Mitochondria-Regulated Information Processing Nanosystem Promoting Immune Cell Communication for Liver Fibrosis Regression.

Liver fibrosis is a coordinated response to tissue injury that is mediated by immune cell interactions. A mitochondria-regulated information-processing (MIP) nanosystem that promotes immune cell communication and interactions to inhibit liver fibrosis is designed. The MIP nanosystem mimics the alkaline amino acid domain of mitochondrial precursor proteins, providing precise targeting of the mitochondria. The MIP nanosystem is driven by light to modulate the mitochondria of hepatic stellate cells, resulting in the release of mitochondrial DNA into the fibrotic microenvironment, as detected by macrophages. By activating the STING signaling pathway, the developed nanosystem-induced macrophage phenotype switches to a reparative subtype (Ly6Clow) and downstream immunostimulatory transcriptional activity, fully restoring the fibrotic liver to its normal tissue state. The MIP nanosystem serves as an advanced information transfer system, allowing precise regulation of trained immunity, and offers a promising approach for effective liver fibrosis immunotherapy with the potential for clinical translation.

Mitigation of ROS-triggered endoplasmic reticulum stress by upregulating Nrf2 retards diabetic nephropathy.

Endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of diabetic nephropathy (DN), and it is often accompanied by an increase in reactive oxygen species (ROS) production. However, the precise relationship between NFE2-related factor-2 (Nrf2), a key regulator of ROS balance, and ERS in DN remains elusive. This study aimed to investigate the impact of Nrf2 on ERS and its therapeutic potential in DN. Herein, ERS-related changes, including increased activating transcription factor-6 (ATF6), glucose-regulated protein 78 (GRP78), and transcription factor C/EBP homologous protein (CHOP) expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose cultured human renal proximal tubular (HK-2) cells. Nrf2 knockdown increased the sensitivity of HK-2 cells to ERS under high glucose conditions, underscoring the regulatory role of Nrf2 in ERS modulation. Notably, upregulating Nrf2 in ezetimibe-treated diabetic mice restored ERS markers and ameliorated albuminuria, glomerular hypertrophy, mesangial expansion, and tubulointerstitial fibrosis. Furthermore, the inhibition of ERS in HK-2 cells by the ROS scavenger, N-acetylcysteine, highlights the interplay between ROS and ERS. This study, for the first time, elucidates that the upregulation of Nrf2 may alleviate the negative influence of ROS-mediated ERS, presenting a promising therapeutic avenue for delaying the progression of DN. These findings suggest a potential strategy for targeting Nrf2 and ERS in developing novel therapeutic interventions for DN.

A Living Microecological Hydrogel with Microbiota Remodeling and Immune Reinstatement for Diabetic Wound Healing.

Dysregulated skin microbiota and compromised immune responses are the major etiological factors for non-healing diabetic wounds. Current antibacterial strategies fail to orchestrate immune responses and indiscriminately eradicate bacteria at the wound site, exacerbating the imbalance of microbiota. Drawing inspiration from the beneficial impacts that probiotics possess on microbiota, a living microecological hydrogel containing Lactobacillus plantarum and fructooligosaccharide (LP/FOS@Gel) is formulated to remodel dysregulated skin microbiota and reinstate compromised immune responses, cultivating a conducive environment for optimal wound healing. LP/FOS@Gel acts as an "evocator," skillfully integrating the skin microecology, promoting the proliferation of Lactobacillus, Ralstonia, Muribaculum, Bacillus, and Allobaculum, while eradicating colonized pathogenic bacteria. Concurrently, LP/FOS@Gel continuously generates lactic acid to elicit a reparative macrophage response and impede the activation of the nuclear factor kappa-B pathway, effectively alleviating inflammation. As an intelligent microecological system, LP/FOS@Gel reinstates the skin's sovereignty during the healing process and effectively orchestrates the harmonious dialogue between the host immune system and microorganisms, thereby fostering the healing of diabetic infectious wounds. These remarkable attributes render LP/FOS@Gel highly advantageous for pragmatic clinical applications.

Imaging and Liquid Biopsy for Distinguishing True Progression From Pseudoprogression in Gliomas, Current Advances and Challenges.

RATIONALE AND OBJECTIVES: Gliomas are aggressive brain tumors with a poor prognosis. Assessing treatment response is challenging because magnetic resonance imaging (MRI) may not distinguish true progression (TP) from pseudoprogression (PsP). This review aims to discuss imaging techniques and liquid biopsies used to distinguish TP from PsP. MATERIALS AND METHODS: This review synthesizes existing literature to examine advances in imaging techniques, such as magnetic resonance diffusion imaging (MRDI), perfusion-weighted imaging (PWI) MRI, and liquid biopsies, for identifying TP or PsP through tumor markers and tissue characteristics. RESULTS: Advanced imaging techniques, including MRDI and PWI MRI, have proven effective in delineating tumor tissue properties, offering valuable insights into glioma behavior. Similarly, liquid biopsy has emerged as a potent tool for identifying tumor-derived markers in biofluids, offering a non-invasive glimpse into tumor evolution. Despite their promise, these methodologies grapple with significant challenges. Their sensitivity remains inconsistent, complicating the accurate differentiation between TP and PSP. Furthermore, the absence of standardized protocols across platforms impedes the reliability of comparisons, while inherent biological variability adds complexity to data interpretation. CONCLUSION: Their potential applications have been highlighted, but gaps remain before routine clinical use. Further research is needed to develop and validate these promising methods for distinguishing TP from PsP in gliomas.

Bioorthogonal/Ultrasound Activated Oncolytic Pyroptosis Amplifies In Situ Tumor Vaccination for Boosting Antitumor Immunity.

Personalized in situ tumor vaccination is a promising immunotherapeutic modality. Currently, seeking immunogenic cell death (ICD) to generate in situ tumor vaccines is still mired by insufficient immunogenicity and an entrenched immunosuppressive tumor microenvironment (TME). Herein, a series of tetrazine-functionalized ruthenium(II) sonosensitizers have been designed and screened for establishing a bioorthogonal-activated in situ tumor vaccine via oncolytic pyroptosis induction. Based on nanodelivery-augmented bioorthogonal metabolic glycoengineering, the original tumor is selectively remolded to introduce artificial target bicycle [6.1.0] nonyne (BCN) into cell membrane. Through specific bioorthogonal ligation with intratumoral BCN receptors, sonosensitizers can realize precise membrane-anchoring and synchronous click-activation in desired tumor sites. Upon ultrasound (US) irradiation, the activated sonosensitizers can intensively disrupt the cell membrane with dual type I/II reactive oxygen species (ROS) generation for a high-efficiency sonodynamic therapy (SDT). More importantly, the severe membrane damage can eminently evoke oncolytic pyroptosis to maximize tumor immunogenicity and reverse immunosuppressive TME, ultimately eliciting powerful and durable systemic antitumor immunity. The US-triggered pyroptosis is certified to effectively inhibit the growths of primary and distant tumors, and suppress tumor metastasis and recurrence in "cold" tumor models. This bioorthogonal-driven tumor-specific pyroptosis induction strategy has great potential for the development of robust in situ tumor vaccines.

Reorganizing Helmholtz Adsorption Plane Enables Sodium Layered-Oxide Cathode Beyond High Oxidation Limits.

Sodium layered-oxides (Nax TMO2 ) sustain severe interfacial stability issues when subjected to battery applications. Particularly at high potential, the oxidation limits including transition metal dissolution and SEI reformation are intertwined upon the cathode, resulting in poor cycle ability. Herein, by rearranging the complex and structure of Helmholtz absorption plane adjacent to Nax TMO2 cathodes, the mechanism of constructing stable cathode/electrolyte interphase to push up oxidation limits is clarified. The strong absorbent fluorinated anions replace the solvents into the inner Helmholtz plane, thereby reorganizing the Helmholtz absorption structure and spontaneously inducing an anion-dominated interphase to envelop more active sites for layered oxides. More importantly, such multi-component cathode/electrolyte interphase proves effective for long-term durability of a series of manganese-based oxide cathodes, which achieves 1500-cycles lifetime against high oxidation voltage limit beyond 4.3 V. This work unravels the key role of breaking high-oxidation limits in attaining higher energy density of layered-oxide systems. This article is protected by copyright. All rights reserved.

Colorimetric and electrochemical dual-mode uric acid determination utilizing peroxidase-mimicking activity of CoCu bimetallic nanoclusters.

We present the preparation of CoCu bimetallic nanoclusters (Co@Cu-BNCs) by a hydrothermal and one-step pyrolysis method to build a colorimetric and electrochemical dual-mode sensing platform for uric acid (UA) detection. In the presence of H2O2, Co@Cu-BNCs with peroxidase-mimicking activity may convert colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue-colored oxidized TMB (oxTMB). However, due to the inhibitory effect of uric acid (UA) on the oxidation process of TMB, the characteristic absorption peak intensity of oxTMB decreased when UA was added into a mixed solution. In this approach, a colorimetric assay platform for the detection of UA was demonstrated, with a linear range of 0.1-195 µM and a low limit of detection of 0.06 µM (S/N ratio of 3). In addition, an even wider detection range is achieved in the electrochemical method, due to the pronounced electrocatalytic activity of Co@Cu-BNCs. The surface of the glassy carbon electrode was modified with Co@Cu-BNCs to build an electrochemical sensor for detecting UA. The sensor achieves a wider linear range from 2 to 1000 µM and a limit of detection of 0.61 µM (S/N ratio of 3). Moreover, the detection of UA in a human serum sample showed satisfactory results. The results proved that the colorimetric and electrochemical dual-mode detection platform was sensitive, convenient and accurate.

Engineering the reductive tricarboxylic acid pathway in Aureobasidium pullulans for enhanced biosynthesis of poly-L-malic acid.

Aureobasidium pullulans produced poly-L-malic acid (PMA) as the main metabolite in fermentation but with relatively low productivity and yield limiting its industrial application. In this study, A. pullulans ZX-10 was engineered to overexpress cytosolic malate dehydrogenase (MDH) and pyruvate carboxylase (PYC) and PMA synthetase (PMS) using a high-copy yeast episomal plasmid with the gpdA promoter from Aspergillus nidulans. Overexpressing endogenous PMS and heterologous MDH and PYC from Aspergillus oryzae respectively increased PMA production by 19 % - 37 % (0.64 - 0.74 g/g vs. 0.54 g/g for wild type) in shake-flask fermentations, demonstrating the importance of the reductive tricarboxylic acid (rTCA) pathway in PMA biosynthesis. A. pullulans co-expressing MDH and PYC produced 96.7 g/L PMA at 0.90 g/L∙h and 0.68 g/g glucose in fed-batch fermentation, which were among the highest yield and productivity reported. The engineered A. pullulans with enhanced rTCA pathway is advantageous and promising for PMA production.

The potential of lactose to inhibit cereulide biosynthesis of emetic Bacillus cereus in milk.

This study aims to investigate the potential role of lactose on cereulide biosynthesis by emetic Bacillus cereus in dairy matrices. The cereulide yields in whole milk and lactose-free milk were investigated using the emetic reference strain F4810/72. To eliminate the influence of complex food substrates, the LB medium model was further used to characterize the effect of lactose on cereulide produced by F4810/72 and five other emetic B. cereus strains. Results showed that the lactose-free milk displayed a 13-fold higher amount of cereulide than whole milk, but the cereulide level could be reduced by 91 % when the lactose content was restored. The significant inhibition of lactose on cereulide yields of all tested B. cereus strains was observed in LB medium, showing a dose-dependent manner with inhibition rates ranging of 89-98 %. The growth curves and lactose utilization patterns of all strains demonstrated that B. cereus cannot utilize lactose as a carbon source and lactose might act as a signal molecule to regulate cereulide production. Moreover, lactose strongly repressed the expression of cereulide synthetase genes (ces), possibly by inhibiting the key regulator Spo0A at the transcriptional level. Our findings highlight the potential of lactose as an effective strategy to control cereulide production in food.

Role of Exchange Cations and Layer Charge on the Dynamics of Confined Water.

Describing the dynamic behavior of water confined in clay minerals is a fascinating challenge and crucial in many research areas, ranging from materials science and geotechnical engineering to environmental sustainability. Water is the most abundant resource on Earth, and the high reactivity of naturally occurring hydrous clay minerals used since prehistoric times for a variety of applications means that water-clay interaction is a ubiquitous phenomenon in nature. We have attempted to experimentally distinguish the rotational dynamics and translational diffusion of two distinct populations of interlayer water, confined and ultraconfined, in the sodium (Na) forms of two smectite clay minerals, montmorillonite (Mt) and hectorite (Ht). Samples hydrated at a pseudo one-layer hydration (1LH) state under ambient conditions were studied with quasi-elastic neutron scattering (QENS) between 150 and 300 K. Using a simplified revised jump-diffusion and rotation-diffusion model (srJRM), we observed that while interlayer water near the ditrigonal cavity in Ht forms strong H-bonds to both adjacent surface O and structural OH, H-bonding of other more prevalent interlayer water with the surface O is weaker compared to Mt, inducing a higher temperature for dynamical changes of confined water. Given the lower layer charge and faster dynamics observed for Ht compared to Mt, we consider this strong evidence confirming the influence of the interlayer cation and surfaces on confined water dynamics.

Ultrasound Alleviates Lipopolysaccharide-Induced Colonic Damage.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the intestinal tract. There is currently no effective cure for IBD. The aim of this study was to evaluate the protective effect of low-intensity pulsed ultrasound (LIPUS) on lipopolysaccharide (LPS)-induced intestinal damage in a C57BL/6 mouse model. Colonic inflammation was induced by LPS injection (0.75 mg/kg, i.p.) for 7 days. A 1.0 MHz ultrasound transducer was used with a duty cycle of 5% and a repetition frequency of 1 Hz. LIPUS was applied to the abdominal region for 15 min/day from days 1 to 6 at both intensity of 0.5 W/cm2 or 1.0 W/cm2. Colonic samples were collected for macroscopic and westerm blotting analysis. First, the optimal dose of LPS for experiments was investigated. Our results demonstrated that LIPUS alleviates colonic damage by reducing colon shortening and increasing the levels of tight junction proteins such as Occludin and ZO-1. These findings show that abdominal LIPUS stimulation may be a novel therapeutic strategy for IBD through enhancement of tight junction protein levels and attenuation of colonic length.

In situ green synthesis of the nanocomposites of MnO2/graphene as an oxidase mimic for sensitive colorimetric and electrochemical dual-mode biosensing.

Herein we report the colorimetry and an electrochemical for the determination of dopamine (DA) by using MnO2 nanoparticles and graphene nanosheets composite (MnO2@G) that display oxidase mimicking property. MnO2@G could directly oxidize colorless 3,3',5,5'-tetramethylbenzidine (TMB) into a blue product (oxTMB) without extra oxidants such as H2O2. Nevertheless, the presence of DA will inhibit the TMB oxidation due to the presence of the competitive reaction of MnO2@G and DA, giving a product color change from blue to colorless. A colorimetric assay for detect the concentration of DA was worked out according to this finding. Response is linear in the 0.1 to 15 µM DA concentration range, and the detection limit is 0.14 µM. Wider detection range is achieved in an electrochemical method which is due to the pronounced electrocatalytic activity of MnO2@G. The MnO2@G was modified on the surface of the glassy carbon electrode in order to fabricate one type electrochemical sensor. The sensor achieves a wide detection two linear ranges from 0.4 to 70 µM, with the detection limit of 1.16 µM. The detection of DA in real serum sample proved that the nanozyme based on MnO2@G could be developed into a colorimetry and electrochemical dual-readout sensing platform.

Dynamic Microenvironment-Adaptable Hydrogel with Photothermal Performance and ROS Scavenging for Management of Diabetic Ulcer.

Persistent bacterial infections and excessive oxidative stress prevent the healing of diabetic ulcers, leading to an increased disability rate. Current treatments fail to kill bacteria while simultaneously relieving oxidative stress. Herein, a dynamic microenvironment-adaptable hydrogel (BP@CAu) with photothermal performance and reactive oxygen species scavenging is presented for diabetic ulcer healing. This hydrogel prepared using a dynamic borate-ester could respond to acidity in the infection microenvironment for a controllable drug release. An excellent photothermal conversion effect was integrated in the hydrogel, which exhibited strong antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. The hydrogel attenuated intracellular oxidative stress and inflammation and promoted cell migration. In a full-thickness skin defect model of diabetic rats, the BP@CAu hydrogel contributed to the fastest wound closure, with ideal reepithelialization, granulation tissue formation, and regeneration of blood vessels. Further mechanistic studies revealed that the hydrogel relieved oxidative stress and downregulated the expression of inflammatory cytokines, resulting in dramatic therapeutic effects on diabetic wounds. Therefore, this study provides a synergistic therapeutic strategy for efficient photothermal performance and reactive oxygen species scavenging in diabetic ulcers.

Predictive Value of Post-Percutaneous Coronary Intervention Quantitative Flow Ratio for Vessel-Oriented Composite Endpoint.

At present, there is a lack of indicators, which can accurately predict the post-percutaneous coronary intervention (post-PCI) vessel-oriented composite endpoint (VOCE). Recent studies showed that the post-PCI quantitative flow ratio (QFR) can predict post-PCI VOCE. PubMed, Embase, and Cochrane were searched from inception to March 27, 2022, and the cohort studies about that the post-PCI QFR predicts post-PCI VOCE were screened. Meta-analysis was performed, including 6 studies involving 4518 target vessels. The results of the studies included in this meta-analysis all showed that low post-PCI QFR was an independent risk factor for post-PCI VOCE after adjusting for other factors, HR (95% CI) ranging from 2.718 (1.347-5.486) to 6.53 (2.70-15.8). Our meta-analysis showed that the risk of post-PCI VOCE was significantly higher in the lower post-PCI QFR group than in the higher post-PCI QFR group (HR: 4.14, 95% CI: 3.00-5.70, P < 0.001, I2 = 27.9%). Post-PCI QFR has a good predictive value for post-PCI VOCE. Trial Registration. This trial is registered with CRD42022322001.

A Bioartificial Pancreas with "Immune Stealth" and Continuous Oxygen Supply for Islet Transplantation.

Transplantation of microencapsulated islet cells remains a promising strategy for the normalization of glucose metabolism control in type 1 diabetes mellitus. However, vigorous host immunologic rejection, fibrotic overgrowth around the microcapsules, and poor oxygen supply often lead to graft failure. Herein, a bioartificial pancreas is constructed, which incorporates the "stealth effect" based on polyethylene glycol copolymers and the high oxygen-carrying performance of fluorinated nanoparticles. Polycationic poly(l-lysine)-grafted-poly(ethylene glycol) is successfully coated on the surface of alginate microcapsules through electrostatic interaction, which can not only resist fibrinogen adhesion and avoid excessive fibrosis around the microcapsules but also isolate the host immune system from attacking, achieving a "stealth effect" of microencapsulated islet cells. Furthermore, the coloading of fluoride-based O2 nanocarriers gives them enhanced oxygen-carrying and continuous oxygen supply capabilities, thereby effectively prolonging the survival of islet cells. The intracapsular islet cells still display similar cell viability and almost normal insulin secretion function even in long-term culture under hypoxic conditions. Collectively, here a new approach is opened for microencapsulated islets to efficiently evade host immune attack and improve oxygen supply and a promising strategy is provided for islet transplantation in type 1 diabetes mellitus.

Roles of Immune and Oxidative Stress-Related Factors in the Diagnosis of Coronary Artery Disease: A Retrospective Study.

BACKGROUND: Coronary artery disease (CAD) is one of the main causes of sudden death, but its exact pathogenesis requires further study. Thus, this study aimed to explore the immune and oxidative stress-related factors in CAD progression and their roles in CAD diagnosis. METHODS: Bioinformatics analysis was used in this study, and the GSE23561 dataset (training set) we used contained the transcriptome sequencing results of six CAD peripheral blood samples and nine control samples. The data were obtained and analysed by querying the Gene Expression Omnibus database. First, the differentially expressed immune and oxidative stress-related genes (DEIOGs) between the groups were identified. DEIOGs were then analysed based on Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. A protein-protein interaction (PPI) network for DEIOGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and hub genes were identified through the PPI network. Moreover, transcription factors and microRNAs (miRNAs) targeting hub genes were identified to explore the potential regulatory mechanisms of hub genes. The receiver operating characteristic (ROC) curve analysis was constructed to examine the role of hub genes in CAD diagnosis. Finally, the data of GSE23561 (validated set) were used to validate the diagnostic potential of these hub genes. RESULTS: Primarily, 66 DEIOGs were identified, which are involved in many important pathways related to CAD, such as the "mitogen-activated protein kinase (MAPK) signalling pathway" and "lipid and atherosclerosis". A PPI network of DEIOGs was then constructed, and 10 hub genes were identified sequentially. A total of 37 transcription factors and 481 miRNAs that played important roles in hub genes regulation were identified. The ROC curves indicated that five special hub genes (Fos, Il6, Jun, Mapk3, and Mmp9) could serve as potential diagnostic biomarkers for CAD. CONCLUSIONS: Bioinformatics analysis technology was used to identify 10 hub DEIOGs that might play a crucial role in CAD progression, and five special hub genes (Fos, Il6, Jun, Mapk3, and Mmp9) could be regarded as potential biomarkers for CAD diagnosis. However, further studies are required to verify the functions of these hub genes.

HDAC1 inhibits beige adipocyte-mediated thermogenesis through histone crotonylation of Pgc1a/Ucp1.

Obesity, one of the most serious public health issues, is caused by the imbalance of energy intake and energy expenditure. Increasing energy expenditure via induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Although histone modifications have been confirmed to regulate cellular energy metabolism, the involved biochemical mechanism of thermogenesis in adipose tissue is not completely understood. Herein, we report that class I histone deacetylases (HDAC) inhibitor MS275 increased PGC1α/UCP1 protein levels in inguinal white adipose tissue (iWAT) concomitant with elevated energy expenditure, reduced obesity and ameliorated glucose tolerance compared to control littermates. H3K18cr and H3K18ac levels were elevated after MS275 treatment. MS275 also promoted the transcription of Pgc1α and Ucp1 by enhancing the enrichment of H3K18cr and H3K18ac in the Pgc1α/Ucp1 enhancer and promoter, with a notable increase in H3K18cr. Mechanistically, the deletion of Hdac1 in beige adipocyte increases H3K18cr levels in enhancers and promoters of Pgc1α and Ucp1 genes, regulated the chromosomal state, thereby affecting the transcription of Pgc1α/Ucp1. Taken together, HDAC1 inhibits beige adipocyte-mediated thermogenesis through histone crotonylation of Pgc1a/Ucp1. This finding may provide a therapeutic strategy through increasing energy expenditure in obesity and related metabolic disorders.

Ultrasound reduces inflammation by modulating M1/M2 polarization of microglia through STAT1/STAT6/PPARγ signaling pathways.

INTRODUCTION: Activated microglia can be polarized to the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype. Low-intensity pulsed ultrasound (LIPUS) can attenuate pro-inflammatory responses in activated microglia. OBJECTIVE: This study aimed to investigate the effects of LIPUS on M1/M2 polarization of microglial cells and the regulatory mechanisms associated with signaling pathways. METHODS: BV-2 microglial cells were stimulated by lipopolysaccharide (LPS) to an M1 phenotype or by interleukin-4 (IL-4) to an M2 phenotype. Some microglial cells were exposed to LIPUS, while others were not. M1/M2 marker mRNA and protein expression were measured using real-time polymerase chain reaction and western blot, respectively. Immunofluorescence staining was performed to determine inducible nitric oxide synthase (iNOS)-/arginase-1 (Arg-1)- and CD68-/CD206-positive cells. RESULTS: LIPUS treatment significantly attenuated LPS-induced increases in inflammatory markers (iNOS, tumor necrosis factor-α, interleukin-1ß, and interleukin-6) as well as the expression of cell surface markers (CD86 and CD68) of M1-polarized microglia. In contrast, LIPUS treatment significantly enhanced the expression of M2-related markers (Arg-1, IL-10, and Ym1) and membrane protein (CD206). LIPUS treatment prevented M1 polarization of microglia and enhanced or sustained M2 polarization by regulating M1/M2 polarization through the signal transducer and activator of transcription 1/STAT6/peroxisome proliferator-activated receptor gamma pathways. CONCLUSIONS: Our findings suggest that LIPUS inhibits microglial polarization and switches microglia from the M1 to the M2 phenotype.

Neuroprotection by Abdominal Ultrasound in Lipopolysaccharide-Induced Systemic Inflammation.

Systemic inflammation is associated with intestinal inflammation and neuroinflammation by imbalancing the gut-brain axis. Low-intensity pulsed ultrasound (LIPUS) has neuroprotective and anti-inflammatory effects. This study explored LIPUS's neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation through transabdominal stimulation. Male C57BL/6J mice were intraperitoneally injected with LPS (0.75 mg/kg) daily for seven days, and abdominal LIPUS was applied to the abdominal area for 15 min/day during the last six days. One day after the last LIPUS treatment, biological samples were collected for microscopic and immunohistochemical analysis. Histological examination showed that LPS administration leads to tissue damage in the colon and brain. Transabdominal LIPUS stimulation attenuated colonic damage, reducing histological score, colonic muscle thickness, and villi shortening. Furthermore, abdominal LIPUS reduced hippocampal microglial activation (labeled by ionized calcium-binding adaptor molecule-1 [Iba-1]) and neuronal cell loss (labeled by microtubule-associated protein 2 [MAP2]). Moreover, abdominal LIPUS attenuated the number of apoptotic cells in the hippocampus and cortex. Altogether, our results indicate that abdominal LIPUS stimulation attenuates LPS-induced colonic inflammation and neuroinflammation. These findings provide new insights into the treatment strategy for neuroinflammation-related brain disorders and may facilitate method development through the gut-brain axis pathway.

AGER1 deficiency-triggered ferroptosis drives fibrosis progression in nonalcoholic steatohepatitis with type 2 diabetes mellitus.

Hyperglycemia is an independent risk factor for the rapid progression of nonalcoholic steatohepatitis (NASH) to liver fibrosis with an incompletely defined mechanism. Ferroptosis is a novel form of programmed cell death that has been identified as a pathogenic mechanism in various diseases. However, the role of ferroptosis in the development of liver fibrosis in NASH with type 2 diabetes mellitus (T2DM) is unclear. Here, we observed the histopathological features of the progression of NASH to liver fibrosis as well as hepatocyte epithelial-mesenchymal transition (EMT) in a mouse model of NASH with T2DM and high-glucose-cultured steatotic human normal liver (LO2) cells. The distinctive features of ferroptosis, including iron overload, decreased antioxidant capacity, the accumulation of reactive oxygen species, and elevated lipid peroxidation products, were confirmed in vivo and in vitro. Liver fibrosis and hepatocyte EMT were markedly alleviated after treatment with the ferroptosis inhibitor ferrostatin-1. Furthermore, a decrease in the gene and protein levels of AGE receptor 1 (AGER1) was detected in the transition from NASH to liver fibrosis. Overexpression of AGER1 dramatically reversed hepatocyte EMT in high-glucose-cultured steatotic LO2 cells, whereas the knockdown of AGER1 had the opposite effect. The mechanisms underlying the phenotype appear to be associated with the inhibitory effects of AGER1 on ferroptosis, which is dependent on the regulation of sirtuin 4. Finally, in vivo adeno-associated virus-mediated AGER1 overexpression effectively relieved liver fibrosis in a murine model. Collectively, these findings suggest that ferroptosis participates in the pathogenesis of liver fibrosis in NASH with T2DM by promoting hepatocyte EMT. AGER1 could reverse hepatocyte EMT to ameliorate liver fibrosis by inhibiting ferroptosis. The results also suggest that AGER1 may be a potential therapeutic target for the treatment of liver fibrosis in patients with NASH with T2DM. Chronic hyperglycemia is associated with increased advanced glycation end products, resulting in the downregulation of AGER1. AGER1 deficiency downregulates Sirt4, which disturbs key regulators of ferroptosis (TFR-1, FTH, GPX4, and SLC7A11). These lead to increased iron uptake, decreasing the antioxidative capacity and enhanced lipid ROS production, ultimately leading to ferroptosis, which further promotes hepatocyte epithelial-mesenchymal transition and fibrosis progression in NASH with T2DM.