Cells

No pharmacological interventions exist that can restore or preserve auditory function in the mammalian cochlea. Auditory hair cells (HCs) do not spontaneously regenerate, leading to permanent hearing loss. In non-mammalian vertebrates, HC regeneration happens through proliferation and differentiation of their clonally related supporting cells (SCs). The present study supports the potential of quinoxaline (Qx), a nonsteroidal anti-inflammatory compound, to stimulate SC proliferation in the auditory sensory epithelium, a process that may prime the tissue for future HC regeneration. We synthesized a series of Qx derivatives by introducing various substitutions, ranging from hydrophilic to lipophilic. Seventy analogs were generated and tested in vitro and in vivo. Among those, only one (Qx-100) exhibited the best medicinal chemistry profile and was further modified to expand the structure–activity relationship of the chemotype, develop additional analogs, and optimize potency, bioavailability, and in vivo efficacy. Ten new lead variants were generated. Of those, Qx-294 and Qx-301 demonstrated promising in vitro Absorption, Distribution, Metabolism, and Excretion (ADME) profiles and were selected for further testing. Overall, both compounds were rapidly absorbed in zebrafish and mice and promoted cell proliferation in vitro and in vivo without signs of apoptosis, supporting their potential for sensory HC regeneration.

Osteoporosis is a major global health challenge, causing millions of fragility fractures each year and imposing an escalating socioeconomic burden worldwide. Despite advances with antiresorptive and anabolic therapies, substantial residual fracture risk persists, and targeting aging biology may yield disease modifying benefits beyond current standards of care. Senescent cells secrete senescence-associated secretory phenotype (SASP) factors, which impair osteoblast differentiation and contribute to bone loss. We investigated foretinib, a quinoline-based multi-tyrosine kinase inhibitor, as a potential anti-aging agent in osteoblast lineage cells. Foretinib inhibited doxorubicin-induced senescence in osteoblast progenitors via the p53/p21 and p16 pathways and reduced the expression of osteogenesis-inhibiting SASP factors, including CCL2, interleukin (IL)-1α, IL-1β, and IL-6. As a result, foretinib restored the impaired osteogenic differentiation of aged osteoblasts to near-normal levels in vitro. In ovariectomized, estrogen-deficient mice, foretinib significantly reduced trabecular and cortical bone loss by enhancing in vivo osteoblast differentiation, as shown by histological analysis and micro-computed tomography of femoral bone. These results suggest that foretinib alleviates osteoblast senescence and enhances osteogenic differentiation, supporting its promise as a therapeutic candidate for postmenopausal osteoporosis.

Multiple myeloma (MM) is an incurable hematologic malignancy arising from clonal plasma cells, with poor long-term outcomes due to inevitable relapse after conventional therapies. Chimeric antigen receptor (CAR) T-cell immunotherapy targeting B-cell maturation antigen (BCMA) has shown remarkable efficacy in relapsed patients. Conventional CARs employ single-chain variable fragments (scFvs), whereas single-domain antibodies (sdAb or VHHs) offer advantages such as small size, high stability, and potentially reduced immunogenicity. We designed and evaluated a novel anti-BCMA nanoCAR-T based on the VHH Nb17, compared with the conventional scFv-based CAR-T CT103a. Nb17 demonstrated strong BCMA binding and was incorporated into a CAR construct. Both nanoCAR-T and CT103a were generated via lentiviral transduction of primary T cells. Their cytotoxicity, cytokine secretion, degranulation, memory phenotype, and gene expression were assessed in vitro, along with antitumor activity in vivo. Nb17-nanoCAR-T demonstrated specific cytotoxicity, cytokine release (IL-2, TFNa, IFNg), and CD107a degranulation comparable to CT103a. Transcriptomic analysis revealed overlapping pathways between both CARs. Upon rechallenge, both CARs showed enhanced proliferation compared with untransduced T cells. In vivo, Nb17-nanoCAR-T and CT103a eradicated tumors in NSG mice. These findings demonstrate Nb17-nanoCAR-T exhibits potent anti-myeloma efficacy comparable to scFv-based CAR-T, supporting its potential as a promising therapeutic alternative.