Sutong Liu’s research while affiliated with First Affiliated Hospital of China Medical University and other places

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Publications (9)


Identification of Ferroptosis -Related Genes in MAFLD/MASH and HQHF Validation
  • Article
  • Full-text available

May 2025

Hepatic Medicine Evidence and Research

Sutong Liu

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Lihui Zhang

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Junjiao Xu

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Wenxia Zhao
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The role of E3s and DUBs in TAK1, ASK1 and mTOR signaling pathway in NAFLD. (1) TAK1, also known as MAP3K7, MAP3K7 promotes lipid deposition, inflammation, and pro-fibrotic factors by phosphorylating its downstream JNK/p38 signaling. The E3 ubiquitin ligases TRIM8, TRAF6, and TRAF3 can ubiquitinate and phosphorylate MAP3K7, activating the downstream JNK/p38 signaling cascade and aggravating liver steatosis, inflammation, and fibrosis. However, the deubiquitinases USP4, USP18, and CYLD can stop this process. Rhbdf2 can activate the MAP3K7 signaling pathway, but TRIM31 can block it through ubiquitination function, which degrades Rhbdf2 and phosphorylates MAP3K7. TRIM16 can also enhance the ubiquitination and degradation of phosphorylated MAP3K7 while inhibiting the downstream JNK/p38 signaling cascade. (2) ASK1, also known as MAP3K5, MAP3K5 promotes lipid deposition, inflammation, and pro-fibrotic factors by phosphorylating its downstream JNK/p38 signaling. The E3 ubiquitin ligases FBXW5 and TRAF6 can ubiquitinate and phosphorylate MAP3K5, activating the downstream JNK/p38 signaling cascade and aggravating liver steatosis, inflammation, and fibrosis. The deubiquitinase OTUB1 directly binds to TRAF6, boosting its deubiquitination, therefore decreasing TRAF6-mediated MAP3K5 ubiquitination and activation, and alleviating NASH. (3) The mTOR signaling pathway can modulate SREBP-1c transcription, inhibit autophagy, promote lipid accumulation, and activate NLRP3. E3 ubiquitin ligase FBW7 can enhance proteasome-mediated degradation of mTOR via ubiquitination, block downstream signal activation, and help avoid NAFLD. CUL4A, an E3 ubiquitin ligase, causes SHIP2 degradation through ubiquitination. The reduction of SHIP2 protein leads to the accumulation of PI3K, which then activates the downstream AKT signaling pathway, promoting adipogenesis, inflammation, and HCC progression. DDX5 may recruit the TSC1/2 complex to mTORC1, preventing downstream signal transduction, whereas the E3 ubiquitin ligase TRIM5 can enhance proteasome-mediated degradation of DDX5 via ubiquitination, reducing its inhibitory effect on mTORC1 signal transduction. MUL1, an E3 ubiquitin ligase, can promote AKT ubiquitination and degradation via BCAAs/BCKAs, inhibiting adipogenesis. CUL4B-DDB1, an E3 ubiquitin ligase, can enhance proteasome-mediated degradation of Raptor via ubiquitination, while inhibiting mTORC1 signaling transduction. USP7 deubiquitinates CREB and ZNF638, triggering the AKT signaling pathway. USP7 can also deubiquitinate Cleaved SREBP-1c, which exacerbates NAFLD.
The role of E3s and DUBs in SIRT, TGF-β, JAK, TLR4 and STING signaling pathway in NAFLD. (1) ATGL stimulates the autophagy signaling pathway via SIRT1, promotes fatty acid beta oxidation, and decreases liver steatosis. E3 ubiquitin ligase RFWD2 targets ATGL proteasome degradation, while E3 ubiquitin ligase Grail targets SIRT1 proteasome degradation, which increases FA and hepatic lipid accumulation. The deubiquitinase USP22 can deubiquitinate SIRT1, stabilize SIRT1, and have anti-NAFLD actions. USP10, a deubiquitinase, can prevent NAFLD by stabilizing SIRT6 and blocking downstream signaling pathways such as NF-κB and SREBP. (2) TrkB can suppress the TGF-β/Smad signaling pathway, alleviating NASH-related liver fibrosis. Ndfip1 can ubiquitinate and degrade TrkB via the E3 ubiquitin ligase Nedd4L, aggravating NASH-associated liver fibrosis. (3) The activation of JAK2/STAT5/PPAR gamma axis increases hepatic lipid accumulation. ARID2 can impede downstream signal transduction by ubiquitinating and degrading JAK2 via the E3 ubiquitin ligase Nedd4L. (4) TLR4 can activate the MVB lysosome signaling pathway, causing inflammation, insulin resistance, and glucose metabolism disorders, aggravating NASH. The E3 ubiquitin ligase Nedd4L activates Tmbim1 via ubiquitination, boosting lysosomal degradation of TLR4 and improving NASH. (5) The E3 ubiquitin ligase RNF13 catalyzes TRIM29, increasing its stability. Ubiquitinated TRIM29 causes STING to be degraded by proteasomes, which inhibits hepatic lipid accumulation and inflammation.
The role of E3s and DUBs in NAFLD-related ERS, mitochondrial malfunction, and lipid autophagy. (1) E3 ubiquitin ligases CHIP and Nedd4L can ubiquitinate and degrade TXNIP in the endoplasmic reticulum stress pathway, inhibiting liver lipid deposition, inflammation, and fibrosis. TRIB3 recruits E3 ubiquitin ligase TRIM8 to degrade HNF4α and prevent NAFLD. E3 ubiquitin ligase Gp78 catalyzes the ubiquitination and degradation of unfolded proteins in the endoplasmic reticulum, relieving endoplasmic reticulum stress and inhibiting NASH and HCC. (2) The deubiquitinase USP14 deubiquitinates both FASN and HSP90AA1, boosting TG production and mitochondrial dysfunction, aggravating liver steatosis, inflammation, and fibrosis. Miz1, which promotes mitochondrial autophagy, can be degraded by ubiquitination, thereby inhibiting mitochondrial autophagy and exacerbating NASH. (3) HMGB1 promotes lipid autophagy, degrades lipid droplets, and helps to avoid NAFLD. In NAFLD, HMGB1 can be ubiquitinated and degraded by E3 ubiquitin ligase RNF186, thereby promoting the development of NAFLD.
The role of other E3s and DUBs in NAFLD. (1) FASN may activate hepatic lipid synthesis, SNX8 can recruit the E3 ubiquitin ligase TRIM28 to degrade FASN protein, and TRIM56 can also trigger FASN proteasomal pathway degradation, slowing the progression of NAFLD. (2) Kindlin-2 can bind to Foxo1 and inhibit Skp2 mediated ubiquitination of Foxo1 protein, enhancing its protein stability and leading to hepatic steatosis. (3) Acly is an enzyme that facilitates the biosynthesis of fatty acids. Hrd1, an E3 ubiquitin ligase, ubiquitinates and degrades Acly, which inhibits liver fat synthesis. Other research has found that overexpression of Hrd1 worsens hepatic steatosis, inflammation, and fibrosis. The E3 ubiquitin ligase RNF5 can ubiquitinate and degrade Hrd1, slowing the progression of NASH. (4) USP15 deubiquitinates FABPs and Perilipins, increasing their stability and promoting liver lipid accumulation. (5) E3 ubiquitin ligase Ubr1 improves hepatic steatosis by degrading Plin2. When essential amino acids are deficient, Ubr1 becomes inactive, and increased Plin2 protein levels limit liver lipolysis, resulting in NAFLD in lean individuals. (6) The E3 ubiquitin ligase UBE3A can enhance proteasome-mediated degradation of PDHA1 and ACAT1 via ubiquitination, while also inhibiting glycolysis and lipid synthesis. (7) The E3 ubiquitin ligase MDM2 enhances proteasome-mediated degradation of HSF1 via ubiquitination, decreasing its inhibitory impact on NLRP3 and activating NLRP3 inflammasomes. (8) MDM2 promotes proteasome-mediated degradation of ALR via ubiquitination, whereas USP36 deubiquitinates ALR. The imbalance between ubiquitination and deubiquitination of ALR causes severe degradation, and ALR depletion is a major exacerbating factor in the progression of NASH-HCC. (9) The deubiquitinase RPN11 stabilizes METTL3, increases m6A modification and ACSS3 expression, upregulates lipid metabolism genes via histone acetylation to generate acetyl CoA, and promotes liver lipid accumulation, IR, and inflammation.
The role of ubiquitination and deubiquitination in the pathogenesis of non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and is closely associated with metabolic abnormalities. The causes of NAFLD are exceedingly complicated, and it is known that a variety of signaling pathways, endoplasmic reticulum stress, and mitochondrial dysfunction play a role in the pathogenesis of NAFLD. Recent studies have shown that ubiquitination and deubiquitination are involved in the regulation of the NAFLD pathophysiology. Protein ubiquitination is a dynamic and diverse post-translational alteration that affects various cellular biological processes. Numerous disorders, including NAFLD, exhibit imbalances in ubiquitination and deubiquitination. To highlight the significance of this post-translational modification in the pathogenesis of NAFLD and to aid in the development of new therapeutic approaches for the disease, we will discuss the role of enzymes involved in the processes of ubiquitination and deubiquitination, specifically E3 ubiquitin ligases and deubiquitinating enzymes that are important in the regulation of NAFLD.


The effect of gut microbiome-targeted therapies in nonalcoholic fatty liver disease: a systematic review and network meta-analysis

January 2025

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1 Citation

Background The incidence of NAFLD is increasing. Preclinical evidences indicate that modulation of the gut microbiome could be a promising target in nonalcoholic fatty liver disease. Method A systematic review and network meta-analysis was conducted to compare the effect of probiotics, synbiotics, prebiotics, fecal microbiota transplant, and antibiotics on the liver-enzyme, metabolic effects and liver-specific in patients with NAFLD. The randomized controlled trails (RCTs), limited to English language were searched from database such as Pubmed, Embase, Web of science and Cochrane Library from inception to November 2024. Review Manager 5.3 was used to to draw a Cochrane bias risk. Inconsistency test and publication-bias were assessed by Stata 14.0. Random effect model was used to assemble direct and indirect evidences. The effects of the intervention were presented as mean differences with 95% confidence interval. Results A total of 1921 patients from 37 RCTs were eventually included in our study. 23 RCTs evaluated probiotics, 10 RCTs evaluated synbiotics, 4 RCTs evaluated prebiotics, 3 RCTs evaluated FMT and one RCT evaluated antibiotics. Probiotics and synbiotics were associated with a significantly reduction in alanine aminotransferase [ALT, (MD: −5.09; 95%CI: −9.79, −0.39), (MD: −7.38, 95CI%: −11.94, −2.82)] and liver stiffness measurement by elastograph [LSM, (MD: −0.37;95%CI: −0.49, −0.25), (MD: −1.00;95%CI: −1.59, −0.41)]. In addition to, synbiotics was superior to probiotics in reducing LSM. Synbiotics was associated with a significant reduction of Controlled Attenuation Parameter [CAP, (MD: −39.34; 95%CI: −74.73, −3.95)]. Both probiotics and synbiotics were associated with a significant reduction of aspartate transaminase [AST, (MD: −7.81; 95%CI: −15.49, −0.12), (MD: −13.32; 95%CI: −23, −3.64)]. Probiotics and Allogenic FMT was associated with a significant reduction of Homeostatic Model Assessment for Insulin Resistance [HOMA-IR, (MD: −0.7, 95%CI: −1.26, −0.15), (MD: −1.8, 95%CI: −3.53, − 0.07)]. Probiotics was associated with a significant reduction of body mass index [BMI, MD: −1.84, 95%CI: −3.35, −0.33]. Conclusion The supplement of synbiotics and probiotics maybe a promising way to improve liver-enzyme, LSM, and steatosis in patients with NAFLD. More randomized controlled trials are needed to determine the efficacy of FMT and antibiotics on NAFLD. And the incidence of adverse events of MTTs should be further explored. Systematic review registration https://www.crd.york.ac.uk/prospero/, CRD42023450093.


Study Overview. In Step 1, path A represents the causal impact of gut microbiota on ALD, while path a denotes the reverse causal effect of ALD on gut microbiota. In Step 2, path B signifies the causal impact of cytokines on ALD, with path b indicating the reverse causal effect between ALD and cytokines. Step 3 involves the mediation analysis of cytokines in the pathway from gut microbiota to ALD: Path A represents the overall impact of gut microbiota on ALD; Path B signifies the causal effect of cytokines on ALD; Path C indicates the causal effect of gut microbiota on cytokines, and path c denotes the reverse causal effect of cytokines on gut microbiota.
Mendelian randomization of causal effects between gut microbiota and ALD. P.FDR is the p-value adjusted for multiple comparisons using the False Discovery Rate (FDR) method; nSNP refers to the number of genetic variants used as instrumental variables in the MR analysis; Beta refers to the estimated causal effect of the exposure on the outcome.
Mendelian randomization of causal effects between inflammatory cytokines and ALD. P.FDR is the p-value adjusted for multiple comparisons using the False Discovery Rate (FDR) method; nSNP refers to the number of genetic variants used as instrumental variables in the MR analysis; Beta refers to the estimated causal effect of the exposure on the outcome.
Mendelian randomization analysis on the causal effect between gut microbiota and ALD.
Causal relationships between the gut microbiota, inflammatory cytokines, and alcoholic liver disease: a Mendelian randomization analysis

October 2024

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Objective Previous studies have suggested a potential association between gut microbiota and the development of alcohol-related liver disease (ALD). However, the causal relationship between gut microbiota and ALD, as well as the role of inflammatory cytokines as mediators, remains unclear. This study aims to explore the causal relationship between gut microbiota and ALD using Mendelian randomization (MR) methods, and to analyze the mediating role of inflammatory cytokines. Methods Gut microbiota, 91 inflammatory cytokines, and ALD were identified from summary data of large-scale genome-wide association studies (GWAS). MR was employed to investigate the causal relationship between gut microbiota, cytokines, and ALD, with the inverse variance-weighted method (IVW) as the primary statistical approach. Additionally, we examined whether inflammatory cytokines act as mediating factors in the pathway from gut microbiota to ALD. Results The IVW results confirmed two positive and one negative causal effect between genetic liability in the gut microbiota and ALD. Escherichia coli (P= 0.003) was identified as a protective factor for ALD, while Roseburia hominis (P=0.023) and Family Porphyromonadaceae (P=0.038) were identified as risk factors for ALD. Furthermore, there were five positive and two negative causal effects between inflammatory cytokines and ALD, with CUB domain-containing protein 1 (P= 0.035), Macrophage colony-stimulating factor 1 (P=0.047), Cystatin D (P = 0.035), Fractalkine (P=0.000000038), Monocyte chemoattractant protein-1 (P=0.004) positively associated with ALD onset. CD40L receptor (P= 0.044) and Leukemia inhibitory factor (P = 0.024) exhibited protective effects against ALD. Mediation MR analysis indicated that CUB domain-containing protein 1 (mediation proportion=1.6%, P=0.035), Cystatin D (mediation proportion=1.5%, P=0.012), and Monocyte chemoattractant protein-1 (mediation proportion=3.3%, P=0.005) mediated the causal effect of Roseburia hominis on ALD. Conclusion In conclusion, our study supports a causal relationship among gut microbiota, inflammatory cytokines and ALD, with inflammatory cytokines potentially acting as mediating factors in the pathway from gut microbiota to ALD.


Standard formulation of HTQSHXF granules
Efficacy and safety of Huatan Qushi Huoxue Fang granules on obese non-alcoholic fatty liver disease: study protocol for a multicenter, randomized, double-blind, placebo-controlled trial

July 2024

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16 Reads

Background The global burden of non-alcoholic fatty liver disease (NAFLD) is parallel to the increasing obesity rates around the world. Phlegm stasis syndrome is a common traditional Chinese medicine syndrome type of obese NAFLD, which is often treated by resolving phlegm, dispelling dampness, and promoting blood circulation. This study mainly explores the clinical efficacy and safety of Huatan Qushi Huoxue Fang (HTQSHXF) granules in the treatment of obese NAFLD. Methods This is a multicenter, randomized, double-blind, placebo-controlled clinical trial that will recruit 248 obese NAFLD patients from three hospitals in China. Randomly allocate patients to either the HTQSHXF group or the placebo group in a 1:1 ratio. The intervention phase lasts for 12 weeks. The primary outcome will be the change in relative liver fat content from baseline to week 12 measured by Magnetic resonance proton density fat fraction (MRI-PDFF). The secondary outcomes will be Body fat percentage (BFR), Waist to hip ratio (WHR), Body Mass Index (BMI), Controlled attenuation parameter (CAP), Liver tiffness value (LSM), serum liver function, blood lipids, blood glucose, Free fatty acids (FFA), Cytokeratin 18-M30 (CK18-M30), and Cytokeratin 18-M65 (CK18-M65). The results will be monitored at baseline and 12 weeks of intervention. Adverse events that occur in this study will be promptly managed and recorded. Discussion This study will use more recognized quantitative methods to explore the efficacy and safety of HTQSHXF granules in treating obese NAFLD, providing clinical evidence for its translational application. Trial registration http://www.chictr.org.cn . Trial number: ChiCTR2200060901. Registered on 14 Jun 2022.


Comparative efficacy of Chinese patent medicines for non-alcoholic fatty liver disease: A network meta-analysis

January 2023

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27 Reads

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3 Citations

Background: The incidence of Non-alcoholic fatty liver disease (NAFLD) is increasing year by year. Researches showed that Chinese patent medicines (CPMs) had achieved good efficacy in the treatment of Non-alcoholic fatty liver disease. However, the debate on optimum Chinese patent medicine (CPM) persists. Therefore, we conducted a network meta-analysis to objectively compare the efficacy of different Chinese patent medicines in the treatment of Non-alcoholic fatty liver disease. Methods: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Database, China Science and Technology Journal Database, and Chinese Biomedical Literature Database were used as databases for RCT researches retrieval. The retrieval time was from establishment of the database to July 2022. After effective data was extracted, Review Manager 5.4 and Cochrane Collaboration System Evaluator’s Manual were used to assess bias risk. STATA 16.0 based on frequency theory was used for the network meta-analysis. Results: Totally 39 studies were included, involving 13 Chinese patent medicines, including 4049 patients, of which 42 patients were lost. In terms of improving clinical efficiency rate, Zhibitai capsule was most likely the best choice of Chinese patent medicine for Non-alcoholic fatty liver disease. Liuwei Wuling tablet had the best effect in reducing serum ALT and AST; Gandan Shukang capsule had the best effect in reducing serum GGT; Qianggan capsule had the best effect in reducing serum TG; Dangfei Liganning capsule had the best effect in reducing serum TC. None of the included studies had serious adverse reactions. Conclusion: For patients with Non-alcoholic fatty liver disease in this NMA, Zhibitai capsule, Liuwei Wuling tablet, Gandan Shukang capsule, Qianggan capsule, Dangfei Liganning capsule might be noteworthy. Due to the uclear risk bias, better designed double-blind, multi center and large sample RCTs are needed which resolve the problems of blinding, selective reporting and allocation concealment. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022341240.


The Comparative Effectiveness of Traditional Chinese Medicine Exercise Therapies in Elderly People With Mild Cognitive Impairment: A Systematic Review and Network Meta-Analysis

March 2022

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31 Reads

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16 Citations

Background Mild cognitive impairment (MCI) in the elderly is a health problem worldwide. Studies have confirmed that traditional Chinese medicine (TCM) exercise therapies can improve MCI. However, which therapy is the best and their impacts on brain function remain controversial and uncertain. This study aims to compare and rank TCM exercise therapies for MCI in the elderly, and analyze their effects on brain function, in order to find an optimal intervention and provide a basis for clinical treatments decision-making. Methods The Web of Science, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Clinical Trials, China National Knowledge Infrastructure (CNKI), Wangfang database, China Science and Technology Journal Database, and Chinese Biomedical Medicine (CBM) were searched through October 28, 2021. Two researchers reviewed all the studies and extracted the data. The ADDIS software version 1.16.8 and the Bayesian hierarchical model were used for pair-wise meta-analysis and network meta-analysis, and the STATA software version 14.0 was used to draw the network evidence plots and funnel plots. Results A total of 23 studies on 2282 participants were included in this study. In the pair-wise meta-analysis, TCM exercise therapies (Baduanjin exercise, Tai Chi, Liuzijue exercise and finger exercise) were superior to non-TCM exercise therapies (stretching and toning exercise, usual care, health education and routine daily activities) in terms of MMSE, MoCA and ADL outcomes. In the network meta-analysis, the MMSE outcome ranked Baduanjin exercise (78%) as the best intervention and Tai Chi (36%) as the second. The MoCA outcome ranked Baduanjin exercise (62%) as the best intervention. For the ADL outcome, Baduanjin exercise (60%) ranked the best, and followed by finger exercise (43%). Conclusion TCM exercise therapies may improve the cognitive function in elderly patients with MCI. Among the four therapies included, the Baduanjin exercise may be the preferred therapy for MCI in the elderly, and its mechanism may be related to the regulation of cognitive-related brain function and structure. Systematic Review Registration https://inplasy.com, identifier: INPLASY202070006.



Citations (4)


... Another study by Stols-Goncalves et al. also confirmed alterations in the gut microbiome following FMT [130]; however, two patients in the study developed extended-spectrum beta-lactamase infections, raising safety concerns particularly amongst immunocompromised patients and highlighting the importance of 'healthy' donor selection. Rigorous experimental protocols and well-designed RCTs are still required to study the potential efficacy (including long-term effects) of FMT in the treatment of NAFLD/MASLD, as has also been shown by a recent systematic review [131,132]. Indeed, that systematic review of RCTs showed that supplementation with probiotics and synbiotics appears promising for improving hepatic steatosis, though additional RCTs are required to study the efficacy of FMT approaches in patients with MASLD [132]. For such microbiome-targeted therapies, and particularly for FMT, challenges relating to potential adverse effect risks (e.g., potential pathogen transmission associated with FMT) and variability in patient responses, as well as the scalability of these therapeutic interventions should be further explored. ...

Reference:

Gut Microbiota and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Emerging Pathogenic Mechanisms and Therapeutic Implications
The effect of gut microbiome-targeted therapies in nonalcoholic fatty liver disease: a systematic review and network meta-analysis

... Therefore, systemic chemotherapy became the major therapeutic means to treat liver cancer. 5-Fluorouracil (5-FU) was one of the first-line chemotherapy drugs for the treatment of malignant tumors including liver, breast and other digestive system tumors [9][10][11]. However, the clinical application of 5-FU was limited due to its inevitable toxicity to normal cells and multidrug resistance caused by long-term use [12,13]. ...

Compound Kushen injection combined with chemotherapy in the treatment of gastric cancer: a meta-analysis of randomized controlled trials
  • Citing Article
  • January 2019

TMR Cancer - Cancer Advances

... 20,31 ML385 (MedChemExpress, New Jersey, USA) was chosen as a protein inhibitor of Nrf2. Zhibitai Capsules (Chengdu Diao Group, China), a proprietary Chinese medicine that has been shown to have good therapeutic effects on NAFLD rats, 36 was chosen as the positive medicine. Mice in the sericin dose groups were given a corresponding dose of sericin every day by intragastric administration for 4 weeks. ...

Comparative efficacy of Chinese patent medicines for non-alcoholic fatty liver disease: A network meta-analysis

... In single-modality interventions, aerobic exercises, including daily activities (eg, brisk walking, stair climbing, household chores) and mind-body exercises (eg, Tai Chi, Baduanjin, and square dancing), have demonstrated significant cognitive benefits for MCI patients, though with varying effects. 74,[80][81][82] For example, studies have shown that Tai Chi can improve overall cognitive function and enhance cognitive flexibility compared to conventional exercise programs. 83 Similarly, Baduanjin has been found to increase attention levels by 12% compared to brisk walking. ...

The Comparative Effectiveness of Traditional Chinese Medicine Exercise Therapies in Elderly People With Mild Cognitive Impairment: A Systematic Review and Network Meta-Analysis