RESUMO
BACKGROUND: Sub-Saharan Africa continues to face the highest rate of mortality from diabetes in the world due to limited access to quality diabetes care. We assessed the quality of diabetes care in a rural diabetes clinic in western Kenya. METHODS: To provide a comprehensive assessment, a set of clinical outcomes, process, and structure metrics were evaluated to assess the quality of diabetes care provided in the outpatient clinic at Webuye District Hospital. The primary clinical outcome measures were the change in HbA1c and point of care blood glucose. In assessing process metrics, the primary measure was the percentage of patients who were lost to follow up. The structure metrics were assessed by evaluating different facets of the operation of the clinic and their accordance with the International Diabetes Federation (IDF) guidelines. RESULTS: A total of 524 patients were enrolled into the diabetes clinic during the predefined period of evaluation. The overall clinic population demonstrated a statistically significant reduction in HbA1c and point of care blood glucose at all time points of evaluation after baseline. Patients had a mean baseline HbA1C of 10.2% which decreased to 8.4% amongst the patients who remained in care after 18 months. In terms of process measures, 38 patients (7.3%) were characterized as being lost to follow up as they missed clinic visits for more than 6 months. Through the assessment of structural metrics, the clinic met at least the minimal standards of care for 14 out of the 19 domains recommended by the IDF. CONCLUSION: This analysis illustrates the gains made in various elements of diabetes care quality which can be used by other programs to guide diabetes care scale up across the region.
Assuntos
Diabetes Mellitus/terapia , Ambulatório Hospitalar , Qualidade da Assistência à Saúde/estatística & dados numéricos , População Rural , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Criança , Diabetes Mellitus/tratamento farmacológico , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Quênia , Perda de Seguimento , Masculino , Pessoa de Meia-Idade , Ambulatório Hospitalar/normas , Ambulatório Hospitalar/estatística & dados numéricos , Qualidade da Assistência à Saúde/normas , Estudos Retrospectivos , Resultado do TratamentoRESUMO
In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by gastrointestinal-hormones/neurotransmitters and growth factors in a PKC-, Src- and small-GTPase-mediated manner. PAK2 was required for enzyme-secretion and ERK/1-2-activation. In the present study we examined PAK2's role in CCK and TPA-activation of important distal signaling cascades mediating their physiological/pathophysiological effects and analyzed its role in pathophysiological processes important in early pancreatitis. In rat pancreatic acini, PAK2-inhibition by the specific, GP.1.PAK-inhibitor, IPA-3-suppressed cholecystokinin (CCK)/TPA-stimulated activation of focal-adhesion kinases and mitogen-activated protein-kinases. PAK2-inhibition reversed the dual stimulatory/inhibitory effect of CCK/TPA on the PI3K/Akt/GSK-3ß pathway. However, its inhibition did not affect PKC activation. PAK2-inhibition protected acini from CCK-induced ROS-generation; caspase/trypsin-activation, important in early pancreatitis; as well as from cell-necrosis. Furthermore, PAK2-inhibition reduced proteolytic-activation of PAK-2p34, which is involved in programmed-cell-death. To ensure that the study did not only rely in the specificity of IPA-3 as a PAK inhibitor, we used two other approaches for PAK inhibition, FRAX597 a ATP-competitive-GP.1-PAKs-inhibitor and infection with a PAK2-dominant negative(DN)-Advirus. Those two approaches confirmed the results obtained with IPA-3. This study demonstrates that PAK2 is important in mediating CCK's effect on the activation of signaling-pathways known to mediate its physiological/pathophysiological responses including several cellular processes linked to the onset of pancreatitis. Our results suggest that PAK2 could be a new, important therapeutic target to consider for the treatment of diseases involving deregulation of pancreatic acinar cells.
Assuntos
Células Acinares/patologia , Pâncreas/patologia , Pancreatite/patologia , Transdução de Sinais , Quinases Ativadas por p21/metabolismo , Células Acinares/enzimologia , Células Acinares/metabolismo , Animais , Morte Celular , Ativação Enzimática , Masculino , Pâncreas/enzimologia , Pâncreas/metabolismo , Pancreatite/enzimologia , Pancreatite/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
P-21-activated kinases (PAKs) are serine/threonine kinases comprising six isoforms divided in two groups, group-I (PAK1-3)/group-II (PAK4-6) which play important roles in cell cytoskeletal dynamics, survival, secretion and proliferation and are activated by diverse stimuli. However, little is known about PAKs ability to be activated by gastrointestinal (GI) hormones/neurotransmitters/growth-factors. We used rat pancreatic acini to explore the ability of GI-hormones/neurotransmitters/growth-factors to activate Group-I-PAKs and the signaling cascades involved. Only PAK2 was present in acini. PAK2 was activated by some pancreatic growth-factors [EGF, PDGF, bFGF], by secretagogues activating phospholipase-C (PLC) [CCK, carbachol, bombesin] and by post-receptor stimulants activating PKC [TPA], but not agents only mobilizing cellular calcium or increasing cyclic AMP. CCK-activation of PAK2 required both high- and low-affinity-CCK1-receptor-state activation. It was partially reduced by PKC- or Src-inhibition, but not with PI3K-inhibitors (wortmannin, LY294002) or thapsigargin. IPA-3, which prevents PAK2 binding to small-GTPases partially inhibited PAK2-activation, as well as reduced CCK-induced ERK1/2 activation and amylase release induced by CCK or bombesin. This study demonstrates pancreatic acini, possess only one Group-I-PAK, PAK2. CCK and other GI-hormones/neurotransmitters/growth-factors activate PAK2 via small GTPases (CDC42/Rac1), PKC and SFK but not cytosolic calcium or PI3K. CCK-activation of PAK2 showed several novel features being dependent on both receptor-activation states, having PLC- and PKC-dependent/independent components and small-GTPase-dependent/independent components. These results show that PAK2 is important in signaling cascades activated by numerous pancreatic stimuli which mediate their various physiological/pathophysiological responses and thus could be a promising target for the development of therapies in some pancreatic disorders such as pancreatitis.
Assuntos
Hormônios Gastrointestinais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neurotransmissores/metabolismo , Pâncreas Exócrino/enzimologia , Transdução de Sinais/fisiologia , Quinases Ativadas por p21/metabolismo , Animais , Ativação Enzimática/fisiologia , Masculino , Pâncreas Exócrino/citologia , Ratos , Ratos Sprague-DawleyRESUMO
In pancreatic acinar cells, the Src family of kinases (SFK) is involved in the activation of several signaling cascades that are implicated in mediating cellular processes (growth, cytoskeletal changes, apoptosis). However, the role of SFKs in various physiological responses such as enzyme secretion or in pathophysiological processes such as acute pancreatitis is either controversial, unknown, or incompletely understood. To address this, in this study, we investigated the role/mechanisms of SFKs in acute pancreatitis and enzyme release. Enzyme secretion was studied in rat dispersed pancreatic acini, in vitro acute-pancreatitis-like changes induced by supramaximal COOH-terminal octapeptide of cholecystokinin (CCK). SFK involvement assessed using the chemical SFK inhibitor (PP2) with its inactive control, 4-amino-7-phenylpyrazol[3,4-d]pyrimidine (PP3), under experimental conditions, markedly inhibiting SFK activation. In CCK-stimulated pancreatic acinar cells, activation occurred of trypsinogen, various MAP kinases (p42/44, JNK), transcription factors (signal transducer and activator of transcription-3, nuclear factor-κB, activator protein-1), caspases (3, 8, and 9) inducing apoptosis, LDH release reflective of necrosis, and various chemokines secreted (monocyte chemotactic protein-1, macrophage inflammatory protein-1α, regulated on activation, normal T cell expressed and secreted). All were inhibited by PP2, not by PP3, except caspase activation leading to apoptosis, which was increased, and trypsin activation, which was unaffected, as was CCK-induced amylase release. These results demonstrate SFK activation is playing a dual role in acute pancreatitis, inhibiting apoptosis and promoting necrosis as well as chemokine/cytokine release inducing inflammation, leading to more severe disease, as well as not affecting secretion. Thus, our studies indicate that SFK is a key mediator of inflammation and pancreatic acinar cell death in acute pancreatitis, suggesting it could be a potential therapeutic target in acute pancreatitis.
Assuntos
Células Acinares/metabolismo , Pancreatite Necrosante Aguda/metabolismo , Quinases da Família src/metabolismo , Células Acinares/efeitos dos fármacos , Animais , Apoptose , Caspases/metabolismo , Células Cultivadas , Quimiocinas/metabolismo , Colecistocinina/farmacologia , Sistema de Sinalização das MAP Quinases , Masculino , Necrose , Pancreatite Necrosante Aguda/patologia , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição/metabolismo , Tripsinogênio/metabolismo , Quinases da Família src/antagonistas & inibidoresRESUMO
Recent studies report the Src-family kinases (SFK's) are important in a number of physiological and pathophysiological responses of pancreatic acinar cells (pancreatitis, growth, apoptosis); however, the role of SFKs in various signaling cascades important in mediating these cell functions is either not investigated or unclear. To address this we investigated the action of SFKs in these signaling cascades in rat pancreatic acini by modulating SFK activity using three methods: adenovirus-induced expression of an inactive dominant-negative CSK (Dn-CSK-Advirus) or wild-type CSK (Wt-CSK-Advirus), which activate or inhibit SFK, respectively, or using the chemical inhibitor, PP2, with its inactive control, PP3. CCK (0.3, 100 nM) and TPA (1 µM) activated SFK and altered the activation of FAK proteins (PYK2, p125(FAK)), adaptor proteins (p130(CAS), paxillin), MAPK (p42/44, JNK, p38), Shc, PKC (PKD, MARCKS), Akt but not GSK3-ß. Changes in SFK activity by using the three methods of altering SFK activity affected CCK/TPAs activation of SFK, PYK2, p125(FAK), p130(CAS), Shc, paxillin, Akt but not p42/44, JNK, p38, PKC (PKD, MARCKS) or GSK3-ß. With chemical inhibition the active SFK inhibitor, PP2, but not the inactive control analogue, PP3, showed these effects. For all stimulated changes pre-incubation with both adenoviruses showed similar effects to chemical inhibition of SFK activity. In conclusion, using three different approaches to altering Src activity allowed us to define fully for the first time the roles of SFKs in acinar cell signaling. Our results show that in pancreatic acinar cells, SFKs play a much wider role than previously reported in activating a number of important cellular signaling cascades shown to be important in mediating both acinar cell physiological and pathophysiological responses.
Assuntos
Pâncreas/citologia , Pâncreas/metabolismo , Quinases da Família src/metabolismo , Animais , Western Blotting , Colecistocinina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Masculino , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
For growth factors, cytokines, G-protein-coupled receptors and numerous other stimuli, the Src Family of kinases (SFK) play a central signaling role. SFKs also play an important role in pancreatic acinar cell function including metabolism, secretion, endocytosis, growth and cytoskeletal integrity, although the specific SFKs involved are not fully known. In the present study we used specific antibodies for the SFK, Yes, to determine its presence, activation by pancreatic secretagogues or growth factors, and interaction with cellular signaling cascades mediated by CCK in which Yes participates in to cause acinar cell responses. Yes was identified in acini and secretagogues known to activate phospholipase C (PLC) [CCK, carbachol, bombesin] as well as post-receptor stimulants activating PKC [TPA] or mobilizing cellular calcium [thapsigargin/calcium ionophore (A23187)] each activated Yes. Secretin, which activates adenylate cyclase did not stimulate Yes, nor did pancreatic growth factors. CCK activation of Yes required both high- and low-affinity CCK(1)-receptor states. TPA-/CCK-stimulated Yes activation was completely inhibited by thapsigargin and the PKC inhibitor, GF109203X. CCK/TPA stimulated the association of Yes with focal adhesion kinases (Pyk2, FAK) and its autophosphorylated forms (pY397FAK, pY402Pyk2). Moreover, CCK/TPA stimulated Yes interacted with a number of other signaling proteins, including Shc, PKD, p130(Cas), PI3K and PTEN. This study demonstrates that in rat pancreatic acini, the SFK member Yes is expressed and activated by CCK and other gastrointestinal hormones/neurotransmitters. Because its activation results in the direct activation of many cellular signaling cascades that have been shown to mediate CCK's effect in acinar cell function our results suggest that it is one of the important pancreatic SFKs mediating these effects.
Assuntos
Células Acinares/enzimologia , Hormônios Gastrointestinais/fisiologia , Neurotransmissores/fisiologia , Pâncreas/citologia , Proteínas Proto-Oncogênicas c-yes/metabolismo , Animais , Bombesina/farmacologia , Calcimicina/farmacologia , Ionóforos de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Carbacol/farmacologia , Colecistocinina/farmacologia , Colecistocinina/fisiologia , Ativação Enzimática , Quinase 1 de Adesão Focal/metabolismo , Quinase 2 de Adesão Focal/metabolismo , Hormônios Gastrointestinais/farmacologia , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Masculino , Maleimidas/farmacologia , Neurotransmissores/farmacologia , Pâncreas/metabolismo , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/fisiologia , Fosforilação , Proteína Quinase C/antagonistas & inibidores , Processamento de Proteína Pós-Traducional , Ratos , Ratos Sprague-Dawley , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologia , Tapsigargina/farmacologiaRESUMO
Bombesin-receptor-subtype-3 (BRS-3) is an orphan G-protein-coupled receptor of the bombesin (Bn) family whose natural ligand is unknown and which does not bind any natural Bn-peptide with high affinity. It is present in the central nervous system, peripheral tissues, and tumors; however, its role in normal physiology/pathophysiology is largely unknown because of the lack of selective ligands. Recently, MK-5046 [(2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol] and Bantag-1 [Boc-Phe-His-4-amino-5-cyclohexyl-2,4,5-trideoxypentonyl-Leu-(3-dimethylamino) benzylamide N-methylammonium trifluoroacetate], a nonpeptide agonist and a peptide antagonist, respectively, for BRS-3 have been described, but there have been limited studies on their pharmacology. We studied MK-5046 and Bantag-1 interactions with human Bn-receptors-human bombesin receptor subtype-3 (hBRS-3), gastrin-releasing peptide receptor (GRP-R), and neuromedin B receptor (NMB-R)-and compared them with the nonselective, peptide-agonist [d-Tyr6,ßAla11,Phe13,Nle14]Bn-(6-14) (peptide #1). Receptor activation was detected by activation of phospholipase C (PLC), mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK), paxillin, and Akt. In hBRS-3 cells, the relative affinities were Bantag-1 (1.3 nM) > peptide #1 (2 nM) > MK-5046 (37-160 nM) > GRP, NMB (>10 µM), and the binding-dose-inhibition curves were broad (>4 logs), with Hill coefficients differing significantly from unity. Curve-fitting demonstrated high-affinity (MK-5046, Ki = 0.08 nM) and low-affinity (MK-5046, Ki = 11-29 nM) binding sites. For PLC activation in hBRS-3 cells, the relative potencies were MK-5046 (0.02 nM) > peptide #1 (6 nM) > GRP, NMB, Bantag-1 (>10 µM), and MK-5046 had a biphasic dose response, whereas peptide #1 was monophasic. Bantag-1 was a specific hBRS-3-antagonist. In hBRS-3 cells, MK-5046 was a full agonist for activation of MAPK, FAK, Akt, and paxillin; however, it was a partial agonist for phospholipase A2 (PLA2) activation. The kinetics of activation/duration of action for PLC/MAPK activation of MK-5046 and peptide #1 differed, with peptide #1 causing more rapid stimulation; however, MK-5046 had more prolonged activity. Our study finds that MK-5046 and Bantag-1 have high affinity/selectivity for hBRS-3. The nonpeptide MK-5046 and peptide #1 agonists differ markedly in their receptor coupling, ability to activate different signaling cascades, and kinetics/duration of action. These results show that their hBRS-3 receptor activation is not always concordant and could lead to markedly different cellular responses.
Assuntos
Imidazóis/farmacologia , Pirazóis/farmacologia , Receptores da Bombesina/agonistas , Receptores da Bombesina/antagonistas & inibidores , Células 3T3 , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Imidazóis/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Pirazóis/metabolismo , Receptores da Bombesina/metabolismoRESUMO
Pituitary adenylate cyclase-activating polypeptide (PACAP) is an autocrine growth factor for some lung cancer cells. The activated PACAP receptor (PAC1) causes phosphatidylinositol turnover, elevates cAMP, and increases the proliferation of lung cancer cells. PAC1 and epidermal growth factor receptor (EGFR) are present in non-small-cell lung cancer (NSCLC) cells, and the growth of NSCLC cells is inhibited by the PAC1 antagonist PACAP(6-38) and the EGFR tyrosine kinase inhibitor gefitinib. Here, the ability of PACAP to transactivate the EGFR was investigated. Western blot analysis indicated that the addition of PACAP but not the structurally related vasoactive intestinal peptide increased EGFR tyrosine phosphorylation in NCI-H838 or H345 cells. PACAP-27, in a concentration-dependent manner, increased EGFR transactivation 4-fold 2 min after addition to NCI-H838 cells. The ability of 100 nM PACAP-27 to increase EGFR or extracellular signal-regulated kinase tyrosine phosphorylation in NCI-H838 cells was inhibited by PACAP(6-38), gefitinib, 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2; Src inhibitor), (R)-N4-hydroxy-N1-[(S)-2-(1H-indol-3-yl)-1-methylcarbamoyl-ethyl]-2-isobutyl-succinamide (GM6001; matrix metalloprotease inhibitor), or antibody to transforming growth factor α (TGFα). By enzyme-linked immunosorbent assay, PACAP addition to NCI-H838 cells increased TGFα secretion into conditioned media. EGFR transactivation caused by the addition of PACAP to NCI-H838 cells was inhibited by N-acetyl-cysteine (antioxidant), tiron (superoxide scavenger), diphenylene iodonium (NADPH oxidase inhibitor), or 1-[6-[[(17ß)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122; phospholipase C inhibitor), but not N-[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide (H89; protein kinase A inhibitor). PACAP addition to NCI-H838 cells significantly increased reactive oxygen species, and the increase was inhibited by tiron. The results indicate that PACAP causes transactivation of the EGFR in NSCLC cells in an oxygen-dependent manner that involves phospholipase C but not protein kinase A.
Assuntos
Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Tirosina/metabolismo , Western Blotting , Ensaio de Imunoadsorção Enzimática , Humanos , Fosforilação , Células Tumorais Cultivadas/metabolismoRESUMO
Low socioeconomic status is associated with late cancer diagnosis and mortality in Argentina. It is important that cancer screening services are accessible to the whole population so that cancer can be detected early. Our aim in this study was to investigate socioeconomic determinants for the disparities in the use of breast, cervical, and colorectal cancer screening services in Argentina, and to measure the country progress in reducing differences in cancer screening participation across socioeconomic levels. We performed a secondary analysis of cross-sectional data from the 2018 National Survey of Risk Factors of Argentina. The sample included data from 49,170 households. We also compared the results with data from the 2013 wave of the same survey in order to assess progress on cancer screening participation across income and education categories. Income, education, health insurance, disability, and marital status were associated with cancer screening underuse in Argentina. Comparison between 2013 and 2018 demonstrated that there has been some progress toward increasing cancer screening uptake, but this increase is not equitably distributed across the population. To further reduce disparities in cancer participation across socioeconomic levels, cancer screening programs in Argentina should reinforce strategies to become more accessible. It is important to proactively reach those populations that are underusers of cancer screening and ensure that barriers that stop people from accessing cancer screening are explored and adequately addressed.
Assuntos
Detecção Precoce de Câncer , Neoplasias do Colo do Útero , Argentina/epidemiologia , Estudos Transversais , Feminino , Humanos , Fatores SocioeconômicosRESUMO
We carried out a systematic review to summarize available data regarding prevalence of high-risk human papillomavirus (HR-HPV) among women living with HIV (WLHIV) in Latin America and the Caribbean (LAC). A literature search in PubMed and LILACS was conducted and supplemented with cross-referencing and grey literature. The primary outcome was prevalence of HR-HPV by age as a major determinant of HPV infection. Pooled prevalence and weighted averages were obtained. A random effects meta-analysis conducted for HPV- and HIV-associated factors. In total, 6157 women from 19 cross-sectional studies were included. Weighted prevalence of HR-HPV in WLHIV was 51.0% (95% CI 42.8-59.1, I2 = 97.4%) with a bimodal trend by age. No association between antiretroviral therapy and HR-HPV prevalence was observed, but low CD4 cell count was associated (PR 1.64, 95% CI 1.07-2.52). Although not significant, a higher HR-HPV prevalence was observed with Hybrid Capture 2 versus PCR. The high prevalence of HR-HPV among WLHIV in LAC underlines the need for improved cervical cancer prevention and early detection in this vulnerable population. Moreover, the high prevalence across age groups, and particularly in young women, deserves careful consideration for defining target populations of HPV-based screening and HPV immunization programs.
Assuntos
Infecções por HIV , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Contagem de Linfócito CD4 , Estudos Transversais , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , América Latina/epidemiologia , Papillomaviridae/genética , Prevalência , Neoplasias do Colo do Útero/epidemiologiaRESUMO
Glucagon-like peptide 1 (GLP-1) controls glucose metabolism in extrapancreatic tissues through receptors other than the pancreatic cAMP-linked GLP-1 receptor; also, GLP-1 induces an insulin- and PTH-independent bone anabolic action in insulin-resistant and type-2 diabetic rats. Here we searched for the presence and characteristics of GLP-1 receptors in osteoblastic MC3T3-E1 cells. [(125)I]-GLP-1 specific binding to MC3T3-E1 cells was time- and temperature-dependent, reaching maximal value at 30 min at 25 degrees C; in these conditions, [(125)I]-GLP-1 binding was dissociable, and displaced by GLP-1, partially by GLP-2, but not by exendin-4 (Ex-4), exendin-9 (Ex-9), glucagon or insulin; Scatchard analysis of the unlabeled GLP-1 data showed high and low affinity binding sites; cross-linking of GLP-1 binding revealed an estimated 70 kDa band, almost undetectable in the presence of 10(-6) M GLP-1. GLP-1, Ex-9, insulin or glucagon failed to modify cellular cAMP content, while GLP-2 and Ex-4 increased it. However, GLP-1 induced an immediate hydrolysis of glycosylphosphatidylinositols (GPIs) generating short-lived inositolphosphoglycans (IPGs), and an increase in phosphatidylinositol-3 kinase (PI3K) and mitogen activated protein kinase (MAPK) activities; Ex-4 also affected GPIs, but its action was delayed with respect to that of GLP-1. This incretin was found to decrease Runx2 but increased osteocalcin gene expression, without affecting that of osteoprotegerin or the canonical Wnt pathway activity in MC3T3-E1 cells which do not express the pancreatic GLP-1 receptor. Our data demonstrate for the first time that GLP-1 can directly and functionally interact with osteoblastic cells, possibly through a GPI/IPG-coupled receptor.
Assuntos
AMP Cíclico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Osteoblastos/metabolismo , Receptores de Glucagon/metabolismo , Células 3T3 , Adenilil Ciclases/metabolismo , Animais , Colforsina/farmacologia , Exenatida , Regulação da Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Camundongos , Osteoblastos/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Peptídeos/farmacologia , Ligação Proteica , Ratos , Receptores de Glucagon/genética , Peçonhas/farmacologiaRESUMO
It has been suggested that hormones released after nutrient absorption, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 2 (GLP-2), could be responsible for changes in bone resorption. However, information about the role of GLP-1 in this regard is scanty. Diabetes-related bone loss occurs as a consequence of poor control of glucose homeostasis, but the relationship between osteoporosis and type 2 diabetes remains unclear. Since GLP-1 is decreased in the latter condition, we evaluated some bone characteristics in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rat models compared to normal (N) and the effect of GLP-1 or saline (control) treatment (3 days by osmotic pump). Blood was taken before and after treatment for plasma measurements; tibiae and femora were collected for gene expression of bone markers (RT-PCR) and structure (microCT) analysis. Compared to N, plasma glucose and insulin were, respectively, higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b were lower; phosphate in IR showed a tendency to be higher; PTH was not different in T2D and IR; all parameters were unchanged after GLP-1 infusion. Bone OC, osteoprotegerin (OPG) and RANKL mRNA were lower in T2D and IR; GLP-1 increased OC and OPG in all groups and RANKL in T2D. Compared to N, trabecular bone parameters showed an increased degree of anisotropy in T2D and IR, which was reduced after GLP-1. These findings show an insulin-independent anabolic effect of GLP-1 and suggest that GLP-1 could be a useful therapeutic agent for improving the deficient bone formation and bone structure associated with glucose intolerance.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Diabetes Mellitus Tipo 2/complicações , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Resistência à Insulina , Fragmentos de Peptídeos/uso terapêutico , Fosfatase Ácida/sangue , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/patologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/ultraestrutura , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Insulina/sangue , Isoenzimas/sangue , Masculino , Osteocalcina/sangue , Osteocalcina/metabolismo , Osteoprotegerina/metabolismo , Hormônio Paratireóideo/sangue , Fragmentos de Peptídeos/metabolismo , Ligante RANK/metabolismo , Ratos , Ratos Wistar , Fosfatase Ácida Resistente a TartaratoRESUMO
Exendin-4, like GLP-1, is insulinotropic, antidiabetic and glucoregulatory among other properties, which are thought to be exerted through the pancreatic GLP-1 receptor; exendin-4 is also an agonist of the GLP-1 stimulatory action upon liver and muscle glucose metabolism, where GLP-1 receptor is distinct from that in the pancreas. We investigated the action of prolonged treatment with exendin-4 upon glucose transport parameters in skeletal muscle and liver of normal rats and streptozotocin-induced type 2 diabetic rats (T2D). Muscle of T2D showed lower than normal glucose transport; exendin-4 did not modify the value in normal but normalized that in the T2D; unlike previously detected with GLP-1, no apparent modification was observed in GLUT-4 expression in either group after exendin-4, except for an increased GLUT-4 protein in normal rats. Yet, exendin-4 significantly stimulated liver GLUT-2-mRNA and -protein in T2D and normal rats, the effect upon GLUT-2-protein in T2D being higher than that in normal animals; this was accompanied by a normalizing action of exendin-4 upon the lower than normal liver glycogen in T2D rats. These data suggest that the liver may represent at least one of the major target organs for exendin-4 to exert its plasma lowering effect in diabetic state.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Fígado , Músculo Esquelético , Peptídeos/farmacologia , Peçonhas/farmacologia , Animais , Diabetes Mellitus Experimental , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glicogênio/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar , Receptores de Glucagon/metabolismoRESUMO
INTRODUCTION: Cancer incidence and mortality in Latin America are rising. While effective cancer screening services, accessible to the whole population and enabling early cancer detection are needed, existing research shows the existence of disparities in screening uptake in the region. OBJECTIVE: We conducted a systematic review to investigate the socioeconomic determinants for the disparities in the use of breast, cervical and colorectal cancer screening services in Latin America. METHODS: We searched for studies reporting on socioeconomic determinants impacting on access to breast, cervical and colorectal cancer screening, published from 2009 through 2018. The studies that qualified for inclusion contained original analyses on utilisation of breast, cervical and colorectal cancer screening across socioeconomic levels in Latin America. For each study, paired reviewers performed a quality analysis followed by detailed review and data extraction. RESULTS: Twenty-four articles that met the eligibility criteria and were of sufficient quality were included in this review. Thirteen of the included articles were written in English, eight in Portuguese and three in Spanish, and they reported on the use of breast or cervical cancer screening. No studies were found on the socioeconomic determinants regarding the utilisation of colorectal cancer screening in Latin America. Low income, low education level, lack of health insurance and single marital status were all found to be determinants of underuse of breast and cervical cancer screening services. CONCLUSIONS: Cancer screening programs in the region must prioritize reaching those populations that underuse cancer screening services to ensure equitable access to preventive services. It is important to develop national screening programmes that are accessible to all (including uninsured people) through, for example, the use of mobile units for mammography and self-screening methods.
Assuntos
Programas de Rastreamento/economia , Neoplasias/diagnóstico , Fatores Socioeconômicos , Escolaridade , Humanos , Renda , Seguro Saúde , América Latina/epidemiologia , Estado Civil , Neoplasias/epidemiologiaRESUMO
[This corrects the article DOI: 10.1155/2018/9262395.].
RESUMO
Background: Effective health systems are needed to care for the coming surge of diabetics in sub-Saharan Africa (SSA). Objective: We conducted a systematic review of literature to determine the capacity of SSA health systems to manage diabetes. Methodology: We used three different databases (Embase, Scopus, and PubMed) to search for studies, published from 2004 to 2017, on diabetes care in SSA. Results: Fifty-five articles met the inclusion criteria, covering the different aspects related to diabetes care such as availability of drugs and diagnostic tools, the capacity of healthcare workers, and the integration of diabetes care into HIV and TB platforms. Conclusion: Although chronic care health systems in SSA have developed significantly in the last decade, the capacity for managing diabetes remains in its infancy. We identified pilot projects to enhance these capacities. The scale-up of these pilot interventions and the integration of diabetes care into existing robust chronic disease platforms may be a feasible approach to begin to tackle the upcoming pandemic in diabetes. Nonetheless, much more work needs to be done to address the health system-wide deficiencies in diabetes care. More research is also needed to determine how to integrate diabetes care into the healthcare system in SSA.
Assuntos
Atenção à Saúde , Diabetes Mellitus/terapia , África Subsaariana , Gerenciamento Clínico , Humanos , PandemiasRESUMO
OBJECTIVE: To appropriately identify and treat noncommunicable diseases (NCDs) among persons living with HIV (PLHIV) in low-and-middle-income countries (LMICs), it is imperative to understand the burden of NCDs among PLHIV in LMICs and the current management of the diseases. DESIGN: Systematic review and meta-analysis. METHODS: We examined peer-reviewed literature published between 1 January 2010 and 31 December 2016 to assess currently available evidence regarding HIV and four selected NCDs (cardiovascular disease, cervical cancer, depression, and diabetes) in LMICs with a focus on sub-Saharan Africa. The databases, PubMed/MEDLINE, Cochrane Review, and Scopus, were searched to identify relevant literature. For conditions with adequate data available, pooled estimates for prevalence were generated using random fixed effects models. RESULTS: Six thousand one hundred and forty-three abstracts were reviewed, 377 had potentially relevant prevalence data and 141 were included in the summary; 57 were selected for quantitative analysis. Pooled estimates for NCD prevalence were hypertension 21.2% (95% CI 16.3-27.1), hypercholesterolemia 22.2% (95% CI 14.7-32.1), elevated low-density lipoprotein 23.2% (95% CI 15.2-33.6), hypertriglyceridemia 27.2% (95% CI 20.7-34.8), low high-density lipoprotein 52.3% (95% CI 35.6-62.8), obesity 7.8% (95% CI 4.3-13.9), and depression 24.4% (95% CI 12.5-42.1). Invasive cervical cancer and diabetes prevalence were 1.3-1.7 and 1.3-18%, respectively. Few NCD-HIV integrated programs with screening and management approaches that are contextually appropriate for resource-limited settings exist. CONCLUSION: Improved data collection and surveillance of NCDs among PLHIV in LMICs are necessary to inform integrated HIV/NCD care models. Although efforts to integrate care exist, further research is needed to optimize the efficacy of these programs.
Assuntos
Doenças Cardiovasculares/epidemiologia , Depressão/epidemiologia , Diabetes Mellitus/epidemiologia , Infecções por HIV/complicações , Neoplasias do Colo do Útero/epidemiologia , Adulto , África Subsaariana/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Países em Desenvolvimento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
PURPOSE OF REVIEW: To summarize the roles of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase activating polypeptide (PACAP) and their receptors (VPAC1, VPAC2, PAC1) in human tumors as well as their role in potential novel treatments. RECENT FINDINGS: Considerable progress has been made in understanding of the effects of VIP/PACAP on growth of various tumors as well as in the signaling cascades involved, especially in the role of transactivation of the epidermal growth factor family. The overexpression of VPAC1/2 and PAC1 on a number of common neoplasms (breast, lung, prostate, central nervous system and neuroblastoma) is receiving increased attention both as a means of tumor imaging the location and extent of these tumors, as well as for targeted directed treatment, by coupling cytotoxic agents to VIP/PACAP analogues. SUMMARY: VIP/PACAP has prominent growth effects on a number of common neoplasms, which frequently overexpressed the three subtypes of their receptors. The increased understanding of their signaling cascades, effect on tumor growth/differentiation and the use of the overexpression of these receptors for localization/targeted cytotoxic delivery are all suggesting possible novel tumor treatments.
Assuntos
Neoplasias/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , HumanosRESUMO
Lung cancer kills approximately 1.3 million citizens in the world annually. The tyrosine kinase inhibitors (TKI) erlotinib and gefitinib are effective anti-tumor agents especially in lung cancer patients with epidermal growth factor receptor (EGFR) mutations. The goal is to increase the potency of TKI in lung cancer patients with wild type EGFR. G protein-coupled receptors (GPCR) transactivate the wild type EGFR in lung cancer cells. The GPCR can be activated by peptide agonists causing phosphatidylinositol turnover or stimulation of adenylylcyclase. Recently, nonpeptide antagonists were found to inhibit the EGFR transactivation caused by peptides. Nonpeptide antagonists for bombesin (BB), neurotensin (NTS) and cholecystokinin (CCK) inhibit lung cancer growth and increase the cytotoxicity of gefitinib. The results suggest that GPCR transactivation of the EGFR may play an important role in cancer cell proliferation.
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Antineoplásicos/farmacologia , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Antineoplásicos/uso terapêutico , Bombesina/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Colecistocinina/antagonistas & inibidores , Sinergismo Farmacológico , Gefitinibe , Humanos , Neoplasias Pulmonares/metabolismo , Neurotensina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêuticoRESUMO
Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor which is classified in the bombesin receptor (BnR) family with which it shares high homology. It is present widely in the central nervous system and peripheral tissues and primarily receptor-knockout studies suggest it is involved in metabolic-glucose-insulin homeostasis, feeding and other CNS behaviors, gastrointestinal motility and cancer growth. However, the role of BRS-3 physiologically or in pathologic disorders has been not well defined because the natural ligand is unknown. Until recently, no selective agonists/antagonists were available; however, recently synthetic high-affinity agonists, chiral-diazepines nonpeptide-analogs (3F, 9D, 9F, 9G) with low CNS penetrance, were described, but are not well-categorized pharmacologically or in different labarotory species. The present study characterizes the affinities, potencies, selectivities of the chiral-diazepine BRS-3 agonists in human and rodents (mice,rat). In human BRS-3 receptors, the relative affinities of the chiral-diazepines was 9G>9D>9F>3F; each was selective for BRS-3. For stimulating PLC activity, in h-BRS-3 each of the four chiral diazepine analogs was fully efficacious and their relative potencies were: 9G (EC50: 9 nM)>9D (EC50: 9.4 nM)>9F (EC50: 39 nM)>3F (EC50: 48 nM). None of the four chiral diazepine analogs activated r,m,h-GRPR/NMBR. The nonpeptide agonists showed marked differences from each other and a peptide agonist in receptor-coupling-stiochiometry and in affinities/potencies in different species. These results demonstrate that chiral diazepine analogs (9G, 9D, 9F, 3F) have high/affinity/potency for the BRS-3 receptor in human and rodent cells, but different coupling-relationships and species differences from a peptide agonist.