[Regulation of electroacupuncture on non-canonical pathway of hepatocellular pyroptosis in rats with nonalcoholic fatty liver disease].

OBJECTIVE: To observe the effect and mechanism of electroacupuncture (EA) on non-canonical pathway of hepatocellular pyroptosis in nonalcoholic fatty liver disease (NAFLD). METHODS: Sixty male SD rats were randomly divided into a normal diet group (n=15) and a high fat modeling group (n=45). The rats in the high fat modeling group were fed with customized high fat diet for 8 weeks to establish NAFLD model. Thirty successfully modeled rats were selected and randomly divided into a model group (n=10), an EA group (n=10) and a non-acupoint with shallow needling group (n=10), and 10 rats were randomly selected from the normal diet group as the control group additionally. In the EA group, EA was applied at bilateral "Fenglong" (ST 40) and "Ganshu" (BL 18), with disperse-dense wave, in frequency of 4 Hz/20 Hz and in intensity of 3 mA. In the non-acupoint with shallow needling group, shallow needling was delivered at points 5 mm from bilateral "Fenglong" (ST 40) and "Ganshu" (BL 18), the EA stimulation parameters were same as the EA group. The intervention was given once a day, 20 min a time, 5 days a week for 4 weeks in the two groups. After intervention, the liver morphology was observed by oil red "O" staining, the serum levels of lipopolysaccharide (LPS), interleukin (IL)-1ß, IL-18 and tumor necrosis factor-α (TNF-α) were detected by ELISA, the protein expression of gasdermin D (GSDMD), GSDMD-N, cysteine aspartic acid specific protease-11 (Caspase-11), IL-1ß, IL-18 and TNF-α in liver tissue were detected by Western blot, the mRNA expression of GSDMD, Caspase-11, IL-1ß, IL-18 and TNF-α in liver tissue was detected by real-time PCR in rats of each group. RESULTS: In the model group, vacuoles in different size were found in the hepatocellular cytoplasm, and the fat droplets were in schistose accumulation. Compared with the model group, the hepatocellular fat droplets and the degree of hepatic steatosis were reduced in the EA group and the non-acupoint with shallow needling group. Compared with the control group, the serum levels of LPS, IL-1ß, IL-18 and TNF-α were increased (P<0.01), the protein and mRNA expression of GSDMD, Caspase-11, IL-1ß, IL-18, TNF-α as well as the protein expression of GSDMD-N in the liver tissue were increased (P<0.01) in the model group. Compared with the model group, the serum levels of LPS, IL-1ß, IL-18 and TNF-α were decreased (P<0.01), the protein and mRNA expression of GSDMD, IL-1ß, IL-18 and TNF-α in the liver tissue were decreased (P<0.01), the protein expression of GSDMD-N and the mRNA expression of Caspase-11 in the liver tissue were decreased (P<0.01) in the EA group and the non-acupoint with shallow needling group. Compared with the model group, the protein expression of Caspase-11 in the liver tissue was decreased (P<0.01) in the EA group. Compared with the non-acupoint with shallow needling group, the serum levels of LPS, IL-1ß, IL-18 and TNF-α were decreased (P<0.01), the protein and mRNA expression of GSDMD, Caspase-11, IL-1ß and IL-18 in the liver tissue were decreased (P<0.01), the protein expression of GSDMD-N and the mRNA expression of TNF-α in the liver tissue were decreased (P<0.01) in the EA group. CONCLUSION: EA can inhibit hepatocellular pyroptosis in NAFLD rats, and its mechanism may be related to reducing the serum level of LPS, and down-regulating the expression of the non-canonical pathway related factors i.e. GSDMD, GSDMD-N, Caspase-11, IL-1ß, IL-18 and TNF-α.

Impact of Synbiotic Intake on Liver Metabolism in Metabolically Healthy Participants and Its Potential Preventive Effect on Metabolic-Dysfunction-Associated Fatty Liver Disease (MAFLD): A Randomized, Placebo-Controlled, Double-Blinded Clinical Trial.

Synbiotics modulate the gut microbiome and contribute to the prevention of liver diseases such as metabolic-dysfunction-associated fatty liver disease (MAFLD). This study aimed to evaluate the effect of a randomized, placebo-controlled, double-blinded seven-week intervention trial on the liver metabolism in 117 metabolically healthy male participants. Anthropometric data, blood parameters, and stool samples were analyzed using linear mixed models. After seven weeks of intervention, there was a significant reduction in alanine aminotransferase (ALT) in the synbiotic group compared to the placebo group (-14.92%, CI: -26.60--3.23%, p = 0.013). A stratified analysis according to body fat percentage revealed a significant decrease in ALT (-20.70%, CI: -40.88--0.53%, p = 0.045) in participants with an elevated body fat percentage. Further, a significant change in microbiome composition (1.16, CI: 0.06-2.25, p = 0.039) in this group was found, while the microbial composition remained stable upon intervention in the group with physiological body fat. The 7-week synbiotic intervention reduced ALT levels, especially in participants with an elevated body fat percentage, possibly due to modulation of the gut microbiome. Synbiotic intake may be helpful in delaying the progression of MAFLD and could be used in addition to the recommended lifestyle modification therapy.

The effects of gut microbiome manipulation on glycemic indices in patients with non-alcoholic fatty liver disease: a comprehensive umbrella review.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a significant risk factor for non-alcoholic fatty liver disease (NAFLD). Increased fasting blood sugar (FBS), fasting insulin (FI), and insulin resistance (HOMA-IR) are observed in patients with NAFLD. Gut microbial modulation using prebiotics, probiotics, and synbiotics has shown promise in NAFLD treatment. This meta-umbrella study aimed to investigate the effects of gut microbial modulation on glycemic indices in patients with NAFLD and discuss potential mechanisms of action. METHODS: A systematic search was conducted in PubMed, Web of Science, Scopus, and Cochrane Library until March 2023 for meta-analyses evaluating the effects of probiotics, prebiotics, and synbiotics on patients with NAFLD. Random-effect models, sensitivity analysis, and subgroup analysis were employed. RESULTS: Gut microbial therapy significantly decreased HOMA-IR (ES: -0.41; 95%CI: -0.52, -0.31; P < 0.001) and FI (ES: -0.59; 95%CI: -0.77, -0.41; P < 0.001). However, no significant effect was observed on FBS (ES: -0.17; 95%CI: -0.36, 0.02; P = 0.082). Subgroup analysis revealed prebiotics had the most potent effect on HOMA-IR, followed by probiotics and synbiotics. For FI, synbiotics had the most substantial effect, followed by prebiotics and probiotics. CONCLUSION: Probiotics, prebiotics, and synbiotics administration significantly reduced FI and HOMA-IR, but no significant effect was observed on FBS.

Metabolic dysfunction-associated steatotic liver disease: Navigating terminological evolution, diagnostic frontiers and therapeutic horizon-an editorial exploration.

Metabolic dysfunction-associated steatotic liver disease (MASLD), once known as non-alcoholic fatty liver disease (NAFLD), represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes. The redefinition of NAFLD in 2023 marked a significant reposition in terminology, emphasizing a broader understanding of liver steatosis and its associated risks. MASLD is now recognized as a major risk factor for liver cirrhosis, hepatocellular carcinoma, and systemic complications such as cardiovascular diseases or systemic inflammation. Diagnostic challenges arise, particularly in identifying MASLD in lean individuals, necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools. Therapeutically, there is an urgent need for effective treatments targeting MASLD, with emerging pharmacological options focusing on, among others, carbohydrate and lipid metabolism. Additionally, understanding the roles of bile acid metabolism, the microbiome, and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches. There is a strong need to emphasize the importance of collaborative efforts in understanding, diagnosing, and managing MASLD to improve physicians' approaches and patient outcomes.

Weight loss treatment for COVID-19 in patients with NCDs: a pilot prospective clinical trial.

COVID-19 comorbid with noncommunicable chronic diseases (NCDs) complicates the diagnosis, treatment, and prognosis, and increases the mortality rate. The aim is to evaluate the effects of a restricted diet on clinical/laboratory inflammation and metabolic profile, reactive oxygen species (ROS), and body composition in patients with COVID-19 comorbid with NCDs. We conducted a 6-week open, pilot prospective controlled clinical trial. The study included 70 adult patients with COVID-19 comorbid with type 2 diabetes (T2D), hypertension, or nonalcoholic steatohepatitis (NASH). INTERVENTIONS: a restricted diet including calorie restriction, hot water drinking, walking, and sexual self-restraint. PRIMARY ENDPOINTS: COVID-19 diagnosis by detecting SARS-CoV-2 genome by RT-PCR; weight loss in Main group; body temperature; C-reactive protein. Secondary endpoints: the number of white blood cells; erythrocyte sedimentation rate; adverse effects during treatment; fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), systolic/diastolic blood pressure (BP); blood lipids; ALT/AST, chest CT-scan. In Main group, patients with overweight lost weight from baseline (- 12.4%; P < 0.0001); 2.9% in Main group and 7.2% in Controls were positive for COVID-19 (RR: 0.41, CI: 0.04-4.31; P = 0.22) on the 14th day of treatment. Body temperature and C-reactive protein decreased significantly in Main group compared to Controls on day 14th of treatment (P < 0.025). Systolic/diastolic BP normalized (P < 0.025), glucose/lipids metabolism (P < 0.025); ALT/AST normalized (P < 0.025), platelets increased from baseline (P < 0.025), chest CT (P < 0.025) in Main group at 14 day of treatment. The previous antidiabetic, antihypertensive, anti-inflammatory, hepatoprotective, and other symptomatic medications were adequately decreased to completely stop during the weight loss treatment. Thus, the fast weight loss treatment may be beneficial for the COVID-19 patients with comorbid T2D, hypertension, and NASH over traditional medical treatment because, it improved clinical and laboratory/instrumental data on inflammation; glucose/lipid metabolism, systolic/diastolic BPs, and NASH biochemical outcomes, reactive oxygen species; and allowed patients to stop taking medications. TRIAL REGISTRATION: ClinicalTrials.gov NCT05635539 (02/12/2022): https://clinicaltrials.gov/ct2/show/NCT05635539?term=NCT05635539&draw=2&rank=1 .

Therapeutic potential of Lactobacillus casei and Chlorella vulgaris in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD)-associated kidney damages: a stereological study.

BACKGROUND: The non-alcoholic fatty liver disease (NAFLD) is prevalent in as many as 25% of adults who are afflicted with metabolic syndrome. Oxidative stress plays a significant role in the pathophysiology of hepatic and renal injury associated with NAFLD. Therefore, probiotics such as Lactobacillus casei (LBC) and the microalga Chlorella vulgaris (CV) may be beneficial in alleviating kidney injury related to NAFLD. MATERIALS AND METHODS: This animal study utilized 30 C57BL/6 mice, which were evenly distributed into five groups: the control group, the NAFLD group, the NAFLD + CV group, the NAFLD + LBC group, and the NAFLD + CV + LBC group. A high-fat diet (HFD) was administered to induce NAFLD for six weeks. The treatments with CV and LBC were continued for an additional 35 days. Biochemical parameters, total antioxidant capacity (TAC), and the expression of kidney damage marker genes (KIM 1 and NGAL) in serum and kidney tissue were determined, respectively. A stereological analysis was conducted to observe the structural changes in kidney tissues. RESULTS: A liver histopathological examination confirmed the successful induction of NAFLD. Biochemical investigations revealed that the NAFLD group exhibited increased ALT and AST levels, significantly reduced in the therapy groups (p < 0.001). The gene expression levels of KIM-1 and NGAL were elevated in NAFLD but were significantly reduced by CV and LBC therapies (p < 0.001). Stereological examinations revealed reduced kidney size, volume, and tissue composition in the NAFLD group, with significant improvements observed in the treated groups (p < 0.001). CONCLUSION: This study highlights the potential therapeutic efficacy of C. vulgaris and L. casei in mitigating kidney damage caused by NAFLD. These findings provide valuable insights for developing novel treatment approaches for managing NAFLD and its associated complications.

Development of an Improved Adenovirus Vector and Its Application to the Treatment of Lifestyle-Related Diseases.

The number of patients with lifestyle-related diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has continued to increase worldwide. Therefore, development of innovative therapeutic methods targeting lifestyle-related diseases is required. Gene therapy has attracted considerable attention as an advanced medical treatment. Safe and high-performance vectors are essential for the practical application of gene therapy. Replication-incompetent adenovirus (Ad) vectors are widely used in clinical gene therapy and basic research. Here, we developed a novel Ad vector, named Ad-E4-122aT, exhibiting higher and longer-term transgene expression and lower hepatotoxicity than conventional Ad vectors. We also elucidated the mechanisms underlying Ad vector-induced hepatotoxicity during the early phase using Ad-E4-122aT. Next, we examined the therapeutic effects of the genes of interest, namely zinc finger AN1-type domain 3 (ZFAND3), lipoprotein lipase (LPL), and lysophospholipid acyltransferase 10 (LPLAT10), on lifestyle-related diseases using Ad-E4-122aT. We showed that the overexpression of ZFAND3 in the liver improved glucose tolerance and insulin resistance. Liver-specific LPL overexpression suppressed hepatic lipid accumulation and improved glucose metabolism. LPLAT10 overexpression in the liver suppressed postprandial hyperglycemia by increasing glucose-stimulated insulin secretion. Furthermore, we also focused on foods to advance research on the pathophysiology and treatment of lifestyle-related diseases. Cranberry and calamondin, which are promising functional foods, attenuated the progression of MASLD/NAFLD. Our findings will aid the development of new therapeutic methods, including gene therapy, for lifestyle-related diseases such as T2DM and MASLD/NAFLD.

The outcomes of nutritional therapy in patients with non-alcoholic fatty liver disease (NAFLD): Pitfalls in getting fit from fat.

Objective: To evaluate the outcomes of nutritional intervention on non-alcoholic fatty liver disease parameters, and to determine the reasons for non-compliance with nutritional therapy. METHODS: The interventional study was conducted from May 2020 to October 2022 at the National Institute of Liver and Gastrointestinal diseases, Dow University Hospital, Ojha Campus, Karachi, and comprised patients of either gender aged 18-65 years who had been diagnosed with non-alcoholic fatty liver disease based on abdominal ultrasound. Anthropometrics, physical activity level, and biochemical markers were evaluated at baseline and 6 months after the intervention that involved nutritional assessment, counselling and guidance related to dietary modification and optimisation of physical activity level. The effect of the intervention was evaluated by improvement in liver enzymes, biochemical parameters, anthropometric indices and any change in the level of physical activity. The reasons for noncompliance were also recorded. Data was analysed using SPSS 22. RESULTS: Out of 118 subjects enrolled, 61(51.69%) completed the study. Most patients were females 81(68.6%), married 25(21.2%) and housewives 64(54.2%). There were 16(26.2%) subjects who had 3-10kg weight reduction. The reduction in serum cholesterol and triglyceride levels was not significant (p>0.05). Also, no significant change was observed in the level of physical activity compared to the baseline (p>0.05). Overall, 27(44.3%) patients showed compliance with treatment. The main reasons for noncompliance were lack of time 21(34.4) and knee joint pain 5(8.2%). Conclusion: Lifestyle modification can be beneficial for weight-loss in the management of non-alcoholic fatty liver disease. However, awareness of its importance and willingness in initiating real-life practical steps with subsequent adherence to dietary therapy was found lacking in the sample studied.

Liver fat as a dietary target by Chinese Medical Nutrition Therapy (CMNT) diet for treating type 2 diabetes with non-alcoholic fatty liver disease: study protocol for a randomised controlled trial.

INTRODUCTION: Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) often coexist and increase risk for developing liver fibrosis and diabetes complications if no effective measures are taken. Dietary intervention is known to be able to achieve diabetes remission, while evidence regarding the long-term effect on liver fat is limited for comorbidity management of type 2 diabetes and NAFLD. This study aims to investigate the long-term effect of a Chinese Medical Nutrition Therapy (CMNT) diet accompanied by intermittent energy restriction on reducing liver fat and glycated haemoglobin (HbA1c) in patients with type 2 diabetes and NAFLD. METHODS AND ANALYSIS: This is a multicentre two-armed parallel randomised controlled trial study. 120 participants with type 2 diabetes and NAFLD will be recruited from the physical examination centres of multiple hospitals in China. Participants will be randomly allocated 1:1 to either the CMNT group or the usual care group. The CMNT group will be instructed to consume the provided specific meal replacement Chinese medicinal foods consisting of 6 cycles of 5 consecutive days followed by 10 days of regular food intake. The usual care group will be given standard dietary advice. Primary outcomes are changes in the controlled attenuation parameter value by transient elastography and HbA1c level. Secondary outcomes include differences in anthropometrics, clinical blood markers, questionnaires, gut microbiota and metabolomics. Further follow-up will be performed at 6 months, 1 year and 2 years. ETHICS AND DISSEMINATION: The study protocol was approved by the Biomedical Research Ethics Committee of Hunan Agricultural University (BRECHAU20200235).The results will be disseminated via relevant peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT05439226.

Hepatic Klf10-Fh1 axis promotes exercise-mediated amelioration of NASH in mice.

Exercise is an effective non-pharmacological strategy for the treatment of nonalcoholic steatohepatitis (NASH), but the underlying mechanism needs further investigation. Kruppel-like factor 10 (Klf10) is a transcriptional factor that is expressed in multiple tissues including liver, whose role in NASH is not well defined. In our study, exercise induces hepatic Klf10 expression through the cAMP/PKA/CREB pathway. Hepatocyte-specific knockout of Klf10 (Klf10LKO) increases lipid accumulation, cell death, inflammation and fibrosis in NASH diet-fed mice and reduces the protective effects of treadmill exercise against NASH, while hepatocyte-specific overexpression of Klf10 (Klf10LTG) works in concert with exercise to reduce NASH in mice. Mechanistically, Klf10 promotes the expression of fumarate hydratase 1 (Fh1), thereby reducing fumarate accumulation in hepatocytes. This decreases the trimethyl (me3) levels of histone 3 lysine 4 (H3K4me3) on lipogenic genes promoters to attenuate lipogenesis, thus ameliorating free fatty acids (FFAs)-induced hepatocytes steatosis, apoptosis, insulin resistance and blunting dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells. Therefore, by regulating the Fh1/fumarate/H3K4me3 pathway, Klf10 acts as a downstream effector of exercise to combat NASH.

Comprehensive study of the interplay between immunological and metabolic factors in hepatic steatosis.

The pathophysiology of hepatic steatosis is thoroughly reviewed in this comprehensive report, with particular attention to the complex interactions between inflammatory pathways, insulin resistance, lipid metabolism, metabolic dysregulation, and immunological responses in the liver including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). The study highlights the role of immune cell regulation in disease progression and explores the potential of immune cell-specific treatments for treating hepatic disorders. The development of liver disorders is significantly influenced by immune cells, including dendritic cells, T cells, and natural killer cells. Clinical investigations show that immune cell-specific treatments can effectively reduce liver fibrosis and inflammation. Future research should focus on finding new immunological targets for therapeutic interventions, as well as addressing the management challenges associated with NAFLD/NASH. Hepatic immune microorganisms also impact liver homeostasis and disorders. Improvements in immune cell regulation and liver transplantation methods give patients hope for better prognoses. Important phases include optimizing the selection of donors for malignancy of the liver, using machine perfusion for organ preservation, and fine-tuning immunosuppressive strategies. For focused treatments in hepatic steatosis, it is imperative to understand the intricate interactions between immune and metabolic variables. Understanding the liver's heterogeneous immune profile, encompassing a range of immune cell subpopulations, is crucial for formulating focused therapeutic interventions. To improve patient care and outcomes in hepatic illnesses, there is an urgent need for further research and innovation. Therefore, to effectively treat hepatic steatosis, it is important to enhance therapeutic techniques and maximize liver transplantation strategies.

Necroptosis contributes to non-alcoholic fatty liver disease pathoetiology with promising diagnostic and therapeutic functions.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease. However, the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies. Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoetiology and suggest functional therapeutic and diagnostic options. Pyroptosis, ferroptosis, and necroptosis are the main subtypes of non-apoptotic regulated cell deaths (RCDs), each of which represents particular characteristics. Considering the complexity of the findings, the present study aimed to review these types of RCDs and their contribution to NAFLD progression, and subsequently discuss in detail the role of necroptosis in the pathoetiology, diagnosis, and treatment of the disease. The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer, hence it has potential in diagnostic and therapeutic approaches. Nevertheless, further studies are necessary.

The Relationship between Pathogenesis and Possible Treatments for the MASLD-Cirrhosis Spectrum.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a term that entails a broad spectrum of conditions that vary in severity. Its development is influenced by multiple factors such as environment, microbiome, comorbidities, and genetic factors. MASLD is closely related to metabolic syndrome as it is caused by an alteration in the metabolism of fatty acids due to the accumulation of lipids because of an imbalance between its absorption and elimination in the liver. Its progression to fibrosis is due to a constant flow of fatty acids through the mitochondria and the inability of the liver to slow down this metabolic load, which generates oxidative stress and lipid peroxidation, triggering cell death. The development and progression of MASLD are closely related to unhealthy lifestyle habits, and nutritional epigenetic and genetic mechanisms have also been implicated. Currently, lifestyle modification is the first-line treatment for MASLD and nonalcoholic steatohepatitis; weight loss of ≥10% produces resolution of steatohepatitis and fibrosis regression. In many patients, body weight reduction cannot be achieved; therefore, pharmacological treatment should be offered in particular populations.

The Many Faces of Metabolic Dysfunction-Associated Fatty Liver Disease Treatment: From the Mediterranean Diet to Fecal Microbiota Transplantation.

The gastrointestinal tract is inhabited by the gut microbiota. The main phyla are Firmicutes and Bacteroidetes. In non-alcoholic fatty liver disease, now renamed metabolic dysfunction-associated fatty liver disease (MAFLD), an alteration in Firmicutes and Bacteroidetes abundance promotes its pathogenesis and evolution into non-alcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. For this reason, early treatment is necessary to counteract its progression. The aim of the present narrative review is to evaluate the different therapeutic approaches to MAFLD. The most important treatment for MAFLD is lifestyle changes. In this regard, the Mediterranean diet could be considered the gold standard in the prevention and treatment of MAFLD. In contrast, a Western diet should be discouraged. Probiotics and fecal microbiota transplantation seem to be valid, safe, and effective alternatives for MAFLD treatment. However, more studies with a longer follow-up and with a larger cohort of patients are needed to underline the more effective approaches to contrasting MAFLD.

Effects of electroacupuncture of different intensities and durations on PERK/ATF4/CHOP signaling pathway in liver of non-alcoholic fatty liver disease rats. / ä¸åŒå¼ºåº¦åŠæ—¶ç¨‹ç”µé’ˆå¹²é¢„å¯¹éžé ’ç²¾æ€§è„‚è‚ªè‚ç— å¤§é¼ è‚è„PERK/ATF4/CHOP通路的影响.

OBJECTIVES: To analyze the effects of electroacupuncture (EA) at "Fenglong" (ST40) and "Zusanli" (ST36) of different intensities and durations on rats with non-alcoholic fatty liver disease (NAFLD) based on the protein kinase R-like endoplasmic reticulum kinase (PERK)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) signaling pathway, so as to explore its mechanism underlying improvement of NAFLD. METHODS: SD rats were randomly divided into normal diet group, high-fat model group, sham EA group, strong stimulation EA (SEA) group, and weak stimulation EA (WEA) group, with 15 rats in each group. Each group was further divided into 2, 3, and 4-week subgroups. NAFLD rat model was established by feeding a high-fat diet. After successful modeling, rats in the SEA and WEA groups received EA at bilateral ST40 and ST36 with dense and sparse waves (4 Hz/20 Hz) at current intensities of 4 mA (SEA group) and 2 mA (WEA group), lasting for 20 minutes, once a day, 5 days a week with 2 days of rest. The sham EA group only had the EA apparatus connected without electricity. Different duration subgroups were intervened for 2, 3, and 4 weeks. After the intervention, the contents of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rats were detected by an automatic biochemical analyzer；liver morphological changes were observed by Oil Red O staining；real-time fluorescence quantitative PCR and Western blot were used to detect the expression of PERK, ATF4, and CHOP mRNAs and proteins in the rat liver tissue. RESULTS: In the high-fat model group, there was a significant accumulation of red lipid droplets in the liver cells, which was reduced significantly in the SEA group at the 4th week. Compared with the normal diet group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated (P<0.01) in the high-fat model group . Compared with the high-fat model group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, CHOP mRNAs and proteins in the liver tissue were decreased (P<0.01, P<0.05) in the SEA and WEA groups. Compared with the sham EA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were decreased (P<0.01, P<0.05) in the SEA and WEA groups, the expression of PERK, ATF4, and CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA group at the 2nd, 3rd, and 4th week, the expression of PERK and CHOP proteins at the 2nd, 3rd, 4th week and ATF4 protein at 2nd week in the liver tissue were decreased (P<0.01, P<0.05) in the WEA group. Compared with the SEA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated (P<0.05, P<0.01) in the WEA group. Compared with the 2-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and PERK proteins in the liver tissue were decreased (P<0.01, P<0.05) in the SEA and WEA groups at 3rd and 4th week, the expression of ATF4 proteins in the liver tissue was decreased (P<0.01) in the SEA group at 3rd and 4th week, and the expression of CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA group at 4th week and in the WEA group at 3rd and 4th week. Compared with the 3-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were significantly decreased (P<0.05, P<0.01) in the SEA and WEA groups at 4th week, the expression of PERK and CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA and WEA groups at 4th week, and the expression of ATF4 protein in the liver tissue was decreased (P<0.05) in the SEA group at 4th week. CONCLUSIONS: EA at ST40 and ST36 can significantly improve liver function in NAFLD rats, and its mechanism of action may involve inhibiting PERK expression thereby targeting the downstream ATF4/CHOP signaling pathway to suppress endoplasmic reticulum stress, exerting a liver protective effect；the optimal effect was observed with EA intensity of 4 mA for 4 weeks.

Establishment and validation of an adherence prediction system for lifestyle interventions in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, affecting about 1/4th of the global population and causing a huge global economic burden. To date, no drugs have been approved for the treatment of NAFLD, making the correction of unhealthy lifestyles the principle method of treatment. Identifying patients with poor adherence to lifestyle correction and attempting to improve their adherence are therefore very important. AIM: To develop and validate a scale that can rapidly assess the adherence of patients with NAFLD to lifestyle interventions. METHODS: The Exercise and Diet Adherence Scale (EDAS) was designed based on compilation using the Delphi method, and its reliability was subsequently evaluated. Demographic and laboratory indicators were measured, and patients completed the EDAS questionnaire at baseline and after 6 months. The efficacy of the EDAS was evaluated in the initial cohort. Subsequently, the efficacy of the EDAS was internally verified in a validation cohort. RESULTS: The EDAS consisted of 33 items in six dimensions, with a total of 165 points. Total EDAS score correlated significantly with daily number of exercise and daily reduction in calorie intake (P < 0.05 each), but not with overall weight loss. A total score of 116 was excellent in predicting adherence to daily reduction in calorie intake (> 500 kacl/d), (sensitivity/specificity was 100.0%/75.8%), while patients score below 97 could nearly rule out the possibility of daily exercise (sensitivity/specificity was 89.5%/44.4%). Total EDAS scores ≥ 116, 97-115, and < 97 points were indicative of good, average, and poor adherence, respectively, to diet and exercise recommendations. CONCLUSION: The EDAS can reliably assess the adherence of patients with NAFLD to lifestyle interventions and have clinical application in this population.

Clinical Service Incorporating Mobile Technology on Weight Loss in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Translation From Research Trial.

BACKGROUND: The prevalence and healthcare cost of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased alongside the epidemic surge in obesity and Type 2 diabetes. Weight loss through lifestyle modification remains the primary effective therapy for MASLD. Incorporation of mobile technology in lifestyle interventions has been previously found to be efficacious and cost-effective in facilitating weight loss. However, there is a paucity of studies that have successfully translated lifestyle research into clinical service for weight loss to alleviate disease burden. Our study aimed to describe the process of translating a mobile technology-enabled trial into a tertiary hospital outpatient dietetics service for patients with MASLD. METHODS: The Iowa Model of Evidence-Based Practice to Improve Quality Care was used as a framework for this paper to guide implementation at the organizational level. RESULTS: Regular engagement of key operational staff and the hospital management team facilitated open discussions of the challenges faced and enabled rapid implementation of strategies that contributed to the smooth piloting of the service. A service adoption rate of 81% was achieved. Preliminary outcome evaluation found that the percentage of patients achieving ≥ 5% weight loss from baseline at 6 months was comparable at 54% and 52% for the service and trial groups, respectively. CONCLUSIONS: Evaluation of the implementation process found that a hybrid model of care (in-person consultation supplemented with app coaching) preserved interpersonal connections while maximizing the convenience and scalability of mobile app-enabled service. Although high digital acceptance and adoption rates propelled by COVID-19-supported telehealth, it is prudent to assess patient's access to technology and digital literacy and offer resources to help them benefit from telehealth services.

The effects of high-intensity interval training and Iranian propolis extract on serum levels of TRPV4 and CYP2E1 proteins in patients with nonalcoholic fatty liver.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver failure, fibrosis, cirrhosis, and liver cancer, which can eventually lead to death. AIM: To investigate the effects of high-intensity interval training (HIIT) and iranian propolis extract on serum levels of transient receptor potential cation channel subfamily V member 4 (TRPV4) and cytochrome P450 2E1 (CYP2E1) proteins in patients with NAFLD. METHODS: Thirty-two patients with NAFLD (mean±standard deviation of age: 45.1±3.6 years; body mass index: 30.0±3.6 kg/m2) were assigned in a randomized control trial to one of the following groups: HIIT (n=8), propolis supplement (n=8), propolis + HIIT (n=8), and controls (n=8). The subjects participated in eight weeks of HIIT (one bout of 1-min intervals at 80-95% of the maximal heart-rate, interspersed by two min at 50-55% of the reserve heart-rate). The Propolis supplement was taken three times a day by the patients in the form of 50 mg tablet after the main meals. Body composition, liver injury test (eg; Alanine- and Aspartate- aminotransferase levels), liver ultrasound and serum levels of TRPV4 and CYP2E1 were measured before and after intervention. One-way analysis of variance was used to compare post-tests among the groups. RESULTS: HIIT significantly reduced serum levels of TRPV4 protein (p=0.001). The reduction in CYP2E1 was not significant in HIIT group (p=0.075). Propolis consumption had no significant effect on serum levels of CYP2E1 protein (p=0.059), and TRPV4 (p=0.072). There was a significant decrease in TRPV4 and CYP2E1 in the HIIT (p=0.001) and propolis supplement (p=0.032) groups. CONCLUSION: HIIT and propolis supplementation can be used to reduce TRPV4 and CYP2E1, which in turn reduces oxidative stress and inflammation in patients with NAFLD.

Research Progress on Lipophagy-Mediated Exercise Intervention in Non-Alcoholic Fatty Liver Disease.

Lipophagy is a cellular pathway targeting the lysosomal degradation of lipid droplets, playing a role in promoting lipid turnover and renewal. Abnormal lipophagy processes can lead to the occurrence and development of non-alcoholic fatty liver disease (NAFLD), characterized by the deposition of lipid droplets (LDs) in the liver. The importance of exercise training in preventing and improving NAFLD has been well-established, but the exact mechanisms remain unclear. Recent research findings suggest that lipophagy may serve as a crucial hub for liver lipid turnover under exercise conditions. Exercise may alleviate hepatic lipid accumulation and mitigate inflammatory responses and fibrosis through lipophagy, thereby improving the onset and progression of NAFLD.