Carboxymethyl Chitosan-Coated Cyanidin-3-O-Glucoside-Beared Nanonutriosomes Suppress Palmitic Acid-Induced Hepatocytes Injury.

Cyanidin-3-O-glucoside (C3G) is classified as an anthocyanin (ACN) and is recognized for its remarkable antioxidant properties. Yet, the inadequate physicochemical stability of C3G restricts its potential for various biological applications. Thus, in this study, carboxymethyl chitosan (CMC)-coated nanonutriosomes (NS) were synthesized as a novel carrier for encapsulating C3G (CMC-C3G-NS) to improve C3G stability. CMC-C3G-NS exhibited a diameter of less than 200 nm along with an encouraging encapsulation efficiency exceeding 90%. Notably, the formulated CMC-C3G-NS possessed better stability under various pH, ionic, and oxygen conditions, improved controlled release properties, and higher hepatocellular uptake than uncoated particles (C3G-NS), indicating a longer retention time of C3G in a physiological environment. Of utmost significance, CMC-C3G-NS demonstrated superior alleviating effects against palmitic acid (PA)-induced oxidative hepatic damage compared to C3G-NS. Our study provided promising nanocarriers with the potential to deliver hydrophilic ACNs and controlled release properties for PA-induced hepatotoxicity alleviation.

Phase-Amplitude Coupling Detection and Analysis of Human 2-Dimensional Neural Cultures in Multi-well Microelectrode Array in Vitro.

BACKGROUND: Human induced pluripotent stem cell (hiPSC)- derived neurons offer the possibility of studying human-specific neuronal behaviors in physiologic and pathologic states in vitro. It is unclear whether cultured neurons can achieve the fundamental network behaviors required to process information in the brain. Investigating neuronal oscillations and their interactions, as occurs in cross-frequency coupling (CFC), addresses this question. NEW METHODS: We examined whether networks of two-dimensional (2D) cultured hiPSC-derived cortical neurons grown with hiPSC-derived astrocytes on microelectrode array plates recapitulate the CFC that is present in vivo. We employed the modulation index method for detecting phase-amplitude coupling (PAC) and used offline spike sorting to analyze the contribution of single neuron spiking to network behavior. RESULTS: We found that PAC is present, the degree of PAC is specific to network structure, and it is modulated by external stimulation with bicuculline administration. Modulation of PAC is not driven by single neurons, but by network-level interactions. COMPARISON WITH EXISTING METHODS: PAC has been demonstrated in multiple regions of the human cortex as well as in organoids. This is the first report of analysis demonstrating the presence of coupling in 2D cultures. CONCLUSION: CFC in the form of PAC analysis explores communication and integration between groups of neurons and dynamical changes across networks. In vitro PAC analysis has the potential to elucidate the underlying mechanisms as well as capture the effects of chemical, electrical, or ultrasound stimulation; providing insight into modulation of neural networks to treat nervous system disorders in vivo.

Strain-insensitive micro torsion and temperature sensor based on a helical taper seven-core fiber structure.

We propose a multimode interference-based optical fiber NHTSN sensor with a helical taper for simultaneous measurement of micro torsion and temperature. The sensor consists of single mode fiber (SMF), no-core fiber (NCF), and seven-core fiber (SCF). A helical taper is fabricated in the SCF using a flame heater, forming the SMF-NCF-Helical Taper SCF-NCF-SMF (NHTSN) structure. Theoretical analysis and experimental results demonstrate that the introduction of helical taper not only imparts directionality to the torsion measurement, but also results in a significant improvement in torsion sensitivity due to the increased inter-mode optical path difference (OPD) and enhanced inter-mode coupling. In the experiment, the torsion sensitivity of the NHTSN sensor reaches -1.255 nm/(rad/m) in the twist rate (TR) range of -3.931 rad/m to 3.931 rad/m, which is a 9-fold improvement over the original structure. Further reduction of the helical taper diameter increases the sensitivity to -1.690 nm/(rad/m). In addition, the sensor has a temperature sensitivity of up to 97 pm/°C from 20 °C to 90 °C, and simultaneous measurement of torsion and temperature is attainable through a dual-parameter measurement matrix. The NHTSN sensor possesses advantages of compact size, high sensitivity, good linearity, and strain-independence, endowing it with potential applications in structural health monitoring (SHM) and engineering machinery.

Ferroptosis is involved in human chorionic trophoblast cells cytotoxicity induced by black phosphorus nanoparticles.

Black phosphorus (BP) is a new type of nanomaterial, which has been widely used in many biomedical fields due to its superior properties, but there are few studies on the toxicity of BP, especially in the reproductive system. To explore the effects of BP exposure on reproduction and reveal its molecular mechanism, we firstly investigated the potential toxicity of black phosphorus nanoparticles (BPNPs) in vivo. The results showed that BP exposure in pregnant mice can reduce the weight of fetal mice and placenta. H&E staining further indicated the changes of placental cross-section and vascular remodeling after BP treatment. Then, human exvillous trophoblast HTR8/SVneo was treated with different concentrations of BPNPs. We found that BPNPs induced significant cytotoxicity, including dose-dependent reduction of cell viability and proliferation. Trophoblast cell migration and invasion were also impaired by BPNPs exposure. Moreover, pretreatment with Cytochalasin D (Cyto-D), a classical phagocytic inhibitor, alleviated the decline of cell viability induced by BPNPs. Transcriptome sequencing showed that BPNPs exposure led to ferroptosis. Subsequently, the related indexes of iron death were detected, including increase of iron ion concentration, decrease of the ferroptosis marker, GPX4 (Glutathione Peroxidase 4), increase of FTL (Ferritin Light Chain), and the increase of lipid peroxidation indexes (MDA level and decrease of GSH level). In addition, ferroptosis inhibitor (Fer-1 and DFO) pretreatment can alleviate both the cytotoxic effects and functional impairment induced by BPNPs. In summary, our study confirmed the reproductive toxicity of BPNPs for the first time, and constructed BPNPs injury model in vitro using human villus ectotrophoblast cells and revealed the role of ferroptosis in this process, which deepened our understanding of the biosafety of black phosphorus nanomaterials.

Isolated Binary Fe-Ni Metal-Nitrogen Sites Anchored on Porous Carbon Nanosheets for Efficient Oxygen Electrocatalysis through High-Temperature Gas-Migration Strategy.

Atomically dispersed dual-site catalysts can regulate multiple reaction processes and provide synergistic functions based on diverse molecules and their interfaces. However, how to synthesize and stabilize dual-site single-atom catalysts (DACs) is confronted with challenges. Herein, we report a facile high-temperature gas-migration strategy to synthesize Fe-Ni DACs on nitrogen-doped carbon nanosheets (FeNiSAs/NC). FeNiSAs/NC exhibits a high half-wave potential (0.88 V) for the oxygen reduction reaction (ORR) and a low overpotential of 410 mV at 10 mA cm-2 for the oxygen evolution reaction (OER). As an air electrode for Zn-air batteries (ZABs), it shows better performances in aqueous ZABs and excellent stability and flexibility in solid-state ZABs. The high specific surface area (1687.32 m2/g) of FeNiSAs/NC is conducive to electron transport. Density functional theory (DFT) reveals that the Fe sites are the active center, and Ni sites can significantly optimize the free energy of the oxygen-containing intermediate state on Fe sites, contributing to the improvement of ORR and the corresponding OER activities. This work can provide guidance for the rational design of DACs and understand the structure-activity relationship of SACs with multiple active sites for electrocatalytic energy conversion.

The potential of astragalus polysaccharide for treating diabetes and its action mechanism.

Type 2 diabetes presents a significant global health burden and is frequently linked to serious clinical complications, including diabetic cardiomyopathy, nephropathy, and retinopathy. Astragalus polysaccharide (APS), extracted from Astragalus membranaceus, exhibits various biochemical and physiological effects. In recent years, a growing number of researchers have investigated the role of APS in glucose control and the treatment of diabetes and its complications in various diabetes models, positioning APS as a promising candidate for diabetes therapy. This review surveys the literature on APS from several databases over the past 20 years, detailing its mechanisms of action in preventing and treating diabetes mellitus. The findings indicate that APS can address diabetes by enhancing insulin resistance, modulating the immune system, protecting islet cells, and improving the intestinal microbiota. APS demonstrates positive pharmacological value and clinical potential in managing diabetic complications, including diabetic retinopathy, nephropathy, cardiomyopathy, cognitive dysfunction, wound healing, and more. However, further research is necessary to explore APS's bioavailability, optimal dosage, and additional clinical evidence.

Lactobacillus Reuteri Vesicles Regulate Mitochondrial Function of Macrophages to Promote Mucosal and Cutaneous Wound Healing.

The interplay between bacteria and their host influences the homeostasis of the human immune microenvironment, and this reciprocal interaction also affects the process of tissue damage repair. A variety of immunomodulatory commensal bacteria reside in the body, capable of delivering membrane vesicles (MVs) to host cells to regulate the local immune microenvironment. This research revealed, for the initial time, the significant enhancement of mucosal and cutaneous wound healing by MVs secreted by the human commensal Lactobacillus reuteri (RMVs) through modulation of the inflammatory environment in wound tissue. Local administration of RMVs reduces the proportion of pro-inflammatory macrophages in inflamed tissues and mitigates the level of local inflammation, thereby facilitating the healing of oral mucosa and cutaneous wounds. The elevated oxidative stress levels in activated pro-inflammatory macrophages can be modulated by RMVs, resulting in phenotypic transformation of macrophages. Furthermore, 3-hydroxypropionaldehyde present in RMVs can decrease the mitochondrial permeability of macrophages and stabilize the mitochondrial membrane potential, thereby promoting the conversion of macrophages to an anti-inflammatory phenotype. This study pioneers the significance of commensal bacterial MVs in tissue injury repair and presents a novel concept for the repair of tissue damage.

Pcgf5: An important regulatory factor in early embryonic neural induction.

Polycomb group RING finger (PCGF) proteins, a crucial subunits of the Polycomb complex, plays an important role in regulating gene expression, embryonic development, and cell fate determination. In our research, we investigated Pcgf5, one of the six PCGF homologs, and its impact on the differentiation of P19 cells into neural stem cells. Our findings revealed that knockdown of Pcgf5 resulted in a significant decrease in the expression levels of the neuronal markers Sox2, Zfp521, and Pax6, while the expression levels of the pluripotent markers Oct4 and Nanog increased. Conversely, Pcgf5 overexpression upregulated the expression of Sox2 and Pax6, while downregulating the expression of Oct4 and Nanog. Additionally, our analysis revealed that Pcgf5 suppresses Wnt3 expression via the activation of Notch1/Hes1, and ultimately governs the differentiation fate of neural stem cells. To further validate our findings, we conducted in vivo experiments in zebrafish. We found that knockdown of pcgf5a using morpholino resulted in the downregulated expression of neurodevelopmental genes such as sox2, sox3, and foxg1 in zebrafish embryos. Consequently, these changes led to neurodevelopmental defects. In conclusion, our study highlights the important role of Pcgf5 in neural induction and the determination of neural cell fate.

Paeoniflorin promotes PPARγ expression to suppress HSCs activation by inhibiting EZH2-mediated histone H3K27 trimethylation.

BACKGROUND: The alleviating effect of paeoniflorin (Pae) on liver fibrosis has been established; however, the molecular mechanism and specific target(s) underlying this effect remain elusive. PURPOSE: This study was to investigate the molecular mechanism underlying the regulatory effect of Pae on hepatic stellate cells (HSCs) activation in liver fibrosis, with a specific focus on the role of Pae in modulating histone methylation modifications. METHODS: The therapeutic effect of Pae was evaluated by establishing in vivo and in vitro models of carbon tetrachloride (CCl4)-induced mice and transforming growth factor ß1 (TGF-ß1)-induced LX-2 cells, respectively. Molecular docking, surface plasmon resonance (SPR), chromatin immunoprecipitation-quantitative real time PCR (ChIP-qPCR) and other molecular biological methods were used to clarify the molecular mechanism of Pae regulating HSCs activation. RESULTS: Our study found that Pae inhibited HSCs activation and histone trimethylation modification in liver of CCl4-induced mice and LX-2 cells. We demonstrated that the inhibitory effect of Pae on the activation of HSCs was dependent on peroxisome proliferator-activated receptor γ (PPARγ) expression and enhancer of zeste homolog 2 (EZH2). Mechanistically, Pae directly binded to EZH2 to effectively suppress its enzymatic activity. This attenuation leaded to the suppression of histone H3K27 trimethylation in the PPARγ promoter region, which induced upregulation of PPARγ expression. CONCLUSION: This investigative not only sheds new light on the precise targets that underlie the remission of hepatic fibrogenesis induced by Pae but also emphasizes the critical significance of EZH2-mediated H3K27 trimethylation in driving the pathogenesis of liver fibrosis.

How hetero-single-atom dispersion reconstructed electronic structure of carbon materials and regulated Fenton-like oxidation pathways.

Single-atom catalysts (SACs) have emerged as competitive candidates for Fenton-like oxidation of micro-pollutants in water. However, the impact of metal insertion on the intrinsic catalytic activity of carrier materials has been commonly overlooked, and the environmental risk due to metal leaching still requires attention. In contrast to previous reports, where metal sites were conventionally considered as catalytic centers, our study investigates, for the first time, the crucial catalytic role of the carbon carrier modulated through hetero-single-atom dispersion and the regulation of Fenton-like oxidation pathways. The inherent differences in electronic properties between Fe and Co can effectively trigger long-range electron rearrangement in the sp2-carbon-conjugated structure, creating more electron-rich regions for peroxymonosulfate (PMS) complexation and initiating the electron transfer process (ETP) for pollutant degradation, which imparts the synthesized catalyst (FeCo-NCB) with exceptional catalytic efficiency despite its relatively low metal content. Moreover, the FeCo-NCB/PMS system exhibits enduring decontamination efficiency in complex water matrices, satisfactory catalytic stability, and low metal leaching, signifying promising practical applications. More impressively, the spatial relationship between metal sites and electron density clouds is revealed to determine whether high-valent metal-oxo species (HVMO) are involved during the decomposition of surface complexes. Unlike single-type single-atom dispersion, where metal sites are situated within electron-rich regions, hetero-single-atom dispersion can cause the deviation of electron density clouds from the metal sites, thus hindering the in-situ oxidation of metal within the complexes and minimizing the contribution of HVMO. These findings provide new insights into the development of carbon-based SACs and advance the understanding of nonradical mechanisms underpinning Fenton-like treatments.

Quantification of metabolic activity from isotope tracing data using automated methodology.

Isotope tracing is a widely used technique to study metabolic activities by introducing heavy labeled nutrients into living cells and organisms. However, interpreting isotope tracing data is often heuristic, and application of automated methods using artificial intelligence is limited due to the paucity of evaluative knowledge. Our study developed a new pipeline that efficiently predicts metabolic activity in expansive metabolic networks and systematically quantifies flux uncertainty of traditional computational methods. We further developed an algorithm adept at significantly reducing this uncertainty, enabling robust evaluations of metabolic activity with limited data. Using this technology, we discovered highly reprogrammed mitochondria-cytosol exchange cycles in tumor tissue of patients, and observed similar metabolic patterns influenced by nutritional conditions in cancer cells. Thus, our refined methodology provides robust automated quantification of metabolism allowing for new insight into metabolic network activity.

Apoptotic Extracellular Vesicles Induced Endothelial Cell-Mediated Autologous Stem Cell Recruitment Dominates Allogeneic Stem Cell Therapeutic Mechanism for Bone Repair.

Although stem cell therapy is proved to be a promising strategy for bone repair and regeneration, transplanted allogeneic stem cells generally suffer from unfavorable apoptosis instead of differentiation into osteocytes. How the apoptotic stem cells promote bone regeneration still needs to be uncovered. In this work, we found that apoptotic extracellular vesicles released by allogeneic stem cells are critical mediators for promoting bone regeneration. Based on the results of in vivo experiments, a mechanism of apoptotic stem cells determined autologous stem cell recruitment and enhance osteogenesis was proposed. The nanoscaled apoptotic extracellular vesicles released from transplanted stem cells were endocytosed by vascular endothelial cells and preferentially distribute at endoplasmic reticular region. The oxidized phosphatidylcholine enriched in the vesicles activated the endoplasmic reticulum stress and triggered the reflective elevation of adhesion molecules, which induced the recruitment of autologous stem cells located in the blood vessels, transported them into the defect region, and promoted osteogenesis and bone repair. These findings not only reveal the mechanism of stem cell therapy of bone defects but also provide a cue for investigation of the biological process of stem cell therapy for other diseases and develop stem cell therapeutic strategies.

Fibrin clot fracture under cyclic fatigue and variable rate loading.

Fibrin clot is a vital class of fibrous materials, governing the mechanical response of blood clots. Fracture behavior of fibrin clots under complex physiological load is relevant for hemostasis and thrombosis. But how they fracture under cyclic and variable rate loading has not been reported. Here we conduct cyclic fatigue and monotonic variable rate loading tests on fibrin clots to characterize their fracture properties in terms of fatigue threshold and rate-dependent fracture toughness. We demonstrate that the fracture behavior of fibrin clots is sensitive to the amplitude of cyclic load and the loading rate. The cyclic fatigue tests show the fatigue threshold of fibrin clots at 1.66 J/m2, compared to the overall fracture toughness 15.8 J/m2. Furthermore, we rationalize the fatigue threshold using a semi-empirical model parameterized by 3D morphometric quantification to account for the hierarchical molecular structure of fibrin fibers. The variable loading tests reveal rate dependence of the overall fracture toughness of fibrin clots. Our analysis with a viscoelastic fracture model suggests the viscoelastic origin of the rate-dependent fracture toughness. The toughening mechanism of fibrin clots is further compared with biological tissues and hydrogels. This study advances the understanding and modeling of fatigue and fracture of blood clots and would motivate further investigation on the mechanics of fibrous materials. STATEMENT OF SIGNIFICANCE: Fibrin clot is a soft fibrous gel, exhibiting nonlinear mechanical responses under complex physiological loads. It is the main load-bearing constituent of blood clots where red blood cells, platelets and other cells are trapped. How the fibrin clot fractures under complex mechanical loads is critical for hemostasis and thrombosis. We study the fracture behavior of fibrin clots under cyclic fatigue and monotonic variable rate loads. We characterize the fatigue-threshold and viscous energy dissipation of fibrin clots. We compare the toughness enhancement of fibrin clots with hydrogels. The findings offer new insights into the fatigue and fracture of blood clots and fibrous materials, which could improve design guidelines for bioengineered materials.

Engineered Extracellular Vesicles Driven by Erythrocytes Ameliorate Bacterial Sepsis by Iron Recycling, Toxin Clearing and Inflammation Regulation.

Sepsis poses a significant challenge in clinical management. Effective strategies targeting iron restriction, toxin neutralization, and inflammation regulation are crucial in combating sepsis. However, a comprehensive approach simultaneously targeting these multiple processes has not been established. Here, an engineered apoptotic extracellular vesicles (apoEVs) derived from macrophages is developed and their potential as multifunctional agents for sepsis treatment is investigated. The extensive macrophage apoptosis in a Staphylococcus aureus-induced sepsis model is discovered, unexpectedly revealing a protective role for the host. Mechanistically, the protective effects are mediated by apoptotic macrophage-released apoEVs, which bound iron-containing proteins and neutralized α-toxin through interaction with membrane receptors (transferrin receptor and A disintegrin and metalloprotease 10). To further enhance therapeutic efficiency, apoEVs are engineered by incorporating mesoporous silica nanoparticles preloaded with anti-inflammatory agents (microRNA-146a). These engineered apoEVs can capture iron and neutralize α-toxin with their natural membrane while also regulating inflammation by releasing microRNA-146a in phagocytes. Moreover, to exploit the microcosmic movement and rotation capabilities, erythrocytes are utilized to drive the engineered apoEVs. The erythrocytes-driven engineered apoEVs demonstrate a high capacity for toxin and iron capture, ultimately providing protection against sepsis associated with high iron-loaded conditions. The findings establish a multifunctional agent that combines natural and engineered antibacterial strategies.

Bone-Targeting Peptide and RNF146 Modified Apoptotic Extracellular Vesicles Alleviate Osteoporosis.

Background: Osteoporosis is a highly prevalent disease that causes fractures and loss of motor function. Current drugs targeted for osteoporosis often have inevitable side effects. Bone marrow mesenchymal stem cell (BMSCs)-derived apoptotic extracellular vesicles (ApoEVs) are nanoscale extracellular vesicles, which has been shown to promote bone regeneration with low immunogenicity and high biological compatibility. However, natural ApoEVs cannot inherently target bones, and are often eliminated by macrophages in the liver and spleen. Thus, our study aimed to reconstruct ApoEVs to enhance their bone-targeting capabilities and bone-promoting function and to provide a new method for osteoporosis treatment. Methods: We conjugated a bone-targeting peptide, (Asp-Ser-Ser)6 ((DSS)6), onto the surface of ApoEVs using standard carbodiimide chemistry with DSPE-PEG-COOH serving as the linker. The bone-targeting ability of (DSS)6-ApoEVs was determined using an in vivo imaging system and confocal laser scanning microscopy (CLSM). We then loaded ubiquitin ligase RING finger protein146 (RNF146) into BMSCs via adenovirus transduction to obtain functional ApoEVs. The bone-promoting abilities of (DSS)6-ApoEVs and (DSS)6-ApoEVsRNF146 were measured in vitro and in vivo. Results: Our study successfully synthesized bone-targeting and gained functional (DSS)6-ApoEVsRNF146 and found that engineered ApoEVs could promote osteogenesis in vitro and exert significant bone-targeting and osteogenesis-promoting effects to alleviate osteoporosis in a mouse model. Conclusion: To promote the bone-targeting ability of natural ApoEVs, we successfully synthesized engineered ApoEVs, (DSS)6-ApoEVsRNF146 and found that they could significantly promote osteogenesis and alleviate osteoporosis compared with natural ApoEVs, which holds great promise for the treatment of osteoporosis.

Applications of artificial intelligence in gastroscopy: a narrative review.

Gastroscopy, a critical tool for the diagnosis of upper gastrointestinal diseases, has recently incorporated artificial intelligence (AI) technology to alleviate the challenges involved in endoscopic diagnosis of some lesions, thereby enhancing diagnostic accuracy. This narrative review covers the current status of research concerning various applications of AI technology to gastroscopy, then discusses future research directions. By providing this review, we hope to promote the integration of gastroscopy and AI technology, with long-term clinical applications that can assist patients.

MSC-derived exosomes protect auditory hair cells from neomycin-induced damage via autophagy regulation.

BACKGROUND: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.

Welded Carbon Nanotube-Graphene Hybrids with Tunable Strain Sensing Behavior for Wide-Range Bio-Signal Monitoring.

Carbon nanotubes (CNTs) and graphene have commonly been applied as the sensitive layer of strain sensors. However, the buckling deformation of CNTs and the crack generation of graphene usually leads to an unsatisfactory strain sensing performance. In this work, we developed a universal strategy to prepare welded CNT-graphene hybrids with tunable compositions and a tunable bonding strength between components by the in situ reduction of CNT-graphene oxide (GO) hybrid by thermal annealing. The stiffness of the hybrid film could be tailored by both initial CNT/GO dosage and annealing temperature, through which its electromechanical behaviors could also be defined. The strain sensor based on the CNT-graphene hybrid could be applied to collect epidermal bio-signals by both capturing the faint skin deformation from wrist pulse and recording the large deformations from joint bending, which has great potential in health monitoring, motion sensing and human-machine interfacing.

Si-Ni-San inhibits hepatic Fasn expression and lipid accumulation in MAFLD mice through AMPK/p300/SREBP-1c axis.

BACKGROUND: Soothing the liver and regulating qi is one of the core ideas of traditional Chinese medicine (TCM) in the treatment of fatty liver. Si-Ni-San (SNS) is a well-known herbal formula in TCM for liver soothing and qi regulation in fatty liver treatment. However, its efficacy lacks modern scientific evidence. PURPOSE: This study was aimed to investigate the impact of SNS on metabolic associated fatty liver disease (MAFLD) in mice and explore the underlying molecular mechanisms, particularly its effects on lipid metabolism in hepatocytes. METHODS: The therapeutic effect of SNS was evaluated using in vivo and in vitro models of high-fat/high-cholesterol (HFHC) diet-induced mice and palmitic acid (PA)-induced hepatocytes, respectively. Molecular biological techniques such as RNA-sequencing (RNA-seq), co-immunoprecipitation (co-IP), and western blotting were employed to elucidate the molecular mechanism of SNS in regulating lipid metabolism in hepatocytes. RESULTS: Our findings revealed that SNS effectively reduced lipid accumulation in the livers of HFHC diet-induced mice and PA-induced hepatocytes. RNA-seq analysis demonstrated that SNS significantly down-regulated the expression of fatty acid synthase (Fasn) in the livers of HFHC-fed mice. Mechanistically, SNS inhibited Fasn expression and lipid accumulation by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK). Activation of AMPK suppressed the activity of the transcriptional coactivator p300 and modulated the protein stability of sterol regulatory element-binding protein-1c (SREBP-1c). Importantly, p300 was required for the inhibition of Fasn expression and lipid accumulation by SNS. Furthermore, SNS activated AMPK by decreasing adenosine triphosphate (ATP) production in hepatocytes. CONCLUSION: This study provided novel evidence on the regulatory mechanisms underlying the effects of SNS on Fasn expression. Our findings demonstrate, for the first time, that SNS exerts suppressive effects on Fasn expression through modulation of the AMPK/p300/SREBP-1c axis. Consequently, this regulatory pathway mitigates excessive lipid accumulation and ameliorates MAFLD in mice.

Effects of inflammation, childhood adversity, and psychiatric symptoms on brain morphometrical phenotypes in bipolar II depression.

BACKGROUND: The neuroanatomical alteration in bipolar II depression (BDII-D) and its associations with inflammation, childhood adversity, and psychiatric symptoms are currently unclear. We hypothesize that neuroanatomical deficits will be related to higher inflammation, greater childhood adversity, and worse psychiatric symptoms in BDII-D. METHODS: Voxel- and surface-based morphometry was performed using the CAT toolbox in 150 BDII-D patients and 155 healthy controls (HCs). Partial Pearson correlations followed by multiple comparison correction was used to indicate significant relationships between neuroanatomy and inflammation, childhood adversity, and psychiatric symptoms. RESULTS: Compared with HCs, the BDII-D group demonstrated significantly smaller gray matter volumes (GMVs) in frontostriatal and fronto-cerebellar area, insula, rectus, and temporal gyrus, while significantly thinner cortices were found in frontal and temporal areas. In BDII-D, smaller GMV in the right middle frontal gyrus (MFG) was correlated with greater sexual abuse (r = -0.348, q < 0.001) while larger GMV in the right orbital MFG was correlated with greater physical neglect (r = 0.254, q = 0.03). Higher WBC count (r = -0.227, q = 0.015) and IL-6 levels (r = -0.266, q = 0.015) was associated with smaller GMVs in fronto-cerebellar area in BDII-D. Greater positive symptoms was correlated with larger GMVs of the left middle temporal pole (r = 0.245, q = 0.03). CONCLUSIONS: Neuroanatomical alterations in frontostriatal and fronto-cerebellar area, insula, rectus, temporal gyrus volumes, and frontal-temporal thickness may reflect a core pathophysiological mechanism of BDII-D, which are related to inflammation, trauma, and psychiatric symptoms in BDII-D.