bluuebunny/crossref_metadata_2025_split huggingface dataset:
The nigro-vagal modulation of the proximal colon is compromised in a model of environmental Parkinson's Disease
Authors: Xing Tiaosi , Nanni Giorgia , Burkholde Cameron , Browning Kirsteen , Travagli R. Alberto 
Published: May 2023

Parkinson’s Disease (PD) is a prevalent neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which results in tremor, rigidity and bradykinesia. Up to 80% of the PD patients suffer from constipation about 10 to 20 years before experiencing motor symptoms. We previously reported that a monosynaptic pathway connects SNpc to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric and proximal colon motility, and gastric motility is impaired in an environmental model of parkinsonism, induced by oral administration of subthreshold doses of paraquat (P) and lectin (L) (PMID 30302391). The current study was designed to test the hypothesis that nigro-vagal modulation of the proximal colon is compromised in the oral P+L model of parkinsonism.Proximal colonic motility and tone were recorded in age-matched male rats via a strain gauge aligned with the colonic circular smooth muscle, approximately 3 cm distal to the ileal-cecal valve. Activation of SNpc neurons via microinjection of the ionotropic glutamate selective agonist, NMDA, increased proximal colonic motility (187±52.6% of baseline, n=13; Paired t test, p<0.0001) and tone (323±97.2mg, n=14). In our rat model of environmental parkinsonism, baseline colonic motility (155.2±49.6mg, n=5) showed no change compared to control rats (146.6±67.8mg, n=5; Unpaired t test, p=0.0387), however, the ability of NMDA-induced SNpc activation to increase colonic tone and motility was decreased (tone 303.4±70.8mg, n=5 vs 500.8±207.5mg in control rats, n=5; unpaired t test, p=0.0395; motility 139.8±24.8% of baseline, n=4 vs 222.6±62.9% of baseline of the age matched control rats, n=3; unpaired t test, p=0.0439). Gastro-cecal transit, measured using the 13C lactose ureide-breath test, showed that transit time was increased in parkinsonian rats from 132.7±28 min (n=7) to 218.4±59.4 min (n=11; one-way ANOVA, p=0.0026). Chemogenetic inhibition of the nigro-vagal pathway attenuated the delay in transit in parkinsonian rats to 173.2±16.3 min (n=5; one-way ANOVA, p=0.2886 vs control rats).These data suggest that intestinal transit is delayed, and the ability of the SNpc to modulate proximal colon motility and tone is attenuated in a model of environmental parkinsonism. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed both in patients and in animal models of Parkinson Disease. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Intrarenal angiotensin II mediated ROCK1 activation promotes hypertension during chronic acidotic conditions
Authors: Aryal Dinesh , Jackson Keith 
Published: May 2023

The newly reported model of experimental hypertension delineates the scope of chronic metabolic acidosis as a cause of hypertension. The observed mechanism to promote hypertension during the acidotic conditions are regulated by intrarenal angiotensin II (Ang II) and oxidative stress functioning synergistically. The present study investigates the role of Rho Kinase (ROCK1) in mediating intrarenal activation of Ang II and the renal cell oxidative state during the observed acidosis elicited hypertension. Chronic metabolic acidosis (CMA) was induced in male Sprague Dawley rats (100-150 g) by providing a weak acid solution of 0.28 M ammonium chloride (NH4CL) in tap water for 8 weeks. To confirm the rats were acidotic, blood pH was measured, while blood pressure was monitored weekly using tail-cuff. Rats were divided into five groups: Control (vehicle treated), CMA (acidotic), CMA+spironolactone (to evaluate aldosterone effect), CMA+captopril (to evaluate Ang II effect), and CMA+tempol (to evaluate free radical effect). Microdialysis probes were implanted to the rat’s renal compartments in each group to collect the interstitial fluid. ELISA was performed to quantifying the ROCK1 in all the dialysate samples. In the CMA rats, sustained elevation in the mean arterial pressure (MAP), associated with the significant decrease in blood pH was observed compared to the Control group over the 8 weeks. A significant decrease in MAP was observed in CMA rats treated with captopril and tempol, whereas spironolactone treatment caused no decrease in MAP as compared to the CMA group. The interstitial ROCK1 was significantly increased in the CMA group vs control but decreased significantly in the CMA+captopril vs CMA and CMA+tempol vs CMA groups respectively. This suggested the intrarenal ROCK1 is regulating the Ang II and ROS generation in the renal compartment. Overall, this supports our hypothesis that ROCK pathway and its interaction with intrarenal Ang II and oxidative stress plays a pivotal role in the pathogenesis of acidosis promoted hypertension. VCOM Departmental funding This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
RAGE availability lessens the degree of dysfunctional mitochondrial bioenergetics following chronic secondhand smoke exposure
Authors: Campbell Kennedy , Curtis Katrina , Clarke Derek , Saito Erin , Bikman Benjamin , Arroyo Juan , Reynolds Paul 
Published: May 2023

The receptor for advanced glycation end products (RAGE) is an immunoglobulin-type receptor abundantly expressed by lung parenchyma that coordinates inflammatory responses. We have previously described roles for RAGE following exposure to tobacco smoke (both primary and secondhand) and environmental diesel particulate matter. While inflammatory signaling, tissue remodeling, and pulmonary function have each been investigated, mitochondrial fitness that may underpin cellular health has not been characterized in a chronic exposure model. The current study assessed mitochondrial bioenergetics in RAGE knock out (RKO) and wild type (WT) mice exposed to 3 months of secondhand smoke (SHS) via a nose-only delivery system (Sireq Scientific, Montreal, Canada) or room air (RA). Select mice were also co-administered SHS and semi-synthetic glycosaminoglycan ethers (SAGEs) that inhibit RAGE/ligand interactions. We discovered that mitochondrial respiration was significantly decreased in WT+SHS mice compared to WT+RA following the addition of glutamate/malate, ADP, succinate, and FCCP. Each of these sequential substrates revealed less severe mitochondrial respiration compromise in RKO +SHS compared to WT+SHS mice, suggesting the absence of RAGE was sufficient to blunt waning mitochondrial fitness. Importantly, mitochondrial respiration was significantly improved in WT+SHS+SAGEs mice compared to WT+SHS mice. These results provide a snapshot of mitochondrial fitness following chronic SHS exposure and suggest a role for RAGE signaling in altering cellular bioenergetics during exposure. This work was supported by funding from the National Institutes of Health (NIH 1R15-HL152257, PRR and JAA). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Establishing a Rat Model of Intestinal Heme-iron Absorption
Authors: Lee Jennifer , He Yue , Shine Jacob , Ebea Pearl , Flores Shireen , Hamza Iqbal , Collins James 
Published: May 2023

Heme iron, derived from hemoglobin and myoglobin of animal products, is efficiently absorbed and utilized by humans. Despite extensive investigation over the last several decades, the exact mechanism(s) of heme-iron absorption and tissue utilization of absorbed heme are unclear. Mice are frequently used for investigation of iron biology; however, mice do not efficiently utilize dietary iron derived from heme, so development of alternative models is warranted. Rats could more efficiently utilize dietary heme iron, but this has not been rigorously tested. Our initial studies demonstrated that dietary heme (derived from porcine RBCs) could partially correct iron-deficiency anemia (IDA) in rats of one strain (rat strain 1), but not in 2 others. We hypothesized that a heme-iron diet would fully replete strain 1 rats with IDA, at a similar rate to a non-heme iron (NHI) diet. We utilized repletion diets containing 50, 75 or 100 ppm heme iron; a control diet contained 50 ppm NHI. Forty-two, three-week-old, female strain 1 rats were weaned onto a low-iron diet with 3-4 ppm NHI, and then after 2 weeks, rats were repleted with the different diets for 8 days. Rats were housed in overhanging wire bottom stainless steel cages during the low-iron feeding period to prevent coprophagia. Blood was collected from the tail vein at baseline and every 4 days thereafter to track correction of anemia. Outcomes showed that repletion of IDA rats with the 50-ppm heme-iron diet resolved the anemia; however, tissue iron depletion indicated that the rats remained iron deficient. Also, the rate of repletion was slightly slower as compared to rats repleted with the control (50 ppm NHI) diet. With higher dietary heme-iron levels, repletion was as fast, or even faster, than in control rats suggesting that a rat strain was identified that can efficiently assimilate dietary heme iron. Our studies support a role for rats as a genetic model to preferentially mimic human nutritional studies of iron and heme absorption. This investigation was funded by grant DK074867 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (JFC, PI), and grant DK109717 from NIDDK and the Office of Dietary Supplements (to JFC, PI). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Epithelial aryl hydrocarbon receptor regulates IL-22 producing colonic group 3 innate lymphoid cells to augment microbial metabolite mediated protection in colitis
Authors: Ghosh Sweta , Vanwinkle Zachary M. , Dryden Gerald W , Kanneganti Thirumala-Devi , Haribabu Bodduluri , JALA Venkatakrishna R 
Published: May 2023

The intestinal barrier dysfunction is intimately associated with inflammatory bowel diseases (IBD) as the gut barrier provides the first line of protection to host from external factors. The pathogenesis of IBD is multifactorial resulting from combinations of genetic polymorphism, environmental factors, diet, altered microbiota and the immune system. Aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor which upon activation can regulate many pathophysiological functions like inflammation and gut barrier homeostasis. Recently, we identified that microbial metabolite Urolithin A (UroA) mitigated colitis in pre-clinical models through activation of AhR-dependent pathways at two distinct levels by preserving the gut barrier function and reducing systemic and acute inflammation. However, the interplay between the enhanced barrier function and reduction in inflammation and the requirement of specific cell types to mediate the UroA activities remains to be established. In the current study, we evaluated the UroA mediated cell specific requirement of AhR by using transgenic mice AhRfx-VillinCre (AhR is deleted in intestinal epithelial cells) and AhRfx-LysMCre (AhR is deleted in myeloid cells) mice. Our studies showed that UroA mediated activation of gut AhR is critical for regulation of intestinal homeostasis in dextran sodium sulphate (DSS) induced colitis. UroA also activated intestinal AhR dependent signaling to induce IL-22 production from type 3 innate lymphoid cells (ILC3). Further, our data from intestinal organoids revealed that AhR dependent-induction of IL-18 from intestinal epithelial cells is responsible for IL-22 production from immune cells. These studies revealed the novel findings that microbial metabolite mediated selective activation of AhR regulates the IL-18/IL-22-axis to maintain gut homeostasis and enhance gut barrier function to attenuate IBD pathogenesis. Current studies are supported by NIH/NIGMS COBRE project P20-GM125504-01 and JHFEREG from University of Louisville. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Altered control of AgRP and metabolic rate during obesity via ERK and KLF4
Authors: Ritter McKenzie , Balapattabi Kirthikaa , Reho John , Claflin Kristin , Sigmund Curt , Grobe Justin 
Published: May 2023

Resting metabolic rate (RMR) adaptation contributes to the maintenance of human obesity, yet mechanisms controlling RMR in lean versus obese states remain poorly defined. Leptin contributes to RMR control in part through suppression of inhibitory Agouti-related peptide (AgRP) neurotransmission in the hypothalamic arcuate nucleus (ARC). Within AgRP neurons, leptin activates the extracellular signal-regulated kinase (ERK) cascade, which is thought to interrupt Agrp transcription through interference with the Krüppel-like factor 4 (KLF4) transcription factor. Our previously published data support altered ARC ERK signaling during obesity. We therefore hypothesized a role for ERK/KLF4 signaling within AgRP neurons for the suppression of AgRP transcription and thereby stimulation of RMR in the lean state, and changes in this pathway during obesity. In the GT1-7 cell model of AgRP neurons, leptin increased the phosphorylated ERK (pERK)/ERK ratio (n=4, 1 uM, 15 min +89% p<0.05) and reduced Agrp mRNA (n=4, 1 uM, 1 hr -43.0% p<0.05); similarly, siRNA knockdown of Klf4 reduced Agrp mRNA (n=4, -21.6% p<0.05). In lean adult C57BL/6J mice, leptin increased the ARC pERK/ERK ratio (n=8, 1 ug/g ip 16.5-fold p<0.05) and stimulated RMR (n=11, 2 ug/g ip 30 min +43.8% p<0.05). Lean transgenic mice with conditional deletion of Klf4 from AgRP neurons ( Agrp-Cre x Klf4-flox) exhibited increased RMR (n=13 KO +13.48% vs controls n=22 p<0.05). These findings support the model that ERK inhibition of KLF4 within AgRP neurons mechanistically contributes to leptin-mediated control of Agrp and RMR in the lean state. Ten weeks of high fat feeding strongly increases endogenous plasma leptin in C57BL/6J mice, and this treatment increased the ARC pERK/ERK ratio (n=5 +54.4% p<0.05), yet ARC KLF4 was increased (n=6 +74.6% p<0.05). Notably, there was a lack of suppression of Agrp mRNA following prolonged high fat feeding (n=4 +1.6-fold, p=ns). Therefore, these data also support the concept that loss of ERK-mediated suppression of KLF4 within the AgRP neuron during obesity may contribute to the pathogenesis of RMR adaptation. 903246, HL134850, HL084207, DK133121, HL150340, 826132, 18EIA33890055 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Specific neuronal populations encode inflammatory responses
Authors: Hashimoto Okito , Hepler Tyler , Tynan Aisling , Tracey Kevin J , Chavan Sangeeta S 
Published: May 2023

The brain maintains a homeostatic condition in the body through neuronal communication with peripheral organs. The immune system is also regulated by the nervous system with principles of reflex regulation. Neuronal pathways, including the vagus nerve-based inflammatory reflex, are physiological regulators of immune function and inflammation. However, it remains unclear whether and how the brain encodes the state of the immune system. We previously showed that the projections from the brainstem dorsal motor nucleus of the vagus nerve control inflammatory responses in the spleen. Furthermore, we found that cytokine-specific information is present in sensory neural signals within the vagus nerve. Based on these findings, we reasoned that the brain encodes and stores cytokine-specific information. In this study, we first investigated physiological parameters and serum levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) that are induced by tumor necrosis factor (TNF) and interleukin-1β (IL-1β). Increased serum levels of IL-6 and MCP-1 are observed after TNF and IL-1β administration. Interestingly, we found that IL-1β, but not TNF administration induces tachycardia. These results suggest activation of specific neural populations in the brain by TNF or IL-1β. Next, we carried out activity-dependent cell labeling in mice. We utilized the targeted-recombination-in-active-populations (TRAP2) mice crossed with a tdTomato reporter line to produce double transgenic TRAP2/tdTomato mice. Administration of TNF or IL-1β induces activation of neurons (expressing tdTomato indicative of neuronal activity) in the paraventricular nucleus (PVN), the bed nuclei of the stria terminalis (BNST) and the nucleus of the solitary tract (NTS), where vagal afferents ascending from peripheral tissues synapse on neurons. Re-exposure of mice to either TNF or IL-1β results in the labeling of additional neuronal populations in the BNST. A significant population of TNF-responsive neurons are found to be localized in the protein kinase C delta (PKCΔ)-positive subnucleus within the BNST, while IL-1β-responsive tdTomato marked neurons are predominantly located in the PKCΔ-negative region within the BNST. Together, these studies suggest that the brain encodes TNF and IL-1β-specific information in specific neuronal population. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Orexin facilitates the hypoxic ventilatory response via the activation of corticotropin-releasing hormone neurons that project to the nucleus of the solitary tract
Authors: Ben Musa Ruwaida , Cornelius-Green Jennifer , Hasser Eileen , Kline David , Cummings Kevin 
Published: May 2023

The paraventricular nucleus of the hypothalamus (PVN) contributes significantly to the peripheral chemoreflex-mediated respiratory and sympathetic responses to hypoxia, in part via reciprocal interactions with nucleus of the solitary tract (nTS). Previously we showed that orexin neurons in the perifornical hypothalamus are activated by hypoxia and facilitate the hypoxic ventilatory response (HVR) in the active phase of the circadian cycle . The neural circuitry through which orexin facilitates the HVR is unknown. Orexin receptors (OxR) are expressed in the PVN, and we recently showed that OxR blockade reduced the activation of both corticotropin-releasing hormone neurons in the PVN as well as nTS neurons. In addition, hypoxia activated orexin neurons projecting to the PVN, but not those projecting to nTS. Here we further explored the hypothesis that orexin facilitates the HVR and arterial blood pressure (ABP) response to hypoxia via the activation of nTS-projecting CRH neurons, and that specific OxR1 knockdown in the PVN would reduce the HVR. To test these hypotheses, we nanoinjected fluorescent retrobeads bilaterally into the nTS to label nTS-projecting neurons. Rats were then exposed to hypoxia (2hrs at 11% O2 during the active phase) following injection of either suvorexant (OxR antagonist; 20 mg/kg i.p.; n=4), or vehicle (DMSO; n=4). Using immunohistochemistry (IHC) we then quantified the number of activated (i.e., Fos-immunoreactive; IR) nTS-projecting CRH neurons. In separate groups of rats we nanoinjected shRNA to knockdown Ox1R expression specifically in the PVN (n=8). PVN of control rats was nanoinjected with scrambled RNA (scRNA; n=3) or aCSF (n=2). Three weeks later, rats were exposed to graded hypoxia (from 21% to 10% inspired O2) over 3-5 minutes to assess the acute HVR and ABP response to different levels of hypoxia. OxR blockade reduced the number of Fos-IR, nTS-projecting CRH neurons by ~32% (drug: p<0.0001). Images confirmed successful targeting of shRNA to PVN, and OxR1 knockdown (by ~50%) was confirmed in subsets of samples by Western Blot and IHC. Ox1R knockdown specifically in the PVN had no effect on resting ventilation, but significantly reduced the HVR (main effect: p=0.02; 22% decrease in VE/VCO2 at 13% O2), due to a reduction in the respiratory frequency response to hypoxia (main effect: p=0.004; 38 breath/min decrease at 13% O2). Ox1R knockdown also decreased ABP (~5 mmHg at all O2 levels; main effect: p=0.0015), but not its response to hypoxia. These data suggest that orexin neurons facilitate the HVR via OxR1 Grants: 5R01HL098602 (EH, DK), 5R01HL136710 (KC) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.