Tacrolimus (Tac) is a common immunosuppressant that used in organ transplantation. However, its therapeutic index is narrow, and it is prone to adverse side effects, along with an increased risk of toxicity, namely, cardio-, nephro-, hepato-, and neurotoxicity. Prior metabolomic investigations involving Tac-driven toxicity primarily focused on changes in individual organs. However, extensive research on multiple matrices is uncommon. Hence, in this research, the authors systemically evaluated Tac-mediated toxicity in major organs, namely, serum, brain, heart, liver, lung, kidney, and intestines, using gas chromatography−mass spectrometry (GC-MS). The authors also employed multivariate analyses, including orthogonal projections to the latent structure (OPLS) and t-test, to screen 8 serum metabolites, namely, D-proline, glycerol, D-fructose, D-glucitol, sulfurous acid, 1-monopalmitin (MG (16:0/0:0/0:0)), glycerol monostearate (MG (0:0/18:0/0:0)), and cholesterol. Metabolic changes within the brain involved alterations in the levels of butanamide, tartronic acid, aminomalonic acid, scyllo-inositol, dihydromorphine, myo-inositol, and 11-octadecenoic acid. Within the heart, the acetone and D-fructose metabolites were altered. In the liver, D-glucitol, L-sorbose, palmitic acid, myo-inositol, and uridine were altered. In the lung, L-lactic acid, L-5-oxoproline, L-threonine, phosphoric acid, phosphorylethanolamine, D-allose, and cholesterol were altered. Lastly, in the kidney, L-valine and D-glucose were altered. Our findings will provide a systematic evaluation of the metabolic alterations in target organs within a Tac-driven toxicity mouse model.

Tissue plasminogen activator (tPA) is a serine protease involved in cleavage of neurotrophic factors. In addition, tPA and neuroserpin can also directly bind to low density lipoprotein receptor-related protein 1 (LRP1), promoting neurogenesis and neurite outgrowth. Given both the cleavage and non-cleavage actions of the fibrinolytic system are crucial in neurological functions, the present study, for the first time, systematically detected the changes of fibrinolytic system factors in rats exposed to chronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS) and patients with depression. In general, our data demonstrated that both CUMS and LPS reduced tPA but elevated plasminogen activator inhibitor-1 (PAI-1; SERPINE1) mRNA expression. Intriguingly, decreased expression of neuroserpin and LRP1 was also observed in rats exposed to CUMS or LPS. The down-regulated neuroserpin and LRP1 signaling were confirmed by western blotting and immunoflurence data. Likewise, elevated PAI-1 but a significant reduction of neuroserpin and LRP1 mRNA expression were observed in the peripheral blood mononuclear cells (PBMCs) of patients with first-episode depression, and the mRNA levels of PAI-1, neuroserpin and LRP1 were correlated with the Beck Depression inventory (BDI) scores, further strengthening the clinical significance and involvement of the fibrinolytic system in depression. Collectively, the present study demonstrated the alterations of fibrinolytic system in stressed and inflamed brain and in patients with first-episode depression, firstly showing that not only the cleavage actions, but also the non-cleavage actions of the system may play an essential role in the development of depression.

Background: Neuroinflammation is a key pathological feature in many neurodegenerative diseases, and the nuclear factor kappa-B (NF-κB) signaling pathway is a central mediator of this response. Aged garlic extract (AGE) is a functional food with well-documented antioxidant and anti-inflammatory properties, but its role in mitigating neuroinflammation remains unclear. Objective: This study investigates the effects of AGE on neuroinflammation by modulating the NF-κB signaling pathway using multi-omics analyses and experimental validation. Design: Lipopolysaccharide (LPS)-induced BV2 microglial cells and LPS-treated C57BL/6 mice were used to assess the effects of AGE. Transcriptomics, metabolomics, and network pharmacology approaches identified potential targets and pathways, focusing on NF-κB signaling. In vitro and in vivo models were employed to evaluate behavioral, biochemical, and histological outcomes. Results: AGE reduced pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and cyclooxygenase-2) in LPS-stimulated BV2 cells and suppressed microglial activation and neuronal damage in LPS-induced mice. Transcriptomic analysis showed that NF-κB pathway inhibition mediated these effects, with molecular docking confirming interactions between aged garlic compounds and NF-κB targets (NF-κB2 and NF-κB3). Conclusion: AGE attenuates neuroinflammation by inhibiting the NF-κB signaling pathway, improving cognitive and motor functions, and reducing neuronal injury in experimental models. These findings suggest aged garlic as a promising neuroprotective agent against neuroinflammation.

Epilepsy is one of the most common chronic disabling neurologic diseases. The purpose of our study was to investigate whether there is an association between t-PA (tissue plasminogen activator, rs2020918 and rs4646972), PAI-1 (plasminogen activator inhibitor 1, rs1799768) polymorphisms and susceptibility to temporal lobe epilepsy (TLE) in Chinese Han population. One hundred and twenty-one cases of patients who were diagnosed as TLE and 146 normal controls were enrolled and the genotypes of t-PA and PAI-1 were detected by polymerase chain reaction-ligase detection reaction (PCR-LDR) method after the genomic DNA being extracted from peripheral blood. There were significant differences for the genotypic frequencies at the two polymorphic sites in t-PA gene between TLE patients and controls (P = 0.019; P = 0.001). Furthermore, the frequency of rs2020918 (C > T) with T (CT + TT) and rs4646972 (311 bp insertion/−) with 311 bp deletion (311 bp/− + −/−) was significantly higher among TLE patients relative to controls respectively (P = 0.006; P = 0.001). However, no significant difference in genotypic and allelic frequency was found at the polymorphic site in PAI-1 gene between TLE patients and controls (P = 0.735). We reported for the first time to our knowledge the significant role of the two SNPs in t-PA gene (rs2020918 and rs4646972) in developing susceptibility to TLE in Chinese Han population.

A correlation between inflammation and cerebral small vessel disease (CSVD) has been hypothesized by earlier observational research, while this correlation has not been well established. Considering the significant clinical value of this causality determination, Mendelian randomization (MR) was implemented to investigate the causality between inflammatory cytokines and CSVD radiological lesions. Using the publicly available Genome-Wide Association Study (GWAS) datasets, a bidirectional two-sample MR analysis was employed to infer causality between 91 inflammatory cytokines and CSVD phenotypes [white matter hyperintensity (WHM), fractional anisotropy (FA), mean diffusivity (MD), cerebral microbleeds (CMBs), and lacunar stroke]. A set of methods was used for sensitivity analysis, including Cochran's Q test, MR-Egger intercept method, and MR pleiotropy residual sum and outlier (MR-PRESSO) global test. Furthermore, the strength of causality was assessed using the Bonferroni correction. Our research discovered a mutually predictive bidirectional link between CSVD phenotypes and inflammatory cytokines. Following the application of the Bonferroni correction, fibroblast growth factor 21 (FGF-21) was significantly inversely correlated with an increased risk of CMBs (OR = 0.579, 95 % CI = 0.425-0.789, P = 0.00055). Using sensitivity analysis, heterogeneity, and horizontal pleiotropy were not detected. In this investigation, we established the causality between CSVD and inflammatory cytokines, with FGF-21 in particular significantly reducing the risk of CMBs. With further validation, these findings may provide new targets for the prevention, detection, and intervention of CSVD.