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In most cases, recurrent chronic colitis is caused by the recurrence of acute colitis after incomplete recovery and re-exposure to irritating factors, and the gut microbiome, which is the largest micro-ecosystem in the human body, plays a crucial role in the development of colitis. Plant polysaccharides have always been reported to have the ability for anti-inflammation, and they are closely related to the gut microbiome. Lycium barbarum Glycopeptide (LbGP), the most potent component obtained by further isolation and purification from Lycium barbarum fruit, has been shown to inhibit inflammation in animal models. However, its therapeutic efficacy in colitis and its mechanism in gut microbiota regulation have not been fully studied. In our study, the dextran sulfate sodium (DSS)-induced mouse model was used to dynamically evaluate the effect of LbGP in the treatment of acute colitis and the mechanism from the perspective of the gut microbiome through the 16S rDNA sequence. The results showed that LbGP treatment significantly alleviated acute colitis and improved the gut microbiome compared with that in the model group. Harmful bacteria, such as Lachnoclostridium spp. and Parabacteroides_distasonis , were inhibited and probiotics, such as Bacteroides_acidifaciens, Lactobacillus spp., Turicibacter spp., and Alistipes spp., were increased by LbGP treatment. Further, a Random Forest analysis with 10-fold cross-validation identified a family named Muribaculaceae representing colitis development and recovery upon LbGP treatment. In conclusion, our study demonstrated the capability of LbGP to prevent the development of acute colitis by regulating the composition and diversity of the gut microbiota and highlighted the dynamic process of gut microbiota with the colitis progression. Further, it provides evidence to develop LbGP as a functional food supplement and future drug acting on intestinal disease.

Aminoglycoside antibiotic‐induced sensorineural hearing loss (SNHL) is a common sensory disorder that requires the development of prophylactic and therapeutic interventions. Lycium barbarum glycopeptide (LBGP) is a peptidoglycan isolated and purified from Lycium barbarum polysaccharides that exhibit significant anti‐inflammatory, antioxidant, and neuroprotective effects, but the role of LBGP in aminoglycoside‐induced SNHL has not been well investigated. Here it is shown that LBGP can protect against neomycin‐induced hearing impairment and alleviate oxidative stress in a neomycin‐induced SNHL mouse model. Moreover, it is further found that inhibition of tryptophan hydroxylase (Tph)‐mediated serotonin (5‐HT) biosynthesis plays a key role in the mechanism of action of LBGP in treating neomycin‐induced hearing loss. Systemic delivery of 5‐HT increased neomycin‐induced apoptosis of cochlear hair cells and spiral ganglion neurons, and pharmacological Tph2 inhibition with P‐chlorophenylalanine or Tph2 knock down by AAV‐ie‐Tph2 effectively attenuated neomycin‐induced hearing dysfunction. Collectively, these results provide a promising strategy for the prevention of SNHL by using natural plant extract which is more available and exhibits lower side effects compared with other otoprotective drugs, and identify Tph2 as a potential pharmacological target for the treatment of aminoglycoside‐induced ototoxicity. Lycium barbarum glycopeptide (LBGP), which is further extracted from Lycium barbarum polysaccharides, exhibits significant protective effects against neomycin‐induced hearing dysfunction including oxidative stress in cochlea and loss of key cells in cochlea. The underlying mechanism of the otoprotective effect of LBGP may be associated with the inhibition of tryptophan hydroxylase‐mediated 5‐HT biosynthesis.

[This corrects the article DOI: 10.3389/fcimb.2022.921075.].[This corrects the article DOI: 10.3389/fcimb.2022.921075.].

In most cases, recurrent chronic colitis is caused by the recurrence of acute colitis after incomplete recovery and re-exposure to irritating factors, and the gut microbiome, which is the largest micro-ecosystem in the human body, plays a crucial role in the development of colitis. Plant polysaccharides have always been reported to have the ability for anti-inflammation, and they are closely related to the gut microbiome. Lycium barbarum Glycopeptide (LbGP), the most potent component obtained by further isolation and purification from Lycium barbarum fruit, has been shown to inhibit inflammation in animal models. However, its therapeutic efficacy in colitis and its mechanism in gut microbiota regulation have not been fully studied. In our study, the dextran sulfate sodium (DSS)-induced mouse model was used to dynamically evaluate the effect of LbGP in the treatment of acute colitis and the mechanism from the perspective of the gut microbiome through the 16S rDNA sequence. The results showed that LbGP treatment significantly alleviated acute colitis and improved the gut microbiome compared with that in the model group. Harmful bacteria, such as Lachnoclostridium spp. and Parabacteroides_distasonis, were inhibited and probiotics, such as Bacteroides_acidifaciens, Lactobacillus spp., Turicibacter spp., and Alistipes spp., were increased by LbGP treatment. Further, a Random Forest analysis with 10-fold cross-validation identified a family named Muribaculaceae representing colitis development and recovery upon LbGP treatment. In conclusion, our study demonstrated the capability of LbGP to prevent the development of acute colitis by regulating the composition and diversity of the gut microbiota and highlighted the dynamic process of gut microbiota with the colitis progression. Further, it provides evidence to develop LbGP as a functional food supplement and future drug acting on intestinal disease.

Osteoarthritis is a common degenerative joint disease characterized by progressive cartilage loss, bone remodeling, and chronic joint inflammation, yet its underlying mechanisms remain incompletely understood. Disrupted iron metabolism, particularly iron accumulation in joint tissues, contributes to oxidative damage and inflammation, suggesting a potential link to disease progression. This review focuses on ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, as a key pathological mechanism in osteoarthritis. We summarize current evidence showing how impaired iron homeostasis, weakened antioxidant defenses, and metabolic alterations make chondrocytes and other joint cells vulnerable to ferroptotic injury. We further describe how inflammatory and metabolic signals interact to amplify ferroptosis, creating a self-reinforcing cycle of tissue damage. Finally, we explore emerging strategies to target ferroptosis, including iron chelation, antioxidant therapy, inhibition of lipid peroxidation, and gene or cell-based interventions. By integrating these findings, this review offers new insights into the role of ferroptosis in joint degeneration and highlights its potential as a therapeutic target in osteoarthritis.

Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15 + CD8 + T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15 + CD8 + T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15 + CD8 + T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15 + CD8 + T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy.

Extrahepatic cholangiocarcinoma (ECC), a highly malignant type of cancer with increasing incidence, has a poor prognosis due to limited treatment options. Based on genomic analysis of ECC patient samples, here we report that aldo-keto reductase family 1 member C1 (AKR1C1) is highly expressed in human ECC tissues and closely associated with ECC progression and poor prognosis. Intriguingly, we show that inducible AKR1C1 knockdown triggers ECC cells to undergo ferroptosis. Mechanistically, AKR1C1 degrades the protein stability of the cytochrome P450 family member CYP1B1, a newly discovered mediator of ferroptosis, via ubiquitin-proteasomal degradation. Additionally, AKR1C1 decreases CYP1B1 mRNA level through the transcriptional factor aryl-hydrocarbon receptor (AHR). Furthermore, the AKR1C1–CYP1B1 axis modulates ferroptosis in ECC cells via the cAMP–PKA signaling pathway. Finally, in a xenograft mouse model of ECC, AKR1C1 depletion sensitizes cancer cells to ferroptosis and synergizes with ferroptosis inducers to suppress tumor growth. Therefore, the AKR1C1–CYP1B1–cAMP signaling axis is a promising therapeutic target for ECC treatment, especially in combination with ferroptosis inducers.

The Leishmania homolog of receptors for activated C kinase (LACK) protein is derived from Leishmania parasites L. major. The polypeptide LACK156–173 has been shown to confer protection against murine autoimmune arthritis. Fibroblast‐like synoviocytes (FLSs) play a pivotal role in the synovial invasion and joint destruction observed in rheumatoid arthritis (RA). The study reveals that LACK156‐173 can inhibit the aggressive phenotype of RA‐FLSs by restoring dysregulated fatty acid synthesis metabolism. In RA‐FLSs, overexpression of fatty acid synthase (FASN) leads to excessive fatty acid accumulation, which in turn promotes mitochondrial fragmentation by enhancing phosphorylation at the ser616 site of dynamin 1‐like protein (DRP1). This process increases reactive oxygen species (ROS) production and activates the PI3K/mTOR/NF‐κB pathway, thereby facilitating the transition of RA‐FLSs to an aggressive inflammatory and bone‐damaging phenotype. LACK156‐173 is internalized into the cytoplasm via CAPN2‐mediated endocytosis, where it directly binds to FASN and inhibits its activity. The findings suggest that targeting the restoration of fatty acid metabolism could potentially alleviate synovial invasion and joint damage in RA. LACK156‐173 may therefore hold therapeutic promise for RA patients. LACK156‐173 is internalized into RA‐FLSs via CAPN2‐mediated endocytosis and inhibits the aggressive phenotype of RA‐FLSs by restoring dysregulated fatty acid synthesis metabolism mediated by overexpressed FASN. The findings suggest that targeting the restoration of fatty acid metabolism could potentially alleviate synovial invasion and joint damage in RA. Therefore, LACK156‐173 may hold therapeutic promise for RA patients.

Characterizing charge transport through single molecules provides a fundamental route to explore correlated quantum states, forming the basis for nanodevices in which quantum effects govern operation. During the non-equilibrium electron transfer, a rich manifold of excited states emerges, whose dynamics encode many-body interactions at the single-molecule level. Disentangling these dynamics is crucial for understanding such interactions, however, it has remained elusive due to the experimental challenge of simultaneously achieving both high temporal and energy resolution. Here, we resolved the dynamics of multiple excited states during non-equilibrium charge transport through a single-molecule radical junction using nanosecond differential conductance spectroscopy. The participation of singlet and triplet states, mediated by doublet states, is revealed in both time and energy domains occurring within ~150 ns. In addition, the transient resonance positions evolve by up to ~440 meV over hundreds of nanoseconds, consistent with a dynamic realignment at the molecule-electrode interface during charge dissipation. We interpret this behavior as a signature of Coulomb-renormalized transport resonances rather than as direct evidence for isolated molecular eigenstates shifting in energy. These results provide insight into transient intermediates in single-molecule charge transport and suggest potential routes for controlling quantum states in molecular-scale devices.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 ( HLA-DRA and DPB1 ), 17q12 ( ORMDL3 ), 3q13.33 ( CD80 ), 2q32.3 ( STAT1 / STAT4 ), 3q25.33 ( IL12A ), 4q24 ( NF-κB ) and 22q13.1 ( RPL3 / SYNGR1 ). We also identified variants in IL21 , IL21R , CD28/CTLA4/ICOS , CD58 , ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC. Primary biliary cholangitis is an autoimmune liver disease. Here, the authors show that variants in interleukin genes which potentially deregulate their expression are associated with this condition, and suggest that the IL21 signalling pathway may have a role in disease aetiology.