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Aberrant deposition of ¦Â©\amyloid (A¦Â) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating ¦Â©\site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen©\activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, A¦Â plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed A¦Â oligomer©\induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c©\Jun N©\terminal kinase (JNK) and extracellular signal©\regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease©\modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease©\modifying candidate with the potential to drive a breakthrough approach targeting AD pathology. Ramalin alleviates Alzheimer's disease pathology by selectively inhibiting HDAC6, reducing BACE1 levels, and suppressing neuroinflammation through downregulation of the NLRP3 inflammasome and iNOS. It restores synaptic function impaired by A¦Â toxicity and improves cognitive performance in AD mouse models, APP/PS1 and 3xTg©\AD. Additionally, ramalin modulates the MAPK signaling pathway, reducing tau phosphorylation by inhibiting JNK and ERK activation.

PurposeNuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial cytoprotective protein that shields cells from electrophilic and oxidative stress. Mice lacking Nrf2 exhibit heightened susceptibility to myelosuppression due to impaired hematopoietic reconstitution. In this study, we examined the altered sensitivity to ionizing radiation (IR) and 7,12-dimethylbenz(a)anthracene (DMBA) in Nrf2?/? mice separately.Materials and MethodsIrradiate Nrf2?/? or wild-type mice with a dose of 4?Gy to observe changes in body weight, survival rate, and blood routine at 12 months. DMBA was used to treat Nrf2?/? and wild-type mice, and the body weight and survival rate of the mice were measured. The changes of heme oxygenase-1(HO1) and NAD(P)H: quinone oxidoreductase 1(NQO1) in mice treated with IR or DMBA were detected by RT-qPCR and western blotting.ResultsOur results indicate that Nrf2 deficiency leads to more severe blood and immune system injury in mice exposed to IR or DMBA. Additionally, long-term monitoring revealed that Nrf2 deletion resulted in more severe myelosuppression, leukemia-like symptoms, and higher cancer rates. At the mRNA and protein levels, there was no significant increase in HO1 and NQO1 levels in the Nrf2?/? mice treated with IR or DMBA. These adverse effects might be attributed to the inhibited protein levels of HO1 and NQO1 and significant DNA damage in hematopoietic stem and progenitor cells (HSPCs).ConclusionsWe demonstrate that the genetic deficiency of Nrf2 in mice leads to reduced antioxidant capacity and suppression of hematopoietic and immune system function, resulting in increased sensitivity to IR or DMBA. Graphical Abstract

SummaryAlthough chimeric antigen receptor (CAR) T cells have demonstrated therapeutic activity in hematopoietic malignancies, tumor heterogeneity has impeded the efficacy of CAR T cells and their extension into successful solid tumor treatment. To address these challenges, induced pluripotent stem cell (iPSC)-derived T (iT) cells are engineered to uniformly express CAR and T cell receptor (TCR), enabling targeting of both surface and intracellular antigens, respectively, along with a high-affinity, non-cleavable variant of CD16a (hnCD16) to support antibody-dependent cellular cytotoxicity (ADCC) when combined with therapeutic antibodies. Co-expression of each antitumor strategy on engineered iT cells enables independent and antigen-specific targeting across a diverse set of liquid and solid tumors. In heterogeneous tumor models, coactivation of these modalities is required for measurable antitumor efficacy, with activation of all three modalities displaying maximal efficacy. These data highlight the therapeutic potential of an off-the-shelf engineered iPSC-derived trimodal T cell expressing CAR, TCR, and hnCD16 to combat difficult-to-treat heterogeneous tumors. Graphical abstract Highlights?CAR, TCR, and hnCD16 can be uniformly co-expressed and can function in iT cells?hnCD16 signals through CD3¦Æ and arms iT cells with targeting flexibility through ADCC?Concurring CAR, TCR, and hnCD16 activation demonstrates a cooperative effect?Multi-targeting with trimodal iT cells can control heterogeneous tumors in vivo Yang et al. show that (1) trimodal iPSC cells expressing CAR, TCR, and hnCD16 can commit to T cell lineage, (2) hnCD16 signals through CD3¦Æ in iT cells and arms iT cells with ADCC targeting flexibility, and (3) trimodal iT cells control antigen-heterogeneous tumors in vivo through multi-modal targeting.