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1.
Biol Invasions ; 24(10): 3119-3131, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669040

RESUMO

Control of non-native, invasive species in groundwater-dependent ecosystems that are also inhabited by regionally endemic or at-risk species represents a key challenge in aquatic invasive species management. Non-native suckermouth armored catfish (SAC; family Loricariidae) have invaded freshwater ecosystems on a global scale, including the groundwater-dependent upper San Marcos River in Texas, USA. We used passive integrated transponder tags to follow the movements and fates of 65 fish in a 1.6 km spring-fed reach of the upper San Macros River to assess the efficacy of a community-based spearfishing bounty hunt for controlling SAC. We found the weekly probability of SAC survival was negatively correlated with the number of fish removed as a part of the bounty hunt each week (P = 0.003, R 2 = 0.86), while the probability of SAC being speared and reported was positively correlated with the number of fish removed (P = 0.011, R 2 = 0.53). The majority of SAC used < 25 m2 of river over a nine-week tracking period, but the area of river fish used correlated positively with the number of relocations (P < 0.001, R 2 = 0.36) as might be expected for a population that disperses through diffusive spread. These findings collectively suggest local-scale suppression of the SAC population is possible through community engagement in spearfishing, but over longer time periods immigration might offset some of the removal success. This conclusion provides an explanation for the pattern in which long-term spearfishing tournaments have reduced biomass but ultimately not resulted in eradication of the population. Supplementary Information: The online version contains supplementary material available at 10.1007/s10530-022-02834-2.

2.
Endocrinology ; 151(11): 5185-94, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20843999

RESUMO

Previous studies have shown that ß-cell M(3) muscarinic acetylcholine receptors (M3Rs) play a key role in maintaining blood glucose homeostasis by enhancing glucose-dependent insulin release. In this study, we tested the hypothesis that long-term, persistent activation of ß-cell M3Rs can improve glucose tolerance and ameliorate the metabolic deficits associated with the consumption of a high-fat diet. To achieve the selective and persistent activation of ß-cell M3Rs in vivo, we generated transgenic mice that expressed the Q490L mutant M3R in their pancreatic ß-cells (ß-M3-Q490L Tg mice). The Q490L point mutation is known to render the M3R constitutively active. The metabolic phenotypes of the transgenic mice were examined in several in vitro and in vivo metabolic tests. In the presence of 15 mm glucose and the absence of M3R ligands, isolated perifused islets prepared from ß-M3-Q490L Tg mice released considerably more insulin than wild-type control islets. This effect could be completely blocked by incubation of the transgenic islets with atropine (10 µm), an inverse muscarinic agonist, indicating that the Q490L mutant M3R exhibited ligand-independent signaling (constitutive activity) in mouse ß-cells. In vivo studies showed that ß-M3-Q490L Tg mice displayed greatly improved glucose tolerance and increased serum insulin levels as well as resistance to diet-induced glucose intolerance and hyperglycemia. These results suggest that chronic activation of ß-cell M3Rs may represent a useful approach to boost insulin output in the long-term treatment of type 2 diabetes.


Assuntos
Glicemia/metabolismo , Células Secretoras de Insulina/metabolismo , Receptor Muscarínico M3/metabolismo , Análise de Variância , Animais , Atropina/farmacologia , Glicemia/efeitos dos fármacos , Genótipo , Homeostase/efeitos dos fármacos , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Antagonistas Muscarínicos/farmacologia , Fenótipo , Receptor Muscarínico M3/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
Consult Pharm ; 25(2): 105-16, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20211823

RESUMO

OBJECTIVE: To describe the results of an initiative to create awareness of coronary heart disease and provide education regarding cardiovascular (CV) risk and cholesterol (lipid) management in a community-based senior population. A multidisciplinary partnership composed of governmental agencies, a member of the pharmaceutical industry, a college of pharmacy, and several community-based health care practitioners collaborated in the program. DESIGN: Prospective CV risk assessment, educational interventions, and follow-up. SETTING: Community centers providing wellness and activity programs for ambulatory seniors. PATIENTS: Ambulatory senior adults who were active participants in senior center programs were invited to participate in a series of health screenngs at a center-based health fair. Those who met specific evidence-based qualifying criteria were enrolled in the program. MAIN OUTCOME MEASURES: Changes in CV risk profile, specifically, total cholesterol, low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), triglycerides (TG), blood glucose levels; and attainment of National Cholesterol Education Program (NCEP) lipid goals of the Adult Treatment Panel III. RESULTS: Initial screening of 501 patients for eligibility allowed 273 patients to qualify and enroll in the program. A total of 112 (41.0%) participants returned for the year 2 follow-up, leaving a loss to follow-up of 161 patients. Compared with baseline, reductions occurred in total cholesterol (206.8 mg/dL vs.182.9 mg/dL), LDL-C (122.2 mg/dL vs. 105.5 mg/dL), HDL-C (51.5 mg/dL vs. 49.6 mg/dL), TG (164.8 mg/dL vs. 136.4 mg/dL), and blood glucose (115 mg/dL vs. 106.3 mg/dL); the number of patients with less than two risk factors decreased from 43 (38.4%) to 28 (25.0%) and those with two or more risk factors increased from 69 (61.6%) to 84 (75.0%); the number of patients at NCEP (lipid) goal increased from 57 (50.9%) to 80 (71.4%). CONCLUSION: For senior adults participating in the program, improvements occurred in both the lipid profiles and the number of patients at their NCEP (lipid) goal, although the number of seniors with > or = two risk factors increased from 69 (61.6%) to 84 (75.0%). A multidisciplinary partnership for improving the CV health and awareness of an ambulatory senior population is a unique opportunity for pharmacists to provide wellness services for seniors.


Assuntos
Colesterol/sangue , Doença das Coronárias/prevenção & controle , Programas de Rastreamento/métodos , Educação de Pacientes como Assunto/métodos , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/métodos , Assistência Ambulatorial/organização & administração , Comportamento Cooperativo , Doença das Coronárias/etiologia , Medicina Baseada em Evidências , Feminino , Seguimentos , Humanos , Comunicação Interdisciplinar , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Farmacêuticos/organização & administração , Papel Profissional , Estudos Prospectivos , Medição de Risco/métodos , Fatores de Risco
4.
Cell Metab ; 3(6): 449-61, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16753580

RESUMO

One of the hallmarks of type 2 diabetes is that pancreatic beta cells fail to release sufficient amounts of insulin in the presence of elevated blood glucose levels. Insulin secretion is modulated by many hormones and neurotransmitters including acetylcholine, the major neurotransmitter of the peripheral parasympathetic nervous system. The physiological role of muscarinic acetylcholine receptors expressed by pancreatic beta cells remains unclear at present. Here, we demonstrate that mutant mice selectively lacking the M3 muscarinic acetylcholine receptor subtype in pancreatic beta cells display impaired glucose tolerance and greatly reduced insulin release. In contrast, transgenic mice selectively overexpressing M3 receptors in pancreatic beta cells show a profound increase in glucose tolerance and insulin release. Moreover, these mutant mice are resistant to diet-induced glucose intolerance and hyperglycemia. These findings indicate that beta cell M3 muscarinic receptors play a key role in maintaining proper insulin release and glucose homeostasis.


Assuntos
Glicemia/metabolismo , Homeostase , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Receptor Muscarínico M3/fisiologia , Animais , Dieta , Glucose/administração & dosagem , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose/métodos , Hiperinsulinismo/metabolismo , Hipoglicemia/metabolismo , Fosfatos de Inositol/biossíntese , Insulina/administração & dosagem , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Knockout , Agonistas Muscarínicos/farmacologia , Fenótipo , Receptor Muscarínico M3/deficiência , Receptor Muscarínico M3/metabolismo , Fatores de Tempo
5.
J Pharmacol Exp Ther ; 313(3): 995-1002, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15764735

RESUMO

Muscarinic acetylcholine receptors (mAChRs) expressed by pancreatic acinar cells play an important role in mediating acetylcholine-dependent stimulation of digestive enzyme secretion. To examine the potential roles of M(1) and M(3) mAChRs in this activity, we used M(1) and M(3) receptor single knockout (KO) and M(1)/M(3) receptor double KO mice as novel experimental tools. Specifically, we examined the ability of the muscarinic agonist carbachol to stimulate amylase secretion in vitro, using dispersed pancreatic acini prepared from wild-type and mAChR mutant mice. Quantitative reverse transcription-polymerase chain reaction studies using RNA prepared from mouse pancreatic acini showed that deletion of the M(1) or M(3) mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes. Moreover, immunoprecipitation studies with M(1) and M(3) mAChR-selective antisera demonstrated that both mAChR subtypes are expressed by mouse pancreatic acini. Strikingly, carbachol-induced stimulation of amylase secretion was significantly impaired in acinar preparations from both M(1) and M(3) receptor single KO mice and abolished in acinar preparations from M(1)/M(3) receptor double KO mice. However, another pancreatic secretagogue, bombesin, retained its ability to fully stimulate amylase secretion in acinar preparations from M(1)/M(3) receptor double KO mice. Together, these studies support the concept that cholinergic stimulation of pancreatic amylase secretion is mediated by a mixture of M(1) and M(3) mAChRs and that other mAChR subtypes do not make a significant contribution to this activity. These findings clarify the long-standing question regarding the molecular nature of the mAChR subtypes mediating the secretion of digestive enzymes from the exocrine pancreas.


Assuntos
Amilases/metabolismo , Pâncreas Exócrino/enzimologia , Receptor Muscarínico M1/fisiologia , Receptor Muscarínico M3/fisiologia , Amilases/sangue , Animais , Carbacol/farmacologia , Imunoprecipitação , Masculino , Camundongos , Camundongos Knockout , Receptor Muscarínico M1/análise , Receptor Muscarínico M1/genética , Receptor Muscarínico M3/análise , Receptor Muscarínico M3/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
Mol Pharmacol ; 66(2): 260-7, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15266016

RESUMO

Identification of the specific muscarinic acetylcholine receptor (mAChR) subtypes mediating stimulation of salivary secretion is of considerable clinical interest. Recent pharmacological and molecular genetic studies have yielded somewhat confusing and partially contradictory results regarding the involvement of individual mAChRs in this activity. In the present study, we re-examined the roles of M(1) and M(3) mAChRs in muscarinic agonist-mediated stimulation of salivary secretion by using M(1) and M(3) receptor single-knockout (KO) mice and newly generated M(1)/M(3) receptor double-KO mice. When applied at a low dose (1 mg/kg, s.c.), the muscarinic agonist pilocarpine showed significantly reduced secretory activity in both M(1) and M(3) receptor single-KO mice. However, when applied at higher doses, pilocarpine induced only modestly reduced (5 mg/kg, s.c.) or unchanged (15 mg/kg, s.c.) salivation responses, respectively, in M(1) and M(3) receptor single-KO mice, indicating that the presence of either M(1) or M(3) receptors is sufficient to mediate robust salivary output. Quantitative reverse transcriptase-polymerase chain reaction studies with salivary gland tissue showed that the inactivation of the M(1) or M(3) mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes. Strikingly, the sialagogue activity of pilocarpine was abolished in M(1)/M(3) receptor double-KO mice. However, salivary glands from M(1)/M(3) receptor double-KO mice remained responsive to stimulation by the beta-adrenergic receptor agonist, (S)-isoproterenol. Taken together these studies support the concept that a mixture of M(1) and M(3) receptors mediates cholinergic stimulation of salivary flow.


Assuntos
Agonistas Muscarínicos/farmacologia , Pilocarpina/farmacologia , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M3/metabolismo , Glândulas Salivares/metabolismo , Salivação/efeitos dos fármacos , Animais , Sítios de Ligação , Relação Dose-Resposta a Droga , Expressão Gênica , Camundongos , Camundongos Knockout , N-Metilescopolamina/metabolismo , Reação em Cadeia da Polimerase , Receptor Muscarínico M1/deficiência , Receptor Muscarínico M1/genética , Receptor Muscarínico M3/deficiência , Receptor Muscarínico M3/genética , Receptores Colinérgicos/metabolismo , Glândulas Salivares/efeitos dos fármacos , Fatores de Tempo , Trítio
7.
J Biol Chem ; 278(16): 13712-8, 2003 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-12551941

RESUMO

Proteins destined for the mitochondrial matrix space have leader sequences that are typically present at the most N-terminal end of the nuclear-encoded precursor protein. The leaders are rich in positive charges and usually deficient of negative charges. This observation led to the acid-chain hypothesis to explain how the leader sequences interact with negatively charged receptor proteins. Here we show using both chimeric leaders and one from isopropyl malate synthase that possesses a negative charge that the leader need not be at the very N terminus of the precursor. Experiments were performed with modified non-functioning leader sequences fused to either the native or a non-functioning leader of aldehyde dehydrogenase so that an internal leader sequence could exist. The internal leader is sufficient for the import of the modified precursor protein. It appears that this leader still needs to form an amphipathic helix just like the normal N-terminal leaders do. This internal leader could function even if the most N-terminal portion contained negative charges in the first 7-11 residues. If the first 11 residues were deleted from isopropyl malate synthase, the resulting protein was imported more successfully than the native protein. It appears that precursors that carry negatively charged leaders use an internal signal sequence to compensate for the non-functional segment at the most N-terminal portion of the protein.


Assuntos
Mitocôndrias/metabolismo , Sinais Direcionadores de Proteínas , Sequência de Aminoácidos , Sistema Livre de Células , Deleção de Genes , Leucina/química , Espectroscopia de Ressonância Magnética , Malato Sintase/química , Malato Sintase/genética , Dados de Sequência Molecular , Mutação , Plasmídeos/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/metabolismo , Saccharomyces cerevisiae/metabolismo , Homologia de Sequência de Aminoácidos
8.
J Biol Chem ; 277(29): 25963-9, 2002 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-12004058

RESUMO

The critical steps in bile acid metabolism have remarkable differences between humans and mice. It is known that human cholesterol 7 alpha-hydroxylase, the enzyme catalyzing the rate-limiting step of bile acid synthesis, is more sensitive to bile acid suppression. In addition, hepatic bile acid export in humans is more dependent on the bile salt export pump (BSEP). To explore the molecular basis for these species differences, we analyzed the function of the ligand-binding domain (LBD) of human and murine farnesoid X receptor (FXR), a nuclear receptor for bile acids. We observed a strong interspecies difference in bile acid-mediated FXR function; in the coactivator association assay, chenodeoxycholate (CDCA) activated human FXR-LBD with 10-fold higher affinity and 3-fold higher maximum response than murine FXR-LBD. Consistently, in HepG2 cells human FXR-LBD increased reporter expression more robustly in the presence of CDCA. The basis for these differences was investigated by preparing chimeric receptors and by site-directed mutagenesis. Remarkably, the double replacements of Lys(366) and Val(384) in murine FXR (corresponding to Asn(354) and Ile(372) in human FXR) with Asn(366) and Ile(384) explained the difference in both potency and maximum activation; compared with the wild-type murine FXR-LBD, the double mutant gained 8-fold affinity and more than 250% maximum response to CDCA in vitro. This mutant also increased reporter expression to an extent comparable with that of human FXR-LBD in HepG2 cells. These results demonstrate that Asn(354) and Ile(372) are critically important for FXR function and that murine FXR can be "humanized" by substituting with the two corresponding residues of human FXR. Consistent with the difference in FXR-LBD transactivation, CDCA induced endogenous expression of human BSEP by 10-12-fold and murine BSEP by 2-3-fold in primary hepatocytes. This study not only provides the identification of critical residues for FXR function but may also explain the species difference in bile acids/cholesterol metabolism.


Assuntos
Asparagina/fisiologia , Ácido Quenodesoxicólico/farmacologia , Proteínas de Ligação a DNA/efeitos dos fármacos , Isoleucina/fisiologia , Fatores de Transcrição/efeitos dos fármacos , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular , Proteínas de Ligação a DNA/química , Humanos , Ligantes , Fígado/metabolismo , Camundongos , Mutagênese Sítio-Dirigida , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares , Relação Estrutura-Atividade , Fatores de Transcrição/química
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