Both type 2 diabetes mellitus (T2DM) and metabolic associated fatty liver disease (MAFLD) fall within the spectrum of metabolic diseases, and they exhibit a bi-directional causal relationship and robust reciprocal association. Their shared pathological cornerstone is insulin resistance (IR), which involves the interplay of mitochondrial dysfunction and chronic inflammation, forming a cascading pathological process of “IR-mitochondrial dysfunction-inflammation”. This largely explains the notable upward trend in T2DM-MAFLD co-occurrence observed over recent years. Exercise intervention, as a safe and effective non-pharmacological approach, can improve the pathological progression of these patients at multiple levels. Following the logical framework of “pathogenesis-efficacy comparison-molecular mechanisms-clinical translation”, this article systematically compares the efficacy and molecular mechanisms of moderate-intensity continuous training (MICT), resistance exercise, high-intensity interval training (HIIT), and combined training. MICT reduces intrahepatic triglycerides by promoting lipolysis and improving cardiorespiratory fitness; resistance exercise increases muscle mass and basal metabolic rate, offering unique advantages in preserving muscle while reducing fat and improving insulin sensitivity; HIIT is a time-efficient exercise modality that enhances patients’ cardiorespiratory fitness and insulin sensitivity by alternating brief periods of vigorous exertion with recovery periods, with a prominent short-term triglyceride-lowering effect; combined training produces synergistic effects, comprehensively improving glucolipid metabolism and showing the best long-term adherence. Mechanistically, exercise exerts its beneficial effects through three common pathways: (1) AMPK-mediated lipid oxidation and mitochondrial biogenesis; (2) IRS/PI3K/Akt-mediated insulin signaling sensitization; and (3) Nrf2/ARE anti-oxidation and TGF-β/Smads anti-fibrosis regulation. Different exercise modalities activate these pathways with distinct emphases: MICT most directly and persistently activates the AMPK pathway; resistance exercise uniquely improves IRS/PI3K/Akt signaling through muscle mass gain; HIIT induces the highest AMPK activation intensity and triggers unique lactate-mediated signaling regulation; combined training integrates the above multiple mechanistic advantages. For clinical translation, multidisciplinary team collaboration is essential to ensure safety and adherence. Individualized prescriptions should be formulated according to the FITT-VP principle and patient phenotypes—frequency of 3-5 sessions/week of aerobic exercise combined with 2-3 sessions/week of resistance exercise; intensity of moderate-intensity (40%-60% heart rate reserve (HRR))aerobic exercise and 60%-80% of one-repetition maximum (1-RM) for resistance exercise; time of at least 150 min/week of moderate-intensity aerobic exercise, 30-60 min per session; type of combined training as the preferred modality; total volume of≥500-1 000 MET-min/week; and progression adjusted every 4-6 weeks—with real-time adjustments supported by wearable devices, ultimately forming a closed-loop management system from initial assessment to long-term follow-up. Notably, current studies have limitations such as small sample sizes and short intervention periods. Future research should focus on long-term follow-up, multi-omics biomarkers, and combined exercise-drug strategies. In conclusion, the systematic integration of structured, individualized, and sustainable exercise interventions into the multidisciplinary management pathway for patients with T2DM complicated by MAFLD is an urgent need in current clinical practice.

ObjectiveType 2 diabetes mellitus (T2DM) often causes severe hepatic metabolic complications, dominated by metabolic associated fatty liver disease (MAFLD). Persistent hepatic steatosis and oxidative stress further trigger steatohepatitis and progressive liver damage, increasing the mortality risk of diabetic patients. Aerobic exercise effectively improves hepatic lipid metabolism and antioxidant capacity, but poor patient adherence restricts its long-term clinical application. Mitochondrial-derived mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a key peptide regulating insulin sensitivity and hepatic redox homeostasis. This study aimed to explore the protective mechanism of MOTS-c against T2DM-related liver injury and its combined beneficial effect with aerobic exercise via the NRF2/PPARγ signaling axis. This study aimed to investigate whether MOTS-c cooperates with aerobic exercise to alleviate T2DM-associated hepatic oxidative stress and metabolic dysfunction by activating the NRF2/PPARγ axis, and to clarify the molecular and transcriptomic characteristics of their combined intervention. MethodsStable MOTS-c overexpression and knockdown HepG2 cell lines were constructed using lentiviral transfection. An oleic acid-induced cellular lipid accumulation model and NRF2-knockout cell model were applied to verify the NRF2-dependent mechanism ofMOTS-c. Intracellular lipid deposition, triglyceride levels, antioxidant enzyme activities, and the expression of NRF2/PPARγ pathway-related genes and proteins were detected. In vivo, a T2DM rat model with obvious hepatic steatosis was established via a high-fat and high-sucrose diet combined with streptozotocin injection. Model rats received aerobic exercise, MOTS-c intraperitoneal injection, or combined intervention. We detected systemic glycolipid metabolic indicators, hepatic histopathological changes, and the expression of core proteins in the hepatic NRF2/PPARγ axis. Hepatic transcriptomic sequencing was performed to screen differentially expressed genes (DEGs) and enrich key pathways co-regulated by MOTS-c and aerobic exercise. ResultsCellular results showed that MOTS-c overexpression significantly reduced oleic acid-induced lipid deposition, enhanced antioxidant enzyme activity, and upregulated NRF2 and PPARγ expression. Conversely, MOTS-c knockdown aggravated hepatic lipid accumulation and oxidative damage and inhibited NRF2/PPARγ pathway activation. NRF2 knockout completely eliminated the protective effects of MOTS-c on lipid metabolism and redox balance, confirming its NRF2-dependent regulatory mechanism. In T2DM rats, both MOTS-c supplementation and aerobic exercise effectively improved insulin resistance, corrected glycolipid metabolic disorders, and alleviated hepatic steatosis, while consistently activating the hepatic NRF2/PPARγ axis. Compared with single intervention, the combined treatment showed a better improvement trend in hepatic metabolic and oxidative injury, without definitive synergistic effects. Transcriptomic analysis revealed that the co-regulated DEGs of MOTS-c and aerobic exercise were primarily enriched in lipid metabolism and PPAR signaling pathways, with multiple antioxidant and lipid-regulating genes significantly modulated by combined intervention. ConclusionMOTS-c exhibits obvious exercise-mimetic hepatoprotective effects in T2DM. It activates the hepatic NRF2/PPARγ axis to strengthen antioxidant defense, stabilize lipid metabolism, and relieve T2DM-associated hepatic steatosis and oxidative damage. Furthermore, MOTS-c produces additive beneficial effects with aerobic exercise, showing a superior intervention trend on diabetic liver dysfunction. This study identifies the NRF2/PPARγ axis as the core mechanism of MOTS-c-regulated hepatic protection, elucidates the transcriptomic basis of combined intervention, and provides a reliable theoretical basis and potential therapeutic target for clinical intervention in T2DM-complicated MAFLD.

In recent years,there has been a significant rise in the incidence of peripheral nerve injury(PNI),highlighting the urgent need for effective treatment strategies.The inflammation and pain hypersensitivity associated with PNI greatly diminish patients'quality of life.Although there are promising treatment approaches for nerve injury,the com-plex pathological mechanisms underlying neuropathic pain caused by PNI present significant challenges for clinical manage-ment.Extensive research has established that the development of neuropathic pain is closely linked to nerve conduction and related signaling molecules.Among these,P2X4 receptor(P2X4R),an ATP-dependent ion channel,is involved in nerve signal transmission and associated pathways-plays a crucial role in the progression of neuropathic pain.This article offers a comprehensive overview of the function and distribution of P2X4R,investigates its pathological mechanisms in PNI-induced neuropathic pain,and elucidates its relationship with peripheral neuropathic pain disorders.Through this explo-ration,we aim to provide valuable insights that could inform the development of novel clinical strategies for pain management.

Objective To investigate the value of gemstone spectral CT multiparameter for risk assessment in acute pulmonary embolism(APE).Methods A total of 83 patients diagnosed with APE were categorized into three groups based on the European Society of Cardiology(ESC)guidelines:high-risk group(n=23),medium-high-risk group(n=29),and medium-low-risk group(n=31).The spectral CT multiparameters for each group were subsequently analyzed and compared.The predictive value of the region of interest perfusion defect iodine group value(ROI vPD),whole lung mean perfusion iodine group value(vMeanIP),and lung perfusion defect volume ratio(rPDvol)in high-risk APE patients were assessed using receiver operating characteristic(ROC)curves.Pearson correlation was employed to analyze the correlation of gemstone spectral CT multiparameter with pulmonary artery obstruction index(PAOI)and right ventricle/left ventricle diameter ratio(rRVD/LVD).Results Whole lung minimum perfusion iodine group value(vMinIP),whole lung maximum perfusion iodine group value(vMaxIP),vMeanIP,rPDvol and right ventricle/left ventricle volume ratio(rRVV/LVV)exhibited significant differences across all groups.The area under the curve(AUC)for ROI vPD,vMeanIP,and rPDvol in high-risk APE patients were 0.792,0.831,and 0.884,respectively.The sensitivity and specificity for ROI vPD(≤0.3),vMeanIP(≤1.1),and rPDvol(≥23.7％)were recorded at 95.7％and 60.0％,78.3％and 75.0％,as well as 91.3％and 75.0％,respectively.Simultaneously,the gemstone spectral CT multiparameter exhibited correlations with PAOI and rRVD/LVD.Conclusion The gemstone spectral CT multiparameter can be utilized to evaluate the severity and progression of patients with APE.

AIM:This study aims to design pH/near-infrared(NIR)dual-responsive metal-organic framework composite nanoparticles co-loaded with indocyanine green(ICG)and sphingosine kinase 1(SphK1)siRNA(siSphK1),and to evaluate their anticancer efficacy against non-small-cell lung cancer A549 cells.METHODS:The ZIF-8 nanopar-ticles were synthesized and loaded with ICG and siSphK1 to prepare ZIF-8@ICG@siSphK1 nanoparticles.Their morpholo-gy,particle size,surface charge,and crystalline structure were characterized through transmission electron microscopy,dynamic light scattering,and X-ray diffraction.Stability,siSphK1 encapsulation and protection,and pH/NIR response were assessed.The gene silencing efficacy and anticancer activity in A549 cells were evaluated using Western blot,RT-qPCR,MTT assay,flow cytometry,and reactive oxygen species(ROS)fluorescence staining.RESULTS:The ZIF-8@ICG@siSphK1 nanoparticles exhibited a typical polyhedral structure with an average particle size of(76.8±0.9)nm and a ζ potential of(9.2±0.1)mV.The nanoparticles effectively encapsulated siSphK1,protecting it from RNase degra-dation,and demonstrated excellent NIR responsiveness with a photothermal conversion efficiency of 39.7%.After 10 h of 808 nm laser irradiation,siRNA cumulative release was significantly higher at pH 5.5 compared with pH 7.4.In A549 cells,the nanoparticles efficiently delivered siSphK1 under NIR irradiation,significantly down-regulated SphK1 gene ex-pression,inhibited cell proliferation,induced apoptosis,and increased intracellular ROS levels.CONCLUSION:The ZIF-8@ICG@siSphK1 nanoparticles effectively induce cytotoxic effects against A549 cells through gene silencing and pho-tothermal therapy.

Background and purpose:In breast cancer surgery,margin status assessment significantly impacts patient prognosis,with positive margins indicating higher recurrence and metastasis risks.Ensuring complete tumor resection is thus critical for surgical success.Indocyanine green(ICG)has garnered attention for its potential real-time imaging of breast cancer lesions under near-infrared light.This study employed ICG for intraoperative assessment of breast cancer lesion margin status and further explored the possibility of optimizing the safe margin distance surround the lesion in normal breast tissue.Methods:Clinical data of patients admitted to the Department of Thyroid and Breast Surgery,the Fourth Affiliated Hospital of Anhui Medical University(Affiliated Chaohu Hospital),from December 2021 to September 2022 were collected.A retrospective clinical study was conducted on breast cancer patients who were randomly assigned to either the ICG group or the conventional surgery group.Two to three hours before surgery,patients in the ICG group received a peripheral intravenous injection of 0.5 mg/kg ICG.Intraoperative fluorescence imaging was performed on the specimen before and after resection,as well as on the residual cavity.Near-infrared fluorescence imaging equipment was used to quantitatively measure fluorescence intensity of resected lesions at 4 directions(12,3,6,and 9 o'clock)and detect fluorescence in the residual cavity after lesion removal.Specimens were promptly sent to the pathology department for pathological examination,and safety margins of normal breast tissue in the 4 directions were recorded.The Strengthening the Reporting of Observational Studies in Epidemiology(STROBE)checklist was followed for this study.This study was approved by the Ethics Committee of the Fourth Affiliated Hospital of Anhui Medical University(Affiliated Chaohu Hospital)(No.KYXM-202310-46).Results:This study included 50 breast cancer patients,with 24 in the ICG group and 26 in the traditional surgery group.In the ICG group,fluorescence signals were detected at all lesion sites.Specifically,fluorescence density values at the lesion center,margin,and surrounding normal breast tissue were measured as 251.08±10.73,208.08±19.74,and 156.76±16.47,respectively,showing a gradual decrease from center outward with statistically significant differences(P＜0.05).Additionally,fluorescence ratios between the lesion center and margin,and center and surrounding normal tissue,were 1.22±0.13 and 1.62±0.19,respectively.After resection,abnormal fluorescence was observed in 2 of 24 cases in the residual cavity,with 1 case being invasive carcinoma with ductal carcinoma in situ and the other normal breast tissue.Ultimately,this study demonstrated that ICG achieved a sensitivity of 95.9%and a specificity of 97.9%in margin assessment.After specimen resection,the safety margins of normal glandular tissue surrounding the lesion were measured.The safety widths for the ICG group and the concurrent breast cancer surgery group were(8.36±6.42)mm and(15.08±4.75)mm,respectively.This difference was statistically significant(P＜0.05).Conclusion:ICG is a real-time,efficient,and cost-effective tracer that can be used to determine breast cancer margins,with excellent sensitivity and specificity.For early-stage breast cancer patients who are eligible for breast-conserving surgery,this tracer helps to reduce the amount of healthy breast tissue that is removed around the lesion.

AIM:This study aims to design pH/near-infrared(NIR)dual-responsive metal-organic framework composite nanoparticles co-loaded with indocyanine green(ICG)and sphingosine kinase 1(SphK1)siRNA(siSphK1),and to evaluate their anticancer efficacy against non-small-cell lung cancer A549 cells.METHODS:The ZIF-8 nanopar-ticles were synthesized and loaded with ICG and siSphK1 to prepare ZIF-8@ICG@siSphK1 nanoparticles.Their morpholo-gy,particle size,surface charge,and crystalline structure were characterized through transmission electron microscopy,dynamic light scattering,and X-ray diffraction.Stability,siSphK1 encapsulation and protection,and pH/NIR response were assessed.The gene silencing efficacy and anticancer activity in A549 cells were evaluated using Western blot,RT-qPCR,MTT assay,flow cytometry,and reactive oxygen species(ROS)fluorescence staining.RESULTS:The ZIF-8@ICG@siSphK1 nanoparticles exhibited a typical polyhedral structure with an average particle size of(76.8±0.9)nm and a ζ potential of(9.2±0.1)mV.The nanoparticles effectively encapsulated siSphK1,protecting it from RNase degra-dation,and demonstrated excellent NIR responsiveness with a photothermal conversion efficiency of 39.7%.After 10 h of 808 nm laser irradiation,siRNA cumulative release was significantly higher at pH 5.5 compared with pH 7.4.In A549 cells,the nanoparticles efficiently delivered siSphK1 under NIR irradiation,significantly down-regulated SphK1 gene ex-pression,inhibited cell proliferation,induced apoptosis,and increased intracellular ROS levels.CONCLUSION:The ZIF-8@ICG@siSphK1 nanoparticles effectively induce cytotoxic effects against A549 cells through gene silencing and pho-tothermal therapy.

Objective To investigate the value of gemstone spectral CT multiparameter for risk assessment in acute pulmonary embolism(APE).Methods A total of 83 patients diagnosed with APE were categorized into three groups based on the European Society of Cardiology(ESC)guidelines:high-risk group(n=23),medium-high-risk group(n=29),and medium-low-risk group(n=31).The spectral CT multiparameters for each group were subsequently analyzed and compared.The predictive value of the region of interest perfusion defect iodine group value(ROI vPD),whole lung mean perfusion iodine group value(vMeanIP),and lung perfusion defect volume ratio(rPDvol)in high-risk APE patients were assessed using receiver operating characteristic(ROC)curves.Pearson correlation was employed to analyze the correlation of gemstone spectral CT multiparameter with pulmonary artery obstruction index(PAOI)and right ventricle/left ventricle diameter ratio(rRVD/LVD).Results Whole lung minimum perfusion iodine group value(vMinIP),whole lung maximum perfusion iodine group value(vMaxIP),vMeanIP,rPDvol and right ventricle/left ventricle volume ratio(rRVV/LVV)exhibited significant differences across all groups.The area under the curve(AUC)for ROI vPD,vMeanIP,and rPDvol in high-risk APE patients were 0.792,0.831,and 0.884,respectively.The sensitivity and specificity for ROI vPD(≤0.3),vMeanIP(≤1.1),and rPDvol(≥23.7％)were recorded at 95.7％and 60.0％,78.3％and 75.0％,as well as 91.3％and 75.0％,respectively.Simultaneously,the gemstone spectral CT multiparameter exhibited correlations with PAOI and rRVD/LVD.Conclusion The gemstone spectral CT multiparameter can be utilized to evaluate the severity and progression of patients with APE.

In recent years,there has been a significant rise in the incidence of peripheral nerve injury(PNI),highlighting the urgent need for effective treatment strategies.The inflammation and pain hypersensitivity associated with PNI greatly diminish patients'quality of life.Although there are promising treatment approaches for nerve injury,the com-plex pathological mechanisms underlying neuropathic pain caused by PNI present significant challenges for clinical manage-ment.Extensive research has established that the development of neuropathic pain is closely linked to nerve conduction and related signaling molecules.Among these,P2X4 receptor(P2X4R),an ATP-dependent ion channel,is involved in nerve signal transmission and associated pathways-plays a crucial role in the progression of neuropathic pain.This article offers a comprehensive overview of the function and distribution of P2X4R,investigates its pathological mechanisms in PNI-induced neuropathic pain,and elucidates its relationship with peripheral neuropathic pain disorders.Through this explo-ration,we aim to provide valuable insights that could inform the development of novel clinical strategies for pain management.

Blue light inactivation technology, particularly at the 405 nm wavelength, has demonstrated distinct and multifaceted mechanisms of action against both Gram-positive and Gram-negative bacteria, offering a promising alternative to conventional antibiotic therapies. For Gram-positive pathogens such as Bacillus cereus, Listeria monocytogenes, and methicillin-resistant Staphylococcus aureus (MRSA), the bactericidal effects are primarily mediated by endogenous porphyrins (e.g., protoporphyrin III, coproporphyrin III, and uroporphyrin III), which exhibit strong absorption peaks between 400-430 nm. Upon irradiation, these porphyrins are photoexcited to generate cytotoxic reactive oxygen species (ROS), including singlet oxygen, hydroxyl radicals, and superoxide anions, which collectively induce oxidative damage to cellular components. Early studies by Endarko et al. revealed that (405±5) nm blue light at 185 J/cm² effectively inactivated L. monocytogenes without exogenous photosensitizers, supporting the hypothesis of intrinsic photosensitizer involvement. Subsequent work by Masson-Meyers et al. demonstrated that 405 nm light at 121 J/cm² suppressed MRSA growth by activating endogenous porphyrins, leading to ROS accumulation. Kim et al. further elucidated that ROS generated under 405 nm irradiation directly interact with unsaturated fatty acids in bacterial membranes, initiating lipid peroxidation. This process disrupts membrane fluidity, compromises structural integrity, and impairs membrane-bound proteins, ultimately causing cell death. In contrast, Gram-negative bacteria such as Salmonella, Escherichia coli, Helicobacter pylori, Pseudomonas aeruginosa, and Acinetobacter baumannii exhibit more complex inactivation pathways. While endogenous porphyrins remain central to ROS generation, studies reveal additional photodynamic contributors, including flavins (e.g., riboflavin) and bacterial pigments. For instance, H. pylori naturally accumulates protoporphyrin and coproporphyrin mixtures, enabling efficient 405 nm light-mediated inactivation without antibiotic resistance concerns. Kim et al. demonstrated that 405 nm light at 288 J/cm² inactivates Salmonella by inducing genomic DNA oxidation (e.g., 8-hydroxy-deoxyguanosine formation) and disrupting membrane functions, particularly efflux pumps and glucose uptake systems. Huang et al. highlighted the enhanced efficacy of pulsed 405 nm light over continuous irradiation for E. coli, attributing this to increased membrane damage and optimized ROS generation through frequency-dependent photodynamic effects. Environmental factors such as temperature, pH, and osmotic stress further modulate susceptibility, sublethal stress conditions (e.g., high salinity or acidic environments) weaken bacterial membranes, rendering cells more vulnerable to subsequent ROS-mediated damage. The 405 nm blue light inactivates drug-resistant Pseudomonas aeruginosa through endogenous porphyrins, pyocyanin, and pyoverdine, with the inactivation efficacy influenced by bacterial growth phase and culture medium composition. Intriguingly, repeated 405 nm exposure (20 cycles) failed to induce resistance in A. baumannii, with transient tolerance linked to transient overexpression of antioxidant enzymes (e.g., superoxide dismutase) or stress-response genes (e.g., oxyR). For Gram-positive bacteria, porphyrin abundance dictates sensitivity, whereas in Gram-negative species, membrane architecture and accessory pigments modulate outcomes. Critically, ROS-mediated damage is nonspecific, targeting DNA, proteins, and lipids simultaneously, thereby minimizing resistance evolution. The 405 nm blue light technology, as a non-chemical sterilization method, shows promise in medical and food industries. It enhances infection control through photodynamic therapy and disinfection, synergizing with red light for anti-inflammatory treatments (e.g., acne). In food processing, it effectively inactivates pathogens (e.g., E. coli, S. aureus) without altering food quality. Despite efficacy against multidrug-resistant A. baumannii, challenges include device standardization, limited penetration in complex materials, and optimization of photosensitizers/light parameters. Interdisciplinary research is needed to address these limitations and scale applications in healthcare, food safety, and environmental decontamination.