Uptake of Mesenchymal Stem Cell-Derived Exosomes in Mouse Brain through Intranasal Delivery.

INTRODUCTION: Exosomes are nanoscale extracellular vesicles that widely participate in intercellular communication. An increasing number of studies have reported on the neuroprotective effects of stem cell-derived exosomes in brain diseases through various delivery methods. However, only a few reports are available on the delivery and uptake of stem cell-derived exosomes in the brains of mice of different ages. METHODS: PKH-26-labelled mesenchymal stem cell-derived exosomes were collected, and their uptake was investigated in the brains of mice aged 2 weeks, 2 months, and >6 months, 24 hours after intranasal delivery. RESULTS: No exosomes were distributed in the whole brains of 2-week-old mice after 24 hours of intranasal delivery. However, a small number of exosomes were found in the olfactory bulb, cortex, and hippocampus of 2-month-old mice, with no exosomes observed in the cerebellum. In contrast, a large number of exosomes were ingested in all brain regions, including the olfactory bulb, cortex, hippocampus, and cerebellum, of >6-month-old mice. CONCLUSION: Exosomes can enter the brains of adult mice through intranasal administration, but there are differences in the uptake rate among mice of different ages. These findings provide a theoretical basis for the future clinical administration of exosomes for treating brain disorders.

Gut microbiota metabolites: potential therapeutic targets for Alzheimer's disease?

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function, which significantly increases pain and social burden. However, few therapeutic interventions are effective in preventing or mitigating the progression of AD. An increasing number of recent studies support the hypothesis that the gut microbiome and its metabolites may be associated with upstream regulators of AD pathology. Methods: In this review, we comprehensively explore the potential mechanisms and currently available interventions targeting the microbiome for the improvement of AD. Our discussion is structured around modern research advancements in AD, the bidirectional communication between the gut and brain, the multi-target regulatory effects of microbial metabolites on AD, and therapeutic strategies aimed at modulating gut microbiota to manage AD. Results: The gut microbiota plays a crucial role in the pathogenesis of AD through continuous bidirectional communication via the microbiota-gut-brain axis. Among these, microbial metabolites such as lipids, amino acids, bile acids and neurotransmitters, especially sphingolipids and phospholipids, may serve as central components of the gut-brain axis, regulating AD-related pathogenic mechanisms including ß-amyloid metabolism, Tau protein phosphorylation, and neuroinflammation. Additionally, interventions such as probiotic administration, fecal microbiota transplantation, and antibiotic use have also provided evidence supporting the association between gut microbiota and AD. At the same time, we propose an innovative strategy for treating AD: a healthy lifestyle combined with targeted probiotics and other potential therapeutic interventions, aiming to restore intestinal ecology and microbiota balance. Conclusion: Despite previous efforts, the molecular mechanisms by which gut microbes act on AD have yet to be fully described. However, intestinal microorganisms may become an essential target for connecting the gut-brain axis and improving the symptoms of AD. At the same time, it requires joint exploration by multiple centers and multiple disciplines.

KNTC1 functions as a potential biomarker and oncogene regulating proliferation, migration and apoptosis in gastric cancer.

BACKGROUND: As one of the most prevalent cancers, gastric cancer (GC) exhibits a remarkably high morbidity and mortality rate. To date, effective diagnostic and prognostic markers and therapeutic targets for GC are still lacking. Kinetochore associated 1 (KNTC1) is one of the proteins involved in chromosome segregation. However, the diagnostic and prognostic value of KNTC1 and its biological function in GC remain unknown. METHODS: In this study, Gene Expression Omnibus (GEO) datasets were utilized to identify differentially expressed genes (DEGs). Prognostic and diagnostic value were assessed by Kaplan-Meier plotter and receiver operating characteristic (ROC) curve. The expression of KNTC1 was verified by q-PCR, immunohistochemistry (IHC) and Western blotting. Subsequently, KNTC1 knockdown was employed to investigate its effect on GC cells. Gene set enrichment analysis (GSEA) revealed a pathway regulated by KNTC1, which was further verified by Western blotting. RESULTS: Four highly expressed genes (ESPL1, RAD54L, KNTC1, TACC3) were identified as biomarkers for GC diagnosis and prognosis. Notably, the value of KNTC1 as a biomarker for GC was newly revealed. Single-cell and immune analyses revealed that KNTC1 contributed to the suppression of the GC immune microenvironment. In clinical samples, we demonstrated high expression of KNTC1 in GC tissues. KNTC1 knockdown suppressed proliferation and migration while promoting apoptosis of GC cells. Additionally, KNTC1 may affect GC cells by regulating the PI3K/Akt/mTOR pathway. CONCLUSIONS: KNTC1 acts as a potential diagnostic and prognostic marker for GC. It may promote proliferation and migration while inhibiting apoptosis of GC cells via the PI3K/Akt/mTOR pathway.

The intervention mechanism of Tanshinone IIA in alleviating neuronal injury induced by HMGB1 or TNF-α-mediated microglial activation.

Tanshinone IIA (Tan IIA), a neuroprotective natural compound extracted from Salvia miltiorrhiza, is used in stroke treatment. However, elucidating Tan IIA's neuroprotective mechanisms remains challenging due to limitations in assessing drug efficacy and biochemical parameters in clinical studies. This study investigated Tan IIA's impact on neuroinflammatory responses and its neuroprotective mechanisms using HMGB1- or TNF-α-stimulated BV2 microglia in a co-culture system with primary neuron cells. The results indicated that Tan IIA significantly reduced microglial activation induced by TNF-α or HMGB1. Concurrently, Tan IIA disrupted the interactions between HMGB1 and toll-like receptor 4 (TLR4), and between TNF-α and TNF receptor 1 (TNFR1), modulating the HMGB1/TLR4/nuclear factor-kappa B (NF-κB) and TNF-α/TNFR1/NF-κB signaling pathways and related protein expressions. Moreover, co-culture experiments showed that neuronal apoptosis induced by microglial activation was reversed by Tan IIA. In conclusion, Tan IIA provides neuroprotection by modulating signaling pathways in microglia, thus preventing neuronal apoptosis. This study offers new insights into therapeutic targets for ischemic stroke.

Extended King integral for modeling of parametric array loudspeakers with axisymmetric profiles.

Parametric array loudspeakers have been widely used in audio applications for generating directional audio beams. However, accurately calculating audio sound with a low computational load remains challenging, even for basic axisymmetric source profiles. This work addresses this challenge by extending the King integral in linear acoustics to incorporate both cumulative and local nonlinear effects, under the framework of the quasilinear solution without the paraxial approximation. The proposed method exploits the azimuthal symmetry in cylindrical coordinates to simplify modeling. To further improve computational efficacy, fast Hankel and Fourier transforms are employed for the radial and beam radiation directions, respectively. Numerical results with both uniform and focusing profiles demonstrate the advantages of the proposed approach over the traditional spherical wave expansion and direct integration methods, especially for larger aperture sizes. Specifically, for typical configurations with source aperture size of 0.2 m, we observe at least a 24-fold improvement in computational speed and a 227-fold reduction in memory requirements. These advancements allow us, for the first time, to present the sound field radiated by parametric array loudspeakers with a large aperture size of up to 0.5 m, without paraxial approximations. The implementation codes are available on https://github.com/ShaoZhe-LI/PAL_King.

The activation of the Notch signaling pathway by UBE2C promotes the proliferation and metastasis of hepatocellular carcinoma.

UBE2C, a ubiquitin-conjugating enzyme, functions as an oncogene in different types of human cancers. Nonetheless, the exact influence of UBE2C on the development of HCC via regulation of ubiquitination remains uncertain. Here, we found that UBE2C displayed elevated levels of expression in HCC and was associated with an unfavorable prognosis, as evidenced by the analysis of the TCGA database and the examination of clinical specimens. The role of UBE2C in HCC revealed its ability to promote the growth and metastasis of HCC. Mechanistically, UBE2C activated Notch signaling, as evidenced by the upregulation of N1ICD and Hes1, crucial components of the Notch pathway, and activation of the RBP-JK luciferase reporter by UBE2C. Finally, rescue experiments demonstrated that the oncogenic role of UBE2C was eliminated through treatment with the Notch inhibitor DAPT, while overexpression of N1ICD alleviated the anticarcinogenic impact of knockdown of UBE2C. Altogether, the results of our study indicate that UBE2C plays a role in the activation of Notch signaling and could potentially serve as a viable target for therapeutic interventions in HCC.

Distribution characteristics of stress on the vertebrae following different ranges of excision during Modified Anterior Cervical Discectomy and Fusion: A correlation study based on finite element analysis.

BACKGROUND: Modified Anterior Cervical Discectomy and Fusion with specific resection ranges is an effective surgical method for the treatment of focal ossification of the posterior longitudinal ligament (OPLL). Herein, we compare and analyse the static stress area distribution by performing different cuts on an original ideal finite element model. METHOD: A total of 96 groups of finite element models of the C4-C6 cervical spine with different vertebral segmentation ranges (width: 1-12 mm, height: 1-8 mm) were established. The same pressure direction and size were applied to observe the size and distribution area of stress following various ranges of excision of the C5 vertebral body. RESULTS: Different cutting areas had similar stress aggregation points. As the contact area decreased, the stress and the bearing above area increased. The correlation of stress area variation was highest between the 1-2 MPa and 6 MPa-Max regions (Rho = - 0.975). In the surface visualisation model fitting, the width and height were of different ratios in different stress regions. The model with the best fitting degree was the 1-2 MPa group, and the equation fitting (Rho = 0.966) was as follows: Area = 908.80 - 25.92 × Width + 2.71 × Height. CONCLUSION: Modified Anterior Cervical Discectomy and Fusion with different resection ranges exhibited different stress areas. In a specific resection range of the cervical spine (1-12 mm, 0-8 mm), area conversion occurred at a threshold of 4 MPa. Additionally, the stress was concentrated at the contact points between the vertebral body and the rigid fixator.

Exploration of potential antidiabetic and antioxidant components from the branches of Mitragyna diversifolia and possible mechanism.

In this study, sixteen compounds were isolated from the branches of Mitragyna diversifolia, including twelve triterpenes (1-12), a phenolic compound (13), and three flavonoids (14-16). Among them, compounds 1-7, and 10-16 were reported for the first time from this plant. Compounds 7, 14, and 15 exhibited significant inhibitory activities against α-glucosidase, with IC50 values of 18.48 ± 2.74, 12.14 ± 1.58 and 35.77 ± 4.52 µM, respectively. Furthermore, the inhibitory kinetics of α-glucosidase revealed that all fractions, active compounds 7, 14, and 15 belong to the mix inhibition type. In molecular docking, the analysis showed that compounds 13, 14, 15, and 16 possessed superior binding capacities with α-glucosidase (-8.3, -9.6, -9.9, and -9.2 kcal/mol, respectively). The results of the glucose uptake experiment indicated that only compound 14 showed a significant promotion effect on the glucose uptake rate of 3T3-L1 adipocytes (P < 0.05). Meanwhile, compounds 13, 14, 15, and 16 possessed potent antioxidant abilities with DPPH, ABTS, and FRAP. In DNA and protein oxidative damage assays, compound 15 had a stronger effect than the positive control Vc. The network-based pharmacological analysis platform was used to predict the diabetes-related target proteins of active compounds 7, 13, 14, 15, and 16, and two candidate targets (ALB and PPARG) related to their therapeutic effects on diabetes were identified.

Optimizing Skin Surface Metabolomics: A Comprehensive Evaluation of Sampling Methods, Extraction Solvents, and Analytical Techniques.

Characterizing the metabolite fingerprint from the skin surface provides invaluable insights into skin biology and microbe-host interactions. To ensure data accuracy and reproducibility, it is essential to develop standard operating procedures (SOPs) for skin surface metabolomics. However, there is a notable lack of studies in this area. Here, we thoroughly evaluated different sampling materials, extraction solvents, taping methods (frequency and number of tapes) and analytical techniques to optimize skin surface metabolomics. Our results showed that the combination of D-Squame® D100 tape with a methyl tert-butyl ether/methanol extractant is optimal for skin surface lipidomics. Performing the skin taping procedure five times with one tape yields sufficient biomass for lipid analysis, while the optimal taping procedure varies for water-soluble compounds. In addition, our study identified associations among the skin surface metabolites, some of which potentially underlie the formation of microbial cutotypes and offer insights into host-microbe interactions.

Increased GluK1 Subunit Receptors in Corticostriatal Projection from the Anterior Cingulate Cortex Contributed to Seizure-Like Activities.

The corticostriatal connection plays a crucial role in cognitive, emotional, and motor control. However, the specific roles and synaptic transmissions of corticostriatal connection are less studied, especially the corticostriatal transmission from the anterior cingulate cortex (ACC). Here, a direct glutamatergic excitatory synaptic transmission in the corticostriatal projection from the ACC is found. Kainate receptors (KAR)-mediated synaptic transmission is increased in this corticostriatal connection both in vitro and in vivo seizure-like activities. GluK1 containing KARs and downstream calcium-stimulated adenylyl cyclase subtype 1 (AC1) are involved in the upregulation of KARs following seizure-like activities. Inhibiting the activities of ACC or its corticostriatal connection significantly attenuated pentylenetetrazole (PTZ)-induced seizure. Additionally, injection of GluK1 receptor antagonist UBP310 or the AC1 inhibitor NB001 both show antiepileptic effects. The studies provide direct evidence that KARs are involved in seizure activity in the corticostriatal connection and the KAR-AC1 signaling pathway is a potential novel antiepileptic strategy.

Sex-dimorphic functions of orexin in neuropsychiatric disorders.

The orexin system regulates a variety of physiological functions, including the sleep-wake cycle, addiction, foraging behavior, stress and cognitive functioning. Orexin levels in central and peripheral are related to the pathogenesis of many diseases, most notably the narcolepsy, eating disorders, stress-related psychiatric disorders, and neurodegenerative diseases. Recently, it has been reported that the orexin system is distinctly sexually dimorphic, and is strongly associated with neuropsychiatric disorders. In this review, we analyzed advancements in the sex differences in the orexin system and their connection to psychoneurological conditions. Considering the scarcity of research in this domain, more research is imperative to reveal the underlying mechanisms.

The influence of forest types including native and non-native tree species on soil macrofauna depends on site conditions.

The ongoing climate change calls for managing forest ecosystems in temperate regions toward more drought-resistant and climate-resilient stands. Yet ecological consequences of management options such as planting non-native tree species and mixing coniferous and deciduous tree species have been little studied, especially on soil animal communities, key in litter decomposition and pest control. Here, we investigated the taxonomic and trophic structure of soil macrofauna communities in five forest types including native European beech (Fagus sylvatica), range-expanding Norway spruce (Picea abies) and non-native Douglas fir (Pseudotsuga menziesii) as well as conifer-beech mixtures across loamy and sandy sites in northern Germany. Abundance of primary decomposers (feeding predominantly on litter) was high in Douglas fir and beech forests, benefiting from less acidic soil and more favorable litter resources compared to spruce forests, while secondary decomposers (feeding predominantly on microorganisms and microbial residues) reached highest densities in spruce forests. Differences in abundance and species richness among forest types generally varied between regions and were most pronounced in Douglas fir of the sandy region. However, trophic guilds differed more between regions than between forest types, indicating that environmental factors outweigh the importance of forest type on soil macrofauna communities. The analysis of stable isotopes (δ15N and δ13C values) supported the general robustness in trophic position of macrofauna trophic guilds against variations in forest types and regions, but indicated reduced detrital shifts and food-chain lengths in coniferous compared to European beech forests with mixtures mitigating these effects. Overall, for evaluating consequences of future forest management practices on the structure and functioning of soil animal communities, regional factors need to be considered, but in particular at loamy sites the taxonomic and trophic structure of soil macrofauna communities are resistant against changes in forest types.

Reduced-dose chemotherapy and blinatumomab as induction treatment for newly diagnosed Ph-negative B-cell precursor acute lymphoblastic leukemia: a phase 2 trial.

Blinatumomab has emerged as a promising component of first-line therapy for acute B-cell precursor lymphoblastic leukemia (BCP-ALL), bolstering treatment efficacy. To mitigate CD19 selection pressure and reduce the incidence of blinatumomab-associated toxicities, pre-treatment chemotherapy is recommended before administering blinatumomab. From September 2022 to December 2023, we conducted a single-arm, multicenter, phase 2 trial (NCT05557110) in newly diagnosed Philadelphia chromosome-negative BCP-ALL (Ph-negative BCP-ALL) patients. Participants received induction treatment with reduced-dose chemotherapy (RDC), comprising idarubicin, vindesine, and dexamethasone over 7 days, followed by 2 weeks of blinatumomab. Those failing to achieve composite complete remission (CRc) received an additional 2 weeks of blinatumomab. The primary endpoint was the CRc rate post initial induction treatment. Of the 35 enrolled patients, 33 (94%) achieved CRc after 2 weeks of blinatumomab, with 30 (86%) achieving measurable residual disease (MRD) negativity. Two patients extended blinatumomab to 4 weeks. With either 2 or 4 weeks of blinatumomab treatment, all patients achieved CR (35/35) and 89% (31/35) were MRD negativity. The median time to CR was 22 days. Immune effector cell-associated neurotoxicity syndrome was limited (14%, all grade 1). Non-hematological adverse events of grade 3 or higher included pneumonia (17%), sepsis (6%), and cytokine release syndrome (9%). With a median follow-up of 11.5 months, estimated 1-year overall survival and 1-year progression-free survival rates were 97.1% and 82.2%, respectively. These findings affirm that RDC followed by blinatumomab is an effective and well-tolerated induction regimen for newly diagnosed Ph-negative BCP-ALL, supporting a shift towards less intensive and more targeted therapeutic approaches. Trial registration: https://www.clinicaltrials.Gov . Identifier NCT05557110.

Development and validation of a nomogram for individualizing fall risk in patients with hematologic malignancies.

Inpatient falls are common adverse events especially for patients with hematologic malignancies. A fall-risk prediction model for patients with hematologic malignancies are still needed. Here we conducted a multicenter study that prospectively included 516 hospitalized patients with hematologic malignancies, and developed a nomogram for fall risk prediction. Patients were divided into the modeling group (n = 389) and the validation group (n = 127). A questionnaire containing sociodemographic factors, general health factors, disease-related factors, medication factors, and physical activity factors was administered to all patients. Logistic regression analysis revealed that peripheral neuropathy, pain intensity, Morse fall scale score, chemotherapy courses, and myelosuppression days were risk factors for falls in patients with hematologic malignancies. The nomogram model had a sensitivity of 0.790 and specificity of 0.800. The calibration curves demonstrated acceptable agreement between the predicted and observed outcomes. Therefore, the nomogram model has promising accuracy in predicting fall risk in patients with hematologic malignancies.

Fine-Tuned Large Language Model for Visualization System: A Study on Self-Regulated Learning in Education.

Large Language Models (LLMs) have shown great potential in intelligent visualization systems, especially for domainspecific applications. Integrating LLMs into visualization systems presents challenges, and we categorize these challenges into three alignments: domain problems with LLMs, visualization with LLMs, and interaction with LLMs. To achieve these alignments, we propose a framework and outline a workflow to guide the application of fine-tuned LLMs to enhance visual interactions for domain-specific tasks. These alignment challenges are critical in education because of the need for an intelligent visualization system to support beginners' self-regulated learning. Therefore, we apply the framework to education and introduce Tailor-Mind, an interactive visualization system designed to facilitate self-regulated learning for artificial intelligence beginners. Drawing on insights from a preliminary study, we identify self-regulated learning tasks and fine-tuning objectives to guide visualization design and tuning data construction. Our focus on aligning visualization with fine-tuned LLM makes Tailor-Mind more like a personalized tutor. Tailor-Mind also supports interactive recommendations to help beginners better achieve their learning goals. Model performance evaluations and user studies confirm that Tailor-Mind improves the self-regulated learning experience, effectively validating the proposed framework.

Double hook-type aptamer-based colorimetric and electrochemical biosensor enables rapid and robust analysis of EpCAM expression.

Epithelial cell adhesion molecule (EpCAM), which is overexpressed in breast cancer cells and participates in cell signaling, migration, proliferation, and differentiation, has been utilized as a biomarker for cancer diagnosis and therapeutic prognosis. Here, a dual-signal readout nonenzymatic aptasensor is fabricated for the evaluation of EpCAM at the level of three breast cancer cell lines. The central principle of this enzyme-free aptasensor is the use of double hook-type aptamers (SYL3C and SJ3C2)-functionalized magnetic iron oxide (Fe3O4) as capture probes and quasi-CoFe prussian blue analogs (QCoFe PBAs) as nonenzymatic signal probes for colorimetric and electrochemical analysis. Following ligand detachment, the CoFe PBA was transformed to QCoFe PBA (calcined at 350 °C for 1 h), with its metal active sites exposed by controllable pyrolysis. We found that the enhanced sensitivity was attributed to the resonance effect of QCoFe PBA with the remarkable enzymatic properties. The dual-signal readout nonenzymatic aptasensor exhibited limits of detection for EpCAM as low as 0.89 pg mL-1 and 0.24 pg mL-1, within a wide linear range from 0.001 to 100 ng mL-1, respectively. We successfully employed this nonenzymatic aptasensor for monitoring EpCAM expression in three breast cancer cell lines, which provides an economical and robust alternative to costly and empirical flow cytometry. The dual-signal readout nonenzymatic aptasensor provides rapid, robust, and promising technological support for the accurate management of tumors.

Exploring Structure-Activity Relationships and Modes of Action of Laterocidine.

A significant increase in life-threatening infections caused by Gram-negative "superbugs" is a serious threat to global health. With a dearth of new antibiotics in the developmental pipeline, antibiotics with novel mechanisms of action are urgently required to prevent a return to the preantibiotic era. A key strategy to develop novel anti-infective treatments is to discover new natural scaffolds with distinct mechanisms of action. Laterocidine is a unique cyclic lipodepsipeptide with activity against multiple problematic multidrug-resistant Gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacterales. Here, we developed a total chemical synthesis methodology for laterocidine and undertook systematic structure-activity relationship studies with chemical biology and NMR. We discovered important structural features that drive the antimicrobial activity of laterocidine, leading to the discovery of an engineered peptide surpassing the efficacy of the original peptide. This engineered peptide demonstrated complete inhibition of the growth of a polymyxin-resistant strain of Pseudomonas aeruginosa in static time-kill experiments.

Naringin and Naringenin: Potential Multi-Target Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative dementia. The etiology of AD is multifactorial, and its complex pathophysiology involves tau and amyloid-ß deposition, increased oxidative stress, neuroinflammation, metabolic disorders, and massive neuronal loss. Due to its complex pathology, no effective cure for AD has been found to date. Therefore, there is an unmet clinical need for the development of new drugs against AD. Natural products are known to be good sources of compounds with pharmacological activity and have potential for the development of new therapeutic agents. Naringin, a naturally occurring flavanone glycoside, is predominantly found in citrus fruits and Chinese medicinal herbs. Mounting evidence shows that naringin and its aglycone, naringenin, have direct neuroprotective effects on AD, such as anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, and anti-neuroinflammatory effects, as well as metal chelation. Furthermore, they are known to improve disordered glucose/lipid metabolism, which is a high risk factor for AD. In this review, we summarize the latest data on the impact of naringin and naringenin on the molecular mechanisms involved in AD pathophysiology. Additionally, we provide an overview of the current clinical applications of naringin and naringenin. The novel delivery systems for naringin and naringenin, which can address their widespread pharmacokinetic limitations, are also discussed. The literature indicates that naringin and naringenin could be multilevel, multitargeted, and multifaceted for preventing and treating AD.

Probiotics and Non-Alcoholic Fatty Liver Disease: Unveiling the Mechanisms of Lactobacillus plantarum and Bifidobacterium bifidum in Modulating Lipid Metabolism, Inflammation, and Intestinal Barrier Integrity.

In recent years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has risen annually, yet due to the intricacies of its pathogenesis and therapeutic challenges, there remains no definitive medication for this condition. This review explores the intricate relationship between the intestinal microbiome and the pathogenesis of NAFLD, emphasizing the substantial roles played by Lactobacillus plantarum and Bifidobacterium bifidum. These probiotics manipulate lipid synthesis genes and phosphorylated proteins through pathways such as the AMPK/Nrf2, LPS-TLR4-NF-κB, AMPKα/PGC-1α, SREBP-1/FAS, and SREBP-1/ACC signaling pathways to reduce hepatic lipid accumulation and oxidative stress, key components of NAFLD progression. By modifying the intestinal microbial composition and abundance, they combat the overgrowth of harmful bacteria, alleviating the inflammatory response precipitated by dysbiosis and bolstering the intestinal mucosal barrier. Furthermore, they participate in cellular immune regulation, including CD4+ T cells and Treg cells, to suppress systemic inflammation. L. plantarum and B. bifidum also modulate lipid metabolism and immune reactions by adjusting gut metabolites, including propionic and butyric acids, which inhibit liver inflammation and fat deposition. The capacity of probiotics to modulate lipid metabolism, immune responses, and gut microbiota presents an innovative therapeutic strategy. With a global increase in NAFLD prevalence, these insights propose a promising natural method to decelerate disease progression, avert liver damage, and tackle associated metabolic issues, significantly advancing microbiome-focused treatments for NAFLD.