Objective To investigate the role and mechanisms of mesenchymal stem cells (MSC) in the survival prognosis of mice with acute liver failure (ALF). MethodsA thioacetamide (TAA)-induced mouse model of ALF was established and treated with MSC via tail vein infusion. The therapeutic effects of MSC were evaluated through survival analysis, measurement of serum biochemical indicators, HE staining of liver tissues and determination of proinflammatory cytokines. Liquid chromatography-mass spectrometry was used to analyze the metabolic profiles of liver tissues, hepatic transcriptomic analysis was performed based on high-throughput sequencing, and integrated multi-omics analysis was conducted. Comparisons of normally distributed data between two groups were performed using the unpaired t test. Comparisons among multiple groups were conducted using one-way analysis of variance, and pairwise comparisons between groups were performed using the Bonferroni method. Comparisons of rates between two groups were conducted using the Chi-square test. Survival curves were plotted using the Kaplan-Meier method, and differences between groups were compared using the Log-rank test. ResultsMSC treatment increased the survival rate of ALF mice (P ＜ 0.05), reduced serum AST and ALT levels (both P ＜ 0.05), alleviated histopathological liver injury, and inhibited the production of proinflammatory cytokines (all P ＜ 0.05). Metabolomic analysis showed that MSC restored pathways related to carbohydrate metabolism and energy production (all P ＜ 0.05). Transcriptomic analysis indicated that MSC might inhibit the mitogen-activated protein kinase (MAPK) signaling pathway and reduced neutrophil infiltration (both P ＜ 0.05). Integrated multi-omics analysis showed that MSC-induced upregulation of Pfkfb1 was correlated with increased levels of fructose-1,6-bisphosphate (F1,6P), a metabolite with anti-inflammatory properties (P ＜ 0.05). In addition, F1,6P levels were negatively correlated with the expression levels of numerous differentially expressed genes in the MAPK signaling pathway and with the degree of neutrophil infiltration (both P ＜ 0.05). Conclusions MSC effectively alleviate TAA-induced ALF, and the underlying systemic immunometabolic mechanism may involve the Pfkfb1-F1,6P pathway. This pathway may participate in inhibiting the MAPK signaling pathway and reducing neutrophil infiltration, thereby ultimately alleviating hepatic inflammation in ALF.

Mesenchymal stromal cells (MSCs) hold great promise for spinal cord injury (SCI) repair owing to their potent immunomodulatory and neuroprotective properties, yet their therapeutic efficacy collapses in the chronic phase. We identify a critical, overlooked barrier: the pathological stiffening of the fibrotic scar microenvironment hijacks the mechanotransduction machinery of transplanted MSCs, driving them toward a maladaptive fibroblast-like phenotype that compromises their immunomodulatory and regenerative functions, ultimately blunting their overall therapeutic potential. Here, we reveal that stiff substrates enforce MSCs into a pro-fibrotic state via a YAP/Smad-dependent mechanism. To overcome this, we developed a "soft-priming" strategy that effectively erases this fibrotic mechanical memory of MSCs. Mechanistically, soft priming does not merely prevent YAP nuclear translocation but promotes its cytoplasmic retention and subsequent lysosomal degradation, effectively dismantling the pro-fibrotic YAP signaling axis and rendering MSCs refractory to future stiffness challenges in vivo. Transplantation of these mechanically-reset MSCs into a SCI mouse model resulted in reduced scar formation, sustained immunomodulation and robust functional recovery by the early chronic stage, compared to standard-culture MSCs. By identifying soft mechanical priming as a scalable, chemical-free manufacturing step to insulate cells against hostile host environments, our findings provide a pragmatic translational pathway to revitalize MSC therapies for fibrosis-associated central nervous system (CNS) disorders.

Chirality is a pivotal determinant in stem cell differentiation, yet discerning the individual effects of chirality across different scales within native three-dimensional (3D) environments remains challenging. Here, a strategy is employed using nanostructures with controlled chirality to precisely assess the impact of molecular and supramolecular chirality on mesenchymal stem cell (MSC) osteogenic differentiation. We synthesized two pairs of enantiomers, l/d-phenylalanine (l/D-Phe) and l/d-1-naphthylalanine (L/D-1-Nap) derivatives, which could form four distinct chiral fibrous hydrogels with different molecular and supramolecular chiralities: L-supP and D-supP (supP indicates supramolecular right-handed helix), and L-supM and D-supM (supM denotes supramolecular left-handed helix). Both experimental and computational analyses reveal that the supramolecular supM/supP helicity is governed by conformational changes in aromatic side chains, switching between outward and inward orientations. Intriguingly, MSCs encapsulated within these chiral fibers displayed osteogenic differentiation that was predominantly influenced by higher-order supramolecular chirality rather than molecular chirality. Specifically, supM-nanofibrils significantly promoted the MSC commitment to the osteoblast lineage, whereas supP-nanofibrils lacked this osteoinductive potential. Additionally, we observed subtle positive and negative modulations of MSC osteogenic differentiation by l- and d-enantiomeric molecular chiralities, respectively. Our study presents a strategy for chiral hydrogel design and delineates how supramolecular chirality surpasses molecular chirality in directing MSC osteogenesis within 3D hydrogels, highlighting the potential of chiral biomaterials in bone tissue engineering.

Acute liver failure (ALF) represents a critical clinical syndrome marked by massive hepatocyte death and severe functional deterioration. While metabolic dysregulation is a recognized hallmark, the pathophysiological implications of iron metabolism disturbance in ALF progression remain poorly understood, which may unveil novel therapeutic targets. Using clinical samples and preclinical murine models, we identified ferroptosis as a predominant pathological feature in ALF-affected livers. Notably, pharmacological inhibition of ferroptosis significantly attenuated disease progression in experimental ALF. Mechanistically, dysregulation of the hepcidin-ferroportin (FPN) axis drives hepatic iron overload, precipitating ferroptotic cell death in ALF. The anti-rheumatoid arthritis drug auranofin restored hepcidin-FPN axis homeostasis and mitigated liver injury, though concomitant upregulation of proinflammatory cytokines limited its therapeutic potential. Strikingly, mesenchymal stromal cells (MSCs) demonstrated superior therapeutic efficacy, coordinately modulating the hepcidin-FPN axis while suppressing ferroptosis through PI3K/Akt/Nrf2 pathway activation. Our findings not only establish the causal relationship between hepcidin-FPN axis dysfunction and ferroptosis-driven liver injury, but also propose MSC-based therapy as a multifaceted strategy targeting both iron homeostasis and ferroptosis for ALF management.

This publisher's note corrects two sentences in Appl. Opt.59, 4404 (2020)APOPAI0003-693510.1364/AO.390663.

A pilot-scale experiment is carried out for treating mixed wastewater containing pharmaceutical wastewater (PW) and domestic wastewater (DW), by a process that is a combination of hydrolysis acidification-ozone-modified anaerobic–anoxic–aerobic-ozone (A2/O) (pre-ozone) or hydrolysis acidification-modified A2/O-ozone (post-ozone). The effects of different mixing ratios of PW and DW and pre-ozone treatment or post-ozone treatment on the removal of nitrogen and phosphorus and chemical oxygen demand (COD) are compared and studied. The optimal ratio of PW in mixing wastewater is 30%, which has the optimal COD removal efficiency and minimum biotoxicity to biological treatment. The pre-ozone treatment shows more advantages in removing nitrogen and phosphate but the post-ozone treatment shows more advantages in COD removal. Analysis of dissolved organic matter (DOM) demonstrates that post-ozone treatment has a more significant effect on the removal of fulvic acid and humic acid than the effect from the pre-ozone treatment, so the COD removal is better. Overall DOM degradation efficiency by post-ozone treatment is 55%, which is much higher than the pre-ozone treatment efficiency of 38%. Microbial community analysis reveals that the genus Thauera and the genus Parasegetibacter take great responsibility for the degradation of phenolics in this process. All the results show that the post-ozone treatment is more efficient for the mixed wastewater treatment in refractory organics removal.

A novel coagulation combined with UV/O-3 process was employed to remove the effluent organic matter (EfOM) from a biotreated pharmaceutical wastewater for harmlessness. The removal behavior of EfOM by UV/O-3 process was characterized by synchronous fluorescence spectroscopy (SFS) integrating two-dimensional correlation (2D-COS) and principal component analysis (PCA) technology. The highest dissolved organic carbon (DOC) and ratio of UV254 and DOC (SUVA) removal efficiency reached 55.8% and 68.7% by coagulation-UV/O-3 process after 60 min oxidation, respectively. Five main components of pharmaceutical tail wastewater (PTW) were identified by SFS. Spectral analysis revealed that UV/O-3 was selective for the removal of different fluorescent components, especially fulvic acid-like fluorescent (FLF) component and humus-like fluorescent (HLF) component. Synchronous fluorescence/UV-visible two-dimensional correlation spectra analysis showed that the degradation of organic matter occurred sequentially in the order of HLF, FLF, microbial humus-like fluorescence component (MHLF), tryptophan-like fluorescent component (TRLF), tyrosine-like fluorescent component (TYLF). The UV/O-3 process removed 95.6% of HLF, 80.0% of FLF, 56.0% of TRLF, 50.8% of MHLF and 44.4% of TYLF. Therefore, the coagulation-UV/O-3 process was proven to be an attractive way to reduce the environmental risks of PTW.