carried out by daily exposure（EXP）， target hazard quotient（THQ） and lifetime cancer risk（LCR）， and the theoretical value of the maximum limit was deduced. ResultsThe optimal processing technology for calcined Haematitum was calcination at 650 ℃， calcination time of 1 h， particle size of 0.2-0.5 cm， spreading thickness of 1 cm， and vinegar quenching for 1 time［Haematitum-vinegar（10：3）］. The contents of 5 heavy metals and harmful elements in 13 batches of calcined Haematitum were all decreased with reductions of up to 5-fold. The cumulative THQ of 2 batches of samples was>1， while the cumulative THQ of all batches of Haematitum was>1. The LCR of As in 1 batches of Haematitum was 1×10^-6-1×10^-4， and the LCR of the rest was<1×10^-6， and the LCRs of calcined Haematitum were all<1×10^-6， indicating that the carcinogenic risk of calcined Haematitum was low， but special attention should still be paid to Haematitum medicinal materials. Preliminary theoretical values of the maximum limits of Cu， As， Cd， Pb and Hg were formulated as 1 014， 25， 17， 27， 7 mg·kg^-1. ConclusionThe optimized processing technology of calcined Haematitum is stable and feasible， and the contents of heavy metals and harmful elements are reduced after processing. Preliminary theoretical values of the maximum limits of Cu， As， Cd， Pb and Hg are formulated to provide a scientific basis for the formulation of standards for the limits of harmful elements in Haematitum.

ObjectiveBased on the concept of quality by design（QbD）， the processing process of calcined Pyritum was optimized， and its X-ray diffraction（XRD） fingerprint was established. MethodsThe safety， effectiveness and quality controllability of calcined Pyritum were taken as the quality profile（QTPP）， the color， hardness， metallic luster， phase composition， the contents of heavy metals and hazardous elements were taken as the critical quality attributes（CQAs）， and the calcination temperature， calcination time， paving thickness and particle size were determined as the critical process parameters（CPPs）. Differential thermal analysis， X-ray diffraction（XRD） and inductively coupled plasma mass spectrometry（ICP-MS） were used to analyze the correlation between the calcination temperature and CQAs of calcined Pyritum. Then， based on the criteria importance through intercriteria correlation（CRITIC）-entropy weight method， the optimal processing process of calcined Pyritum was optimized by orthogonal test. Powder XRD was used to analyze the phase of calcined Pyritum samples processed according to the best process， and the mean and median maps of calcined Pyritum were established by the superposition of geometric topological figures， and similarity evaluation and cluster analysis were carried out. ResultsThe results of single factor experiments showed that the physical phase of Pyritum changed from FeS₂ to Fe₇S₈ during the process of temperature increase， the color gradually deepened from dark yellow， and the contents of heavy metals and harmful elements decreased. The optimized processing process of calcined Pyritum was as follows：calcination temperature at 750 ℃， calcination time of 2.5 h， paving thickness of 3 cm， particle size of 0.8-1.2 cm， vinegar quenching 1 time［Pyritum-vinegar（10∶3）］. After calcination， the internal structure of Pyritum was honeycomb-shaped， which was conducive to the dissolution of active ingredients. XRD fingerprints of 13 batches of calcined Pyritum characterized by 10 common peaks were established. The similarities of the relative peak intensities of the XRD fingerprints of the analyzed samples were>0.96， and it could effectively distinguish the raw products and unqualified products. ConclusionTemperature is the main factor affecting the quality of calcined Pyritum. After processing， the dissolution of the effective components in Pyritum increases， and the contents of heavy metals and harmful substances decrease， reflecting the function of processing to increase efficiency and reduce toxicity. The optimized processing process is stable and feasible， and the established XRD fingerprint can be used as one of the quality control standards of calcined Pyritum.

ObjectiveTo investigate the processing technology of calcined Haematitum based on the concept of quality by design（QbD） and to assess its health risk. MethodsTaking whole iron content， Fe²⁺ dissolution content and looseness as critical quality attributes（CQAs）， and calcination temperature， calcination time， spreading thickness and particle size as critical process parameters（CPPs） determined by the failure mode and effect analysis（FMEA）， the processing technology of calcined Haematitum was optimized by orthogonal test combined with analytic hierarchy process-criteria importance through intercriteria correlation（AHP-CRITIC） hybrid weighting method. The contents of heavy metals and harmful elements were determined by inductively coupled plasma mass spectrometry， and the health risk assessment was carried out by daily exposure（EXP）， target hazard quotient（THQ） and lifetime cancer risk（LCR）， and the theoretical value of the maximum limit was deduced. ResultsThe optimal processing technology for calcined Haematitum was calcination at 650 ℃， calcination time of 1 h， particle size of 0.2-0.5 cm， spreading thickness of 1 cm， and vinegar quenching for 1 time［Haematitum-vinegar（10：3）］. The contents of 5 heavy metals and harmful elements in 13 batches of calcined Haematitum were all decreased with reductions of up to 5-fold. The cumulative THQ of 2 batches of samples was>1， while the cumulative THQ of all batches of Haematitum was>1. The LCR of As in 1 batches of Haematitum was 1×10^-6-1×10^-4， and the LCR of the rest was<1×10^-6， and the LCRs of calcined Haematitum were all<1×10^-6， indicating that the carcinogenic risk of calcined Haematitum was low， but special attention should still be paid to Haematitum medicinal materials. Preliminary theoretical values of the maximum limits of Cu， As， Cd， Pb and Hg were formulated as 1 014， 25， 17， 27， 7 mg·kg^-1. ConclusionThe optimized processing technology of calcined Haematitum is stable and feasible， and the contents of heavy metals and harmful elements are reduced after processing. Preliminary theoretical values of the maximum limits of Cu， As， Cd， Pb and Hg are formulated to provide a scientific basis for the formulation of standards for the limits of harmful elements in Haematitum.

ObjectiveBased on the concept of quality by design（QbD）， the processing process of calcined Pyritum was optimized， and its X-ray diffraction（XRD） fingerprint was established. MethodsThe safety， effectiveness and quality controllability of calcined Pyritum were taken as the quality profile（QTPP）， the color， hardness， metallic luster， phase composition， the contents of heavy metals and hazardous elements were taken as the critical quality attributes（CQAs）， and the calcination temperature， calcination time， paving thickness and particle size were determined as the critical process parameters（CPPs）. Differential thermal analysis， X-ray diffraction（XRD） and inductively coupled plasma mass spectrometry（ICP-MS） were used to analyze the correlation between the calcination temperature and CQAs of calcined Pyritum. Then， based on the criteria importance through intercriteria correlation（CRITIC）-entropy weight method， the optimal processing process of calcined Pyritum was optimized by orthogonal test. Powder XRD was used to analyze the phase of calcined Pyritum samples processed according to the best process， and the mean and median maps of calcined Pyritum were established by the superposition of geometric topological figures， and similarity evaluation and cluster analysis were carried out. ResultsThe results of single factor experiments showed that the physical phase of Pyritum changed from FeS₂ to Fe₇S₈ during the process of temperature increase， the color gradually deepened from dark yellow， and the contents of heavy metals and harmful elements decreased. The optimized processing process of calcined Pyritum was as follows：calcination temperature at 750 ℃， calcination time of 2.5 h， paving thickness of 3 cm， particle size of 0.8-1.2 cm， vinegar quenching 1 time［Pyritum-vinegar（10∶3）］. After calcination， the internal structure of Pyritum was honeycomb-shaped， which was conducive to the dissolution of active ingredients. XRD fingerprints of 13 batches of calcined Pyritum characterized by 10 common peaks were established. The similarities of the relative peak intensities of the XRD fingerprints of the analyzed samples were>0.96， and it could effectively distinguish the raw products and unqualified products. ConclusionTemperature is the main factor affecting the quality of calcined Pyritum. After processing， the dissolution of the effective components in Pyritum increases， and the contents of heavy metals and harmful substances decrease， reflecting the function of processing to increase efficiency and reduce toxicity. The optimized processing process is stable and feasible， and the established XRD fingerprint can be used as one of the quality control standards of calcined Pyritum.

ObjectiveTo explore the possible mechanisms of electroacupuncture at Fengchi （GB 20）， Waiguan （TE 5）， and Yanglingquan （GB 34） in treating chronic migraine from the perspective of nociceptive sensitization. MethodsForty SPF-grade SD rats were randomly divided into blank group， model group， electroacupuncture group， electroacupuncture + agonist group， and inhibitor group， with 8 rats in each group. Except for the blank group， rats were injected intraperitoneally with nitroglycerin to establish a chronic migraine rat model. After successful modeling， the electroacupuncture group received electroacupuncture at bilateral "Fengchi" （GB 20）， "Waiguan" （TE 5）， and "Yanglingquan" （GB 34） for 30 minutes each session. The electroacupuncture + agonist group received the same electroacupuncture treatment and additional injection of protein kinase C （PKC） agonist Phorbol 12-myristate 13-acetate （1.0 ng/μl， 25 μl） via the infraorbital foramen. The inhibitor group received PKC inhibitor Chelerythrine Chloride （1.0 ng/μl， 10 μl） via the infraorbital foramen. The blank group， model group， and inhibitor group underwent restraint for 30 minutes without other interventions. All groups were continuously intervened for 5 days. After the intervention， the nociceptive thresholds （mechanical and thermal pain） of the periorbital area and hind paw were measured. The expression levels of transient receptor potential vanillic acid subtype 1 （TRPV1）， phosphorylated TRPV1 （p-TRPV1）， PKC proteins， Trpv1， Pkc mRNA， and the average fluorescence intensity of transient receptor potential vanillic acid subtype 1 （TRPV1） and PKC in the trigeminal ganglion were detected using Western Blot， real-time fluorescence quantitative PCR， and immunofluorescence methods. ResultsCompared with the blank group， the mechanical and thermal pain thresholds of the periorbital area and hind paw were reduced in the model group， and the protein levels of TRPV1， PKC， p-TRPV1， as well as the mRNA expression of Trpv1 and Pkc， and the average fluorescence intensity of TRPV1 and PKC in the trigeminal ganglion significantly increased （P＜0.05 or P＜0.01）. Compared with the model group， the electroacupuncture group exhibited increased mechanical and thermal pain thresholds in the periorbital and hind paw areas， and decreased protein levels of TRPV1， PKC， p-TRPV1， mRNA expression of Trpv1 and Pkc， and average fluorescence intensity of TRPV1. In the electroacupuncture + agonist group， the average fluorescence intensity of TRPV1 in the trigeminal ganglion decreased. The inhibitor group exhibited increased mechanical pain thresholds in the periorbital area and thermal pain thresholds in the hind paw， along with decreased protein levels of TRPV1， PKC， p-TRPV1， and the average fluorescence intensity of TRPV1 and PKC （P＜0.05 or P＜0.01）. Compared with the electroacupuncture group， the electroacupuncture + agonist group showed an increase in the protein levels of TRPV1， PKC， p-TRPV1， and the mRNA expression of Trpv1 （P＜0.05 or P＜0.01）. ConclusionElectroacupuncture at the "Fengchi" （GB 20）， "Waiguan" （TE 5）， and "Yanglingquan" （GB 34） acupoints can increase the mechanical and thermal pain thresholds in chronic migraine rats and alleviate nociceptive sensitization. The mechanism may be related to the inhibition of PKC/TRPV1 pathway.

Objective To explore the association between the relative expression level of SNORD55 in peripheral blood and the outcomes of all-cause mortality and stroke in patients with atrial fibrillation(AF),and to evaluate the predictive value of SNORD55 for prognosis.Methods A total of 133 patients with non-valvular AF admitted in Department of Cardiology of the First Affiliated Hospital of Army Medical University from January 2014 to December 2017 were enrolled in this study.Their baseline information was collected,and the relative expression level of plasma SNORD55 was detected.Cox proportional hazards model was used to explore the association between the relative expression level of SNORD55 in peripheral blood and all-cause mortality as well as stroke in the patients.The predictive performance of CHA2DS2-VASc score for all-cause mortality and stroke was compared with the score combined with the relative expression level of SNORD55 in the AF patients.The area under the receiver operating characteristic curve(AUC)was utilized to evaluate the discrimination,and the net reclassification index(NRI)and comprehensive discriminant improvement index(IDI)were calculated to evaluate the improvement of reclassification ability.Decision curve analysis(DCA)was applied to analyze the change in clinical net benefit.Results The results of multivariate Cox regression showed that high expression of SNORD55 in peripheral blood was an independent risk factor for all-cause mortality and stroke in the AF patients.In predicting the outcomes of all-cause mortality and stroke,the addition of relative expression SNORD55 level with the CHA2DS2-VASc score obtained higher AUC value[0.80(95％CI:0.67～0.93)vs 0.67(95％CI:0.53～0.81),P＜0.05].In predicting the outcome of all-cause death and stroke,combination of the relative expression level of SNORD55 with CHA2DS2-VASc score increased both NRI[54.3(95％CI:10.6～61.9)vs 31.9(95％CI:2.8～47.5),P＜0.05]and IDI[16.1(95％CI:2.4～27.0)vs 7.9(95％CI:0.5～14.8),P＜0.05].The results of DCA showed that our combination of CHA2DS2-VASc score relative expression level of SNORD55 had higher clinical net benefits than the foreign ABC score in the prediction of the outcomes.Conclusion Peripheral blood SNORD55 level is an independent risk factor for all-cause mortality and stroke in AF patients,and has good predictive performance for all-cause mortality and stroke in the patients.

Objectives To explore the association of peripheral blood PIWI-interacting RNA,piR-hsa-2700592,with all-cause mortality and stroke outcomes in patients with atrial fibrillation(AF),and to determine whether piR-hsa-2700592 has the potential to be an AF biomarker.Methods A total of 127 patients with non-valvular AF were enrolled,and the relative expression level of plasma piR-hsa-2700592 was detected.Cox proportional hazard regression was used to analyze the correlation between the expression of piR-hsa-2700592 and all-cause death as well as stroke outcome in the patients.Then the molecule expression level was combined with CHA2DS2-VASc score and ABC stroke(or death)score to establish 2 new prediction models,the improvement of the predictive performance was compared and analyzed.Receiver operating characteristic(ROC)curve analysis(area under the curve,AUC),net reclassification index(NRI),and comprehensive discriminant improvement index(IDI)were used to evaluate the predictive performance,and decision curve analysis(DCA)was employed to assess the clinical benefit.Results Multivariate Cox regression analysis showed that the patients with higher expression level of piR-hsa-2700592 in peripheral blood had a higher risk of stroke(HR:2.203,95%CI:1.120～4.332;P=0.022).In the stroke outcome,combination of plasma piR-hsa-2700592 expression level with CHA2DS2-VASc score and ABC stroke score obtained an AUC of 0.70(95%CI:0.55～0.85,P＜0.001)and 0.84(95%CI:0.73～0.96,P=0.02),respectively.But,no significant association was observed between high plasma piR-hsa-2700592 level and all-cause mortality in the AF patients(HR:1.997;95%CI:0.884～4.509;P=0.096).Combination of plasma piR-hsa-2700592 level improved the discriminative capability than the single CHA2DS2-VASc score and ABC stroke score models,with an NRI and IDI value of 44.20%(95%CI:3.40～59.90,P＜0.001)and 8.20%(95%CI:0.60～15.40,P＜0.001),respectively for the new CHA2DS2-VASc score model,and an NRI and IDI value of 44.20%(95%CI:9.80～58.90,P＜0.001)and 10.40%(95%CI:0.70～21.40,P＜0.001),respectively for the new ABC stroke score model.The DCA curve showed that both new prediction models obtained better net clinical benefits.Conclusion High peripheral blood expression of piR-hsa-2700592 is an independent risk factor for stroke in the AF patients,and the indicator has a good predictive value for prognosis of the patients.piR-hsa-2700592 might be used as a potential biomarker in the diagnosis and prevention of cardiovascular diseases.