Alzheimer’s disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory loss. As the incidence of AD continues to rise annually, researchers have shown keen interest in the active components found in natural plants and their neuroprotective effects against AD. Quercetin, a flavonol widely present in fruits and vegetables, has multiple biological effects including anticancer, anti-inflammatory, and antioxidant. Oxidative stress plays a central role in the pathogenesis of AD, and the antioxidant properties of quercetin are essential for its neuroprotective function. Quercetin can modulate multiple signaling pathways related to AD, such as Nrf2-ARE, JNK, p38 MAPK, PON2, PI3K/Akt, and PKC, all of which are closely related to oxidative stress. Furthermore, quercetin is capable of inhibiting the aggregation of β‑amyloid protein (Aβ) and the phosphorylation of tau protein, as well as the activity of β‑secretase 1 and acetylcholinesterase, thus slowing down the progression of the disease.The review also provides insights into the pharmacokinetic properties of quercetin, including its absorption, metabolism, and excretion, as well as its bioavailability challenges and clinical applications. To improve the bioavailability and enhance the targeting of quercetin, the potential of quercetin nanomedicine delivery systems in the treatment of AD is also discussed. In summary, the multifaceted mechanisms of quercetin against AD provide a new perspective for drug development. However, translating these findings into clinical practice requires overcoming current limitations and ongoing research. In this way, its therapeutic potential in the treatment of AD can be fully utilized.

OBJECTIVE To explore the effect and potential mechanism of the compatibility of Astragali Radix-Puerariae Lobatae Radix on ferroptosis of liver cells in type 2 diabetes mellitus （T2DM） insulin resistance （IR） rats. METHODS Sixty male SD rats were randomly divided into control group （12 rats） and modeling group （48 rats）. The modeling group was fed with a high- fat diet for 4 consecutive weeks and then given a one-time tail vein injection of 1% streptozotocin to establish T2DM IR model. The model rats were randomly divided into model group， the compatibility of Astragali Radix-Puerariae Lobatae Radix group [QG group， 4.05 g/（kg·d）， intragastric administration]， ferroptosis inhibitor ferrostatin-1 group [Fer-1 group， 5 mg/kg by intraperitoneal injection， once every other day]， the compatibility of Astragali Radix-Puerariae Lobatae Radix+ferroptosis inducer erastin group [QG+erastin group， 4.05 g/（kg·d） by intragastric administration+erastin 10 mg/（kg·d）， intraperitoneal injection]. After 4 weeks of intervention， serum fasting blood glucose （FBG） and fasting insulin （FINS） were measured in each group of rats， and homeostasis model assessment of insulin resistance （HOMA-IR） and the natural logarithm of insulin action index（IAI） were calculated； the serum levels of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， aspartate transaminase （AST） and alanine transaminase （ALT）， Fe2+ and Fe content， glutathione （GSH）， malondialdehyde （MDA） and superoxide dismutase （SOD） levels， NADP+/NADPH ratio and reactive oxygen species （ROS） were determined. The pathological morphology of its liver tissue was observed； the protein expressions of glutathione peroxidase 4 （GPX4）， ferritin heavy chain 1 （FTH1）， long-chain acyl-CoA synthetase 3 （ACSL3）， ACSL4， ferritin mitochondrial （FTMT）， and cystine/glutamate anti-porter （xCT） in the liver tissue of rats were detected. RESULTS Compared with control group， the liver cells in the model group of rats showed disordered arrangement， swelling， deepened nuclear staining， and more infiltration of inflammatory cells， as well as a large number of hepatocyte vacuoles and steatosis； FBG （after medication）， the levels of TC， TG， LDL-C， AST， ALT， FINS， MDA and ROS， HOMA-IR， Fe2+ and Fe content， NADP+/NADPH ratio and protein expression of ACSL4 were significantly increased or up-regulated， while the levels of HDL-C， GSH and SOD， IAI， protein expressions of GPX4， FTH1， ACSL3， FTMT and xCT were significantly reduced or down-regulated （P＜0.01）. Compared with the model group， both QG group and Fer-1 group showed varying degrees of improvement in pathological damage of liver tissue and the levels of the above indicators， the differences in the changes of most indicators were statistically significant （P＜0.01 or P＜0.05）. Compared with QG group， the improvement of the above indexes of QG+erastin group had been reversed significantly （P＜0.01）. CONCLUSIONS The compatibility decoction of Astragali Radix-Puerariae Lobatae Radix can reduce the level of FBG in T2DM IR rats， and alleviate IR degree， ion overload and pathological damage of liver tissue. The above effects are related to the inhibition of ferroptosis.

As one of the core pathogenesis during treatment with traditional Chinese medicine，liver heat runs through different stages of liver disease. The interpretation of its meaning in different medicine categories（traditional Chinese medicine，Tibetan medicine，Mongolian medicine，Uygur medicine，Dai medicine，Yao medicine，etc.） is not unified， and the phenomena of the same name with different meanings，confusion， and misappropriation emerge. This seriously restricts the inheritance，innovation， and clinical application of traditional Chinese medicine and ethnomedicine. By tracing and analyzing liver heat， it is found that liver heat in traditional Chinese medicine is caused by disordered rest and diet， as well as internal injury due to emotional disorder， which leads to liver dysfunction， Qi stagnation， and heat turning to fire in the liver meridian. The liver heat in Tibetan medicine is caused by the accumulated heat of the liver nature and the evil heat in the liver， which stimulates the toxin of Chiba fever. The liver heat in Mongolian medicine derives from the abnormal diet and rest， making excessive Sheila accumulate in the liver and causing disease. The above etiologies are all related to diet， rest，exogenous evil，emotion，and so on， and the pathogenesis is related to the imbalance of Qi and the metabolic disorder of organs. The clinical symptoms are pain in the liver region，yellow eyes， bitter mouth， fever，digestion，and loss of appetite. The principle of treatment and compatibility of prescription are heat-based， with auxiliary detoxification. Other ethnomedicine， such as Uygur medicine， Dai medicine， Yao Medicine，Miao medicine， and She medicine do not have a clear discussion on liver heat，and their etiology， pathogenesis， treatment，and prescription are not systematic，mostly based on a single drug or proven prescriptions.Through the systematic tracing，mining，induction，analysis， and arrangement of the liver heat based on existing literature information database in China，this paper regarded syndrome as the outline and disease as the goal，clarified the similarities and differences of the pathogenesis of liver heat in traditional Chinese medicine，and determined the relationship between liver heat and liver disease and the status quo of syndrome and treatment.This review provides evidence and reference for clinical prevention and treatment，as well as drug development for liver disease.

ObjectiveTo investigate the value of noninvasive imaging detection （FibroScan）， two serological models of gamma-glutamyl transpeptidase-to-platelet ratio （GPR） score and S index， and two inflammatory factors of interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） in predicting liver fibrosis in patients with HBeAg-positive chronic hepatitis B （CHB）， as well as the consistency of liver biopsy in pathological staging， and to provide early warning for early intervention of CHB. MethodsA retrospective analysis was performed for 131 HBeAg-positive CHB patients who underwent liver biopsy in The Third People’s Hospital of Kunming from January 2019 to December 2023. The results of liver biopsy were collected from all patients， and related examinations were performed before liver biopsy， including total bilirubin， alanine aminotransferase， platelet count， gamma-glutamyl transpeptidase， albumin， IL-6， TNF-α， liver stiffness measurement （LSM）， and abdominal ultrasound. An analysis of variance was used for comparison of normally distributed continuous data between groups， and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between groups； the chi-square test was used for comparison of categorical data between groups. A Kappa analysis was used to investigate the consistency between LSM noninvasive histological staging and pathological staging based on liver biopsy， and the Spearman analysis was used to investigate the correlation between each variable and FibroScan in the diagnosis of liver fibrosis stage. The Logistic regression analysis was used to construct joint predictive factors. The receiver operating characteristic （ROC） curve was used to evaluate the value of each indicator alone and the joint predictive model in the diagnosis of liver fibrosis， and the Delong test was used for comparison of the area under the ROC curve （AUC）. ResultsIn the consistency check， inflammation degree based on liver biopsy had a Kappa value of 0.807 （P<0.001）， and liver fibrosis degree based on liver biopsy had a Kappa value of 0.827 （P<0.001）， suggesting that FibroScan noninvasive histological staging and liver biopsy showed good consistency in assessing inflammation degree and liver fibrosis stage. Age was positively correlated with LSM， GPR score， S index， IL-6， and TNF-α （all P<0.05）， and GPR score， S index， IL-6， and TNF-α were positively correlated with LSM （all P<0.05）. GPR score， S index， IL-6， and TNF-α were all independent risk factors for diagnosing significant liver fibrosis （≥S2） and progressive liver fibrosis （≥S3） （all P<0.05）. As for each indicator alone， GPR score had the highest value in the diagnosis of significant liver fibrosis （≥S2）， followed by S index， IL-6， and TNF-α， while S index had the highest value in the diagnosis of progressive liver fibrosis （≥S3）， followed by GPR score， TNF-α， and IL-6. The joint model had a higher predictive value than each indicator alone （all P<0.05）. ConclusionThere is a good consistency between FibroScan noninvasive histological staging and pathological staging based on liver biopsy. GPR score， S index， IL-6， and TNF-α are independent risk factors for evaluating different degree of liver fibrosis in CHB， and the combined prediction model established by them can better diagnose liver fibrosis.

ObjectiveTo investigate the role of 4-week high-intensity interval training (HIIT) in modulating the metabolic homeostasis of the pyruvate-lactate axis in the hippocampus of rats with chronic unpredictable mild stress (CUMS) to improve their depressive-like behavior. MethodsForty-eight SPF-grade 8-week-old male SD rats were randomly divided into 4 groups: the normal quiet group (C), the CUMS quiet group (M), the normal exercise group (HC), and the CUMS exercise group (HM). The M and HM groups received 8 weeks of CUMS modeling, while the HC and HM groups were exposed to 4 weeks of HIIT starting from the 5th week (3 min (85%-90%) S_max+1 min (50%-55%) S_max, 3-5 cycles, S_max is the maximum movement speed). A lactate analyzer was used to detect the blood lactate concentration in the quiet state of rats in the HC and HM groups at week 4 and in the 0, 2, 4, 8, 12, and 24 h after exercise, as well as in the quiet state of rats in each group at week 8. Behavioral indexes such as sucrose preference rate, number of times of uprightness and number of traversing frames in the absenteeism experiment, and other behavioral indexes were used to assess the depressive-like behavior of the rats at week 4 and week 8. The rats were anesthetized on the next day after the behavioral test in week 8, and hippocampal tissues were taken for assay. LC-MS non-targeted metabolomics, target quantification, ELISA and Western blot were used to detect the changes in metabolite content, lactate and pyruvate concentration, the content of key metabolic enzymes in the pyruvate-lactate axis, and the protein expression levels of monocarboxylate transporters (MCTs). Results4-week HIIT intervention significantly increased the sucrose preference rate, the number of uprights and the number of traversed frames in the absent field experiment in CUMS rats; non-targeted metabolomics assay found that 21 metabolites were significantly changed in group M compared to group C, and 14 and 11 differential metabolites were significantly dialed back in the HC and HM groups, respectively, after the 4-week HIIT intervention; the quantitative results of the targeting showed that, compared to group C, lactate concentration in the hippocampal tissues of M group, compared with group C, lactate concentration in hippocampal tissue was significantly reduced and pyruvate concentration was significantly increased, and 4-week HIIT intervention significantly increased the concentration of lactate and pyruvate in hippocampal tissue of HM group; the trend of changes in blood lactate concentration was consistent with the change in lactate concentration in hippocampal tissue; compared with group C, the LDHB content of group M was significantly increased, the content of PKM2 and PDH, as well as the protein expression level of MCT2 and MCT4 were significantly reduced. The 4-week HIIT intervention upregulated the PKM2 and PDH content as well as the protein expression levels of MCT2 and MCT4 in the HM group. ConclusionThe 4-week HIIT intervention upregulated blood lactate concentration and PKM2 and PDH metabolizing enzymes in hippocampal tissues of CUMS rats, and upregulated the expression of MCT2 and MCT4 transport carrier proteins to promote central lactate uptake and utilization, which regulated metabolic homeostasis of the pyruvate-lactate axis and improved depressive-like behaviors.

ObjectiveThis study aimed to investigate the effects of 4-week high-intensity interval training (HIIT) on synaptic plasticity in the prefrontal cortex (PFC) of rats exposed to chronic unpredictable mild stress (CUMS), and to explore its potential mechanisms. MethodsA total of 48 male Sprague-Dawley rats were randomly divided into 4 groups: control (C), model (M), control plus HIIT (HC), and model plus HIIT (HM). Rats in groups M and HM underwent 8 weeks of CUMS to establish depression-like behaviors, while groups HC and HM received HIIT intervention beginning from the 5th week for 4 consecutive weeks. The HIIT protocol consisted of repeated intervals of 3 min at high speed (85%-90% maximal training speed, S_max) alternated with one minute at low speed (50%-55% S_max), with 3 to 5 sets per session, conducted 5 d per week. Behavioral assessments and tail-vein blood lactate levels were measured at the end of the 4th and 8th weeks. After the intervention, rat PFC tissues were collected for Golgi staining to analyze synaptic morphology. Enzyme-linked immunosorbent assays (ELISA) were employed to detect brain-derived neurotrophic factor (BDNF), monocarboxylate transporter 1 (MCT1), lactate, and glutamate levels in the PFC, as well as serotonin (5-HT) levels in serum. Additionally, Western blot analysis was conducted to quantify the expression of synaptic plasticity-related proteins, including c-Fos, activity-regulated cytoskeleton-associated protein (Arc), and N-methyl-D-aspartate receptor 1 (NMDAR1). ResultsCompared to the control group (C), the CUMS-exposed rats (group M) exhibited significant reductions in sucrose preference rates, number of grid crossings, frequency of upright postures, and entries into and duration spent in open arms of the elevated plus maze, indicating marked depressive-like behaviors. Additionally, the group M showed significantly reduced dendritic spine density in the PFC, along with elevated levels of c-Fos, Arc, NMDAR1 protein expression, and increased concentrations of lactate and glutamate. Conversely, BDNF and MCT1 contents in the PFC and 5-HT levels in serum were significantly decreased. Following HIIT intervention, rats in the group HM displayed considerable improvement in behavioral indicators compared with the group M, accompanied by significant elevations in PFC MCT1 and lactate concentrations. Furthermore, HIIT notably normalized the expression levels of c-Fos, Arc, NMDAR1, as well as glutamate and BDNF contents in the PFC. Synaptic spine density also exhibited significant recovery. ConclusionFour weeks of HIIT intervention may alleviate depressive-like behaviors in CUMS rats by increasing lactate levels and reducing glutamate concentration in the PFC, thereby downregulating the overexpression of NMDAR, attenuating excitotoxicity, and enhancing synaptic plasticity.

The two core causes of obesity in modern lifestyle are high-fat diet (HFD) and insufficient physical activity. HFD can lead to disruption of gut microbiota and abnormal lipid metabolism, further exacerbating the process of obesity. The small intestine, as the “first checkpoint” for the digestion and absorption of dietary lipids into the body, plays a pivotal role in lipid metabolism. The small intestine is involved in the digestion, absorption, transport, and synthesis of dietary lipids. The absorption of lipids in the small intestine is a crucial step, as overactive absorption leads to a large amount of lipids entering the bloodstream, which affects the occurrence of obesity. HFD can lead to insulin resistance, disruption of gut microbiota, and inflammatory response in the body, which can further induce lipid absorption and metabolism disorders in the small intestine, thereby promoting the occurrence of chronic metabolic diseases such as obesity. Long term HFD can accelerate pathological structural remodeling and lipid absorption dysfunction of the small intestine: after high-fat diet, the small intestine becomes longer and heavier, with excessive villi elongation and microvilli elongation, thereby increasing the surface area of lipid absorption and causing lipid overload in the small intestine. In addition, overexpression of small intestine uptake transporters, intestinal mucosal damage induced “intestinal leakage”, dysbiosis of intestinal microbiota, ultimately leading to abnormal lipid absorption and chronic inflammation, accelerating lipid accumulation and obesity. Exercise, as one of the important means of simple, economical, and effective proactive health interventions, has always been highly regarded for its role in improving lipid metabolism homeostasis. The effect of exercise on small intestine lipid absorption shows a dose-dependent effect. Moderate to low-intensity aerobic exercise can improve the intestinal microenvironment, regulate the structure and lipid absorption function of the small intestine, promote lipid metabolism and health, while vigorous exercise, excessive exercise, and long-term high-intensity training can cause intestinal discomfort, leading to the destruction of intestinal structure and related symptoms, affecting lipid absorption. Long term regular exercise can regulate the diversity of intestinal microbiota, inhibit inflammatory signal transduction such as NF-κB, enhance intestinal mucosal barrier function, and improve intestinal lipid metabolism disorders, further enhancing the process of small intestinal lipid absorption. Exercise also participates in the remodeling process of small intestinal epithelial cells, regulating epithelial structural homeostasis by activating cell proliferation related pathways such as Wnt/β-catenin. Exercise can regulate the expression of lipid transport proteins CD36, FATP, and NPC1L1, and regulate the function of small intestine lipid absorption. However, the research on the effects of long-term exercise on small intestine structure, villus structure, absorption surface area, and lipid absorption related proteins is not systematic enough, the results are inconsistent, and the relevant mechanisms are not clear. In the future, experimental research can be conducted on the dose-response relationship of different intensities and forms of exercise, exploring the mechanisms of exercise improving small intestine lipid absorption and providing theoretical reference for scientific weight loss. It should be noted that the intestine is an organ that is sensitive to exercise response. How to determine the appropriate range, threshold, and form of exercise intensity to ensure beneficial regulation of intestinal lipid metabolism induced by exercise should become an important research direction in the future.

Objective: To evaluate the incremental vaccine effectiveness (VE) of two dose of the mumps containing vaccine (MuCV) in chidren, so as to provide a basis for optimizing mumps immunization strategies. Methods: A 1∶2 frequency matched case-control study was conducted by using reported mumps cases in childcare centers or schools from Lu an, Hefei, Ma anshan and Huainan cities of Anhui Province from September 1, 2023 to June 30, 2024, as a case group(383 cases). And healthy children in the same classroom were selected as a control group(766 cases). The MuCV immunization histories of participants were collected to estimate the incremental VE of the second dose of MuCV against mumps. Group comparisons were performed using the Chi square test or t-test. For matched case-control pairs, the Cox regression model was employed to calculate the odds ratio (OR) with 95% confidence interval (CI) for two dose MuCV vaccination and to estimate the incremental vaccine effectiveness (VE). Results: There were no statistically significant differences between the case and control groups regarding gender, age, dosage of MuCV vaccination and the time interval since the last dose vaccination( χ 2/t=0.05, 0.20, 0.94, -0.02, P >0.05). The proportions of the case and control groups vaccinated with two doses of MuCV were 26.63% and 29.37%, respectively, and the overall incremental VE of the second dose of MuCV was 40.73% (95% CI=3.03%-63.77%, P <0.05). Subgroup analyses revealed that the incremental VE for children with a period of ≥1 year between the two doses of MuCV was 54.13% (95% CI=1.90%-78.56%, P <0.05), while for children with a period of <1 year, it was 30.63% (95% CI=-28.59%-62.58%, P >0.05). The incremental VE of the second dose of MuCV was 30.36% (95% CI=-25.95%-61.50%, P >0.05) in kindergarten children and 66.73% (95% CI=14.92%-86.99%, P <0.05) in elementary and secondary school students. The incremental VE was 28.78% (95% CI=-27.46%-60.21%, P >0.05) within five years of the last dose of MuCV vaccination and 66.07% (95% CI=-41.56%-91.87%, P >0.05) for vaccinations administered beyond five years. Conclusions The second dose of MuCV may offer additional protection for children; however, extending the interval between two dose of MuCV (<1 year) has shown limited incremental protective effects. Therefore, it is crucial to consider optimizing current immunization strategies for mumps.

To report a case of an immunocompetent young adult male patient diagnosed with intracranial Aspergillus flavus infection， and to investigate the clinical features of this disease and related experience in diagnosis and treatment.A retrospective analysis was performed for the clinical data of a patient who had the initial presentation of high fever and headache and then progressed to meningoencephalitis， and the results of cerebrospinal fluid （CSF） metagenomic next-generation sequencing （mNGS） and treatment outcomes were summarized.The patient had an acute onset， with no response to empirical anti-infective therapy in the incipient stage， and then he gradually developed disturbance of consciousness and meningeal irritation sign. CSF analysis showed inflammatory changes， while conventional pathogen tests yielded negative results， and mNGS detected 27 specific sequences of Aspergillus flavus. The symptoms of the patient was significantly improved after antifungal therapy with voriconazole， with no recurrence after follow-up for 3 months.For unexplained central nervous system infections， especially those with negative results from conventional tests， mNGS can improve the detection rate of rare pathogens（e.g.，Aspergillus flavus）. Early diagnosis and targeted antifungal therapy are crucial for improving prognosis. This case highlights that invasive fungal infections should be considered even in immunocompetent individuals.
Aspergillus flavus

Metaflammation is a crucial mechanism in the onset and advancement of metabolic disorders, primarily defined by the activation of immune cells and increased concentrations of pro-inflammatory substances. The function of brain-derived neurotrophic factor (BDNF) in modulating immune and metabolic processes has garnered heightened interest, as BDNF suppresses glial cell activation and orchestrates inflammatory responses in the central nervous system via its receptor tyrosine kinase receptor B (TrkB), while also diminishing local inflammation in peripheral tissues by influencing macrophage polarization. Exercise, as a non-pharmacological intervention, is extensively employed to enhance metabolic disorders. A crucial mechanism underlying its efficacy is the significant induction of BDNF expression in central (hypothalamus, hippocampus, prefrontal cortex, and brainstem) and peripheral (liver, adipose tissue, intestines, and skeletal muscle) tissues and organs. This induction subsequently regulates inflammatory responses, ameliorates metabolic conditions, and decelerates disease progression. Consequently, BDNF is considered a pivotal molecule in the motor-metabolic regulation axis. Despite prior suggestions that BDNF may have a role in the regulation of exercise-induced inflammation, systematic data remains inadequate. Since that time, the field continues to lack structured descriptions and conversations pertinent to it. As exercise physiology research has advanced, the academic community has increasingly recognized that exercise is a multifaceted activity regulated by various systems, with its effects contingent upon the interplay of elements such as type, intensity, and frequency of exercise. Consequently, it is imperative to transcend the prior study paradigm that concentrated solely on localized effects and singular mechanisms and transition towards a comprehensive understanding of the systemic advantages of exercise. A multitude of investigations has validated that exercise confers health advantages for individuals with metabolic disorders, encompassing youngsters, adolescents, middle-aged individuals, and older persons, and typically enhances health via BDNF secretion. However, exercise is a double-edged sword; the relationship between exercise and health is not linearly positive. Insufficient exercise is ineffective, while excessive exercise can be detrimental to health. Consequently, it is crucial to scientifically develop exercise prescriptions, define appropriate exercise loads, and optimize health benefits to regulate bodily metabolism. BDNF mitigates metaflammation via many pathways during exercise. Initially, BDNF suppresses pro-inflammatory factors and facilitates the production of anti-inflammatory factors by modulating bidirectional transmission between neural and immune cells, therefore diminishing the inflammatory response. Secondly, exercise stimulates the PI3K/Akt, AMPK, and other signaling pathways via BDNF, enhancing insulin sensitivity, reducing lipotoxicity, and fostering mitochondrial production, so further optimizing the body’s metabolic condition. Moreover, exercise-induced BDNF contributes to the attenuation of systemic inflammation by collaborating with several organs, enhancing hepatic antioxidant capacity, regulating immunological response, and optimizing “gut-brain” axis functionality. These processes underscore the efficacy of exercise as a non-pharmacological intervention for enhancing anti-inflammatory and metabolic health. Despite substantial experimental evidence demonstrating the efficacy of exercise in mitigating inflammation and enhancing BDNF levels, numerous limitations persist in the existing studies. Primarily, the majority of studies have concentrated on molecular biology and lack causal experimental evidence that explicitly confirms BDNF as a crucial mediator in the exercise regulation of metaflammation. Furthermore, the outcomes of current molecular investigations are inadequately applicable to clinical practice, and a definitive pathway of “exercise-BDNF-metaflammation” remains unestablished. Moreover, the existing research methodology, reliant on animal models or limited human subject samples, constrains the broad dissemination of the findings. Future research should progressively transition from investigating isolated and localized pathways to a comprehensive multilevel and multidimensional framework that incorporates systems biology and exercise physiology. Practically, there is an immediate necessity to undertake extensive, double-blind, randomized controlled longitudinal human studies utilizing multi-omics technologies (e.g., transcriptomics, proteomics, and metabolomics) to investigate the principal signaling pathways of BDNF-mediated metaflammation and to elucidate the causal relationships and molecular mechanisms involved. Establishing a more comprehensive scientific evidence system aims to furnish a robust theoretical framework and practical guidance for the mechanistic interpretation, clinical application, and pharmaceutical development of exercise in the prevention and treatment of metabolic diseases.