Integrative cross-tissue analysis unveils complement-immunoglobulin augmentation and dysbiosis-related fatty acid metabolic remodeling during mammalian aging.

Aging-related decline and adaptation are complex, multifaceted processes that affect various tissues and increase risk of chronic diseases. To characterize key changes in cross-tissue aging, we performed comprehensive proteomic and metabolomic analyses across 21 solid tissues and plasma samples, alongside shotgun metagenomic profiling of fecal microbial communities in young and aged mice. Our findings revealed widespread aging-rewired chronic inflammation, characterized by complement system activation in plasma and universal immunoglobulins accumulation across multiple solid tissues.

Heat Shock Strengthens the Protective Potential of MSCs in Liver Injury by Promoting EV Release Through Upregulated Autophagosome Formation.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show powerful potential in the treatment of multiple diseases. However, the low yield of MSC-EVs severely restricts their clinical application. Here, heat shock (HS), a moderate external stimulus, can enhance EVs release of MSCs by upregulating autophagosome formation.

Lactate accumulation drives hepatocellular carcinoma metastasis through facilitating tumor-derived exosome biogenesis by Rab7A lactylation.

Previous studies have demonstrated that lactate accumulation, a common hallmark for metabolic deprivation in solid tumors, could actively drive tumor invasion and metastasis. However, whether lactate influences the biogenesis of tumor-derived exosomes (TDEs), the prerequisite for distant metastasis formation, remains unknown. Here, we demonstrated that extracellular lactate, after taken up by tumor cells via lactate transporter MCT1, drove the release of TDE mainly through facilitating multivesicular body (MVB) trafficking towards plasma membrane instead of lysosome.

Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells.

Fibrosis is a disease that negatively affects liver regeneration, resulting in severe complications after liver surgery. However, there is still no clinically effective treatment for promoting fibrotic liver regeneration because the underlying hepatocellular mechanism remains poorly understood. Through microRNA microarrays combined with the application of AAV6, we found that high expression of miR-181a-5p in activated hepatic stellate cells (HSCs) suppressed the expression of hepatic growth factor (HGF) and partially contributed to impaired regeneration potential in mice with hepatic fibrosis that had undergone two-thirds partial hepatectomy.

Mesenchymal stem cell-derived extracellular vesicles attenuate ferroptosis in aged hepatic ischemia/reperfusion injury by transferring miR-1275.

With an aging global population, the proportion of aged donor livers in graft pools is steadily increasing. Compared to young livers, aged livers exhibit heightened susceptibility to hepatic ischemia/reperfusion injury (HIRI), which significantly limits their utilisation in liver transplantation (LT) and exacerbates organ shortages. Our previous study demonstrated that ferroptosis is a pivotal trigger for HIRI vulnerability in aged livers.

Molecular Insights into the Control Mechanism of the Solid-Liquid Interface Interaction on Shale Oil Occurrence: Grand Canonical Monte Carlo and Molecular Dynamics Simulations Investigation.

The strong solid-liquid interaction leads to the complicated occurrence characteristics of shale oil. However, the solid-liquid interface interaction and its controls of the occurrence state of shale oil are poorly understood on the molecular scale. In this work, the adsorption behavior and occurrence state of shale oil in pores of organic/inorganic matter under reservoir conditions were investigated by using grand canonical Monte Carlo (GCMC) and molecular dynamics (MD) simulations.

Expeditious chemical synthesis of xylomannans disproves the proposed antifreeze activities.

Cold-adapted species are able to generate cryoprotective proteins and glycoproteins to prevent freezing damage. The [→4)--D-Man-(1→4)--D-Xyl-(1→] xylomannan from the Alaska beetle was disclosed by Walters and co-workers in 2009 as the first glycan-based antifreeze agent, which was later reported to be found in diverse taxa. Here, we report the rapid synthesis of four types of xylomannans, including the proposed antifreeze xylomannan up to a 64-mer (Type I), the regioisomeric [→3)--D-Man-(1→4)--D-Xyl-(1→] 16-mer (Type II), the diastereomeric [→4)--L-Man-(1→4)--D-Xyl-(1→] 16-mer (Type III) and the block-wise [→4)--D-Man-(1→] [→4)--D-Xyl-(1→] 32-mer (Type IV), by employing a strategic iterative exponential glycan growth (IEGG) process.

Mesenchymal Stem Cell Membrane-Camouflaged Liposomes for Biomimetic Delivery of Cyclosporine A for Hepatic Ischemia-Reperfusion Injury Prevention.

Hepatic ischemia-reperfusion injury (HIRI) is a prevalent issue during liver resection and transplantation, with currently no cure or FDA-approved therapy. A promising drug, Cyclosporin A (CsA), ameliorates HIRI by maintaining mitochondrial homeostasis but has systemic side effects due to its low bioavailability and high dosage requirements. This study introduces a biomimetic CsA delivery system that directly targets hepatic lesions using mesenchymal stem cell (MSC) membrane-camouflaged liposomes.

FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC.

Older livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation. The potential mechanism remains unclear. Here, we demonstrate older livers exhibit increased ferroptosis during HIRI.

5-aminolevulinate and CHIL3/CHI3L1 treatment amid ischemia aids liver metabolism and reduces ischemia-reperfusion injury.

Liver resection and transplantation surgeries are accompanied by hepatic ischemia-reperfusion (HIR) injury that hampers the subsequent liver recovery. Given that the liver is the main organ for metabolism and detoxification, ischemia-reperfusion in essence bestows metabolic stress upon the liver and disrupts local metabolic and immune homeostasis. Most of the recent and current research works concerning HIR have been focusing on addressing HIR-induced hepatic injury and inflammation, instead of dealing with the metabolic reprogramming and restoration of redox homeostasis.

Single-cell immune profiling of mouse liver aging reveals Cxcl2+ macrophages recruit neutrophils to aggravate liver injury.

Background And Aims: Immune cells play a crucial role in liver aging. However, the impact of dynamic changes in the local immune microenvironment on age-related liver injury remains poorly understood. We aimed to characterize intrahepatic immune cells at different ages to investigate key mechanisms associated with liver aging.

Combined inhibition of surface CD51 and γ-secretase-mediated CD51 cleavage improves therapeutic efficacy in experimental metastatic hepatocellular carcinoma.

Background & Aims: Integrin αv (ITGAV, CD51) is regarded as a key component in multiple stages of tumor progression. However, the clinical failure of cilengitide, a specific inhibitor targeting surface CD51, suggests the importance of yet-unknown mechanisms by which CD51 promotes tumor progression.

Methods: In this study, we used several hepatocellular carcinoma (HCC) cell lines and murine hepatoma cell lines.

Synergy of 5-aminolevulinate supplement and CX3CR1 suppression promotes liver regeneration via elevated IGF-1 signaling.

Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy (PHx), while few clinical treatments focus on safely accelerating regeneration. Recently, we discovered that supplementing 5-aminolevulinate (5-ALA) improves liver cold adaptation and functional recovery, leading us to uncover a correlation between 5-ALA metabolic activities and post-PLT recovery. In a mouse 2/3 PHx model, 5-ALA supplements enhanced liver regeneration, promoting infiltration and polarization of anti-inflammatory macrophages via P53 signaling.

MSC-derived extracellular vesicles as nanotherapeutics for promoting aged liver regeneration.

Aging is one of the critical factors to impair liver regeneration leading to a high incidence of severe complications after hepatic surgery in the elderly population without any effective treatment for clinical administration. As cell-free nanotherapeutics, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been demonstrated the therapeutic potentials on liver diseases. However, the effects of MSC-EVs on the proliferation of aged hepatocytes are largely unclear.

Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia-reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps.

As nanotherapeutics, mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are considered a potent alternative for whole-cell therapy and are gradually entering the clinical field of liver diseases. In this study, neutrophil extracellular traps (NETs) formation in liver tissue was verified as a critical factor for liver ischaemia-reperfusion injury (IRI) in both clinical samples and animal models. Human umbilical cord-derived MSC-EVs (hUC-MSC-EVs) might function to reduce the NETs formation and subsequently improve liver IRI.

MiR-34a regulates mitochondrial content and fat ectopic deposition induced by resistin through the AMPK/PPARα pathway in HepG2 cells.

Resistin is an adipocyte-derived cytokine and was named for its role in the development of insulin resistance. Increased serum resistin levels are also associated with steatohepatitis and non-alcoholic fatty liver disease. In a previous study, resistin was observed to reduce mitochondrial content and upregulate miR-34a significantly in the liver.