Metabolic associated fatty liver disease (MAFLD) is fundamentally driven by an imbalance in hepatic fatty-acid flux: the influx of fatty acids exceeds the liver’s capacity for disposal, resulting in excessive hepatic lipid accumulation, predominantly in the form of triglycerides (TGs). The occurrence and progression of MAFLD depend on disordered regulation across multiple metabolic steps, including fatty-acid uptake, de novo lipogenesis (DNL), fatty-acid oxidation (FAO), and very low-density lipoprotein (VLDL) export. Forkhead box protein O1 (FOXO1) is a key transcriptional regulator within the hepatic network coordinating glucose and lipid metabolism. Under metabolic stress and insulin resistance (IR), FOXO1 expression is frequently increased, whereas its inhibitory phosphorylation is reduced. These changes enhance FOXO1 nuclear localization and transcriptional activity, thereby reprogramming the expression of genes related to metabolism in the liver. Because hepatic lipid deposition is the central pathological feature of MAFLD, the functional status of FOXO1 directly influences hepatic lipid homeostasis. Growing evidence suggests that FOXO1 can exert bidirectional, environment-dependent effects on hepatic lipid accumulation; however, the molecular basis for this functional switch remains incompletely understood. This review systematically summarizes the biological functions and regulatory mechanisms of FOXO1 and its roles in hepatic lipid metabolism, with a particular focus on its crosstalk with insulin signaling. FOXO1 expression is shaped by RNA modifications and epigenetic regulation mediated by non-coding RNAs. Its transcriptional output is precisely governed by post-translational modifications—such as phosphorylation and acetylation—as well as by coordinated nucleocytoplasmic shuttling. Notably, these regulatory patterns vary markedly across nutritional states, degrees of insulin resistance, and stages of disease. In the fed state, insulin/IGF-1 signaling activates the PI3K-AKT pathway, promoting the inhibitory phosphorylation of FOXO1 and facilitating additional modifications, including acetylation, methylation, and ubiquitination. Together, these events drive FOXO1 export from the nucleus and dampen its transcriptional activity, suppressing gluconeogenesis and constraining lipogenic programs. Conversely, during fasting or when insulin signaling is weakened, FOXO1 inhibition is relieved. FOXO1 accumulates in the nucleus, binds to DNA, and regulates the transcription of downstream target genes. Mechanistically, FOXO1 can aggravate hepatic lipid accumulation by activating genes involved in TG synthesis while repressing FAO-related pathways, thereby favoring storage over oxidation. However, under specific conditions, FOXO1 may also alleviate the hepatic lipid burden by promoting TG hydrolysis and enhancing VLDL secretion, thereby reducing the net hepatic lipid load. In addition, lipotoxic signals mediated by ceramides and diacylglycerols (Cer/DAG) activate atypical protein kinase C (aPKC), further exacerbating the disruption of the AKT-FOXO1 axis. This vicious cycle ultimately produces a metabolic paradox in which increased hepatic glucose output coexists with persistent, insulin-independent lipogenesis, accelerating MAFLD progression. Importantly, FOXO1 regulation is not uniform: during early metabolic overload, insulin-mediated suppression may remain effective, whereas in advanced insulin resistance, the loss of AKT control permits sustained FOXO1 activity. Such stage-dependent dynamics may help explain why FOXO1 can either promote steatosis or, in certain contexts, support programs that facilitate lipid turnover. Accordingly, interventions should be liver-specific and tuned to the disease stage, aiming to curb maladaptive FOXO1 signaling while preserving its capacity to promote triglyceride hydrolysis and VLDL secretion when advantageous. Overall, this review offers an important perspective on MAFLD pathogenesis, emphasizing FOXO1 as a potential therapeutic target and providing a theoretical basis for developing liver-specific, disease-course-dependent precision interventions.

eIF3a is a N ⁶-methyladenosine (m⁶A) reader that regulates mRNA translation by recognizing m⁶A modifications of these mRNAs. It has been suggested that eIF3a may play an important role in regulating translation initiation via m⁶A during infection when canonical cap-dependent initiation is inhibited. However, the death of animal model studies impedes our understanding of the functional significance of eIF3a in immunity and regulation in vivo. In this study, we investigated the in vivo function of eIF3a using eIF3a knockout and knockdown mouse models and found that eIF3a deficiency resulted in splenic tissue structural disruption and multi-organ damage, which contributed to severe sepsis induced by Lipopolysaccharide (LPS). Ectopic eIF3a overexpression in the eIF3a knockdown mice rescued mice from LPS-induced severe sepsis. We further showed that eIF3a maintains a functional and healthy immune system by regulating B cell function and quantity through m⁶A modification of mRNAs. These findings unveil a novel mechanism underlying sepsis, implicating the pivotal role of B cells in this complex disease process regulated by eIF3a. Furthermore, eIF3a may be used to develop a potential strategy for treating sepsis.

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective To observe the effects of Bushen Huoxue Prescription on the pathway related to necroptosis of nucleus pulposus cells in a model rabbit of intervertebral disc degeneration;To explore its mechanisms in delaying intervertebral disc degeneration.Methods A intervertebral disc degeneration rabbit model was established using the spinal instability method.Totally 40 model rabbits were randomly divided into model group,ibuprofen group and Bushen Huoxue Prescription low-,medium-and high-dosage groups.Additionally,a normal control group and a sham-operation group were set up,with 8 rabbits in each group.Each treatment groups received the corresponding drugs via gavage for two consecutive weeks.HE staining was used to observe morphology of nucleus pulposus tissue,transmission electron microscopy was used to observe ultrastructure in nucleus pulposus cells,immunohistochemical staining was used to assess the expressions of Aggrecan and Collagen Ⅱ in nucleus pulposus tissue,Western blot was used to detect the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein in nucleus pulposus tissue.Results Compared with the sham-operation group,the model group showed a significant decrease in nucleus pulposus cells,disordered cell arrangement,reduced extracellular matrix,interrupted cell membrane continuity under transmission electron microscopy,organelle swelling,nuclear membrane disruption,partial chromatin loss,and positive expression of Aggrecan and Collagen Ⅱ in nucleus pulposus tissue decreased(P<0.01),while the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein significantly increased(P<0.01).Compared with the model group,the treatment groups showed an increased number of nucleus pulposus cells with orderly arrangement and more extracellular matrix,the ultrastructural damage of the cell membrane,organelle and nucleus in nucleus pulposus cells was partially restored under transmission electron microscopy,the positive expressions of Aggrecan and Collagen Ⅱ significantly increased in Bushen Huoxue Prescription medium-and high-dosage groups and the ibuprofen group(P<0.05,P<0.01),while the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein significantly decreased(P<0.05,P<0.01).Conclusion Bushen Huoxue Prescription may delay intervertebral disc degeneration of the model rabbit by inhibiting the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein in nucleus pulposus cells,and promoting the generation of extracellular matrix components Aggrecan and Collagen Ⅱ.

Objective To observe the effects of Bushen Huoxue Prescription on pressure-induced necroptosis in human nucleus pulposus cells and the expressions of RIPK1/RIPK3/MLKL pathway;To explore its potential mechanism in delaying intervertebral disc degeneration.Methods Human primary nucleus pulposus cells were cultured in vitro,and a model of nucleus pulposus cell degeneration was established using continuous load pressure method.After modeling,the nucleus pulposus cells were divided into model group,Bushen Huoxue Prescription group and inhibitor group,blank serum,Bushen Huoxue Prescription containing serum and necroptotic apoptosis inhibitor(Nec-1)intervention were administered,respectively.Normal group nucleus pulposus cells were cultured routinely.AO/EB fluorescence dual staining method was used for detecting cell apoptosis,flow cytometry was used to detect the necroptosis rate of nucleus pulposus cells,Western blot was used to detect the protein expressions of p-receptor interacting protein kinase(RIPK)1,p-RIPK3 and p-mixed lineage kinase domain like protein(MLKL),RT-qPCR was used to detect the mRNA expressions of RIPK1,RIPK3 and MLKL.Results Compared with the normal group,the model group showed more red fluorescence under AO/EB staining of nucleus pulposus cells,which were round and condensed,the necroptosis rate of nucleus pulposus cells increased(P<0.05),the protein expressions of p-RIPK1,p-RIPK3 and p-MLKL increased(P<0.05,P<0.01),while there was no significant difference in RIPK1 mRNA expression(P>0.05),and RIPK3 and MLKL mRNA expression increased(P<0.01).Compared with the model group,Bushen Huoxue Prescription group and the inhibitor group had less red condensed chromatin in the nucleus pulposus cells,Bushen Huoxue Prescription group had a lower rate of necroptosis(P<0.05),while the inhibitor group showed a decreasing trend in necroptosis rate(P>0.05),the protein expressions of p-RIPK1,p-RIPK3 and p-MLKL decreased in Bushen Huoxue Prescription group and the inhibitor group(P<0.05,P<0.01),while there was no significant difference in RIPK1 mRNA expression(P>0.05),and RIPK3 and MLKL mRNA expressions decreased(P<0.01).Conclusion Bushen Huoxue Prescription can alleviate pressure-induced damage to nucleus pulposus cells and inhibit necroptosis,thereby slowing the progression of intervertebral disc degeneration.Its mechanism may be related to the RIPK1/RIPK3/MLKL pathway mediated necroptosis.

Germplasm degeneration occurs during the long-term cultivation of root-and rhizome-derived traditional Chinese medicine(RR-TCM), which seriously restricts the high-quality development of their industry. Therefore, it is urgent to solve the problem of germplasm degeneration through variety breeding. In this paper, based on previously published research articles, monographs, and news reports, the research progresses on the number and origins, breeding methods, and selection of new varieties of RR-TCM listed in the Chinese Pharmacopoeia(Edition 2020) were summarized and analyzed. The results show that there are 169 kinds of RR-TCM listed in the Chinese Pharmacopoeia(Edition 2020), originated from 223 origins with three breeding methods(i.e., seed propagation, vegetative reproduction, and tissue culture), and there are 215 species derived from seed propagation, 177 species derived from vegetative reproduction, and 164 species derived from tissue culture. To date, there are 62 origins breeding new varieties through conventional breeding, cross breeding, mutation breeding, ploidy breeding, or modern biotechnology breeding methods, including 57 origins breeding 145 new varieties through conventional breeding, 10 origins breeding 43 new varieties through mutation breeding, and seven origins breeding 12 new varieties through cross breeding method. They are used mainly to improve yield, disease resistance, and active ingredient content, but only a few new varieties have been widely used. This review will provide useful references in variety breeding, quality breeding, and standardized planting of RR-TCM.
Plant Breeding/methods* ; Plant Roots/growth & development* ; Rhizome/growth & development* ; Drugs, Chinese Herbal ; Plants, Medicinal/classification* ; Medicine, Chinese Traditional

A high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS) method was established for simultaneous determination of seven characteristic components from the active fraction of Alpiniae Officinarum Rhizoma in rat plasma, including galangin, kaempferol, kaempferide, pinocembrin, 1,7-diphenyl-4-en-3-heptanone, 5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-phenyl-3-heptanone(DHPA), and 7-(4-hydroxy-3-methoxyphenyl)-1-phenyl-4-en-3-heptanone(DPHB). The new developed HPLC-MS/MS method was applied to study the pharmacokinetics of the 7 characteristic components in rats with Helicobacter pylori gastritis. A Waters Sunfire C_(18) column(2.1 mm×150 mm, 3.5 μm) was used. The acetonitrile-aqueous solution(containing 0.1% formic acid) was adopted as the mobile phase for gradient elution. Seven components and internal standard(chlorogenic acid) were separated within 12 min. Mass spectrometric detection was performed in multiple reaction monitoring(MRM) mode using electrospray ionization(ESI) source with fast switching between positive and negative ions. The method was verified by specificity, linearity, precision, accuracy, recovery, matrix effect, and stability and met the requirements of pharmacokinetic study on the 7 components in rat plasma. Pharmacokinetic results showed that the average peak time(T_(max)) of the 7 components was 0.31-2.19 h, their elimination half-life(t_(1/2)) was 5.26-16.65 h, and the average residence time(MRT) was 6.29-31.03 h after the oral administration of the active fraction of Alpiniae Officinarum Rhizoma to rats with H. pylori gastritis. The plasma exposure levels of galangin and DHPA were higher than those of the other components. The concentration-time curves of four detected flavonoids showed obvious double peaks. This study elucidated the pharmacokinetic characteristics of 7 characteristic components from the active fraction of Alpiniae Officinarum Rhizoma in rats with H. pylori gastritis, providing a scientific basis for the identification of the pharmacodynamic substances of Alpiniae Officinarum Rhizoma for treatment of H. pylori gastritis and the clinical application of Alpiniae Officinarum Rhizoma in the prevention and treatment of H. pylori gastritis.
Animals ; Rats ; Chromatography, High Pressure Liquid/methods* ; Tandem Mass Spectrometry/methods* ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Helicobacter pylori/drug effects* ; Alpinia/chemistry* ; Rats, Sprague-Dawley ; Gastritis/metabolism* ; Helicobacter Infections/metabolism* ; Flavonoids/blood* ; Rhizome/chemistry* ; Liquid Chromatography-Mass Spectrometry

One of the most common adverse reactions associated with cancer and its treatment is sarcopenia,a syndrome primarily caused by the disruption of muscle homeostasis,leading to excessive muscle atrophy and decreased muscle strength.For cancer patients,sarcopenia reflects not only a state of muscle mass loss but also serves as an important factor affecting treatment efficacy and survival rates.However,cancer-related sarcopenia often has a more insidious onset,is not visible to the naked eye,and is easily overlooked.Therefore,it is necessary to recognize the dangers of sarcopenia throughout the cancer treatment process and to identify low muscle mass early.In recent years,as healthcare professionals have increasingly focused on sarcopenia,research on cancer-related sarcopenia has gradually deepened,with new advancements in its assessment,diagnosis,intervention,and impact on anti-cancer treatment.This article provides a review of these key areas to offer a theoretical basis for the clinical practice of cancer-related sarcopenia.

Objective To develop and validate a prediction model to identify high-risk individuals who are at-risk to develop acute liver injury(ALI)within 180 days in new statin users,and to support early clinical intervention.Methods Data were sourced from the Yinzhou Regional Health Information Platform,covering statin initiators aged 18 years and older from January 1,2010,to October 31,2021.The dataset was divided into a derivation cohort and a temporal validation cohort based on the time of statin initiation.Predictors were selected using LASSO regression,and the model was constructed using the extreme gradient boosting(XGBoost)algorithm combined with cost-sensitive learning.Model performance was evaluated using Brier scores,Harrell's C-index,and calibration curves.Results A total of 126,440 statin initiators were included,with 90,542 in the derivation cohort and 35,898 in the validation cohort.Within 180 days of initial statin use,412(0.33％)patients developed ALI,including 305(0.34％)in the derivation cohort and 107(0.30％)in the validation cohort.The final model incorporated 16 predictors,which included demographic characteristics,lifestyle factors,family history,medical history,statin use,and concomitant medication use.The model demonstrated excellent overall performance[Brier score=0.0043,95％CI(0.0038,0.0049)],discrimination[Harrell's C-index=0.761,95％CI(0.725,0.794)],and calibration in internal validation.In temporal validation,the model also performed well[Brier score=0.0044,95％CI(0.0036,0.0052),Harrell's C-index=0.703,95％CI(0.614,0.781)].Conclusion This study develope and validate a prediction model for ALI in statin users,providing clinicians with a reliable tool for individualized risk assessment.This model can help achieve risk stratification and reduce the occurrence of ALI.

Objective:To analyze the current management status of real-world studies (RWS) in the medical institutions in China and suggest improvement focus for the management optimization.Methods:Surveys were conducted in 81 medical institutions nationwide. Convenience sampling was used to recruit survey subjects, and data were collected through self-administered questionnaires, followed by statistical analysis using descriptive methods.Results:The survey results indicated that 92.6% (75/81) of the medical institutions surveyed had undertaken RWS projects, with electronic medical records being the primary data source (89.3%, 67/75). Retrospective and prospective observational studies were the main types of study designs. Additionally, 96.3% (78/81) of the research subjects indicated that their medical institution expressed willingness to participate in or undertake RWS projects in the future. In terms of management, all types of RWS projects were managed by clinical trial center (24.0, 18/75), but differences existed in the management practices among medical institutions. Moreover, the challenges in data quality and standardization, study design and staff training, data and privacy protection and information technology support appeared in the management of RWS projects.Conclusions:It suggests to optimize the management processes of RWS projects in medical institutions and improve relevant laws and regulations to promote the development of RWS in China.