Rapid versus Delayed Stimulation of Feeding by the Endogenously Released AgRP Neuron Mediators GABA, NPY, and AgRP

SummaryAgouti-related peptide (AgRP) neurons of the hypothalamus release a fast transmitter (GABA) in addition to neuropeptides (neuropeptide Y [NPY] and Agouti-related peptide [AgRP]). This raises questions as to their respective functions. The acute activation of AgRP neurons robustly promotes food intake, while central injections of AgRP, NPY, or GABA agonist results in the marked escalation of food consumption with temporal variance. Given the orexigenic capability of all three of these neuroactive substances in conjunction with their coexpression in AgRP neurons, we looked to unravel their relative temporal role in driving food intake. After the acute stimulation of AgRP neurons with DREADD technology, we found that either GABA or NPY is required for the rapid stimulation of feeding, and the neuropeptide AgRP, through action on MC4 receptors, is sufficient to induce feeding over a delayed yet prolonged period. These studies help to elucidate the neurochemical mechanisms of AgRP neurons in controlling temporally distinct phases of eating

A Novel Excitatory Paraventricular Nucleus to AgRP Neuron Circuit that Drives Hunger

Summary Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to its control. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake1-5. Consistent with their obligatory role in regulating appetite, genetic ablation or pharmacogenetic inhibition of AgRP neurons decreases feeding3,6,7. Excitatory input to AgRP neurons is key in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric state-dependent synaptic plasticity8-10. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing Thyrotropin-releasing hormone (TRH) and Pituitary adenylate cyclase-activating polypeptide (PACAP). Pharmaco-genetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated

Evaluation of Important Treatment Parameters in Supraphysiological Thermal Therapy of Human Liver Cancer HepG2 Cells

This study was aimed at simulating the effect of various treatment parameters like heating rate (HR), peak temperature (PT) and hold/total treatment time on the viability of human liver cancer HepG2 cells subjected to different thermal therapy conditions. The problem was approached by investigating the injury kinetics obtained using experimentally measured viability of the cells, heated to temperatures of 50–70°C for 0–9 min at HRs of 100, 200, 300 and 525°C min(−1). An empirical expression obtained between the activation energy (E) and HR was extended to obtain the E values over a broad range of HRs from 5 to 600°C min(−1) that mimic the actual conditions encountered in a typical thermal therapy protocol. Further, the effect of the HR (5–600°C min(−1)) and PT (50–85°C) on the cell survival was studied over a range of hold times. A significant drop in survival from 90% to 0% with the simultaneous increase in HR and PT was observed as the hold time increased from 0 to 5 min. For complete cell death, the hold time increased with the increase in the HR for a given PT, while the total time showed presence of minima for 60, 65 and 70°C at HRs of 50, 100 and 200°C min(−1), respectively

Dynamic GABAergic afferent modulation of AgRP neurons

Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues prior to ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the pre-consummatory modulation of ARCAgRP neurons. In a manner reciprocal to ARCAgRP neurons, ARC-projecting leptin receptor (LepR)-expressing GABAergic DMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, DMHLepR neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARCAgRP neuron activity and feeding behavior

Arrhythmia and death following percutaneous revascularization in ischemic left ventricular dysfunction: Prespecified analyses from the REVIVED-BCIS2 trial

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82–1.30]; P =0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920048

Targeting Fat-Sensitive Pathways In Enteroendocrine Cells Using Nanoparticle-Mediated Drug Delivery

The current epidemic of obesity has been linked to an increase in fat intake associated with the Western diet. Nutrient-induced stimulation of enteroendocrine cells in the small intestine leads to the release of hormones that contribute to satiety and the control of food intake. In particular, ingested fat, specifically in the form of free fatty acids, is potent activator of enteroendocrine cells in the proximal small intestine. However, the underlying signaling cascade that free fatty acids initiate in these enteroendocrine cells, which leads to secretion of satiety hormones, is not known. In general, my research is focused on identifying nutrient-responsive pathways in enteroendocrine cells involved with the release of satiety signals and using this information to begin to develop novel drug delivery strategies to reduce food intake. In general, my results revealed that activation of the fatty acid receptor GPR120 was ecessary for the linoleic acid-induced intracellular calcium rise, a necessary precursor for hormone release. Using patch clamp recording, I discovered that linoleic acid activated enteroendocrine cells by inducing membrane depolarization, a process requiring the calcium-activated, monovalent cation permeable channel TRPM5, which is activated downstream of GPR120. To validate the unexpected finding that TRPM5 was involved in fattyacid signaling, I performed experiments using bitter compounds, whose transduction pathway is known to involve TRPM5. Enteroendocrine cells express the bitter taste receptors and release cholecystokinin in response to bitter stimuli, suggesting the probable role of gut in initiation of protective behavior against ingestion of potentially harmful substances. Armed with the data on the specifics of the fatty acid transduction, I performed experiments using nanoparticles to determine their utility for delivering pharmaceuticals specifically to the enteroendocrine cells. I fabricated and characterized PLGA nanoparticles and performed intracellular uptake studies in order to optimally delivery payloads inside cells. Finally, I validated their use by using cell-based assays to determine the effects of internalized PLGA nanoparticles on ion channels and signaling pathways involved in CCK release. Taken together, this dissertation research has identified the signaling pathways (pharmacological targets) involved in fatty acid-mediated satiety hormone release and validated the potential therapeutic use of nanoparticle-mediated drug delivery for the eventual control of food intake

The ‘qRBBB myocardial infarction’: Unwrapping an old enigma

This single-center, prospective, observational study was conducted at a tertiary-care center over a span of two years. Patients presenting with acute Anterior-Wall STEMI were included as a study population. The subgroups included qRBBB pattern on ECG and non-qRBBB group. Among 1128 patients included in the study, 100 (11.28 %) patients presented with qRBBB pattern. Increased risk of cardiogenic shock, increased hospital-stay, a higher Killip class on presentation, high incidence of recanalized IRA, remarkably depressed LVEF were significantly associated with qRBBB-MI, which is a menacing form of ACS that leads not only to a high mortality but also to a long-term morbidity