Notch receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The canonical Notch signalling pathway has four type I transmembrane Notch receptors (Notch1-4) and five ligands (DLL1, 2 and 3, and Jagged 1-2). Each member of this highly conserved receptor family plays a unique role in cell-fate determination during embryogenesis, differentiation, tissue patterning, proliferation and cell death [2]. As the Notch ligands are also membrane bound, cells have to be in close proximity for receptor-ligand interactions to occur. Cleavage of the intracellular domain (ICD) of activated Notch receptors by γ-secretase is required for downstream signalling and Notch-induced transcriptional modulation [15, 3, 11, 22]. This is why γ-secretase inhibitors can be used to downregulate Notch signalling and explains their anti-cancer action. One such small molecule is RO4929097 [8], although development of this compound has been terminated following an unsuccessful Phase II single agent clinical trial in metastatic colorectal cancer [19].Aberrant Notch signalling is implicated in a number of human cancers [12, 20, 6, 16], with demcizumab and tarextumab identified as antibody inhibitors of ligand:receptor binding [13]

Notch receptors in GtoPdb v.2021.2

Aberrant Notch signalling is implicated in a number of human cancers [18, 26, 13, 21], and there is intense pharmaceutical activity being directed towards achieving clinically effective Notch pathway inhibition [7, 16]

Nitroxyl, the novel redox sibling of NO, suppresses cerebrovascular NADPH oxidase

Background: Nitroxyl (HNO), the reduced and protonated congener of nitric oxide (NO), is emerging as a novel entity with distinct pharmacology and therapeutic advantages over NO• [1]. Importantly, HNO has vasoprotective actions with the potential to serve as an antioxidant. Here we explored the ability of HNO to modulate cerebrovascular NADPH oxidase activity, a major source of superoxide (.O2-) in the vasculature. Materials and methods: Intracranial (pooled middle cerebral and basilar) and extracranial (carotid) cerebral arteries from male C57BL/6J mice were treated with angiotensin II (10 nM) acutely (30 min) and chronically (24 h), respectively, in the absence and presence of the HNO donor, Angeli's salt (AS). NADPH (100 μM)-stimulated .O2- production was then measured using lucigenin (5 μM)-enhanced chemiluminescence. Results: AS (1 μM) did not scavenge .O2- generated in a cell free xanthine (100 μM)/xanthine oxidase (0.05 U/ml) activity assay (control: 447.9 ± 90.8; AS 507.1 ± 113.3 counts, n = 4). In contrast, acute and chronic treatment with AS (0.01–1 μM) caused a concentration-dependent decrease in NADPH oxidase-derived .O2- production by intracranial and extracranial cerebral arteries, respectively (carotid 0.59 ± 0.05; AS 0.1 μM 0.33 ± 0.08; AS 1 μM 0.16 ± 0.03 103 counts/s/mg, P < 0.05, n = 8). The effects of AS were reversed by the HNO scavenger, L-cysteine (3 mM) but unchanged in the presence of the NO• scavenger carboxy-PTIO (200 μM) and sGC inhibitor, ODQ (10 μM). Conclusion: HNO suppresses vascular NADPH-oxidase activity both acutely and chronically, possibly via a cGMP-independent mechanism. Such antioxidant actions of HNO may confer therapeutic advantages in the treatment of cerebrovascular disorders

Nox2 Oxidase Activity Accounts for the Oxidative Stress and Vasomotor Dysfunction in Mouse Cerebral Arteries following Ischemic Stroke

Background and Purpose: Post-ischemic oxidative stress and vasomotor dysfunction in cerebral arteries may increase the likelihood of cognitive impairment and secondary stroke. However, the underlying mechanisms of post-stroke vascular abnormalities, as distinct from those causing primary brain injury, are poorly understood. We tested whether augmented superoxide-dependent dysfunction occurs in the mouse cerebral circulation following ischemia-reperfusion, and evaluated the role of Nox2 oxidase. Methods: Cerebral ischemia was induced in male C57Bl6/J wild-type (WT) and Nox2-deficient (Nox2 -/-) mice by middle cerebral artery occlusion (MCAO; 0.5 h), followed by reperfusion (23.5 h). Superoxide production by MCA was measured by L-012-enhanced chemiluminescence. Nitric oxide (NO) function was assessed in cannulated and pressurized MCA via the vasoconstrictor response to N ω-nitro-L-arginine methyl ester (L-NAME; 100 μmol/L). Expression of Nox2, the nitration marker 3-nitrotyrosine, and leukocyte marker CD45 was assessed in cerebral arteries by Western blotting. Results: Following ischemia-reperfusion, superoxide production was markedly increased in the MCA of WT, but not Nox2 -/- mice. In WT mice, L-NAME-induced constriction was reduced by ~50% in ischemic MCA, whereas ischemia-reperfusion had no effect on responses to L-NAME in vessels from Nox2 -/- mice. In ischemic MCA from WT mice, expression of Nox2 and 3-nitrotyrosine were ~1.4-fold higher than in the contralateral MCA, or in ischemic or contralateral vessels from Nox2 -/- mice. Vascular CD45 levels were unchanged by ischemia-reperfusion. Conclusions: Excessive superoxide production, impaired NO function and nitrosative stress occur in mouse cerebral arteries after ischemia-reperfusion. These abnormalities appear to be exclusively due to increased activity of vascular Nox2 oxidase

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions

Fasting triglycerides are positively associated with cardiovascular mortality risk in people with diabetes

Aims: We investigated the association of fasting triglycerides with cardiovascular disease (CVD) mortality. Methods and results: This cohort study included US adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. CVD mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of triglycerides for CVD mortality. The cohort included 26 570 adult participants, among which 3978 had diabetes. People with higher triglycerides had a higher prevalence of diabetes at baseline. The cohort was followed up for a mean of 12.0 years with 1492 CVD deaths recorded. A 1-natural-log-unit higher triglyceride was associated with a 30% higher multivariate-adjusted risk of CVD mortality in participants with diabetes (HR, 1.30; 95% CI, 1.08–1.56) but not in those without diabetes (HR, 0.95; 95% CI, 0.83–1.07). In participants with diabetes, people with high triglycerides (200–499 mg/dL) had a 44% (HR, 1.44; 95% CI, 1.12–1.85) higher multivariate-adjusted risk of CVD mortality compared with those with normal triglycerides (<150 mg/dL). The findings remained significant when diabetes was defined by fasting glucose levels alone, or after further adjustment for the use of lipid-lowering medications, or after the exclusion of those who took lipid-lowering medications. Conclusion: This study demonstrates that fasting triglycerides of ≥200 mg/dL are associated with an increased risk of CVD mortality in patients with diabetes but not in those without diabetes. Future clinical trials of new treatments to lower triglycerides should focus on patients with diabetes

Dietary fatty acids and mortality risk from heart disease in US adults: an analysis based on NHANES

We investigated the association of dietary intake of major types of fatty acids with heart disease mortality in a general adult cohort with or without a prior diagnosis of myocardial infarction (MI). This cohort study included US adults who attended the National Health and Nutrition Examination Surveys from 1988 to 2014. Heart disease mortality was ascertained by linkage to the National Death Index records through 31 December 2015. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of fatty acid intake for heart disease mortality. This cohort included 45,820 adults among which 1,541 had a prior diagnosis of MI. Participants were followed up for 532,722 person-years (mean follow-up, 11.6 years), with 2,313 deaths recorded from heart disease being recorded. Intake of saturated (SFAs) and monounsaturated fatty acids (MUFAs) was associated with heart disease mortality after adjustment for all the tested confounders. In contrast, a 5% higher calorie intake from polyunsaturated fatty acids (PUFAs) was associated with a 9% (HR, 0.91; 95% CI 0.83–1.00; P = 0.048) lower multivariate-adjusted risk of heart disease mortality. Sub-analyses showed that this inverse association was present in those without a prior diagnosis of MI (HR,0.89; 95% CI 0.80–0.99) but not in those with the condition (HR, 0.94; 95% CI 0.75–1.16). The lack of association in the MI group could be due to a small sample size or severity and procedural complications (e.g., stenting and medication adherence) of the disease. Higher PUFA intake was associated with a favourable lipid profile. However, further adjustment for plasma lipids did not materially change the inverse association between PUFAs and heart disease mortality. Higher intake of PUFAs, but not SFAs and MUFAs, was associated with a lower adjusted risk of heart disease mortality in a large population of US adults supporting the need to increase dietary PUFA intake in the general public

Proteasome inhibition reduces plasma cell and antibody secretion, but not angiotensin II-induced hypertension

IntroductionDepletion of mature B cells affords protection against experimental hypertension. However, whether B cell-mediated hypertension is dependent on differentiation into antibody-secreting cells (ASCs) remains unclear. Using the proteasome inhibitor, bortezomib, the present study tested the effect of ASC reduction on angiotensin II-induced hypertension.MethodsMale C57BL6/J mice were infused with angiotensin II (0.7 mg/kg/day; s.c.) for 28 days via osmotic minipump to induce hypertension. Normotensive control mice received saline infusion. Bortezomib (750 μg/kg) or vehicle (0.1% DMSO) was administered (i.v.) 3 days prior to minipump implantation, and twice weekly thereafter. Systolic blood pressure was measured weekly using tail-cuff plethysmography. Spleen and bone marrow B1 (CD19+B220−), B2 (B220+CD19+) and ASCs (CD138hiSca-1+Blimp-1+) were enumerated by flow cytometry. Serum immunoglobulins were quantified using a bead-based immunoassay.ResultsBortezomib treatment reduced splenic ASCs by ∼68% and ∼64% compared to vehicle treatment in normotensive (2.00 ± 0.30 vs. 0.64 ± 0.15 × 105 cells; n = 10–11) and hypertensive mice (0.52 ± 0.11 vs. 0.14 ± 0.02 × 105 cells; n = 9–11), respectively. Bone marrow ASCs were also reduced by bortezomib in both normotensive (4.75 ± 1.53 vs. 1.71 ± 0.41 × 103 cells; n = 9–11) and hypertensive mice (4.12 ± 0.82 vs. 0.89 ± 0.18 × 103 cells; n = 9–11). Consistent with ASC reductions, bortezomib reduced serum IgM and IgG2a in all mice. Despite these reductions in ASCs and antibody levels, bortezomib did not affect angiotensin II-induced hypertension over 28 days (vehicle: 182 ± 4 mmHg vs. bortezomib: 177 ± 7 mmHg; n = 9–11).ConclusionReductions in ASCs and circulating IgG2a and IgM did not ameliorate experimental hypertension, suggesting other immunoglobulin isotypes or B cell effector functions may promote angiotensin II-induced hypertension

Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension

OBJECTIVE: To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension. METHODS: Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11 days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys. RESULTS: By 10 days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3+/-2.4mmHg) compared to control mice (121.7+/-2.7mmHg; n=18, P\u3c0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by approximately 20mmHg (n=16, P\u3c0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced ( approximately 30%) renal expression of some (CCL5, CCL2; n=7-8; P\u3c0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n=7-8, P \u3e 0.05). Anakinra reduced renal collagen content (n=6, P\u3c0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P\u3c0.001) that accompanied 1K/DOCA/salt-induced hypertension. CONCLUSION: Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain

Untersuchungen zur Stabilisierung der frühen postnatalen Adaptationsvorgänge bei Kälbern in Mutterkuhhaltung - ein Beitrag zur Charakterisierung postnataler Anpassungsreaktionen

Ziel dieser Arbeit war es, die sensible Phase der ersten und frühen zweiten Adaptationsphase, von der Geburt bis zur 72. Lebensstunde, bei Kälbern fleischbetonter Rassen in einem geschlossenen Mutterkuhbestand zu untersuchen, um daraus folgend einen Beitrag zur Erstellung von nicht parametrischen Referenzbereichen für klinische und labordiagnostische Parameter für diese Zeitspanne zu leisten. Korrelationen zwischen klinischen und labordiagnostischen Parametern sollten aufgedeckt werden, um so klinisch relevante Beziehungen herstellen zu können Eine Einschätzung der Vitalität anhand leicht zu erhebender ethologischer Befunde, wie erstes Kopfheben post natum, erstes sicheres Stehen und erste Kolostrumaufnahme wurde durchgeführt. Als Probanden standen insgesamt 115 mature Kälber verschiedener Rassen aus einem geschlossenen Mutterkuhbestand zur Verfügung. Die Untersuchung erstreckte sich von der Geburt bis zu 72 Stunden p. n.. Folgende 20 Parameter kamen dabei zur Auswertung: pH, Base Excess, Kohlendioxidpartialdruck, Hä­¡tokrit, Gesamtprotein, Glukose, Triglyzeride, Cholesterin, Harnstoff, Kreatinin, Natrium, Kalium, Chlorid, Magnesium, AST, ALT, AP, GGT, GLDH und CK. Die statistische Auswertung der Ergebnisse wurde unter Berücksichtigung der Faktoren Alter, Rasse, Geschlecht und Geburtsart der Kälber sowie Geburtsziffer des Muttertieres vorgenommen. Die einzelnen Messgrössen bis auf das Plasmachlorid wurden über den Untersuchungszeitraum hochsignifikant (p < 0,001) durch das Alter beeinflusst. Einflí²í³¥ der Rasse zeigten sich im Verlauf des Blut-pH-Wertes (p <= 0,01), des Base Excess (p <= 0,05) sowie der Enzyme ALT (p <= 0,05) und GLDH (p <= 0,05). Das erste sichere Stehen post natum wurde schwach signifikant durch das Geschlecht (p <= 0,05) beeinflusst. Die Parameter pH-Wert (p <= 0,05) und Kohlendioxidpartialdruck (p <= 0,01) im venösen Blut sowie die Blutglukose (p <= 0,01) zeigten bis zum dritten Lebenstag ebenfalls Einflüsse durch das Geschlecht der Kälber. Die Geburtsart übte einen signifikanten Einfluss auf die ethologischen Parameter des ersten Stehens (p <= 0,01) und des ersten Saugens post natum (p <= 0,01) aus, die Einstufung nach APGAR wurde sogar hoch signifikant (p <= 0,001) durch die Geburtsart beeinflusst. Labordiagnostisch konnte ein signifikanter Einfluss auf die CK-Aktivität (p <= 0,01) ermittelt werden. pH-Wert, Kaliumkonzentration und AST-Aktivität erfuhren schwach signifikante (p <= 0,05) Beeinflussungen durch die Art der Geburt. Die Parität der Muttertiere, beeinflusste die Geburtsart signifikant (p <= 0,01). Ebenso wiesen die Serumspiegel des Gesamtproteins (p <= 0,05), von Harnstoff (p <= 0,01), Kalium (p <= 0,05), ALT (p <= 0,05) und GLDH (p <= 0,05) Einflüsse der die Geburtsziffer auf. Im Verlauf der AP-Aktivitäten zeigten sich hoch signifikante Wechselwirkungen (p <= 0,001) mit den verschiedenen Rassen. Das Geschlecht der Kälber wies ebenso hoch signifikante Wechselwirkungen (p <= 0,001) zur GLDH-Aktivität auf. Wechselwirkungen der Geburtsart und der Zeit waren bei den Messgrössen pH-Wert (p <= 0,001), Kohlendioxidpartialdruck (p <= 0,01), Base Excess (p <= 0,001), Hämatokrit (p <= 0,001), Harnstoff (p <= 0,05) und AST-Aktivität (p <= 0,05) statistisch nachweisbar. Auf die Parameter Harnstoff (p <= 0,001), Natrium (p <= 0,05), Kalium (p <= 0,05), Chlorid (p <= 0,05) und ALT-Aktivität (p <= 0,05) waren Wechselwirkungen der Geburtsziffer der Muttertiere von der Geburt bis zur 72. Lebensstunde darstellbar. Die Körpertemperatur der Kälber korrelierte unmittelbar nach der Geburt signifikant (p <= 0,01) mit dem Blut-pH-Wert (r = -0,283) und dem Kohlendioxidpartialdruck (r = +0,284). Zum Base Excess bestand postnatal eine schwach signifikante (p <= 0,05) Korrelation (r = -0,193). Die Blutglukosewerte korrelierten unmittelbar post natum schwach signifikant (p <= 0,05) mit dem Blut-pH (r = -0,207), dem Kohlendioxidpartialdruck (r = +0,089) und dem Base Excess (r = 0,210). Das erste Kopfheben post natum stand in hoch signifikantem (p <= 0,001) Zusammenhang mit der Vitalitätseinschätzung nach APGAR. Das erste Stehen zeigte einen signifikante (p <= 0,01) und der Zeitpunkt der ersten Kolostrumaufnahme noch einen schwach signifikanten (p <= 0,05) Zusammenhang. Zur exakten Einschätzung der labordiagnostisch ermittelten Blutwerte bei neugeborenen Kälbern ist eine vom genauen Alter abhängige Erstellung von Referenzbereichen unter Berücksichtigung nicht parametrischer Referenzbereiche notwendig.The aim of the present study was to illustrate the sensitive time of the first and the early second adaptation period from birth to the 72. hour of life in different races of beef cattle in one herd. Furthermore non parametric reference values for clinical and laboratory diagnostic parameters for this period of adaptation were described. Another aim was to find correlations between clinical and laboratory parameters to show relations of clinical relevance. Ethological findings such as: first raising of the head post natum, first firm standing and colostrum intake were evaluated. For tests, a total of 115 mature calves of different races out of a close suckler cow management system herd was available. The evaluation was made from immediately after birth to 72 hours p. n.. The following 20 parameters were evaluated: pH, base excess, carbondioxide partial pressure, hematocrit, total protein, glucose, triglyceride, cholesterol, uric acid, creatinin, sodium, calium, potassium, chloride, magnesium, AST, ALT, AP, GGT, GLDH and CK. When doing the statistical evaluation of the results factors such as: age, race, sex, kind of birth of the calves as well as the number of births given by the mother cow were considered. The development of the single values over the time period of the research was highly influenced by the age (p <= 0.001). Influence of the race was found during the course of the blood-pH-value (p <= 0.01), of the base excess (p <= 0.05) and also of the enzymes ALT (p <= 0.05) and GLDH (p <= 0.05). The time of first firm standing post natum as a qualifying factor was only weak significantly (p <= 0.05) influenced by the sex. The parameter blood-pH (p <= 0.05), blood glycose (p <= 0.01) and carbondioxide partial pressure (p <= 0.01) also proved influence of the sex of the calves during the first 3 days after birth. The kind of birth had a significant influence on the ethological parameter of the first standing (p <= 0.01) and the first suckling post natum (p <= 0.01). When judging according to APGAR the correlation was even highly significant (p <= 0.001). In the laboratory diagnostics a significant influence on the CK-activity (p <= 0.01) could be found. pH-value, potassium concentration and AST-activity were weak significantly influenced (p <= 0.05) by the kind of birth. The kind of birth was significantly influenced (p <= 0.01) by the fact how often a mother cow already had given birth to calves. The serum level of the total protein (p <= 0.05), of the uric acid (p <= 0.01), potassium (p <=0.05), ALT (p <= 0.05) and GLDH (p <= 0.05) also showed their correlation to the number of birth. During the course of the AP activities of the different races significant interactions became obvious (p <= 0.001). The sex of the calves also showed highly significant interactions (p <= 0.001) towards the GLDH activity. Interactions of the kind and time of birth could also statistically be proven for the parameters: pH value (p <= 0.001), carbondioxide partial pressure (p <= 0.01), base excess (p <= 0.001), hematocrit (p <= 0.001), uric acid (p <= 0.05) and AST activity (p <= 0.05). For the parameters uric acid (p <= 0.001), sodium (p <= 0.05), potassium (p <= 0.05), chloride (p <= 0.05) and AST activity (p <= 0.05), an interaction could be found to the number of births given by the mother cow from the date of birth till the 72nd hour after birth. Correlation was discovered between body temprature and blood glycose to pH, carbondioxide partial pressure and base excess. The body temperature of the calves correlated after birth directly and significantly (p <= 0.01) with the blood-pH-value (r = -0.283) and the carbondioxide partial pressure (r = +0.284). There existed a slightly significant (p <= 0.05) correlation (r = -0.193) to the base excess. The blood glycose values correlated directly post natum slightly significantly (p <= 0.05) with the blood-pH (r = -0.207) with the carbondioxide partial pressure (r = +0.089) and with the base excess (r = 0.210). The first raising of the head post natum was in a highly significant connection (p <= 0.001) with the judgement of the vitality by APGAR. The first standing up showed a significant (p <= 0.01) and the time of first intake of cholostrum still a weak significant (p <=0.05) correlation. For the exact evaluation of the blood values derived from laboratory diagnostics for newly born calves, a table with values referring to the exact age and also considering the non-parameter values must be created