ObjectiveTo investigate the effects of modified Ditan tang on genes related to the transcription-translation feedback loop （TTFL） of biorhythm in the rat model of non-alcoholic fatty liver disease （NAFLD） and its mechanism for prevention and treatment of NAFLD. MethodsSixty-five healthy SPF male SD rats were randomly assigned into blank （n=20）， model （n=15）， and low-， medium-， and high-dose （2.68， 5.36， and 10.72 g·kg^-1·d^-1， respectively） modified Ditan tang （n=10） groups. Other groups except the blank group were fed a high-fat diet for 12 weeks. The modified Ditan tang groups were treated with the decoction at corresponding doses by gavage， and the blank and model groups were treated with an equal volume of normal saline from the 9th week for 4 weeks. The levels of triglyceride （TG）， total cholesterol （TC）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， aspartate aminotransferase （AST）， and alanine aminotransferase （ALT） in the serum were measured by an automatic biochemical analyzer. TG and non-esterified fatty acid （NEFA） assay kits were used to measure the levels of TG and NEFA in the liver. The pathological changes in the hypothalamus and liver were observed by hematoxylin-eosin staining， and the lipid deposition in the liver was observed by oil red O staining. The levels of brain-muscle ARNT-like protein 1 （BMAL1/ARNTL） in the hypothalamus and liver were determined by immunohistochemical staining. The mRNA and protein levels of BMAL1， circadian locomotor output cycles kaput （CLOCK）， period circadian clock 2 （PER2）， and cryptochrome1 （Cry1） in the hypothalamus and liver were determined by Real-time PCR and Western blot， respectively. ResultsCompared with the blank group， the model group showed elevated levels of TG， TC， LDL-C， AST， and ALT （P<0.01） and a lowered level of HDL-C （P<0.05） in the serum， elevated levels of TG and NEFA in the liver （P<0.01）， pyknosis and deep staining of hypothalamic neuron cells， and a large number of vacuoles in the brain area. In addition， the model group showed lipid deposition in the liver， up-regulated mRNA and protein levels of CLOCK and BMAL1 （P<0.01）， and down-regulated mRNA and protein levels of Cry1 and PER2 （P<0.01） in the hypothalamus and liver. Compared with the model group， all the three modified Ditan tang groups showed lowered levels of TG， TC， LDL-C， ALT， and AST （P<0.05， P<0.01） and an elevated level of HDL-C （P<0.05） in the serum， and lowered levels of TG and NEFA （P<0.05， P<0.01） in the liver. Furthermore， the three groups showed alleviated pyknosis and deep staining of hypothalamic neuron cells， reduced lipid deposition in the liver， down-regulated mRNA and protein levels of CLOCK and BMAL1 （P<0.05， P<0.01）， and up-regulated mRNA and protein levels of Cry1 and PER2 （P<0.05， P<0.01） in the hypothalamus and liver. ConclusionModified Ditan tang can reduce lipid deposition in the liver and regulate the expression of CLOCK， BMAL1， Cry1， and PER2 in the TTFL of NAFLD rats.

ObjectiveTo explore the effect of gypenosides （GPs） on liver lipid deposition in metabolism-associated fatty liver disease （MAFLD） mice and its mechanism based on classical/non-classical ferroptosis. MethodsEight male C57BL/6 mice in a blank group and 32 male apolipoprotein E gene knockout （ApoE^-/-） mice were randomly divided into a model group， a low-dose GPs （GPs-L） group， a high-dose GPs （GPs-H） group， and a simvastatin （SV） group. Starting from the second week， mice in the blank group were given a maintenance diet， and the other four groups were fed a high-fat diet daily. After eight weeks of feeding， mice in the GPs-L and GPs-H groups were given GPs of 1.487 mg·kg^-1·d^-1 and 2.973 mg·kg^-1·d^-1， respectively， and mice in the SV group were given simvastatin of 2.275 mg·kg^-1·d^-1. Mice in the blank group and the model group were given saline of equal volume by gavage for four weeks. The content of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， alanine aminotransferase （ALT）， and aspartate aminotransferase （AST） in the serum of mice in each group was detected by an automatic biochemical analyzer. The level of non-esterified fatty acid （NEFA） and TG in the mouse liver was measured by the kit. The change in liver tissue structure and lipid deposition was observed by hematoxylin-eosin （HE） and oil red O staining. The levels of coenzyme Q₁₀ （CoQ₁₀）， glutathione （GSH）， malondialdehyde （MDA）， and Fe²⁺ in serum， as well as nicotinamide adenine dinucleotide phosphate ［NAD（P）H］ in the liver were detected by enzyme-linked immunosorbent assay （ELISA）. The expression of ferroptosis suppressor protein 1 （FSP1） in the liver of mice was observed by the immunohistochemical （IHC） method， and the expression of genes and proteins related to classical and non-classical ferroptosis pathways was analyzed by real-time polymerase chain reaction （Real-time PCR） and Wes automated protein expression analysis system. ResultsCompared with those in the blank group， the levels of TC， TG， LDL-C， ALT， and AST in serum and TG and NEFA in the liver in the model group were significantly increased， and the level of HDL-C in serum was significantly decreased （P<0.01）. The liver tissue structure changed， and there were fat vacuoles of different sizes and a large number of red lipid droplets， with obvious lipid deposition. The level of CoQ10 and GSH in serum and NADH in the liver were significantly decreased， while the level of MDA and Fe²⁺ in serum was significantly increased （P<0.01）. The mRNA and protein expressions of cystine/glutamate transporter （xCT/SLC7A11）， glutathione peroxidase （GPX4）， p62， nuclear factor E₂-related factor 2 （Nrf2）， and FSP1 were significantly decreased， and the mRNA and protein expressions of tumor antigen （p53）， spermidine/spermine N1-acetyltransferase 1 （SAT1）， arachidonate 15-lipoxygenase （ALOX15）， and Kelch-like epichlorohydrin-associated protein-1 （Keap1） were significantly increased （P<0.01）. Compared with those in the model group， the level of TC， TG， LDL-C， ALT， and AST in serum and TG and NEFA in the liver of mice in the GPs-L， GPs-H， and SV groups were decreased， while the level of HDL-C in serum was significantly increased （P<0.05， P<0.01）. The liver tissue structure and lipid deposition were improved. The levels of CoQ10 and GSH in serum and NADH in the liver were significantly increased， while the levels of MDA and Fe²⁺ in serum were significantly decreased （P<0.05， P<0.01）. The mRNA and protein expressions of xCT， GPX4， p62， Nrf2， and FSP1 were significantly increased， while the mRNA and protein expressions of p53， SAT1， ALOX15， and Keap1 were significantly decreased （P<0.05， P<0.01）. ConclusionGPs can interfere with liver lipid deposition in MAFLD mice through classical/non-classical ferroptosis pathways.

ObjectiveTo explore the effect of gypenosides （GPs） on liver lipid deposition in metabolism-associated fatty liver disease （MAFLD） mice and its mechanism based on classical/non-classical ferroptosis. MethodsEight male C57BL/6 mice in a blank group and 32 male apolipoprotein E gene knockout （ApoE^-/-） mice were randomly divided into a model group， a low-dose GPs （GPs-L） group， a high-dose GPs （GPs-H） group， and a simvastatin （SV） group. Starting from the second week， mice in the blank group were given a maintenance diet， and the other four groups were fed a high-fat diet daily. After eight weeks of feeding， mice in the GPs-L and GPs-H groups were given GPs of 1.487 mg·kg^-1·d^-1 and 2.973 mg·kg^-1·d^-1， respectively， and mice in the SV group were given simvastatin of 2.275 mg·kg^-1·d^-1. Mice in the blank group and the model group were given saline of equal volume by gavage for four weeks. The content of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， alanine aminotransferase （ALT）， and aspartate aminotransferase （AST） in the serum of mice in each group was detected by an automatic biochemical analyzer. The level of non-esterified fatty acid （NEFA） and TG in the mouse liver was measured by the kit. The change in liver tissue structure and lipid deposition was observed by hematoxylin-eosin （HE） and oil red O staining. The levels of coenzyme Q₁₀ （CoQ₁₀）， glutathione （GSH）， malondialdehyde （MDA）， and Fe²⁺ in serum， as well as nicotinamide adenine dinucleotide phosphate ［NAD（P）H］ in the liver were detected by enzyme-linked immunosorbent assay （ELISA）. The expression of ferroptosis suppressor protein 1 （FSP1） in the liver of mice was observed by the immunohistochemical （IHC） method， and the expression of genes and proteins related to classical and non-classical ferroptosis pathways was analyzed by real-time polymerase chain reaction （Real-time PCR） and Wes automated protein expression analysis system. ResultsCompared with those in the blank group， the levels of TC， TG， LDL-C， ALT， and AST in serum and TG and NEFA in the liver in the model group were significantly increased， and the level of HDL-C in serum was significantly decreased （P<0.01）. The liver tissue structure changed， and there were fat vacuoles of different sizes and a large number of red lipid droplets， with obvious lipid deposition. The level of CoQ10 and GSH in serum and NADH in the liver were significantly decreased， while the level of MDA and Fe²⁺ in serum was significantly increased （P<0.01）. The mRNA and protein expressions of cystine/glutamate transporter （xCT/SLC7A11）， glutathione peroxidase （GPX4）， p62， nuclear factor E₂-related factor 2 （Nrf2）， and FSP1 were significantly decreased， and the mRNA and protein expressions of tumor antigen （p53）， spermidine/spermine N1-acetyltransferase 1 （SAT1）， arachidonate 15-lipoxygenase （ALOX15）， and Kelch-like epichlorohydrin-associated protein-1 （Keap1） were significantly increased （P<0.01）. Compared with those in the model group， the level of TC， TG， LDL-C， ALT， and AST in serum and TG and NEFA in the liver of mice in the GPs-L， GPs-H， and SV groups were decreased， while the level of HDL-C in serum was significantly increased （P<0.05， P<0.01）. The liver tissue structure and lipid deposition were improved. The levels of CoQ10 and GSH in serum and NADH in the liver were significantly increased， while the levels of MDA and Fe²⁺ in serum were significantly decreased （P<0.05， P<0.01）. The mRNA and protein expressions of xCT， GPX4， p62， Nrf2， and FSP1 were significantly increased， while the mRNA and protein expressions of p53， SAT1， ALOX15， and Keap1 were significantly decreased （P<0.05， P<0.01）. ConclusionGPs can interfere with liver lipid deposition in MAFLD mice through classical/non-classical ferroptosis pathways.

During the Jin dynasty,the two major academic schools of Hejian and Yishui emerged in northern China.At this time,the Song dynasty migrated southward,accompanied by the southward movement of the Han ethnic culture and economic center.The dissemination of medicine also showed a trend of spreading from the north to the south.The late Yuan dynasty was an important period for the academic dissemination of the Yishui school to the south.On the one hand,ZHU Danxi,GE Yinglei,HUA Shou,and other clinicians studied the academic works of LI Dongyuan,comprehended his academic ideas,and further disseminated them through their disciples and Confucian scholars.On the other hand,academic works such as Jisheng Bacui and Weisheng Baojian carrying the study of Yishui were published in the south,playing an essential role in disseminating Yishui's study in the south.The dissemination of Yishui's learning to the south adopted a combination of book learning and mentorship,effectively breaking down the academic barriers between the Hejian and Yishui schools.The network formed by the interaction between medical scholars and Confucian scholars was an essential medium for academic dissemination.The study of Yishui was transmitted to the south and integrated with the original spleen and stomach theory in the south,promoting the further development of traditional Chinese medicine spleen and stomach theory.

Background::Dilated cardiomyopathy (DCM) has a high mortality rate and is the most common indication for heart transplantation. Our study sought to develop a multiparametric nomogram to assess individualized all-cause mortality or heart transplantation (ACM/HTx) risk in DCM patients.Methods::The present study is a retrospective cohort study. The demographic, clinical, blood test, and cardiac magnetic resonance imaging (CMRI) data of DCM patients in the tertiary center (Fuwai Hospital) were collected. The primary endpoint was ACM/HTx. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied for variable selection. Multivariable Cox regression was used to develop a nomogram. The concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance of the nomogram.Results::A total of 218 patients were included in the present study. They were randomly divided into a training cohort and a validation cohort. The nomogram was established based on eight variables, including mid-wall late gadolinium enhancement, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, left ventricular end-diastolic diameter, left ventricular end-diastolic volume index, free triiodothyronine, and N-terminal pro-B type natriuretic peptide. The AUCs regarding 1-year, 3-year, and 5-year ACM/HTx events were 0.859, 0.831, and 0.840 in the training cohort and 0.770, 0.789, and 0.819 in the validation cohort, respectively. The calibration curve and DCA showed good accuracy and clinical utility of the nomogram.Conclusions::We established and validated a circulating biomarker- and CMRI-based nomogram that could provide a personalized prediction of ACM/HTx for DCM patients, which might help risk stratification and decision-making in clinical practice.

During the Jin dynasty,the two major academic schools of Hejian and Yishui emerged in northern China.At this time,the Song dynasty migrated southward,accompanied by the southward movement of the Han ethnic culture and economic center.The dissemination of medicine also showed a trend of spreading from the north to the south.The late Yuan dynasty was an important period for the academic dissemination of the Yishui school to the south.On the one hand,ZHU Danxi,GE Yinglei,HUA Shou,and other clinicians studied the academic works of LI Dongyuan,comprehended his academic ideas,and further disseminated them through their disciples and Confucian scholars.On the other hand,academic works such as Jisheng Bacui and Weisheng Baojian carrying the study of Yishui were published in the south,playing an essential role in disseminating Yishui's study in the south.The dissemination of Yishui's learning to the south adopted a combination of book learning and mentorship,effectively breaking down the academic barriers between the Hejian and Yishui schools.The network formed by the interaction between medical scholars and Confucian scholars was an essential medium for academic dissemination.The study of Yishui was transmitted to the south and integrated with the original spleen and stomach theory in the south,promoting the further development of traditional Chinese medicine spleen and stomach theory.

During the Jin dynasty,the two major academic schools of Hejian and Yishui emerged in northern China.At this time,the Song dynasty migrated southward,accompanied by the southward movement of the Han ethnic culture and economic center.The dissemination of medicine also showed a trend of spreading from the north to the south.The late Yuan dynasty was an important period for the academic dissemination of the Yishui school to the south.On the one hand,ZHU Danxi,GE Yinglei,HUA Shou,and other clinicians studied the academic works of LI Dongyuan,comprehended his academic ideas,and further disseminated them through their disciples and Confucian scholars.On the other hand,academic works such as Jisheng Bacui and Weisheng Baojian carrying the study of Yishui were published in the south,playing an essential role in disseminating Yishui's study in the south.The dissemination of Yishui's learning to the south adopted a combination of book learning and mentorship,effectively breaking down the academic barriers between the Hejian and Yishui schools.The network formed by the interaction between medical scholars and Confucian scholars was an essential medium for academic dissemination.The study of Yishui was transmitted to the south and integrated with the original spleen and stomach theory in the south,promoting the further development of traditional Chinese medicine spleen and stomach theory.

During the Jin dynasty,the two major academic schools of Hejian and Yishui emerged in northern China.At this time,the Song dynasty migrated southward,accompanied by the southward movement of the Han ethnic culture and economic center.The dissemination of medicine also showed a trend of spreading from the north to the south.The late Yuan dynasty was an important period for the academic dissemination of the Yishui school to the south.On the one hand,ZHU Danxi,GE Yinglei,HUA Shou,and other clinicians studied the academic works of LI Dongyuan,comprehended his academic ideas,and further disseminated them through their disciples and Confucian scholars.On the other hand,academic works such as Jisheng Bacui and Weisheng Baojian carrying the study of Yishui were published in the south,playing an essential role in disseminating Yishui's study in the south.The dissemination of Yishui's learning to the south adopted a combination of book learning and mentorship,effectively breaking down the academic barriers between the Hejian and Yishui schools.The network formed by the interaction between medical scholars and Confucian scholars was an essential medium for academic dissemination.The study of Yishui was transmitted to the south and integrated with the original spleen and stomach theory in the south,promoting the further development of traditional Chinese medicine spleen and stomach theory.

During the Jin dynasty,the two major academic schools of Hejian and Yishui emerged in northern China.At this time,the Song dynasty migrated southward,accompanied by the southward movement of the Han ethnic culture and economic center.The dissemination of medicine also showed a trend of spreading from the north to the south.The late Yuan dynasty was an important period for the academic dissemination of the Yishui school to the south.On the one hand,ZHU Danxi,GE Yinglei,HUA Shou,and other clinicians studied the academic works of LI Dongyuan,comprehended his academic ideas,and further disseminated them through their disciples and Confucian scholars.On the other hand,academic works such as Jisheng Bacui and Weisheng Baojian carrying the study of Yishui were published in the south,playing an essential role in disseminating Yishui's study in the south.The dissemination of Yishui's learning to the south adopted a combination of book learning and mentorship,effectively breaking down the academic barriers between the Hejian and Yishui schools.The network formed by the interaction between medical scholars and Confucian scholars was an essential medium for academic dissemination.The study of Yishui was transmitted to the south and integrated with the original spleen and stomach theory in the south,promoting the further development of traditional Chinese medicine spleen and stomach theory.

During the Jin dynasty,the two major academic schools of Hejian and Yishui emerged in northern China.At this time,the Song dynasty migrated southward,accompanied by the southward movement of the Han ethnic culture and economic center.The dissemination of medicine also showed a trend of spreading from the north to the south.The late Yuan dynasty was an important period for the academic dissemination of the Yishui school to the south.On the one hand,ZHU Danxi,GE Yinglei,HUA Shou,and other clinicians studied the academic works of LI Dongyuan,comprehended his academic ideas,and further disseminated them through their disciples and Confucian scholars.On the other hand,academic works such as Jisheng Bacui and Weisheng Baojian carrying the study of Yishui were published in the south,playing an essential role in disseminating Yishui's study in the south.The dissemination of Yishui's learning to the south adopted a combination of book learning and mentorship,effectively breaking down the academic barriers between the Hejian and Yishui schools.The network formed by the interaction between medical scholars and Confucian scholars was an essential medium for academic dissemination.The study of Yishui was transmitted to the south and integrated with the original spleen and stomach theory in the south,promoting the further development of traditional Chinese medicine spleen and stomach theory.