bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small Molecule Inhibition of MEKK2 Signal Transduction in Cancer Cells
Authors: Noll Jessica , Scott John E. , Cuevas Bruce 
Published: November 2023

Most cancer patient deaths are due to secondary tumors called metastases that are frequently resistant to therapy. Effective treatment options for metastatic cancer are very limited; therefore the development of new drugs to treat metastases is necessary to improve cancer patient survival. An enzyme critical to metastases can be utilized as a potential therapeutic target if a corresponding small‐molecule inhibitor can be identified and optimized. Our group has demonstrated that the protein kinase, MEKK2, is required for xenograft breast tumor growth and metastasis. We screened small molecule libraries for potential MEKK2 inhibitors and identified several lead compounds that inhibit MEKK2 in vitro that could be modified as future cancer therapeutics. In this work, we examined how these lead compounds affect MEKK2‐dependent functions of tumor cells in culture and if that effect could be extended as a potential therapeutic. Four analogues of one hit were further developed as potential lead compounds (referred to as #1, #2, 82A, and 527), and then we determined whether exposure to the compounds inhibited MEKK2‐dependent tumor cell functions of ERK5 activation, cell migration, and gene expression. We investigated ERK5 pathway activation by ERK5 electrophoretic mobility shift, and MEKK2‐dependent gene expression was analyzed via luciferase‐based reporter assays of NFκB and AP‐1 activation. A modified wound assay was developed to measure velocity in correspondence to cell migration. We discovered that 10μM 82A significantly reduced MEKK2‐dependent NFκB and AP‐1 reporter activity, blocked MEKK2‐dependent ERK5 phosphorylation, and inhibited breast tumor cell migration. Taken together, our data strongly suggest that the 82A lead compound significantly inhibits multiple known MEKK2‐dependent cellular functions. We conclude that the 82A small‐molecule is a suitable lead molecule that can be developed into novel therapeutic MEKK2 inhibitors for treatment of cancer metastases and other MEKK2‐dependent diseases.Support or Funding InformationThis work was supported by a grant from the National Institutes of Health (NIH) and the American Society for Pharmacology and Experimental Therapeutics (ASPET).
Resveratrol can enhance as well as relax contractions of the rat tail artery. Possible role of endothelial potassium channels
Authors: Peuler Jacob D. , Stom Sayra M. , Phelps Laura E. 
Published: November 2023

Last year we reported that resveratrol can directly relax adrenergically‐precontracted rings prepared from the ventral tail artery of the rat (FASEB J. 29, supplement 1, 783.6, 2015). In addition, this effect was no different in proximal (conductance) vs. distal (resistance) portions of the same vessel. Our present aim was to determine if that relaxation could be blocked by agents known to block different subpopulations of potassium (K) channels in arterial smooth muscle. We found that it could not. However, we uncovered a novel unanticipated action which has not been reported by others. In over half of our arterial ring preparations (proximal and distal alike), resveratrol enhanced the magnitude of adrenergically‐induced precontractions beginning well before its more delayed and sustained relaxant effect became apparent. Although transient in duration, this enhancing action lasted nearly two hours at the lower more therapeutically‐relevant test concentrations that we employed. This action provides the first reasonable explanation for previously unexplained increases in arterial pressures observed during acute intravenous administration of resveratrol to animal models of severe ischemic tissue injury, in which marked hypotension is often present and in need of correction. Also unanticipated, this same resveratrol‐induced enhancement of adrenergic contraction was notably inhibited by some of the same K channel blockers (particularly tetraethylammonium and glibenclamide) that failed to influence its relaxant effect. As smooth muscle is not a likely site for such a paradoxical finding, we suspect resveratrol is acting on K‐selective mechano‐sensitive ion channels located in the endothelium where they are thought to participate in release of contracting factors.Support or Funding InformationMidwestern University Master's Program
Renal Oxygenation and Microcirculation in Relation to Fluid Therapy During Kidney Transplantation in a Porcine Model
Authors: Moeslund Niels , Nielsen Lise Have , Eriksen Jonathan Kunisch 
Published: November 2023

The Study is ongoing hence no conclusive results can be describedThe objective of the study is to investigate the renal oxygenation and microcirculation in a high volume fluid therapy against an individualized goal directed fluid therapy (IGDT) during renal transplantation in a porcine model.BackgroundA significant number of kidney recipients experience complications after transplantation ranging from delayed graft function to obstipation and poor wound healing. Iatrogenic over hydration peri‐ and postoperatively is a suspected culprit. Complications are more common in kidneys from brain dead donors. A pilot study showed that the kidney increase in weight and volume after reperfusion due to edema; it is not known if tissue oxygenation is affected by this.MethodsThe study is a prospective randomized animal study, with four groups: high volume fluid therapy, individualized goal directed fluid therapy each group is subdivided so half receives a low dose norepinephrine.In order to mimic the clinical situation a brain dead donor model is used. Brain death is achieved by raising the intracranial pressure until it exceeds the systolic BP, this is done by inflating a 60 cc urinary catheter epidural. After four hours the kidneys are perfused with “Bridge to life®” cold storage solution and kept on cold ischemia for 18 hours. Two recipient swine have their native kidneys removed and each get one kidney from the donor. After the transplantation the recipients are monitored under anesthesia for ten hours.Fluid responsiveness in the individualized goal directed fluid therapy group is determined by change in stroke volume after fluid challenges.The renal oxygenation and microcirculation are measured using the NF‐BF/OFT/E combined oxygen and the microcirculation probe with the OxyLite™ and OxyFlo™ system from Oxford Optronix. The probes are inserted in the medulla, as it is prone to ischemia if the microcirculatory blood flow is compromised.ResultsThe preliminary results indicate that the renal oxygenation is correlated to urine production, with high oxygen tension in kidneys with high urine production. The fluid therapy does not seem to influence on the oxygenation other than by urine production. The edema seems to equal in the high volume and the individualized fluid therapy. The amount of fluid administered in the individualized group is significantly less than the high volume therapyPreliminary conclusionsInvasive measurements of oxygen and microcirculation is a indicator for the metabolic activity in the kidney, from the preliminary results we can se the metabolic oxygen demand is increased in a low volume fluid therapy due to increased reabsorption.Support or Funding InformationNovo Nordisk Fondennnfond@novo.dk+45 35276600
Systemic and Microcirculatory Effects of Severe Hemorrhage and Resuscitation Using a PEGylated Carboxyhemoglobin (PEG‐COHb)
Authors: Song Bjorn K , Nugent William H 
Published: November 2023

This study investigated the systemic (heart rate, mean arterial pressure) and microcirculatory (vasoactivity, interstitial fluid oxygenation [ISF PO2]) impact of two resuscitation fluids: a novel carbon monoxide/oxygen delivery agent (PEG‐COHb [Sanguinate™] Prolong Pharmaceuticals™, South Plainfield, NJ), and a non‐oxygen carrying colloid volume control (Hextend™; Hospira, Inc, Lake Forest, IL). Male Sprague‐Dawley rats underwent a controlled 45% blood volume hemorrhage at 3.5 ml × min−1 × kg−1 through a cannulated carotid artery and were maintained in this hypovolemic, hemorrhagic shock phase for 30 minutes. Resuscitation fluids were infused at a rate of 3.5 ml × min−1 × kg−1 to a volume equal to 20% of the total estimated blood volume through a cannulated jugular vein. Systemic measurements were recorded via a cannulated femoral artery that was connected to a pressure transducer (MP150; Biopac Systems, Inc, Goleta, CA) while microcirculatory parameters were collected through phosphorescence quenching and intravital microscopic examination of the exteriorized spinotrapezius muscle. Compared to baseline, the 45% hemorrhage produced a significant reduction in heart rate, blood pressure, arterial diameter and ISF PO2 in all animals. Resuscitation with either PEG‐COHb or Hextend™ animals improved the systemic parameters towards baseline, but only PEG‐COHb‐treated animals showed an improvement in ISF PO2. The impact of improved systemic variables was evident in mortality with untreated animals (sham) expiring an hour after hemorrhage, while Hextend resuscitated animals expired after 4 hours. PEG‐COHb animals survived for the entire 8 hour observation period. In addition to extended survival times, PEG‐COHb animals showed steady systemic and microcirculatory parameters. Hextend™ resuscitated animals, however, developed rigor mortis in their limbs at approximately 3 hours post‐hemorrhage, which was concurrent with a rapid decline in systemic variables. These results demonstrate that while reestablishing blood pressure is acutely important for post‐hemorrhage survival, restoring oxygen delivery to peripheral tissues is critical for improving long‐term outcomes.Support or Funding InformationSupport: Prolong Pharmaceuticals™
Transient exposure to Serotonin + L‐NAME activates early processes mediating inward remodeling of cremasteric arterioles, in vivo
Authors: Foote Christopher 
Published: November 2023

Hypertension and other cardiovascular pathologies are associated with inward remodeling of the resistance vasculature. It has been demonstrated ex vivo that prolonged (4 hr) exposure to vasoconstrictor agonists, is sufficient to induce remodeling via mechanisms that include both the polymerization of actin and the activation of transglutaminases. Here we report that in vivo, a brief, 10 min exposure to serotonin (5‐Hydroxytryptamine, 5‐HT) + Nω‐nitro‐L‐arginine methyl ester hydrochloride (L‐NAME) induces inward remodeling of rat cremasteric feed arterioles (100–200 μm lumen diameter), absent changes to systemic blood pressure. This process was blocked by the addition of the transglutaminase inhibitor, cystamine. Furthermore, we demonstrate ex vivo, that 5‐HT + L‐NAME activates transglutaminases and increases the phosphorylation state of cofilin, a negative regulator of actin polymerization. In addition, we demonstrate a new approach to examine actin polymerization dynamics in live vessels. We show that in isolated functional arterioles, the ratio of filamentous actin (labeled with silicon rhodamine jasplakanolide) to globular actin (labeled with DNAse1‐488) increases in individual smooth muscle cells exposed to 5‐HT + L‐NAME. We also report that, in isolated arterioles, 5‐HT + L‐NAME induced remodeling that is blocked by inhibiting Lim Kinase, an enzyme that phosphorylates cofilin and positively regulates actin polymerization. These results are the first to examine the remodeling process as it unfolds in vivo in real time, and further bolster the hypothesis that both actin polymerization and the activation of transglutaminases mediate early stages of the transition from a structurally normal vessel to an inwardly remodeled one.Support or Funding InformationNIH HL‐088105 to LAM, 1PO1HL095486 to GAM
Metaboreflex Contribution to Peak Pressor Response Achieved During Fatiguing Intermittent Static Exercise Is Attenuated in Postmenopausal Women
Authors: Barrett Megan A , Kim Jin‐Kwang , Garvin Nathan M , De Souza Mary Jane , Pawelczyk James A , Proctor David N 
Published: November 2023

Postmenopausal women have been shown to experience greater increases in blood pressure during static exercise than their premenopausal counterparts. However, the mechanisms by which this augmented pressor response is achieved remains incompletely understood. As a result, our study sought to determine the relative contribution of the muscle metaboreflex to the peak blood pressure response during fatiguing, intermittent static exercise with graded occlusion in pre and postmenopausal women. In this study, we hypothesized that the muscle metaboreflex would provide a larger contribution to the peak pressor response in postmenopausal women than in premenopausal women. Eighteen healthy women participated in this study (8 postmenopausal women, between 57–64 years; 10 premenopausal women, between 20–28 years). On the experimental day, after quiet rest, subjects were asked to squeeze a handgrip device (Stoelting Co.) at a rate of 30 contractions/minute at 10% of their maximum voluntary contraction (MVC). Following a 4‐minute free flow exercise period, a blood pressure cuff on the subject's upper arm was progressively inflated at a rate of 20 mmHg/minute. Subjects continued to exercise until volitional fatigue. Blood pressure was recorded continuously on the contralateral hand (Finometer). As expected, postmenopausal women had a significantly higher systolic blood pressure at fatigue compared to premenopausal women (DSBP from rest of 40 mmHg and 24 mmHg, respectively) (p = 0.005). Consistent with our working hypothesis, postmenopausal women exhibited a metaboreflex mediated blood pressure response that tended to be greater than that in premenopausal women (DSBP from rest of 27 mmHg and 20 mmHg, respectively)(p = 0.11). However, this response contributed significantly less to the peak blood pressure response in postmenopausal women than it did in premenopausal women (SBPpeak – SBPPECA of 13 mmHg and 4 mmHg, respectively) (p = 0.037). These findings suggest that while postmenopausal women exhibit a greater metaboreflex mediated blood pressure response compared to premenopausal women, the response contributes less to the peak blood pressure response in postmenopausal women. This suggests that postmenopausal women may be less reliant on the metaboreflex to generate the peak blood pressure response during fatiguing small muscle mass exercise than their premenopausal counterparts.Support or Funding InformationPenn State Ambulatory Research Fund (Jaffe Endowment)
The early postmenopausal phase is associated with a decline in vascular function: is the prostanoid system to blame?
Authors: Nyberg Michael , Egelund Jon , Nielsen Mads Bernhard , Mogensen Alexander , Hellsten Ylva 
Published: November 2023

Menopause is associated with a decline in vascular function; however, whether this is an effect of age and/or menopause and the mechanisms underlying this decline remains unclear. We examined the vascular response to femoral arterial infusion of vasoactive compounds in 20 pre‐and 17 recent postmenopausal women of similar age (49±2 vs. 53±2 years). The postmenopausal women had not experienced a menstrual cycle during the previous 12 months but were less than 5 years past their final menstrual period (2.9±0.6 years). The change in leg vascular conductance (LVC) in response to infusion of the endothelium‐dependent vasodilator acetylcholine (ACh) was lower (~25%, P<0.05) in the postmenopausal compared to the premenopausal women. Co‐infusion of ketorolac to inhibit prostanoid formation reduced the vasodilator response to ACh to a similar extent in the two groups of women. Despite the similar effect of ketorolac, the change in LVC with infusion of the prostacyclin analog epoprostenol was lower (~40%, P<0.05) in the postmenopausal compared to the premenopausal women. These findings suggest that vascular function is adversely altered already within the first years following menopause. The early onset of this altered function indicates that this change is more related to menopausal status than aging per se. The reduced endothelial function does not appear to be related to an altered function of the prostanoid system despite a reduced vascular sensitivity to prostacyclin.Support or Funding InformationFinancial support for the study was provided by the faculty of SCIENCE at University of Copenhagen.
AMELIORATIVE EFFECT OF GALLIC ACID ON DOXORUBICIN INDUCED CARDIOTOXICITY IN ADULT WISTAR RATS
Authors: Adejumobi Olumuyiwa A , Orotusin Oyetola , Oyagbemi Ademola , Adedapo Adeolu , Olaogun Charles , Omóbòwálé Temidayo Olutayo 
Published: November 2023

Doxorubicin is a potent antineoplastic anthracycline drug however, its use is greatly limited by its toxic side effects which occurs by formation of reactive oxygen species that disruption of cell function. This present study was conducted to assess the possible cardioprotective effect of gallic acid against doxorubicin‐ induced cardiotoxicity in rats.In this study, sixty (60) male Wistar rats were divided into six groups. Group A was the control. Group B rats was intoxicated with Doxorubicin (Dox) at 15 mg/kg body weight i.p. Group C pre‐treated with 60 mg/kg Gallic Acid (GA) orally for 7 days prior to administration of Dox 15 mg/kg, Group D pre‐treated with 120 mg/kg Gallic Acid (GA) orally for 7 days prior to administration of Dox 15 mg/kg, Group E received 60 mg/kg Gallic Acid (GA) orally alone for 7 days and Group F received 120 mg/kg Gallic Acid (GA) orally alone for 7 days. The parameters of study were cardiac antioxidant status, serum biomarker of cardiac damage and electrocardiography measurements.Exposure of rats to doxorubicin led to a significant (p < 0.05) decrease in cardiac glutathione peroxadise (GPx), glutathione‐S‐transferase (GST), reduced glutathione (GSH) content, superoxide dismutase (SOD) and catalase (CAT) activity. Similarly, a significant (p < 0.05) increase in protein thiol was recorded in doxorubicin treated rats while it was reduced in those pre‐treated with GA. Dox also caused elevation of Creatinine kinase‐muscle brain (CK‐MB) and Lactate Dehydrogenase (LDH). Histopathology of rats exposed to Dox showed focal areas of infiltration by inflammatory cells and degeneration of myofibres. Electrocardiography results showed a significant decrease in heart rate; increase in P wave duration, R‐amplitude, PR interval, QRS and QT‐segment prolongation.Pre‐treatment with GA significantly alleviated Dox associated ECG abnormalities, restored the antioxidant enzyme and decreased serum Creatinine kinase‐muscle brain CK‐MB and LDH. However, administration of GA alone in a set of groups led to a significant prolongation of QT interval which could predispose to the potentially fatal ventricular tachycardia, torsades de pointes. All these findings confirm the efficacy of GA against Dox induced cardiotoxicity but caution must be taken in its use.Support or Funding InformationNone
Renal Salt and Water Homeostasis: a New Regulatory Pathway Involving the Ser/Thr Kinase PIM‐3
Authors: Spirli Alessia , Ronzaud Caroline , Debonneville Anne , Staub Olivier 
Published: November 2023

Since many years now, scientists believe that a great credit for the blood pressure regulation goes to the kidneys, as their inability in maintaining salt balance and water homeostasis can result in the development of hypertension, the most common disease in the human population. Aldosterone is the key hormone in the control of sodium balance, blood volume and blood pressure, acting in the aldosterone‐sensitive distal nephron (ASDN) and stimulating a complex transcriptional, translational and cellular program.We have carried out a gene expression profiling in a mouse cortical collecting duct cell model (mpkCCD), stimulated or not by aldosterone and identified the PIM‐3 Ser/Thr kinase as a novel aldosterone‐induced protein. PIM kinases (PIM‐1, ‐2 and ‐3), and in particular PIM‐3, are overexpressed in different tumors and are known to be regulators of apoptosis, cell proliferation and cell metabolism. PIM‐3, the PIM kinase family member most expressed in the kidney, has similar substrate specificities to other Ser/Thr kinases (e.g. SGK1, PKB), and despite its circadian expression in several organs including the kidney, its renal role is largely unknown.Here we studied a possible new role of PIM‐3 in the regulation of renal salt and water handling, both in vitro (mCCDcl1 cells) and in vivo (PIM‐3 KO mice). In mCCD cells, we confirmed that PIM‐3 expression is stimulated by aldosterone in a dose dependent manner and observed that shRNA‐based suppression of PIM‐3 reduces the aldosterone‐mediated sodium currents as well as the activation of the aldosterone‐mineralocorticoid receptor pathway. In PIM‐3 KO mice, we found decreased body weight, increased circulating renin activity and elevated plasma aldosterone levels compared to control littermates. Moreover, challenging WT and KO mice with standard, low Na+ or high‐Na+ diet, we observed a tendency of impaired expression of the most important electrolytes transporters in case of PIM‐3 deficiency, leading to a different sodium and water handling between WT and KO mice.In conclusion, our data suggest a possible novel function of the PIM‐3 kinase and its potentially important role in the control of sodium and water homeostasis to finely regulate blood pressure.