Ko, H.-K. | Search bioRxiv

bioRxiv2025

Human Neural Synergy when combining Stevia with a Flavor Modifer and the Neural effects of Sucrose vs Stevia

There is a drive to improve the acceptability of sweeteners like stevia by reducing their off-tastes. The main aim was to examine the synergistic neural effects of combining stevia with a flavor modifier and secondly to examine stevia vs. sucrose due to limited human neuroimaging data and concerns that sweeteners may be more addictive than sugar. In a within-subjects fMRI study, 34 healthy adults (Mean age = 25) tasted four conditions: stevia, stevia plus a flavor modifier, the modifier alone, and sucrose. We analyzed whole-brain responses and focused on regions of interest (ROIs) including the insula, postcentral gyrus, and hypothalamus (identified via meta-analysis of sweet taste processing), as well as the nucleus accumbens (NAcc) and amygdala due to their roles in reward and aversion. Stevia combined with the modifier evoked super-additive responses in the postcentral gyrus, parietal cortex, and occipital gyrus (p < 0.05, FWE-corrected). Compared to stevia alone, the stevia-modifier combination elicited reduced hypothalamic activity (p = 0.008) and the hypothalamus tracked pleasantness and mouth fullness only in this condition. The NAcc tracked mouth fullness more for the modified stevia than for stevia alone, and the amygdala tracked bitterness only in the plain stevia condition. Sucrose elicited higher postcentral gyrus activation than stevia (p = 0.01). We provide first evidence that combining stevia with a flavour modifier reveals synergistic neural activity associated with taste sensation, intensity and multisensory integration. Adding a modifier to stevia could increase unconscious desirability for stevia by masking its bitterness and increasing its mouth fullness.

neuroscience↗

bioRxiv2024

Understanding the development of enzalutamide resistance based on a functional single-cell approach

Most metastatic prostate cancers (PCa) initially depend on androgen for survival and proliferation. Thus, anti-androgen or castration therapies are the mainstay treatment. Although effective at first, androgen-dependent PCa (ADPC) universally develops therapy resistance, thereby evolving to the incurable disease, called castration resistant PCa (CRPC). Currently, mechanisms underlying the emergence of CRPC from ADPC are largely unclear. We used single-cell RNA-sequencing (scRNA-Seq) to determine how a therapy-naive ADPC cell line - LNCaP responds to the anti-androgen drug, enzalutamide. We found that most cells expressed the drug-target androgen receptor (AR+), while a small subpopulation ([~]12%) expressed low or no AR (ARlow/-). Gene set enrichment analysis (GSEA) revealed that AR+ and ARlow/- cells were enriched with significantly different gene expressions and signaling pathways. Unexpectedly, ARlow/- cells displayed robust transcriptional response, including upregulations of genes and pathways involved in clinical CRPC. Next, we isolate ARlow/- and AR+ cells from the LNCaP cell line, and functionally confirmed the enzalutamide resistant phenotype of ARlow/- cells in vitro and in xenograft models in vivo. Finally, to explore a therapeutic option for ARlow/- cells, we found that ARlow/- cells expressed low levels of NAD+ biosynthesis genes, notably NAPRT, indicating a possible vulnerability to inhibitors blocking NAD+ synthesis. Indeed, treating ARlow/- cells with NAD+ synthesis inhibitors, FK866 and OT-82, significantly inhibited the survival and proliferation of ARlow/- cells, thus suggesting a possible novel therapeutic option for ADT and enzalutamide resistant PCa. SUMMARYSingle-cell RNA-Sequencing reveals heterogeneities of tumor cell populations. In most cases, however, the functional significance of the observed heterogeneity is not tested. In this study, we first identified a possible therapy-resistant prostate cancer cell subpopulation with scRNA-Seq, then confirmed the resistant phenotype with single cell and colony - based cloning and functional testing. In addition, we also identified a therapeutic vulnerability of the resistant cells.

cancer biology↗