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American Journal of Physiology. Renal... Nov 2020Diabetes is a prevalent metabolic disease that contributes to ∼50% of all end-stage renal disease and has limited treatment options. We previously demonstrated that...
Diabetes is a prevalent metabolic disease that contributes to ∼50% of all end-stage renal disease and has limited treatment options. We previously demonstrated that the β-adrenergic receptor agonist formoterol induced mitochondrial biogenesis and promoted recovery from acute kidney injury. Here, we assessed the effects of formoterol on mitochondrial dysfunction and dynamics in renal proximal tubule cells (RPTCs) treated with high glucose and in a mouse model of type 2 diabetes. RPTCs exposed to 17 mM glucose exhibited increased electron transport chain (ETC) complex I, II, III, and V protein levels and reduced ATP levels and uncoupled oxygen consumption rate compared with RPTCs cultured in the absence of glucose or osmotic controls after 96 h. ETC proteins, ATP, and oxygen consumption rate were restored in RPTCs treated with formoterol. RPTCs exposed to high glucose had increased phospho-dynamin-related protein 1 (Drp1), a mitochondrial fission protein, and decreased mitofusin 1 (Mfn1), a mitochondrial fusion protein. Formoterol treatment restored phospho-Drp1 and Mfn1 to control levels. / and nondiabetic (/m) mice (10 wk old) were treated with formoterol or vehicle for 3 wk and euthanized. / mice showed increased renal cortical ETC protein levels in complexes I, III, and V and decreased ATP; these changes were prevented by formoterol. Phospho-Drp1 was increased and Mfn1 was decreased in / mice, and formoterol restored both to control levels. Together, these findings demonstrate that hyperglycemic conditions in vivo and exposure of RPTCs to high glucose similarly alter mitochondrial bioenergetic and dynamics profiles and that treatment with formoterol can reverse these effects. Formoterol may be a promising strategy for treating early stages of diabetic kidney disease.
Topics: Adrenergic Agonists; Animals; Disease Models, Animal; Formoterol Fumarate; Kidney; Kidney Tubules, Proximal; Mice; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Organelle Biogenesis
PubMed: 32954853
DOI: 10.1152/ajprenal.00427.2020 -
Revista Brasileira de Terapia Intensiva 2022Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last...
Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last remaning challenges. As conventional sedation is suboptimal and as the sedation evoked by alpha-2 adrenergic agonists ("cooperative" sedation with dexmedetomidine, clonidine or guanfacine) represents a valuable alternative, this manuscript covers three practical topics for which evidence-based medicine is lacking: a) Switching from conventional to cooperative sedation ("switching"): the short answer is the abrupt withdrawal of conventional sedation, immediate implementation of alpha-2 agonist infusion and the use of "rescue sedation" (midazolam bolus[es]) or "breakthrough sedation" (haloperidol bolus[es]) to stabilize cooperative sedation. b) Switching from conventional to cooperative sedation in unstable patients (e.g., refractory delirium tremens, septic shock, acute respiratory distress syndrome, etc.): to avoid hypotension and bradycardia evoked by sympathetic deactivation, the short answer is to maintain the stroke volume through volume loading, vasopressors and inotropes. c) To avoid these switches and associated difficulties, alpha-2 agonists may be considered first-line sedatives. The short answer is to administer alpha-2 agonists slowly from admission or endotracheal intubation up to stabilized cooperative sedation. The "take home" message is as follows: a) alpha-2 agonists are jointly sympathetic deactivators and sedative agents; b) sympathetic deactivation implies maintaining the stroke volume and iterative assessment of volemia. Evidence-based medicine should document our propositions.
Topics: Adrenergic alpha-2 Receptor Agonists; Clonidine; Critical Care; Dexmedetomidine; Humans; Hypnotics and Sedatives
PubMed: 35081245
DOI: 10.5935/0103-507X.20210087 -
The Journal of Biological Chemistry Jun 2005We converted Ser-207, located in helix 5 of the beta2-adrenergic receptor, into all other natural amino acids. To quantify receptor activation as a receptor...
We converted Ser-207, located in helix 5 of the beta2-adrenergic receptor, into all other natural amino acids. To quantify receptor activation as a receptor number-independent parameter and directly related to G(s) activation, we expressed the mutants in a G alpha(s)-tethered form. GTP exchange in such constructs is restricted to the fused alpha-subunit and is a linear function of the receptor concentration. Except S207R, all other mutants were expressed to a suitable level for investigation. All mutations reduced the binding affinities of the catechol agonists, epinephrine and isoproterenol, and the extent of reduction was unrelated to the residue ability to form hydrogen bonds. Instead, both enhancements and reductions of affinity were observed for the partial agonist halostachin and the antagonist pindolol. The mutations also enhanced and diminished ligand-induced receptor activation, but the effects were strictly ligand-specific. Polar residues such as Asp and His exalted the activation by full agonists but suppressed that induced by the partial agonists halostachin and dichloroisoproterenol. In contrast, hydrophobic residues such as Ile and Val augmented partial agonist activation. Only Ile and Lys produced a significant increase of constitutive activity. The effects on binding and activity were not correlated, nor did such parameters show any clear correlation with up to 78 descriptors of amino acid physicochemical properties. Our data question the idea that Ser-207 is exposed to the polar crevice in the unbound receptor. They also suggest that the active receptor form induced by a full agonist might be substantially different from that caused by constitutive activation.
Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Animals; Cell Line; Humans; Models, Molecular; Mutagenesis; Protein Conformation; Receptors, Adrenergic, beta-2; Structure-Activity Relationship
PubMed: 15845544
DOI: 10.1074/jbc.M502901200 -
Animal : An International Journal of... Aug 2018Immunocastration (ImC) has been proposed as an animal welfare-friendly alternative to reduce sexual and aggressive behavior and to increase carcass fat deposition with...
Immunocastration (ImC) has been proposed as an animal welfare-friendly alternative to reduce sexual and aggressive behavior and to increase carcass fat deposition with positive effects on meat quality. The β-adrenergic agonists (β-AA) are known as repartitioning agents that acts increasing lean tissue deposition. The combined use of these technologies can positively affect meat quality and increase retail cuts yield. Thus, this research was conducted to evaluate the combined effects of ImC and β-AA (zilpaterol hydrochloride (ZH) and ractopamine hydrochloride (RH)) on retail cuts, bones, and fat trim of feedlot finished Bos indicus (Nellore) cattle. No interaction was observed between sexual condition and diet for any trait. The ImC decreased cold carcass, hindquarter (HQ), forequarter (FQ) and combined brisket, short ribs and flank (BSF) weights. The ImC also showed smaller weights of retail cuts and bones on the HQ and on the FQ than non-castrated (NoC). Fat trim weights did not differ from ImC and NoC. The most of subprimal cuts were heavier in NoC than in ImC. Feeding β-AA did not affect cold carcass weight; however, animals fed ZH had higher weights of HQ and retail cuts in HQ when compared with RH and control (CO) group, with no differences between RH and CO for both traits. The weights of FQ, BSF, retail cuts in FQ, as well as bones and fat trimmings were not affected by β-AA. In summary, ImC decreases carcass and retail cut weights, whereas ZH supplementation leads to an improvement in carcass lean tissue and retail cuts.
Topics: Adrenergic beta-Agonists; Animals; Body Composition; Castration; Cattle; Diet; Meat
PubMed: 29254512
DOI: 10.1017/S1751731117003317 -
The Journal of Veterinary Medical... Mar 2001Chronic stimulation of the beta3-adrenergic receptor (AR) in obese animals resulted in a reduced adiposity associated with an increased expression of thermogenic...
Chronic stimulation of the beta3-adrenergic receptor (AR) in obese animals resulted in a reduced adiposity associated with an increased expression of thermogenic uncoupling protein (UCP)1 in adipose tissues. In this study, the mRNA expression of newly cloned UCP isoforms (UCP2 and UCP3) were examined in obese yellow KK and C57BL control mice. UCP2 mRNA was found in all tissues examined, with higher levels in adipose tissues and skeletal muscle of the obese mice. UCP3 mRNA was expressed in skeletal muscle, heart and brown adipose tissue similarly in the two mouse strains. Daily injection of a selective beta3-adrenergic agonist, CL316,243 (0.1 mg/kg), for 10 days resulted in a marked reduction of white fat pad weight and 1.8-4.8-fold increase in the mRNA levels of UCP2 and UCP3 in skeletal muscle of obese mice. No noticeable change in the UCP2 and 3 mRNA levels was found in brown and white adipose tissues. It was also found that CL316,243 injection produced a marked and sustained elevation of the plasma free fatty acid level. These results, together with our previous findings of the fatty acid-induced UCP expression in a myocyte cell line in vitro, suggest that the beta3-AR agonist-induced UCP expression in skeletal muscle may be mediated through the elevated plasma free fatty acids. It was also suggested that anti-obesity effect of beta3-AR agonists is attributable to increased thermogenesis not only by UCP1 but also by UCP2 and UCP3.
Topics: Adipose Tissue, Brown; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Blood Glucose; Blotting, Northern; Carrier Proteins; Dioxoles; Disease Models, Animal; Fatty Acids; Female; Ion Channels; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondrial Proteins; Muscle, Skeletal; Protein Biosynthesis; Proteins; RNA, Messenger; Uncoupling Protein 2; Uncoupling Protein 3; Up-Regulation
PubMed: 11307932
DOI: 10.1292/jvms.63.309 -
Cell Stem Cell Sep 2019Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic...
Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.
Topics: Adrenergic Agonists; Aging; Aging, Premature; Animals; Bone Marrow; Cell Differentiation; Cell Encapsulation; Cell Proliferation; Disease Models, Animal; Hematopoietic Stem Cells; Humans; Interleukin-6; Megakaryocytes; Mice; Myeloid Cells; Nitric Oxide Synthase Type I; Progeria; Receptors, Adrenergic, beta-2; Signal Transduction; Stem Cell Niche
PubMed: 31303548
DOI: 10.1016/j.stem.2019.06.007 -
ACS Chemical Neuroscience Nov 2019Agonists at the α adrenergic receptor produce sedation, increase focus, provide analgesia, and induce centrally mediated hypotension and bradycardia, yet neither their...
Agonists at the α adrenergic receptor produce sedation, increase focus, provide analgesia, and induce centrally mediated hypotension and bradycardia, yet neither their dynamic interactions with adrenergic receptors nor their modulation of neuronal circuit activity is completely understood. Photoaffinity ligands of α adrenergic agonists have the potential both to capture discrete moments of ligand-receptor interactions and to prolong naturalistic drug effects in discrete regions of tissue in vivo. We present here the synthesis and characterization of a novel α adrenergic agonist photolabel based on the imidazole medetomidine called . Azi-medetomidine shares protein association characteristics with its parent compound in experimental model systems and by molecular dynamics simulation of interactions with the α adrenergic receptor. Azi-medetomidine acts as an agonist at α adrenergic receptors, and produces hypnosis in tadpoles. Azi-medetomidine competes with the α agonist clonidine at α adrenergic receptors, which is potentiated by photolabeling, and azi-medetomidine labels moieties on the α adrenergic receptor as determined by mass spectrometry in a manner consistent with a simulated model. This novel α adrenergic agonist photolabel can serve as a powerful tool for in vitro and in vivo investigations of adrenergic signaling.
Topics: Adrenergic alpha-2 Receptor Agonists; Amino Acid Sequence; Animals; Dose-Response Relationship, Drug; Humans; Ligands; Medetomidine; Photoaffinity Labels; Protein Structure, Secondary; Receptors, Adrenergic, alpha-2; Xenopus laevis
PubMed: 31638765
DOI: 10.1021/acschemneuro.9b00484 -
Physiological Reports Mar 2023Activation of thermogenic adipose tissue depots has been linked to improved metabolism and weight loss. To study the molecular regulation of adipocyte thermogenesis, we...
Activation of thermogenic adipose tissue depots has been linked to improved metabolism and weight loss. To study the molecular regulation of adipocyte thermogenesis, we performed RNA-Seq on brown adipose tissue (BAT), gonadal white adipose tissue (gWAT), and inguinal white adipose tissue (iWAT) from mice treated with β3-adrenoreceptor agonist CL316,243 (CL). Our analysis revealed diverse transcriptional profile and identified pathways in response to CL treatment. Differentially expressed genes (DEGs) in iWATCL were associated with the upregulation of pathways involved in cellular immune responses and with the upregulation of the browning program. We identified 39 DEGs in beige adipose which included certain heat shock proteins (Hspa1a and Hspa1b), and others suggesting potential associations with browning. Our results highlight transcriptional heterogeneity across adipose tissues and reveal genes specifically regulated in beige adipose, potentially aiding in identifying novel browning pathways.
Topics: Mice; Animals; Transcriptome; Adipose Tissue, White; Adipose Tissue; Adipose Tissue, Brown; Adipocytes; Adrenergic beta-3 Receptor Agonists; Obesity; Thermogenesis; Mice, Inbred C57BL
PubMed: 36967237
DOI: 10.14814/phy2.15646 -
Trials Apr 2023Urgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive...
TReating Incontinence for Underlying Mental and Physical Health (TRIUMPH): a study protocol for a multicenter, double-blinded, randomized, 3-arm trial to evaluate the multisystem effects of pharmacologic treatment strategies for urgency-predominant urinary incontinence in ambulatory older women.
BACKGROUND
Urgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive impairment, physical mobility impairment, and depression. Observational studies have raised concern about potentially higher rates of delirium and dementia in older adults taking anticholinergic bladder medications, but few prospective data are available to evaluate the effects of these and other pharmacologic treatments for urgency incontinence on cognition and other multisystem functional domains important to older women.
METHODS
The TRIUMPH study is a randomized, double-blinded, 3-arm, parallel-group trial comparing the multisystem effects of anticholinergic versus beta-3-adrenergic agonist bladder therapy and versus no active bladder anti-spasmodic pharmacotherapy in older women with urgency incontinence. Women aged 60 years and older (target N = 270) who have chronic urgency-predominant urinary incontinence and either normal or mildly impaired cognition at baseline are recruited from the community by investigators based in northern California, USA. Participants are randomized in equal ratios to take identically encapsulated oral anticholinergic bladder therapy (in the form of tolterodine 2 mg extended release [ER]), oral beta-3 adrenergic agonist bladder therapy (mirabegron 25 mg ER), or placebo daily for 24 weeks, with the option of participant-directed dose titration (to tolterodine 4 mg ER, mirabegron 50 mg ER, or matching placebo daily). Participants also receive patient-oriented information and instructions about practicing first-line behavioral management strategies for incontinence. The primary outcome is change in composite cognitive function over 24 weeks assessed by a comprehensive battery of cognitive tests, with a secondary exploration of the persistence of change at 36 weeks. Secondary outcomes include changes over 24 and 36 weeks in domain-specific cognitive function; frequency, severity, and impact of urgency-associated urinary symptoms; physical function and balance; sleep quality and daytime sleepiness; psychological function; and bowel function.
DISCUSSION
The TRIUMPH trial addresses the need for rigorous evidence to guide counseling and decision-making for older women who are weighing the potential multisystem benefits and risks of pharmacologic treatments for urgency incontinence in order to preserve their day-to-day functioning, quality of life, and independence in older age.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05362292. Registered on May 5, 2022.
Topics: Humans; Female; Middle Aged; Aged; Tolterodine Tartrate; Muscarinic Antagonists; Urinary Bladder, Overactive; Quality of Life; Prospective Studies; Urinary Incontinence; Cholinergic Antagonists; Adrenergic Agonists; Treatment Outcome; Double-Blind Method; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37085880
DOI: 10.1186/s13063-023-07279-z -
Obesity (Silver Spring, Md.) Jul 2015Mice are typically housed at environmental temperatures below thermoneutrality, whereas humans live near thermoneutrality. This difference affects energy physiology and,... (Comparative Study)
Comparative Study
OBJECTIVE
Mice are typically housed at environmental temperatures below thermoneutrality, whereas humans live near thermoneutrality. This difference affects energy physiology and, potentially, anti-obesity drug efficacy. Here β3-adrenergic agonist treatment at thermoneutrality (30°C) versus room temperature (22°C) is compared.
METHODS
Male C57BL/6J mice were singly housed at 30°C or 22°C and treated with vehicle or CL316243, a β3-agonist, for 4 weeks. Food intake, energy expenditure, body and adipose weight, brown adipose activity, white adipose browning, and glucose tolerance were evaluated. CL316243 treatment was studied in both chow- and high-fat diet-fed mice.
RESULTS
Mice at 30°C, compared to 22°C, had reduced food intake, metabolic rate, and brown adipose activity, as well as increased adiposity. At both temperatures, CL316243 treatment increased brown adipose activation and energy expenditure and improved glucose tolerance. At 30°C, CL316243 increased energy expenditure disproportionately to changes in food intake, thus reducing adiposity, while at 22°C these changes were matched, yielding unchanged adiposity.
CONCLUSIONS
CL316243 treatment can have beneficial metabolic effects in the absence of adiposity changes. In addition, the interaction between environmental temperature and CL316243 treatment is different from the interaction between environmental temperature and 2,4-dinitrophenol treatment reported previously, suggesting that each drug mechanism must be examined to understand the effect of environmental temperature on drug efficacy.
Topics: Adipose Tissue; Adrenergic Agonists; Adrenergic beta-3 Receptor Agonists; Animals; Anti-Obesity Agents; Body Weight; Dioxoles; Eating; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Temperature; Thermogenesis; Weight Loss
PubMed: 26053335
DOI: 10.1002/oby.21124