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Journal of Pharmacological Sciences Aug 2024We examined the inhibitory effects of α-linolenic acid (ALA) on the contractions of pig coronary arteries. ALA concentration-dependently inhibited the contractions...
We examined the inhibitory effects of α-linolenic acid (ALA) on the contractions of pig coronary arteries. ALA concentration-dependently inhibited the contractions elicited by U46619 and prostaglandin F without affecting those elicited by 80 mM KCl, histamine, acetylcholine, and serotonin. ALA rightward shifted the concentration-response curve of U46619, and Schild plot analysis revealed that ALA competitively antagonized U46619. Furthermore, ALA inhibited the increase in intracellular Ca concentration caused by TP receptor stimulation but not that caused by FP receptor stimulation. These results suggest that ALA behaves as a selective antagonist of TP receptors in coronary arteries.
Topics: Animals; Coronary Vessels; alpha-Linolenic Acid; Swine; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Calcium; Receptors, Thromboxane; Dose-Response Relationship, Drug; Male; Dinoprost; Muscle Contraction
PubMed: 38880549
DOI: 10.1016/j.jphs.2024.06.001 -
International Journal of Circumpolar... Dec 2024It has previously been shown that EpiPen® autoinjectors are likely to activate normally following up to five excursions to -25°C but data about the post-freezing...
It has previously been shown that EpiPen® autoinjectors are likely to activate normally following up to five excursions to -25°C but data about the post-freezing performance of other brands of adrenaline autoinjectors has not previously been published. Additionally, conditions experienced by polar medics may be substantially colder than this and the performance of adrenaline autoinjectors following more extreme freeze-thaw cycles remains uncharacterised. Investigators in Antarctica and the United Kingdom performed laboratory testing on two brands of adrenaline autoinjector, EpiPen® and Jext® (12 devices of each type). A single freeze-thaw cycle involved freezing the device to -80°C then allowing it to come to room temperature. Devices were exposed to 0, 1, 5 or 15 freeze-thaw cycles. The mass of liquid ejected from each device, when activated, was then measured. No significant differences in the mass of the liquid ejected was found between the test groups. Multiple freeze-thaw cycles to -80°C are unlikely to significantly impact the amount of adrenaline solution expelled from EpiPen® and EpiPen® autoinjectors. This preliminary finding encourages further work investigating the safety and effectiveness of adrenaline autoinjectors after exposure to very low temperatures. This information would be valuable for future polar medics planning and delivering medical provision in extreme environments.
Topics: Epinephrine; Freezing; Humans; Cold Temperature; Injections, Intramuscular
PubMed: 38875453
DOI: 10.1080/22423982.2024.2367273 -
European Journal of Sport Science Jun 2024To investigate the effect of forced even pacing through virtual pacing assistance and an opponent in a competitive setting on end-spurt behaviour in freestyle swimmers,...
To investigate the effect of forced even pacing through virtual pacing assistance and an opponent in a competitive setting on end-spurt behaviour in freestyle swimmers, including related physiological underpinnings. Twenty-seven competitive swimmers and triathletes were recruited. There were four 1500 m freestyle trials: (i) familiarisation time trial, (ii) self-paced time trial (STT), (iii) head-to-head competition time trial (CTT) and (iv) forced even pacing through virtual pacing assistance time trial (FET). Eventually, 12 swimmers met the criteria for the CTT and FET to be included in the analysis. Changes in end-spurt behaviour, finishing time and physiological parameters (lactate, cortisol, noradrenaline and heart rate) were analysed using a linear mixed model with fixed effects for trials and a random effect for swimmer identity. A separate linear model was computed for competition outcome. The end-spurt for each race was determined by means of an end-spurt indicator (ESI; ESI > 0 greater end-spurt). Swimmers demonstrated a significantly greater ESI in FET (+2.6; p < 0.001) and CTT (+1.4; p = 0.022) compared to STT. Blood lactate concentration in FET (+1.0 mmol L; p < 0.001) and CTT (+1.6 mmol L; p < 0.001) was significantly higher than in STT. Winners had a significantly greater ESI than losers in CTT (+1.6 and p = 0.005). Swimmers utilised a greater end-spurt through metabolically optimal forced even pacing by virtual pacing assistance and in a head-to-head competition due a larger mobilisation of anaerobic reserves as indicated by greater blood lactate concentrations. Winners had a significantly greater end-spurt than losers despite similar metabolic disturbances.
Topics: Humans; Swimming; Lactic Acid; Male; Competitive Behavior; Heart Rate; Athletic Performance; Adult; Young Adult; Female; Hydrocortisone; Norepinephrine; Athletes
PubMed: 38874951
DOI: 10.1002/ejsc.12102 -
Frontiers in Immunology 2024About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with...
BACKGROUND
About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis.
METHODS
We conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers.
RESULTS
Pancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers.
CONCLUSION
Donor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.
Topics: Humans; Pancreas Transplantation; Male; Female; Hypertension; Middle Aged; Adult; Thrombosis; Tissue Donors; Angiotensin II; Risk Factors; Graft Survival; Allografts; Retrospective Studies; Graft Rejection
PubMed: 38873595
DOI: 10.3389/fimmu.2024.1359381 -
PloS One 2024Acute kidney injury (AKI) is a common complication of septic shock and together these conditions carry a high mortality risk. In septic patients who develop severe AKI,... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Acute kidney injury (AKI) is a common complication of septic shock and together these conditions carry a high mortality risk. In septic patients who develop severe AKI, renal cortical perfusion is deficient despite normal macrovascular organ blood flow. This intra-renal perfusion abnormality may be amenable to pharmacological manipulation, which may offer mechanistic insight into the pathophysiology of septic AKI. The aim of the current study is to investigate the effects of vasopressin and angiotensin II on renal microcirculatory perfusion in a cohort of patients with septic shock.
METHODS AND ANALYSIS
In this single centre, mechanistically focussed, randomised controlled study, 45 patients with septic shock will be randomly allocated to either of the study vasopressors (vasopressin or angiotensin II) or standard therapy (norepinephrine). Infusions will be titrated to maintain a mean arterial pressure (MAP) target set by the attending clinician. Renal microcirculatory assessment will be performed for the cortex and medulla using contrast-enhanced ultrasound (CEUS) and urinary oxygen tension (pO2), respectively. Renal macrovascular flow will be assessed via renal artery ultrasound. Measurement of systemic macrovascular flow will be performed through transthoracic echocardiography (TTE) and microvascular flow via sublingual incident dark field (IDF) video microscopy. Measures will be taken at baseline, +1 and +24hrs following infusion of the study drug commencing. Blood and urine samples will also be collected at the measurement time points. Longitudinal data will be compared between groups and over time.
DISCUSSION
Vasopressors are integral to the management of patients with septic shock. This study aims to further understanding of the relationship between this therapy, renal perfusion and the development of AKI. In addition, using CEUS and urinary pO2, we hope to build a more complete picture of renal perfusion in septic shock by interrogation of the constituent parts of the kidney. Results will be published in peer-reviewed journals and presented at academic meetings.
TRIAL REGISTRATION
The REPERFUSE study was registered on Clinical Trials.gov (NCT06234592) on the 30th Jan 24.
Topics: Humans; Shock, Septic; Vasoconstrictor Agents; Microcirculation; Acute Kidney Injury; Kidney; Vasopressins; Angiotensin II; Male; Female; Norepinephrine; Renal Circulation; Middle Aged; Adult
PubMed: 38870103
DOI: 10.1371/journal.pone.0304227 -
Frontiers in Endocrinology 2024Given its putative roles in mediating prosocial behavior, attachment bonds, and stress physiology, oxytocin modulation has been hypothesized to be a biological correlate...
BACKGROUND
Given its putative roles in mediating prosocial behavior, attachment bonds, and stress physiology, oxytocin modulation has been hypothesized to be a biological correlate of the salubrious effects of meditation practice. Here we investigated the effects of a month-long silent meditation retreat on changes in oxytocin, and the related hormone and vasopressin, in relation to psychosocial changes in attachment style, anxiety, personality measures, and feelings of social connectedness with fellow meditators.
METHODS
Plasma oxytocin and vasopressin and self-report questionnaires were measured in retreat participants ( = 28) at the beginning of, and 3 weeks into, a residential meditation retreat. Control participants ( = 34), who were similar in age, gender, and meditation experience, were also assessed across a 3-week interval. Linear mixed effects models were used to assess outcomes.
RESULTS
The retreat group showed a small but significant decrease in oxytocin compared to controls who showed no change. In the retreat group, higher openness to experience at Time 1 predicted greater reductions in oxytocin during the retreat, and lower oxytocin at Time 2 was related to stronger feelings of personal connection with fellow meditators. The changes in oxytocin were not related to attachment style or anxiety. Vasopressin decreased over time across both groups, suggesting no specific effect of retreat.
CONCLUSION
These preliminary findings suggest that meditation training in the context of a silent residential retreat may reduce circulating levels of oxytocin. We interpret this finding from multiple theoretical perspectives, discussing key measurement limitations and proposing future study designs that may help to differentiate the effects of different meditation practices and contexts on oxytocin signaling.
Topics: Humans; Oxytocin; Meditation; Female; Male; Adult; Middle Aged; Vasopressins; Anxiety
PubMed: 38863930
DOI: 10.3389/fendo.2024.1345527 -
F1000Research 2023The open field assay is used to study anxiety-related traits and anxiolytic drugs in rodents. This assay entails measuring locomotor activity and time spent in the...
BACKGROUND
The open field assay is used to study anxiety-related traits and anxiolytic drugs in rodents. This assay entails measuring locomotor activity and time spent in the center of a chamber that is maintained at ambient room temperature. However, the ambient temperature in most laboratories varies daily and seasonally and can differ between buildings. We sought to evaluate how varying ambient temperature and core body temperature (CBT) affected open field locomotor activity and center time of male wild-type (WT, C57BL/6) and Transient Receptor Potential Subfamily M Member 8 ( ) knock-out ( ) mice. TRPM8 is an ion channel that detects cool temperatures and is activated by icilin.
METHODS
Mice were placed in the open field at 4°C and 23°C for 30 minutes. Distance traveled and time spent in the center were measured. Mice were injected with icilin, M8-B, diazepam, or saline, and changes in activity level were recorded.
RESULTS
The cooling agent icilin increased CBT and profoundly reduced distance traveled and center time of WT mice relative to controls. Likewise, cooling the ambient temperature to 4°C reduced distance traveled and center time of WT mice relative to mice. Conversely, the TRPM8 antagonist (M8-B) reduced CBT and increased distance traveled and center time of WT mice when tested at 4°C. The TRPM8 antagonist (M8-B) had no effect on CBT or open field behavior of mice. The anxiolytic diazepam reduced CBT in WT and mice. When tested at 4°C, diazepam increased distance traveled and center time in WT mice but did not alter open field behavior of mice.
CONCLUSIONS
Environmental temperature and drugs that affect CBT can influence locomotor behavior and center time in the open field assay, highlighting temperature (ambient and core) as sources of environmental and physiologic variability in this commonly used behavioral assay.
Topics: Animals; Male; TRPM Cation Channels; Temperature; Mice; Body Temperature; Mice, Inbred C57BL; Mice, Knockout; Diazepam; Anti-Anxiety Agents; Pyrimidinones; Open Field Test; Locomotion
PubMed: 38863500
DOI: 10.12688/f1000research.130474.3 -
Learning & Memory (Cold Spring Harbor,... May 2024Octopamine, the functional analog of noradrenaline, modulates many different behaviors and physiological processes in invertebrates. In the central nervous system, a few... (Review)
Review
Octopamine, the functional analog of noradrenaline, modulates many different behaviors and physiological processes in invertebrates. In the central nervous system, a few octopaminergic neurons project throughout the brain and innervate almost all neuropils. The center of memory formation in insects, the mushroom bodies, receive octopaminergic innervations in all insects investigated so far. Different octopamine receptors, either increasing or decreasing cAMP or calcium levels in the cell, are localized in Kenyon cells, further supporting the release of octopamine in the mushroom bodies. In addition, different mushroom body (MB) output neurons, projection neurons, and dopaminergic PAM cells are targets of octopaminergic neurons, enabling the modulation of learning circuits at different neural sites. For some years, the theory persisted that octopamine mediates rewarding stimuli, whereas dopamine (DA) represents aversive stimuli. This simple picture has been challenged by the finding that DA is required for both appetitive and aversive learning. Furthermore, octopamine is also involved in aversive learning and a rather complex interaction between these biogenic amines seems to modulate learning and memory. This review summarizes the role of octopamine in MB function, focusing on the anatomical principles and the role of the biogenic amine in learning and memory.
Topics: Octopamine; Mushroom Bodies; Animals; Memory; Learning; Dopamine; Insecta; Neurons
PubMed: 38862169
DOI: 10.1101/lm.053839.123 -
Nutrition & Diabetes Jun 2024Vitamin D was shown to directly exert a protective effect on diabetic kidney disease (DKD) in our previous study. However, whether it has an effect on perirenal adipose...
BACKGROUND
Vitamin D was shown to directly exert a protective effect on diabetic kidney disease (DKD) in our previous study. However, whether it has an effect on perirenal adipose tissue (PRAT) or the intestinal flora and its metabolites (trimethylamine N-oxide, TMAO) is unclear.
METHODS
DKD mice were received different concentrations of 1,25-(OH)D for 2 weeks. Serum TNF-α levels and TMAO levels were detected. 16S rRNA sequencing was used to analyze gut microbiota. qPCR was used to detect the expression of TLR4, NF-Κb, PGC1α, and UCP-1 in kidney and adipose tissue. Histological changes in kidney and perirenal adipose tissue were observed using HE, PAS, Masson and oil red staining. Immunofluorescence and immunohistochemistry were used to detect the expression of VDR, PGC1α, podocin, and UCP-1 in kidney and adipose tissue. Electron microscopy was used to observe the pathological changes in the kidney. VDR knockout mice were constructed to observe the changes in the gut and adipose tissue, and immunofluorescence and immunohistochemistry were used to detect the expression of UCP-1 and collagen IV in the kidney.
RESULTS
1,25-(OH)D could improve the dysbiosis of the intestinal flora of mice with DKD, increase the abundance of beneficial bacteria, decrease the abundance of harmful bacteria, reduce the pathological changes in the kidney, reduce fat infiltration, and downregulate the expression of TLR4 and NF-κB in kidneys. The serum TMAO concentration in mice with DKD was significantly higher than that of the control group, and was significantly positively correlated with the urine ACR. In addition, vitamin D stimulated the expression of the surface markers PGC1α, UCP-1 and VDR in the PRAT in DKD mice, and TMAO downregulated the expression of PRAT and renal VDR.
CONCLUSIONS
The protective effect of 1,25-(OH)D in DKD mice may affect the intestinal flora and its related metabolite TMAO on perirenal fat and kidneys.
Topics: Animals; Gastrointestinal Microbiome; Mice; Kidney; Methylamines; Male; Receptors, Calcitriol; Mice, Knockout; Diabetic Nephropathies; Adipose Tissue; Mice, Inbred C57BL; Vitamin D; Calcitriol
PubMed: 38858392
DOI: 10.1038/s41387-024-00297-z -
Cancer Biology & Therapy Dec 2024Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of...
BACKGROUND
Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood.
METHODS
Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or β-adrenergic receptor (β-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-β (TGF-β) receptor Type I kinase (Ly2157299) . TGF-β1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested.
RESULTS
Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-β1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion.
CONCLUSIONS
Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-β1 signaling during this process. In addition, β-AR/TGF-β1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.
Topics: Animals; Colorectal Neoplasms; Humans; Neovascularization, Pathologic; Mice; Transforming Growth Factor beta1; Hypoxia-Inducible Factor 1, alpha Subunit; Signal Transduction; Bevacizumab; Propranolol; Cell Line, Tumor; Vascular Endothelial Growth Factor A; Male; Cell Movement; Norepinephrine; Stress, Psychological; Adrenergic beta-Antagonists; Angiogenesis; Pyrazoles; Quinolines
PubMed: 38857055
DOI: 10.1080/15384047.2024.2366451