Combining uretdione and disulfide reversibly degradable polyurethanes : route to alternating block copolymers

Uretdione (temperature and catalyst controlled) and disulphide (REDOX controlled) functionalised polyurethanes have been described and the reversibility of these bonds tested. The polymers have been synthesised with reversible covalent groups present throughout their backbone, developing routes to reversibly degradable polyurethanes. These materials degrade and reheal in response to different external stimuli, which supplies a proof of concept for controlling the molecular weight, and therefore, the physical properties of a polyurethane. Further, a unique route to an alternating block copolymer is also discussed that utilises a mixture of disulphide and uretdione functionalised polymers as the reagents to form a thiourethane. The dramatically reduced safety hazards of dealing with the functionalised polymers, in comparison to the free isocyanate and thiols, could be of great interest to industrial application for current drives towards safer routes to polyurethanes

Adrenoceptors in GtoPdb v.2023.1

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [64, 194]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, α2 The three α2-adrenoceptor subtypes α2A, α2B and α2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [33] and veterinary medicine and has sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, β The three β-adrenoceptor subtypes β1, β2 and β3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for β1- and β2- relative to β3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate between the three β- subtypes [332] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [528]. Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [197]

Earthquake forecasting in Italy, before and after Umbria-Marche seismic sequence 1997. A review of the earthquake occurrence modeling at different spatio-temporal-magnitude scales.

The main goal of this work is to review the scientific researches carried out before and after the Umbria-Marche sequence related to the earthquake forecasting/prediction in Italy. In particular, I focus the attention on models that aim addressing three main practical questions: was (is) Umbria-Marche a region with high probability of occurrence of a destructive earthquake? Was a precursory activity recorded before the mainshock(s)? What was our capability to model the spatio-temporal-magnitude evolution of that seismic sequence? The models are reviewed pointing out what we have learned after the Umbria-Marche earthquakes, in terms of physical understanding of earthquake occurrence process, and of improving our capability to forecast earthquakes and to track in real-time seismic sequences

Role of G protein‐coupled receptor kinases (GRKs) in β2‐adrenoceptor‐mediated glucose uptake

Truncation of the C‐terminal tail of the β2‐AR, transfection of βARKct or over‐expression of a kinase‐dead GRK mutant reduces isoprenaline‐stimulated glucose uptake, indicating that GRK is important for this response. We explored whether phosphorylation of the β2‐AR by GRK2 has a role in glucose uptake or if this response is related to the role of GRK2 as a scaffolding protein. CHO‐GLUT4myc cells expressing wild‐type and mutant β2‐ARs were generated and receptor affinity for [3H]‐CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344. Following receptor activation by β2‐AR agonists, cAMP accumulation, GLUT4 translocation, [3H]‐2‐deoxyglucose uptake, and β2‐AR internalization were measured. Bioluminescence resonance energy transfer was used to investigate interactions between β2‐AR and β‐arrestin2 or between β2‐AR and GRK2. Glucose uptake after siRNA knockdown or GRK inhibitors was measured in response to β2‐AR agonists. BRL37344 was a poor partial agonist for cAMP generation but displayed similar potency and efficacy to isoprenaline for glucose uptake and GLUT4 translocation. These responses to β2‐AR agonists occurred in CHO‐GLUT4myc cells expressing β2‐ARs lacking GRK or GRK/PKA phosphorylation sites as well as in cells expressing the wild‐type β2‐AR. However, β2‐ARs lacking phosphorylation sites failed to recruit β‐arrestin2 and did not internalize. GRK2 knock‐down or GRK2 inhibitors decreased isoprenaline‐stimulated glucose uptake in rat L6 skeletal muscle cells. Thus, GRK phosphorylation of the β2‐AR is not associated with isoprenaline‐ or BRL37344‐stimulated glucose uptake. However, GRKs acting as scaffold proteins are important for glucose uptake as GRK2 knock‐down or GRK2 inhibition reduces isoprenaline‐stimulated glucose uptake

Relaxin-1–deficient mice develop an age-related progression of renal fibrosis

Relaxin-1–deficient mice develop an age-related progression of renal fibrosis.BackgroundRelaxin (RLX) is a peptide hormone that stimulates the breakdown of collagen in preparation for parturition and when administered to various models of induced fibrosis. However, its significance in the aging kidney is yet to be established. In this study, we compared structural and functional changes in the kidney of aging relaxin-1 (RLX-/-) deficient mice and normal (RLX+/+) mice.MethodsThe kidney cortex and medulla of male and female RLX+/+ and RLX-/- mice at various ages were analyzed for collagen content, concentration, and types. Histologic analysis, reverse transcription-polymerase chain reaction (RT-PCR) of relaxin and relaxin receptor mRNA expression, receptor autoradiography, glomerular isolation/analysis, and serum/urine analysis were also employed. Relaxin treatment of RLX-/- mice was used to confirm the antifibrotic effects of the peptide.ResultsWe demonstrate an age-related progression of renal fibrosis in male, but not female, RLX-/- mice with significantly (P < 0.05) increased tissue dry weight, collagen (type I) content and concentration. The increased collagen expression in the kidney was associated with increased glomerular matrix and to a lesser extent, interstitial fibrosis in RLX-/- mice, which also had significantly increased serum creatinine (P < 0.05) and urinary protein (P < 0.05). Treatment of RLX-/- mice with relaxin in established stages of renal fibrosis resulted in the reversal of collagen deposition.ConclusionThis study supports the concept that relaxin may provide a means to regulate excessive collagen deposition during kidney development and in diseased states characterized by renal fibrosis

Adrenoceptors in GtoPdb v.2021.3

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [60, 186]. Adrenoceptors, &#945;1 The three &#945;1-adrenoceptor subtypes &#945;1A, &#945;1B and &#945;1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for &#945;1- relative to &#945;2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of &#945;1-adrenoceptors. &#945;1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being &#945;1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The &#945;1- and &#946;2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of &#945;1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are &#945;1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, &#945;2 The three &#945;2-adrenoceptor subtypes &#945;2A, &#945;2B and &#945;2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for &#945;2- relative to &#945;1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the &#945;2A-adrenoceptor. Multiple mutations of &#945;2-adrenoceptors have been described, some associated with alterations in function. Presynaptic &#945;2-adrenoceptors regulate many functions in the nervous system. The &#945;2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [31] and veterinary medicine and has sympatholytic and anxiolytic properties. The &#945;2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The &#945;2B subtype appears to be involved in neurotransmission in the spinal cord and &#945;2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, &#946; The three &#946;-adrenoceptor subtypes &#946;1, &#946;2 and &#946;3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for &#946;-adrenoceptors relative to &#945;1- and &#945;2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for &#946;1- and &#946;2- relative to &#946;3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for &#946;1- relative to &#946;2-adrenoceptors. Pharmacological differences exist between human and mouse &#946;3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human &#946;3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human &#946;3-adrenoceptors [88]. &#946;3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at &#946;3-adrenoceptors, but does not discriminate between the three &#946;- subtypes [320] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label &#946;1- and &#946;2- adrenoceptors and &#946;3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with &#946;1- and &#946;2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track &#946;-adrenoceptors at the cellular level [8]. Somewhat selective &#946;1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. &#946;1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [507]. Cardiac failure is also treated with carvedilol that blocks &#946;1- and &#946;2-adrenoceptors, as well as &#945;1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting &#946;2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation &#946;-adrenoceptor antagonists (propranolol) block both &#946;1- and &#946;2-adrenoceptors and there are no &#946;2-adrenoceptor-selective antagonists used therapeutically. The &#946;3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that &#946;-adrenoceptor antagonists can reduce metastasis in certain types of cancer [189]

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

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [58], see also [180]. Adrenoceptors, &#945;1&#945;1-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. phenylephrine, methoxamine and cirazoline are agonists and prazosin and cirazoline antagonists considered selective for &#945;1- relative to &#945;2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy PLprazosin- QAPB) are used to examine cellular localisation of &#945;1-adrenoceptors. Selective &#945;1-adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). The &#945;1- and &#946;2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of &#945;1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are &#945;1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension and extrapyramidal effects.Adrenoceptors, &#945;2 &#945;2-Adrenoceptors are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for &#945;2- relative to &#945;1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There is species variation in the pharmacology of the &#945;2A-adrenoceptor. Multiple mutations of &#945;2-adrenoceptors have been described, some associated with alterations in function. Presynaptic &#945;2-adrenoceptors regulate many functions in the nervous system. The &#945;2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is used as a sedative and analgesic in human and veterinary medicine with sympatholytic and anxiolytic properties. The &#945;2-adrenoceptor antagonist yohimbine has been used to treat erectile dysfunction and mirtazapine as an anti-depressant. The &#945;2B subtype appears to be involved in neurotransmission in the spinal cord and &#945;2C in regulating catecholamine release from adrenal chromaffin cells.Adrenoceptors, &#946;&#946;-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for &#946;-adrenoceptors relative to &#945;1- and &#945;2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively &#946;1 and &#946;2 adrenoceptor-selective antagonists. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for &#946;1- relative to &#946;2-adrenoceptors. Pharmacological differences exist between human and mouse &#946;3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human &#946;3-adrenoceptor whereas CGP 12177 and L 755507 activate human &#946;3-adrenoceptors [88]. &#946;3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at &#946;3-adrenoceptors, but does not discriminate well between the three &#946;- subtypes whereas L 755507 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label &#946;1- and &#946;2- adrenoceptors and &#946;3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with &#946;1- and &#946;2-adrenoceptor antagonists. [3H]-L-748337 is a &#946;3-selective radioligand [474]. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track &#946;-adrenoceptors at the cellular level [8]. Somewhat selective &#946;1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. &#946;1-Adrenoceptor-preferring antagonists are used to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol), cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol). Cardiac failure is also treated with carvedilol that blocks &#946;1- and &#946;2-adrenoceptors, as well as &#945;1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting &#946;2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation &#946;-adrenoceptor antagonists (propranolol) block both &#946;1- and &#946;2-adrenoceptors and there are no &#946;2-adrenoceptor-selective antagonists used therapeutically. The &#946;3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome

Tissue functions mediated by β3-adrenoceptors—findings and challenges

As β3-adrenoceptor agonists metamorphose from experimental tools into therapeutic drugs, it is vital to obtain a comprehensive picture of the cell and tissue functions mediated by this receptor subtype in humans. Human tissues with proven functions and/or a high expression of β3-adrenoceptors include the urinary bladder, the gall bladder, and other parts of the gastrointestinal tract. While several other β3-adrenoceptor functions have been proposed based on results obtained in animals, their relevance to humans remains uncertain. For instance, β3-adrenoceptors perform an important role in thermogenesis and lipolysis in rodent brown and white adipose tissue, respectively, but their role in humans appears less significant. Moreover, the use of tools such as the agonist BRL 37344 and the antagonist SR59230A to demonstrate functional involvement of β3-adrenoceptors may lead in many cases to misleading conclusions as they can also interact with other β-adrenoceptor subtypes or even non-adrenoceptor targets. In conclusion, we propose that many responses attributed to β3-adrenoceptor stimulation may need re-evaluation in the light of the development of more selective tools. Moreover, findings in experimental animals need to be extended to humans in order to better understand the potential additional indications and side effects of the β3-adrenoceptor agonists that are beginning to enter clinical medicine