👤 Hwei Fen Leong

Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone, and pharmacologic modulation of central GIP receptors (GIPRs) improves energy homeostasis and prevents conditioned taste avoidance (CTA). However, the mechanisms by which GIPR signaling impact food intake and aversion are incompletely understood. Here, we show that GIPR agonism abrogates the aversive and enhances the anorexigenic effects of the pro-inflammatory cytokine interleukin-1β (IL-1β). Aversion-encoding parabrachial calcitonin gene-related peptide (CGRP) neurons were required for IL-1β-induced CTA but not anorexia. Moreover, systemic IL-1β increased CGRP neural activity in vivo, and this was significantly attenuated by co-administration of a GIPR agonist. By contrast, GIPR in the dorsal vagal complex was required for the acute anorectic effect of GIPR agonism but not its anti-aversive effect. Taken together, our data suggest that GIPR agonism reduces food intake and prevents aversion via distinct circuits and that GIPR agonism may represent an effective approach to alleviate inflammation-induced aversion. Show less

Alzheimer's Disease (AD) is associated with reduced laryngeal sensation, decreased pharyngeal strength, and silent aspiration. Aspiration pneumonia is a leading cause of death in advanced AD. Superior laryngeal nerve(SLN) dysfunction is hypothesized to be responsible for poor laryngeal sensation and aspiration pneumonia. The purpose of this study was to compare SLN neurophysiology in an AD rat model to control animals. SLN-evoked studies were performed via stimulation of the main trunk in 4-month-old adult apolipoprotein-E4 (ApoE4-KI) rats (n = 8) versus wild-type rats (n = 10). Recording electrodes were placed on the internal branch of the SLN (iSLN) and cricothyroid muscles. Stimulated swallow force measurements from hyoid elevation were compared between groups. Outcome measures included both sensory and motor evoked responses. Additionally, force and frequency of electrically and tactile stimulated swallow reflexes were analyzed. Sensory nerve action potential duration was significantly longer in APOE-KI rats than controls with a mean difference (95% CI) of 2.24 ms (1.08-3.41). Both compound motor action potential latency and total duration were significantly longer in the APOE4-KI rats than controls with a mean difference (95% CI) of 0.22 (0.115-0.33) and 2.18 (0.90-3.4) respectively. Tactile-stimulated swallow frequency was significantly lower in the AD cohort vs. controls with a mean difference of -5.4 swallows/10 s (-7.6, -3.2). SLN evoked responses were significantly longer with a decrease in swallow frequency in an AD rat model compared to age-matched controls. This work suggests differences in SLN signaling between the cohorts. This work may provide a mechanistic understanding of SLN dysfunction and a tractable model to test new treatments for swallow dysfunction. N/A. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone, and pharmacologic modulation of central GIP receptors (GIPR) improves energy homeostasis. Recent reports have demonstrated that GIPR agonism is also anti-aversive. However, the mechanisms by which GIPR signaling impact food intake and aversion are incompletely understood. Here, we show that GIPR agonism abrogates the aversive and enhances the anorexigenic effects of the pro-inflammatory cytokine interleukin-1β (IL-1β). Aversion-encoding parabrachial calcitonin-gene related peptide (CGRP) neurons were required for IL-1β-induced conditioned taste avoidance (CTA) but not anorexia. Moreover, systemic IL-1β increased Show less

Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E leads to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identify the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate the expression of EMT markers, phenocopying NELF ablation. Elevated expression of NELF-E and KAT2B is associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Taken together, we uncover a crucial role of the NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis. Show less

Recent advances in CRISPR present attractive genome-editing toolsets for therapeutic strategies at the genetic level. Here, a liposome-coated mesoporous silica nanoparticle (lipoMSN) is reported as an effective CRISPR delivery system for multiplex gene-editing in the liver. The MSN provides efficient loading of Cas9 plasmid as well as Cas9 protein/guide RNA ribonucleoprotein complex (RNP), while liposome-coating offers improved serum stability and enhanced cell uptake. Hypothesizing that loss-of-function mutation in the lipid-metabolism-related genes pcsk9, apoc3, and angptl3 would improve cardiovascular health by lowering blood cholesterol and triglycerides, the lipoMSN is used to deliver a combination of RNPs targeting these genes. When targeting a single gene, the lipoMSN achieved a 54% gene-editing efficiency, besting the state-of-art Lipofectamine CRISPRMax. For multiplexing, lipoMSN maintained significant gene-editing at each gene target despite reduced dosage of target-specific RNP. By delivering combinations of targeting RNPs in the same nanoparticle, synergistic effects on lipid metabolism are observed in vitro and vivo. These effects, such as a 50% decrease in serum cholesterol after 4 weeks of post-treatment with lipoMSN carrying both pcsk9 and angptl3-targeted RNPs, could not be reached with a single gene-editing approach. Taken together, this lipoMSN represents a versatile platform for the development of efficient, combinatorial gene-editing therapeutics. Show less

During radiotherapy, normal tissue is unavoidably exposed to radiation which results in severe normal tissue reactions in a small fraction of patients. Because those who are sensitive cannot be determined prior to radiotherapy, the doses are limited to all patients to avoid an unacceptable number of severe adverse normal tissue responses. This limitation restricts the optimal treatment for individuals who are more tolerant to radiation. Genetic variation is a likely source for the normal tissue radiosensitivity variation observed between individuals. Therefore, understanding the radiation response at the genomic level may provide knowledge to develop individualized treatment and improve radiotherapy outcomes. Exon arrays were utilized to compare the basal expression profile between cell lines derived from six cancer patients with and without severe fibrosis. These data were supported by qRT-PCR and RNA-Seq techniques. A set of genes (FBN2, FST, GPRC5B, NOTCH3, PLCB1, DPT, DDIT4L and SGCG) were identified as potential predictors for radiation-induced fibrosis. Many of these genes are associated with TGFβ or retinoic acid both having known links to fibrosis. A combinatorial gene expression approach provides a promising strategy to predict fibrosis in cancer patients prior to radiotherapy. Show less