Lactobacillus reuteri mitigates hepatic ischemia/reperfusion injury by modulating gut microbiota and metabolism through the Nrf2/HO-1 signaling.

BACKGROUND: This study seeks to investigate the impacts of Lactobacillus reuteri (L. reuteri) on hepatic ischemia-reperfusion (I/R) injury and uncover the mechanisms involved. METHODS: Mice in the I/R groups were orally administered low and high doses of L.reuteri (L.reuteri-low and L. reuteri-hi; 1 × 1010 CFU/d and 1 × 1011 CFU/d), for 4 weeks prior to surgery. Following this, mice in the model group were treated with an Nrf2 inhibitor (ML-385), palmitoylcarnitine, or a combination of both. RESULTS: After treatment with L. reuteri, mice exhibited reduced levels of serum aminotransferase (ALT), aspartate aminotransferase (AST), and myeloperoxidase (MPO) activity, as well as a lower Suzuki score and apoptosis rate. L. reuteri effectively reversed the I/R-induced decrease in Bcl2 expression, and the significant increases in the levels of Bax, cleaved-Caspase3, p-p65/p65, p-IκB/IκB, p-p38/p38, p-JNK/JNK, and p-ERK/ERK. Furthermore, the administration of L. reuteri markedly reduced the inflammatory response and oxidative stress triggered by I/R. This treatment also facilitated the activation of the Nrf2/HO-1 pathway. L. reuteri effectively counteracted the decrease in levels of beneficial gut microbiota species (such as Blautia, Lachnospiraceae NK4A136, and Muribaculum) and metabolites (including palmitoylcarnitine) induced by I/R. Likewise, the introduction of exogenous palmitoylcarnitine demonstrated a beneficial impact in mitigating hepatic injury induced by I/R. However, when ML-385 was administered prior to palmitoylcarnitine treatment, the previously observed effects were reversed. CONCLUSION: L. reuteri exerts protective effects against I/R-induced hepatic injury, and its mechanism may be related to the promotion of probiotic enrichment, differential metabolite homeostasis, and the Nrf2/HO-1 pathway, laying the foundation for future clinical applications.

Landscape of circulating metabolic fingerprinting for keloid.

Background: Keloids are a fibroproliferative disease characterized by unsatisfactory therapeutic effects and a high recurrence rate. Objective: This study aimed to investigate keloid-related circulating metabolic signatures. Methods: Untargeted metabolomic analysis was performed to compare the metabolic features of 15 keloid patients with those of paired healthy volunteers in the discovery cohort. The circulating metabolic signatures were selected using the least absolute shrinkage. Furthermore, the selection operators were quantified using multiple reaction monitoring-based target metabolite detection methods in the training and test cohorts. Results: More than ten thousand metabolic features were consistently observed in all the plasma samples from the discovery cohort, and 30 significantly different metabolites were identified. Four differentially expressed metabolites including palmitoylcarnitine, sphingosine, phosphocholine, and phenylalanylisoleucine, were discovered to be related to keloid risk in the training and test cohorts. In addition, using linear and logistic regression models, the respective risk scores for keloids based on a 4-metabolite fingerprint classifier were established to distinguish keloids from healthy volunteers. Conclusions: In summary, our findings show that the characteristics of circulating metabolic fingerprinting manifest phenotypic variation in keloid onset.

Inhibition of mouse skin tumor promotion by adriamycin and daunomycin in combination with verapamil or palmitoylcarnitine.

The anti-cancer drugs Adriamycin (ADR) and Daunomycin (DAU) alone were unable to inhibit the promotion of skin papillomas by repeated applications of 8.5 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated mice. Pretreatments with 50 micrograms of ADR also failed to alter the tumor-promoting activities of smaller doses of TPA. Therefore, the effects of the anthracycline antibiotics on skin tumor promotion were evaluated in combination with the Ca2+ antagonist verapamil (VRP) and the protein kinase C (PKC) inhibitor palmitoylcarnitine (PC), compounds known to circumvent drug resistance. When applied simultaneously with each promotion treatment with 8.5 nmol of TPA, 2.5 mg of VRP inhibited the number of papillomas/mouse by 26%. But the combination of VRP + 50 micrograms of ADR or DAU inhibited the yields of papillomas by 50 or 47%, respectively, suggesting that VRP was required to reveal the antitumor-promoting activities of otherwise ineffective drugs. Similarly, the promotion of skin tumors by TPA was inhibited synergistically by the combinations of 2 mumol of PC + 50 micrograms of ADR or DAU. For instance, ADR and DAU had no effects alone but inhibited the incidence of skin papillomas by 78 and 86%, respectively, in the presence of PC, a compound which alone inhibited the tumor incidence by only 44%. The results indicate that ADR and DAU are effective against the promoting component of skin carcinogenesis only if they are applied in combination with Ca2+ antagonists or PKC inhibitors at a time when they can inhibit the early biochemical effects induced by TPA.

Protection by acyl-carnitines and phenylmethylsulfonyl fluoride of rat heart subjected to ischemia and reperfusion.

Perfusion of rat hearts according to the Langendorff technique with micromolar concentrations of palmitoylcarnitine or millimolar concentrations of phenylmethylsulfonyl fluoride protect the heart from deterioration by reperfusion after total-ischemia. This is based on the retention of the cytosolic enzymes determined (lactate dehydrogenase, glycogen phosphorylase and glycogen synthase) and of myoglobin, as well as on the resumption of contractile activity. Palmitoylcarnitine, like phenylmethylsulfonyl fluoride, could protect through plasma membrane stabilization, since more hydrophilic compounds had no effect.