bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanosensitive Responses of Resident Alveolar
Authors: Mthunzi Liberty , Gusarova Galina A. , Islam Mohammad N. , Bhattacharya Jahar 
Published: May 2022

BackgroundThe extent of micromechanical coupling between resident alveolar macrophages (AMs) and the surrounding tissue niche remains unclear. Lung overexpansion due to therapeutic mechanical ventilation imposes distortional stresses on the alveolar epithelium (AE), causing acute lung injury (ALI). Sessile AMs, lying adjacent to the AE, are causally implicated in ALI. However, it is not clear whether micromechanical coupling with the AE induces proinflammatory distortional stresses in sessile AMs. We addressed this question in live mouse lungs by real‐time confocal microscopy (RCM).MethodsFor RCM, we inflated and blood‐perfused mouse lungs at physiological pressures. To detect cytosolic Ca2+ (cCa2+), we microinfused fluo‐4 by alveolar micropuncture. To detect sessile AMs, we microinfused fluorophore‐conjugated anti‐Siglec‐F and anti‐CD11c Abs. To induce transient lung overexpansion, we increased the alveolar pressure from 5 to 15 cmH2O for 15 seconds. We determined alveolar diameter in terms of fluo‐4 fluorescence, which marked the epithelial margins. We determined cell diameter of sessile AMs in terms of Siglec‐F fluorescence, which marked the cell boundary. We detected gap junctional communication (GJC) by fluorescence recovery after photobleaching (FRAP).ResultsSessile AMs were exclusively located in non‐distending microniches of the alveolus and therefore, did not stretch during lung expansion. Nevertheless, a subset of AMs responded to lung overexpansion by transiently increasing cCa2+. The cCa2+ increase initiated in 5 min, reaching peak at two‐times baseline in 20 min, then subsiding to baseline after a further 20 min. Concomitantly, in AE adjacent to AMs, there was marked increase in cCa2+ oscillations, but no increase in mean cCa2+. In lungs with AM‐specific Cx43 deletion, the transient cCa2+ response was blocked in AMs, but not in adjoining AE. FRAP revealed GJC only in cCa2+‐responsive AMs. In paired comparisons, AMs lacking GJC failed to show expansion‐induced Ca2+ responses (p<0.05).ConclusionsWe report the unexpected finding that sessile AMs were exclusively located in immobile microniches of alveoli and therefore did not stretch during lung expansion. Nevertheless, following expansion there was Cx43‐mediated Ca2+communication with the AE, causing cCa2+ increases in sessile AMs. Although further studies are required to evaluate the potentially proinflammatory responses induced by this Ca2+ response, we propose Cx43 of sessile AMs might be a therapeutic target to mitigate lung expansion‐induced ALI.
Functional Annotation and Cross‐study Comparison of DNA Methylation Regions uniquely associated with 24‐hour Blood Pressure Phenotypes in African Americans
Authors: Roberts Michelle L. , Kotchen Theodore , Pan Xiaoqing , Li Yingchuan , Yang Chun , Liu Pengyuan , Wang Tao , Laud Purushottam , Chelius Thomas H. , Munyura Yannick , Mattson David L. , Liu Yong , Cowley Allen W. , Kidambi Srividya , Liang Mingyu 
Published: May 2022

Epigenetics may reflect the interactions between DNA and environment and lifestyle and DNA methylation marks have been implicated in the development and progression of hypertension. In an African American (AA) cohort of hypertensives and normotensives (n = 281), we have recently discovered up to 72 methylation regions (MRs) in whole blood DNA that were significantly associated with 24‐h BP phenotypes (False Discovery Rate (FDR) < 0.05) via reduced representation bisulfite sequencing (RRBS). One‐time clinic BP measurements were not associated with MRs. Upon adjustments for covariates age, sex, and body mass index, 13 MRs remained associated with 24‐h BP phenotypes (FDR < 0.05), each explaining 6.5% ‐ 9.4% of BP variance. Analysis of the chr19 MR in an independent cohort (n=117) using Bisulfite ULtrapLEx Targeted Sequencing (BULLET‐Seq), a new method that we developed, validated its association with 24‐h avg BP phenotypes (FDR < 0.05).In the current study, we functionally annotated the MRs that we identified as uniquely associated with 24‐h BP phenotypes and examined CpG sites previously reported to be associated with BP. Two MRs were near chr1 linkage disequilibrium (LD) regions within genes, PRDM16 and CASZ1, containing BP‐associated sentinel single nucleotide polymorphisms (SNPs). Although no MRs were found to directly overlap with reported BP‐relevant expression or methylation quantitative trait loci (eQTLs or meQTLs), many overlapped with enhancer regions, CTCF‐binding sites, or genes related to hypertension and stroke. To demonstrate consistency with prior studies, we found associations between reported clinic BP‐associated methylation array chip CpGs and the 24‐h BP phenotypes in our study. Of the 16 BP‐associated CpGs from two reports that were detected in both the methylation chip and our RRBS data, several CpGs were significantly associated with 24‐h and clinic BP phenotypes in our cohort (p < 0.05) but not after adjustment for both covariates and FDR. A chr7 CpG (cg06340364) showed significant negative associations with all studied BP phenotypes except nighttime and clinic DBPs (p < 0.05, unadjusted). These investigations highlight the value of regional DNA methylation and the ability to capture the overall effect of environmental and genetic factors that influence BPs over a 24‐h period which have functional epigenomic relevance.
Modulatory effect of Luteolin on potassium dichromate‐induced nephrotoxicity, cardiotoxicity and genotoxicity via Kim‐1/Nrf2 signaling pathways
Authors: Hassan Fasilat O. , Awoyomi Omolola V. , Oyagbemi Ademola A. , Falayi Olufunke O. , Ogunpolu Blessing O. , Omobowale Temidayo O. , Adedapo Adeolu A. 
Published: May 2022

Environmental and occupational exposure to chromium compounds has become a potential aetiologic agent for kidney disease through excessive generation of free radicals, induction of apoptosis and exaggerated inflammatory responses. These are some pathophysiologic mechanisms of potassium dichromate (K2Cr2O7) toxicity with attendant nephrotoxicity and cardiotoxicity. The cardioprotective and nephroprotective effects of Luteolin, a known potent antioxidant were evaluated in this study as described; Group A (normal saline), Groups B (30 mg/kg K2Cr2O7), Group C (Luteolin 100 mg/kg and K2Cr2O7 30 mg/kg), and Group D (Luteolin 200 mg/kg and K2Cr2O7 30 mg/kg), respectively.Markers of antioxidant defense system, oxidative stress, blood pressure and micronucleated polychromatic erythrocytes (MnPEs) were determined. Immunohistochemistry of Kidney Injury molecule (Kim‐1), nuclear factor erythroid 2‐related factor 2 (Nrf2), and cardiac troponin I (CTnI) were also determined.Our results showed that administration of K2Cr2O7increased systolic, diastolic and mean arterial blood pressures, markers of oxidative stress, the frequency of micronucleated polychromatic erythrocytes together with a significant reduction in serum nitric oxide bioavailability.Immunohistochemical staining revealed higher expression of renal Kim‐1 and cardiac troponin I in rats intoxicated with K2Cr2O7. However, lower expression of renal and cardiac Nrf2 were also observed in Luteolin co‐administered rats. Furthermore, co‐treatment with Luteolin restored blood pressure parameters, with concomitant reduction in oxidative stress indicators, augmented in vivo antioxidant status and improved serum NO levels. Lowered expressions of Kim‐1, CTnI and up‐regulation of both cardiac and renal Nrf2, and reduced frequency of micronucleated polychromatic. Taken together, this study demonstrates for the first time the antihypertensive, cardioprotective, nephroprotective and antigenotoxic effects of Luteolin against potassium dichromate induced‐toxicity through antioxidant and radical scavenging mechanisms.
The Trunk of Henle and its Variants
Authors: Streicher Johannes , Kiehling Felix , Lechner Peter 
Published: May 2022

OjectiveIn colon, pancreatic and hepatobiliary surgical research, an increasing interest developed in the Gastrocolic Trunk of Henle (GTH) due to its broad variability and its importance especially for right hemicolectomy with complete mesocolic excision. The purpose of this study was to further corroborate details of the anatomical variants of the Gastrocolic Trunk, in particular with respect to pancreaticoduodenal veins and the jejunal drainage into the superior mesenteric vein.MethodsIn 15 cadaveric bodies the venous drainage into the superior mesenteric vein was dissected first in a ventral, in situ approach as well as by a subsequent dorsal approach following careful abdominal exenteration.ResultsThe most frequent configuration was the tripodal gastropancreaticocolic trunk (GPCT) with an occurrence of 54.5%, followed by the gastropancreatic trunk (GPT) with 36.4% (figure 1). The right gastroepiploic vein was a constant structure draining into the trunk of Henle in 100% of the cases. During the dissection of the pancreatic drainage, a previously undescribed, middle anterior pancreatic vein, was found in 46.67% of the specimens, which drained in 85.71% into the trunk of Henle.ConclusionThe trunk of Henle drains blood from several abdominal organs and bundles them into a short and vulnerable structure. The most common variant is a tripodal trunk, collecting veins from the pancreas, right colon, and the stomach. Dependent on the surgical approach, the right gastroepiploic vein or the superior right colic vein may serve as guiding structures towards the trunk of Henle. Preoperative imaging in conjunction with awareness of variants is essential for a personalized surgical pocedure. In addition, the finding of a middle anterior pancreatic vein prompts for further studies regarding venous drainage of the pancreatic head.
Soluble Epoxide Hydrolase Inhibitors: Design, Synthesis, in vitro Profiling and in vivo Evaluation in Murine Models of Pain
Authors: Vázquez Santiago , Codony Sandra , Entrena José M. , Jora Beatrice , González‐Cano Rafael , Loza M. I. , Brea Jose , Morisseau Christophe , Bartra Clara , Sanfeliu Coral , Hammock Bruce D. , Cobos Enrique J. 
Published: May 2022

Epoxyeicosatrienoic acids (EETs) are endogenous chemical mediators that show anti‐inflammatory, antihypertensive, and analgesic effects. Soluble epoxide hydrolase (sEH) converts EETs to their corresponding dihydroxyeicosatrienoic acids, whereby the biological effects of EETs are modified. Therefore, inhibition of sEH has been suggested as a novel pharmacological approach for the treatment of inflammatory and pain‐related disorders.1Recently, we have discovered a new family of sEH inhibitors (sEHI) featuring a unique benzohomoadamantane scaffold. In a murine model of cerulein‐induced acute pancreatitis, the administration of a selected candidate significantly reduced pancreatic damage and improved the health status of the animals.2Herein we report further structure‐activity relationships within this series of benzohomoadamantane‐derived sEHI. Most of the novel derivatives were endowed with low nanomolar or even subnanomolar IC50values at the human, murine and rat sEH. Further in vitro profiling (solubility, cytotoxicity, metabolic stability, selectivity, permeability, etc.) and pharmacokinetic studies permitted us to select a candidate for in vivo efficacy studies. This candidate reduced pain in the capsaicin‐induced model of allodynia in a dose‐dependent manner and outperformed other sEHI tested.In summary, these novel results and the previously reported studies using other families of sEHI, strongly suggest that sEH may be a target of clinical interest for managing pain.3References:

1‐Sun, C.‐P.; Zhang, X.‐Y.; Morisseau, C.; Hwang, S. H.; Zhang, Z.‐J.; Hammock, B. D.; Ma, X.‐C. J. Med. Chem. 2021, 64, 184–215.
2‐Codony, S.; Calvó‐Tusell, C.; Valverde, E.; Osuna, S.; Morisseau, C.; Loza, M.I.; Brea, J.; Pérez, C.; Rodríguez‐Franco, M.I.; Pizarro‐Delgado, J.; Corpas, R.; Griñán‐Ferré, C.; Pallàs, M.; Sanfeliu, C.; Vázquez‐Carrera, M.; Hammock, B. D.; Feixas, F.; Vázquez, S. J. Med. Chem., 2021, 64, 5429–5446.
3‐McReynolds, C.; Morisseau, C.; Wagner, K.; Hammock, B. D. Adv. Exp. Med. Biol. 2020, 1274, 71–99.
Cortistatin Inhibits Intestinal Ion Secretion via Activating the Somatostatin‐2 Receptor in the Submucosal Neurons of the Mouse Colon
Authors: Liu Sumei 
Published: May 2022

Background and AimsCortistatin (CST) is a somatostatin‐like neuropeptide that is found in both the central and peripheral nervous system. CST binds with high affinity to all somatostatin receptors and also has actions not shared by somatostatin. We previously found that CST is expressed by enteric neurons in the guinea pig ileum and acts as an inhibitory neurotransmitter in the submucosal plexus. The aim of the present study was to evaluate the effect of CST on neurogenic intestinal secretion.MethodsMucosal/submucosal flat‐sheet preparations from mouse proximal colon were mounted in Ussing flux chambers for measurement of short‐circuit current (Isc) as an indicator of mucosal secretion. Transmural electrical field stimulation (EFS) evoked characteristic biphasic increases in Isc, with an early rapidly rising phase followed by a sustained phase.ResultsApplication of CST‐14, CST‐17, or CST‐29 to the basolateral side of the mucosal/submucosal preparation decreased baseline Isc in a concentration‐dependent manner with an IC50 of 90.5 nM, 52.1 nM, or 102.9 nM, respectively. The somatostatin‐2 receptor (SSTR‐2) antagonist CYN 154806 (1 mM) significantly suppressed CST‐14 (100 nM), CST‐17 (100 nM), or CST‐29 (100 nM)‐evoked ΔIsc by 36.0 ± 8.2% (n=5; P < 0.05), 47.2 ± 11.2% (n=5; P < 0.01), or 51.7.0 ± 8.4% (n=5; P < 0.01), respectively. The neuronal blocker tetrodotoxin (300 nM) significantly reduced CST‐14 (100 nM), CST‐17 (100 nM), or CST‐29 (100 nM)‐evoked ΔIsc by 36.5 ± 2.7% (n=5; P < 0.01), 48.9 ± 11.2% (n=5; P < 0.01), or 49.5 ± 3.6% (n=5; P < 0.01), respectively. All of the CSTs (1 nM – 1 mM) also produced a concentration‐dependent reduction of the EFS‐evoked biphasic secretory responses. The effect of CSTs on the EFS‐evoked responses was antagonized by CYN 154806 (1 mM). Immunohistochemical staining with a CST‐17 polyclonal antibody revealed expression of CST‐17 immunoreactivity (IR) in mouse colonic submucosal neurons. CST‐17‐IR was localized in cholinergic secretomotor neurons but was absent from non‐cholinergic secretomotor neurons and calbindin‐IR neurons.ConclusionsThe results suggest that CST acts at SST‐2 receptors in the submucosal plexus to suppress secretomotor neuronal excitability and neurogenic intestinal secretion in the mouse colon.
Medium‐chain fatty acids inhibit jejunal SGLT1 activity in vitro and suppress glucose absorption in vivo in mice
Authors: Mizoguchi Akinori , Akiba Yasutada , Nishii Shin , Kaunitz Jonathan D. 
Published: May 2022

Medium‐chain triglycerides (MCT) in diet improves glucose tolerance and insulin sensitivity, compared to long‐chain triglycerides (LCT). However, the direct effects of medium‐chain fatty acids (MCFA) on glucose transport have not been studied. Luminal glucose is absorbed in the small intestine through the electrogenic sodium‐dependent glucose transporter SGLT1 and electroneutral glucose transporter GLUT2. We thus examined the effects of luminal MCFA on electrogenic SGLT1 activity and glucose absorption in mice.SGLT1 activity was assessed in the Ussing chambered, muscle‐stripped jejunal mucosa by measuring phlorizin (Phz)‐sensitive short‐circuit current (Isc) evoked by luminal addition of glucose (10 mM). Sodium propionate (C3), caproate (C6), caprylate (C8), caprate (C10), laurate (C12) and myristate (C14) were luminally added before or after glucose application. Furthermore, the effects of C10 on glucose absorption were assessed by oral glucose tolerance test (OGTT, glucose 2g/kg body weight, ig) with or without C10 treatment (1.94g/kg, ig) in conscious mice. Moreover, the portal venous (PV) blood glucose levels were measured though the PV cannulation, followed by intraduodenal bolus injection of glucose solution (100 mM) with or without C10 (10 mM) in the anesthetized mice.Luminal pretreatment of C10 and C12 dose‐dependently inhibited the glucose‐induced Isc increase at IC50 = 1.02 mM and 1.06 mM, respectively. C8 also inhibited the glucose‐induced Isc increase, but less effective (IC50 8.4 mM), whereas C3, C6 and C14 had little effect. C10 (10 mM) also inhibited methyl α‐D‐glucopyranoside (αMG)‐induced Isc increase. Post‐treatment of C10 and C12 (10 mM) rapidly reduced the increased Isc by glucose, mimicking the inhibitory effect of Phz (1 mM). OGTT showed that glucose levels reached the peak at 30 min, while C10 pretreatment remarkably inhibited glucose increase. Furthermore, intraduodenal injection of glucose solution increased the PV glucose levels at 10 – 20 min, while the addition of C10 in the glucose solution abolished the response.These data suggest that C10 and C12 act as the SGLT1 inhibitor. Since MCT releases C10 and C12 via digestion by pancreatic lipase, slower than glucose release by maltase/sucrase, free C10/C12 solution may be more effective therapeutics for the treatment of type 2 diabetes.
Unconventional GPCR‐PKA Signaling in the Hedgehog Pathway
Authors: Myers Benjamin , Happ John , Arveseth Corvin , Bruystens Jessica , Bertinetti Daniela , Nelson Isaac , Olivieri Cristina , Hedeen Danielle , Zhu Ju‐Fen , Capener Jacob , Broeckel Jan , Vu Lily , King C. C. , Ruiz‐Perez Victor , Veglia Gianluigi , Herberg Friedrich , Taylor Susan 
Published: May 2022

The Hedgehog pathway controls tissue and organ development throughout animal evolution and drives several widespread skin and brain cancers. A pivotal step in Hh signal transduction is the activation of GLI transcription factors by the atypical G protein‐coupled receptor (GPCR) Smoothened (SMO). How SMO activates GLI has remained unclear for decades. The principal issue is that SMO appears to defy standard signaling paradigms utilized by nearly all other GPCRs.Here we show that SMO employs a decoy substrate sequence to physically block the active site of the PKA catalytic subunit (PKA‐C) and extinguish its enzymatic activity. As a result, GLI is released from phosphorylation‐induced inhibition. Using a combination of in vitro, cellular, and organismal models, we demonstrate that interfering with SMO / PKA pseudosubstrate interactions prevents Hh signal transduction. The mechanism we uncovered echoes one utilized by the Wnt cascade, revealing an unexpected similarity in how these two essential developmental and cancer pathways signal intracellularly.Our findings help to resolve a longstanding mystery in developmental and cancer signaling, and reveal a new mechanism of receptor‐kinase communication that may apply broadly throughout the GPCR superfamily. Our work also suggests new mechanism‐inspired therapeutic strategies to manage cancers driven by ectopic Hedgehog pathway activity.
Human Hyoid Descent is Adaptive rather than Maladaptive for Swallowing Performance: An Experimental and Computational Argument
Authors: Orsbon Courtney P. , Ross Callum 
Published: May 2022

PurposeDistinctive features of the human supralaryngeal vocal tract have been argued to be adaptive for speech and maladaptive for swallowing. However, this maladaptive hypothesis has not been thoroughly tested and in fact is refuted by studies of normal human feeding physiology. This study validates a computational model of hyolingual biomechanics derived from an previously validated experimental nonhuman primate model system and examines how changes in hyolingual and craniofacial morphology over the course of human evolution and ontogeny affect hyolingual biomechanics during swallowing. In particular, we examine superoanterior excursion of the hyoid, which is often reduced in human patients with dysphagia and therefore used here as a surrogate for swallowing performance.MethodsA computational model of hyolingual range of motion during swallowing in Macaca mulatta was developed in R using in vivo data. Model outputs were compared against in vivo macaque data to determine the model's goodness of fit using a receiver operating characteristics (ROC) curve; model predictive power was estimated using the area under the ROC curve. Several aspects of macaque craniofacial and hyoid morphology were then altered towards the human condition with consequent adjustments made to muscle lengths, and the model calculated hyoid displacement during swallowing for each condition. A model was considered viable if its range of motion included a target of hyoid excursion derived from in vivo macaque and human data.ResultsThe macaque model had a sensitivity of 0.79, specificity of 0.82, and accuracy of 88% compared to in vivo data. A humanoid model predicts hyoid excursion within normal limits of healthy humans. Altering macaque morphology to approach the human condition by lowering the hyoid and making the symphysis vertical had little effect on model performance. Isolated shortening of the mandible significantly decreased hyoid excursion unless the symphysis was also made more vertical. Moreover, as the model was made more humanoid, both hyoid descent and physiologically maximal muscle shortening were necessary to approximate target hyoid excursion.ConclusionsHyoid descent—which is commonly assumed to be detrimental to swallowing—may actually maintain swallowing performance as the human face has shortened in recent evolutionary history. Moreover, because mandibular morphology affects suprahyoid muscle length, selective pressure to maintain swallowing performance may have resulted in the emergence of humanity’s characteristic vertical mandibular symphysis. Geometric constraints require human suprahyoid muscles to perform at their physiological limits when the hyoid is descended. Such extreme performance requirements may leave humans vulnerable to dysphagia not because of airway morphology alone but because of physiologic constraints.
Localizing the expression of Piezo2 in healthy and diseased lung tissue
Authors: Hennis Lauren , Hambright Parker , Eden Kristin , Binks Andrew , LeClair Renee 
Published: May 2022

Intractable air hunger remains one of the most impactful symptoms of chronic cardiopulmonary disease and current pharmacological management remains limited. However, an endogenous mechanism for air hunger relief exists. Pulmonary stretch receptors (PSRs) responding to lung inflation reduce the brainstem drive to breathe and mitigate air hunger. Harnessing this mechanism could form the basis of a novel therapy. Recent animal studies suggest Piezo2, a mechanically‐gated cation channel, causes PSR depolarization when airway smooth muscle is stretched during inflation. We have assessed whether Piezo2 is associated with PSRs in healthy and diseased human airways to determine whether Piezo2 is a potential pharmaceutical target.MethodsHuman lung biopsies from NIH Lung Tissue Research Consortium were used for identification of Piezo2 receptors in emphysema, fibrosis, bronchiolitis, and normal lung tissue. Localization of Piezo2 was determined with immunofluorescent staining and imaged with confocal microscopy (Zeiss LSM880). As PSR fiber endings are associated with airway smooth muscle, co‐staining for Smooth Muscle Antibody (SMA) and Calcitonin Gene‐Related Peptide (CGRP) was performed to determine whether Piezo2 is associated with PSR.Summary of resultsPiezo2 is associated with airway smooth muscle (as evidenced by SMA, figure 1) and neuroepithelial bodies in normal human lung tissue (evidenced by cGRP, figure 2) and expression persisted in all disease states tested.ConclusionsPiezo2 location is consistent with that of PSR in human lungs, making it a candidate for the mechanoreceptive transducer of human PSRs as has been demonstrated in animal studies. Expression persists in disease, making Piezo2 a potential therapeutic target, but it is still yet to be determined if Piezo2 is more significantly associated with airway or vascular smooth muscle in different disease states.