Jiajia Wang

The discovery of selective immunosuppressants for T cell-mediated diseases like Ulcerative Colitis (UC) is a significant challenge. While traditional screening is inefficient, Artificial intelligence (AI)-driven approaches are often hindered by the scarcity of high-quality labeled data, challenging the accurate identification of functional molecules. In this study, we leveraged a transfer learning strategy to compensate for the lack of high-quality data, establishing a screening platform to identify potential T cell inhibitors. Using this approach, we identified Lutein as a novel, specific immunomodulatory candidate from a natural product library. Integrated multi-omics analyses revealed that Lutein activates peroxisome proliferator-activated receptor gamma (PPARγ), suppressing glucose uptake and glycolysis, thereby selectively inhibiting Th1 cell differentiation. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis, Lutein treatment significantly restored Th1-mediated immune balance and alleviated pathological tissue damage. Our findings highlight the feasibility of using a few-shot learning strategy based on transfer learning to screen for specific immunosuppressants and indicate that Lutein is a promising therapeutic candidate for ulcerative colitis. An AI screening platform leveraging the Uni-Mol model identifies Lutein as a selective Th1 immunomodulator, which targets PPARγ-mediated glucose metabolism to inhibit Th1 differentiation and ameliorate colitis.

The epigenetic modification of histone H3 lysine 27 trimethylation (H3K27me3) by the embryonic ectoderm development (EED) protein is closely associated with the regulation of transcriptional programs and is implicated in autoimmune diseases. However, the efficacy of targeting H3K27me3 for the treatment of neuroinflammation remains unclear. In this study, we demonstrate that systemic administration of an EED inhibitor diminishes the inflammatory response mediated by dendritic cells (DCs), thereby alleviating experimental autoimmune encephalitis (EAE), a representative mouse model of autoimmune diseases in the central nervous system (CNS). Our findings indicate that EED inhibitors suppress DC migration by upregulating genes in the WNT signaling pathway that are epigenetically marked by H3K27me3. Conversely, inhibiting the WNT pathway partially reverses the impaired DC migration caused by EED inhibitors. Additionally, the genetic deletion of Eed inhibits DC migration and effectively mitigates autoimmune symptoms and inflammatory infiltration into the CNS in EAE. These results highlight EED as a critical regulator of DC migration and suggest its potential as a therapeutic target for autoimmune disorders.

Background Neuronal surface antibody-associated autoimmune encephalitis (NSAE) is a group of neuro-inflammatory disorders that is mediated by autoantibodies against the cell-surface and synaptic antigens. Studies have explored the role of neurofilament light chain (NfL) in NSAE and provided inconsistent data. We performed a systematic review and meta-analysis to evaluate the NfL levels in the serum and cerebrospinal fluid (CSF) of patients with NSAE. Methods The National Center for Biotechnology Information (NCBI, PubMed), Web of Knowledge, and the Cochrane Library databases were searched for studies reporting NfL levels in patients with NSAE. Random-effects meta-analysis was used to pool results across studies. Results Thirteen studies were included in the final systematic review and meta-analysis. The serum NfL levels were significantly higher in patients with NSAE compared to unaffected controls (standardized mean difference [SMD] = 0.909, 95% confidence interval [CI]: 0.536–1.282). Similarly, the CSF NfL levels were elevated in patients with NSAE (SMD = 0.897, 95% CI: 0.508–1.286). The serum and CSF NfL levels were not significantly correlated with disease severity, prognosis, and abnormalities in magnetic resonance imaging, electroencephalography, and CSF. Conclusions NfL levels in the serum and CSF were higher in patients with NSAE compared to unaffected controls. However, the NfL levels were not shown to be significantly associated with clinical or paraclinical features.

Chromatin-remodeling protein BRG1/SMARCA4 is pivotal for establishing oligodendrocyte (OL) lineage identity. However, its functions for oligodendrocyte-precursor cell (OPC) differentiation within the postnatal brain and during remyelination remain elusive. Here, we demonstrate that Brg1 loss profoundly impairs OPC differentiation in the brain with a comparatively lesser effect in the spinal cord. Moreover, BRG1 is critical for OPC remyelination after injury. Integrative transcriptomic/genomic profiling reveals that BRG1 exhibits a dual role by promoting OPC differentiation networks while repressing OL-inhibitory cues and proneuronal programs. Furthermore, we find that BRG1 interacts with EED/PRC2 polycomb-repressive-complexes to enhance H3K27me3-mediated repression at gene loci associated with OL-differentiation inhibition and neurogenesis. Notably, BRG1 depletion decreases H3K27me3 deposition, leading to the upregulation of BMP/WNT signaling and proneurogenic genes, which suppresses OL programs. Thus, our findings reveal a hitherto unexplored spatiotemporal-specific role of BRG1 for OPC differentiation in the developing CNS and underscore a new insight into BRG1/PRC2-mediated epigenetic regulation that promotes and safeguards OL lineage commitment and differentiation.

Rationale: Spinal cord injury (SCI) is an acute damage to the central nervous system that results in severe morbidity and permanent disability. Locally implanted scaffold systems with immobilized mesenchymal stem cells (MSCs) have been widely proven to promote locomotor function recovery in SCI rats; however, the underlying mechanism remains elusive.

Curcumol, a natural product isolated from the traditional Chinese medicine Rhizoma curcumae, possesses various potential therapeutic values in many diseases. However, evidence of its toxicological profile is currently lacking. In this study, a repeated toxicity study of curcumol was conducted for the first time. SD rats were exposed to doses of 250, 500, 1000 mg/kg in a selected dose formulation for 28 days through oral administration. The potential toxic effects of curcumol on the blood system were observed and further validated in vivo and in vitro. Moreover, other hematology and biochemistry parameters as well as the weight of organs were altered, but no related histopathological signs were observed, indicating these changes were not regarded as toxicologically relevant. Our current findings provide a complete understanding of the safety profile of curcumol, which may contribute to its further study of investigational new drug application.

Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 μM) and kaempferol (10 μM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.