Análisis cienciométrico de la producción científica sobre la hipoxantina y xantina en el ejercicio, publicada en la base de datos Scopus (2016-2021) / Scientometric Analysis of the Scientific Production on Hypoxanthine and Xanthine in Exercise, Published in Scopus Database (2016-2021)

La hipoxantina y la xantina son biomarcadores metabólicos que resultan de la degradación de las proteínas purinas. Los análisis cienciométricos constituyen una herramienta para estudiar las publicaciones científicas en torno a un determinado tema con la finalidad de determinar tendencias en la literatura. Se realizó un análisis cienciométrico de la producción científica reciente sobre la hipoxantina y xantina en el ejercicio, publicada en la base de datos Scopus durante el período 2016 - 2021. Para la búsqueda en Scopus se utilizaron las palabras clave en idioma inglés: exercise, hypoxanthine y xanthine. Se realizó un análisis cuantitativo, tomando en cuenta los artículos encontrados, así como la información proporcionada por el software VOSviewer. Se identificaron 64 artículos, de estos, 56 fueron de investigación aplicada y ocho de revisión. La categoría de efecto del ejercicio tuvo una mayor cantidad de estudios con 23; dentro de esta se encuentra la subcategoría de metabolismo que presentó 21 artículos. Tanto Estados Unidos como Polonia son los países con mayor número de publicaciones. Existen distintos enfoques y protocolos de ejercicio utilizados para cuantificar la respuesta de la hipoxantina y xantina, así como los perfiles de los sujetos de estudio utilizados como muestra para las investigaciones. La cuantificación de hipoxantina y xantina en el cuerpo es importante para la investigación en el campo de las ciencias del ejercicio(AU)

Hypoxanthine and xanthine are metabolic biomarkers that result from the degradation of purine proteins. Scientometric analyzes constitute a tool to study scientific publications around a certain topic in order to determine trends in the literature. A scientometric analysis was carried out of the recent scientific production on hypoxanthine and xanthine in exercise, published in Scopus database during the period 2016-2021. For the search in Scopus, we used the English keywords exercise, hypoxanthine and xanthine. A quantitative analysis was carried out, taking into account the articles found, as well as the information provided by VOSviewer software. Sixty-four articles were identified, 56 of them were applied research and eight were review. The exercise effect category had a larger number of studies (23). Here there is a subcategory of metabolism that had 21 articles. The United States and Poland are both the countries with the highest number of publications. There are different approaches and exercise protocols used to quantify the response of hypoxanthine and xanthine, as well as the profiles of the study subjects used as a sample for the investigations. The quantification of hypoxanthine and xanthine in the body is important for research in the field of exercise science(AU)

Ilex paraguariensis: the effect of genotypes and growth phase on biomass, secondary metabolism and antioxidant activity of in vitro cultivated calli / Ilex paraguariensis: el efecto de los genotipos y la fase de crecimiento sobre la biomasa, metabolismo secundario y la actividad antioxidante de los callos cultivados in vitro

Yerba mate ( Ilex paraguariensis ) produces several secondary metabolites of interest to the phar maceutical industry, such as chlorogenic acids and methylxanthines. These compounds have been produced in vitro by callus culture from different species. However, for I. paraguariensis , no studies upon the production of these compounds in vitro have been p erformed to date. In this work, we show that the concentration of secondary metabolites from I. paraguariensis callus is possible and highly dependent on the callus growth phase. We observed that the best phase for the production of secondary compounds in calli of yerba mate is the stationary growth phase on both genotypes tested. In this phase, higher levels of phenolic compounds, chlorogenic acid and 3,5 - dicaffeoylquinic acid and greater antioxidant activity were observed. Chlorogenic acid and 3,5 - dicaffe oylquinic acid presented positive correlation with antioxidant activity. For the first time, secondary compounds were reported in yerba mate calli cultivated in vitro .

La yerba mate ( Ilex paraguariensis ) produce varios metabolitos secundarios de interés para la industria farmacéutica, como los ácidos clorogénicos y las metilxantinas. Estos compuestos se han producido in vitro mediante cultivo de ca llos de diferentes especies. Sin embargo, para I. paraguariensis , hasta la fecha no se han realizado estudios sobre la producción de estos compuestos in vitro . En este trabajo, mostramos que la concentración de metabolitos secundarios desde callos de I. pa raguariensis es posible y altamente dependiente de la fase de crecimiento del callo. Observamos que la mejor fase para la producción de compuestos secundarios en callos de yerba mate es la fase de crecimiento estacionario en ambos genotipos probados. En es ta fase se observaron niveles más altos de compuestos fenólicos, ácido clorogénico y ácido 3,5 - dicafeoilquínico y una mayor actividad antioxidante. El ácido clorogénico y el ácido 3,5 - dicafeoilquínico presentaron correlación positiva con la actividad antio xidante. Por primera vez, se reportaron compuestos secundarios en callos de yerba mate cultivados in vitro .

Involvement of adenosine A1 receptor in electroacupuncture-mediated inhibition of astrocyte activation during neuropathic pain / Envolvimento do receptor de adenosina A1 na inibição da ativação de astrócitos mediada por eletroacupuntura durante a dor neuropática

ABSTRACT Neuropathic pain is a chronic pain condition caused by damage or dysfunction of the central or peripheral nervous system. Electroacupuncture (EA) has an antinociceptive effect on neuropathic pain, which is partially due to inhibiting astrocyte activation in the spinal cord. We found that an intrathecal injection of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist, reversed the antinociceptive effects of EA in a chronic constriction injury-induced neuropathic pain model. The expression of GFAP in L4-L6 spinal cord was significantly upgraded, while DPCPX suppressed the effect of the EA-mediating inhibition of astrocyte activation, as well as wiping out the EA-induced suppression of cytokine content (TNF-α). These results indicated that the adenosine A1 receptor is involved in EA actions during neuropathic pain through suppressing astrocyte activation as well as TNF-α upregulation of EA, giving enlightenment to the mechanisms of acupuncture analgesia and development of therapeutic targets for neuropathic pain.

RESUMO A dor neuropática é uma condição de dor crônica causada por dano ou disfunção do sistema nervoso central ou periférico. A eletroacupuntura (EA) tem um efeito antinociceptivo durante a dor neuropática, que é parcialmente devido à inibição da ativação de astrócitos na medula espinhal. Descobrimos que a injeção intratecal de 8-ciclopentil-1,3-dipropilxantina (DPCPX), um antagonista seletivo do receptor de adenosina A1, reverteu os efeitos antinociceptivos da EA no modelo de dor neuropática induzida por lesão por constrição crônica (CCI). A expressão da GFAP na medula espinal L4-L6 foi significativamente melhorada, enquanto a DPCPX suprimiu o efeito da inibição mediadora da EA na ativação de astrócitos, bem como eliminou a supressão induzida pela EA do conteúdo de citocina (TNF-α). Esses resultados indicam que o receptor de adenosina A1 está envolvido nas ações da EA durante a dor neuropática, suprimindo a ativação astrocitária, bem como o aumento da TNF-α na EA, fornecendo esclarecimentos sobre os mecanismos de analgesia da acupuntura e o desenvolvimento de alvos terapêuticos para dor neuropática.

Propentofylline decreases hypothalamic astrogliosis induced by hypercaloric diet in the rat / A propentofilina diminui a astrogliose hipotalâmica induzida pela dieta hipercalórica no rato

ABSTRACT Obesity is associated with a chronic and low-grade inflammatory response in the hypothalamus, where astrogliosis occurs with the upregulation of the astrocyte structural protein GFAP. As propentofylline (PPF) has inhibitory effects on astrocyte and microglial activation during inflammation, this study aimed to investigate if this xanthine derivative could decrease the astrocyte reaction induced by a hypercaloric diet (HD). Male Wistar rats were divided into four groups: NDS - rats receiving a normocaloric diet (ND) and daily saline solution; NDP - rats receiving ND and daily PPF (12.5 mg/kg/day, intraperitoneal route); HDS - rats receiving HD and saline solution, HDP - rats receiving HD and PPF. On the 21st day, rats were anesthetized, and perfused, and brains were collected for GFAP immunohistochemical study in the hypothalamus. Results showed that HD induced increased weight gain and hypothalamic astrogliosis. Propentofylline decreased the expression of GFAP in the HDP group, although it did not affect the weight gain induced by this diet.

RESUMO A obesidade está associada com uma resposta inflamatória crônica e de baixo grau no hipotálamo, onde ocorre astrogliose com a superexpressão da proteína astrocitária GFAP. Como a propentofilina (PPF) possui efeitos inibitórios sobre a ativação astrocitária e microglial durante a inflamação, este estudo visou a investigar se esta xantina podia diminuir a reação astrocitária induzida pela dieta hipercalórica (HD). Ratos Wistar machos foram divididos em 4 grupos: NDS- ratos recebendo dieta normocalórica (ND) e solução salina diária; NDP- ratos recebendo ND e PPF diária (12.5 mg/kg/dia, via intraperitoneal); HDS- ratos recebendo HD e solução salina, HDP- ratos recebendo HD e PPF. No 21° dia, os ratos foram perfundidos e os encéfalos, coletados para estudo imuno-histoquímico para a GFAP no hipotálamo. Os resultados mostram que a HD induziu aumento do ganho de peso e astrogliose no hipotálamo. A PPF diminuiu a expressão de GFAP no grupo HD, embora não tenha afetado o ganho de peso induzido por esta dieta.

Propentofylline reduces glial scar development following gliotoxic damage in the rat brainstem / Propentofilina reduz o desenvolvimento da cicatriz glial após dano gliotóxico no tronco encefálico de ratos

ABSTRACT Propentofylline is a xanthine derivative that depresses activation of glial cells, whose responses contribute to neural tissue damage during inflammation. Ethidium bromide injection into the central nervous system induces local oligodendroglial and astrocytic loss, resulting in primary demyelination, neuroinflammation and blood-brain barrier disruption. Surviving astrocytes present a vigorous reaction around the injury site with increased immunoreactivity to glial fibrillary acidic protein (GFAP). Objective This study aimed to evaluate the effect of propentofylline administration on astrocytic response following gliotoxic injury. Method Wistar rats were injected with ethidium bromide into the cisterna pontis and treated or not with propentofylline (12.5mg/kg/day, intraperitoneal) during the experimental period. Brainstem sections were collected from 15 to 31 days after gliotoxic injection and processed for GFAP immunohistochemistry. Results and Conclusion Results demonstrate that propentofylline decreased astrocytic activation until the 21st day, suggesting that this drug may have a role in reducing glial scar development following injury.

RESUMO A propentofilina é uma xantina que deprime a ativação das células gliais, cujas respostas contribuem para o dano neural durante inflamação. A injeção de brometo de etídio no sistema nervoso central induz a perda oligodendroglial e astrocitária, resultando em desmielinização, neuroinflamação e ruptura da barreira hematoencefálica. Os astrócitos sobreviventes apresentam vigorosa reação ao redor da lesão com aumento da imunorreatividade à proteína glial fibrilar ácida (GFAP). Objetivo Este estudo objetivou avaliar o efeito da propentofilina sobre a resposta astrocitária após injúria gliotóxica. Método Ratos Wistar foram injetados com brometo de etídio na cisterna basal e tratados ou não com propentofilina (12.5mg/kg/dia, intraperitoneal). Amostras do tronco encefálico foram coletadas dos 15 aos 31 dias pós-injeção do gliotóxico e processadas para estudo ultraestrutural e imuno-histoquímico para GFAP. Resultados e Conclusão Os resultados demonstram que a propentofilina reduziu a ativação astrocitária até o 21o dia, sugerindo que essa droga pode atuar na redução da cicatriz glial após injúria.

Propentofylline reverses delayed remyelination in streptozotocin-induced diabetic rats

Objective The diabetic state induced by streptozotocin injection is known to impair oligodendroglial remyelination in the rat brainstem following intracisternal injection with the gliotoxic agent ethidium bromide (EB). In such experimental model, propentofylline (PPF) recently showed to improve myelin repair, probably due to its neuroprotective, antiinflammatory and antioxidant effects. The aim of this study was to evaluate the effect of PPF administration in diabetic rats submitted to the EB-demyelinating model. Materials and methods Adult male rats, diabetic or not, received a single injection of 10 microlitres of 0.1% EB solution into the cisterna pontis. For induction of diabetes mellitus the streptozotocin-diabetogenic model was used (50 mg/kg, intraperitoneal route – IP). Some diabetic rats were treated with PPF (12.5 mg/kg/day, IP route) during the experimental period. The animals were anesthetized and perfused from 7 to 31 days after EB injection and brainstem sections were collected for analysis of the lesions by light and transmission electron microscopy. Results Diabetic rats injected with EB showed larger amounts of myelin-derived membranes in the central areas of the lesions and considerable delay in the remyelinating process played by surviving oligodendrocytes and invading Schwann cells after the 15th day. On the other hand, diabetic rats that received PPF presented lesions similar to those of non-diabetic animals, with rapid remyelination at the edges of the lesion site and fast clearance of myelin debris from the central area. Conclusion The administration of PPF apparently reversed the impairment in remyelination induced by the diabetic state. Arch Endocrinol Metab. 2015;59(1):47-53 .

Adenosine Al Receptor Mediated Neuroprotection of Shenmai Injection on Rat Cerebral Ischemia/Reperfusion Injury: an Experimental Study / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe whether adenosine Al receptor (Al R) mediated neuroprotection of Shenmai Injection (SI) on rat cerebral ischemia/reperfusion (I/R) injury.</p><p><b>METHODS</b>The focal cerebral I/R model was established by middle cerebral artery occlusion (MCAO). Totally 60 successfully modeled rats was divided into 5 groups according to randomized block principle, i.e., the model group, the SI group, the SI + AlR antagonist (1,3-dipropyl-8-cyclopentylxanthine, DPCPX) group, the AlR antagonist control group, and the dimethyl sulfoxide (DMSO) control group, 12 in each group. Besides, a sham-operation group was set up (n =12). SI at 15 mL/kg was peritoneally injected to mice in the SI group immediately after cerebral I/R. Equal volume of normal saline was injected to mice in the model group and the sham-operation group. DPCPX at 1 mg/mL was peritoneally injected to mice in the Al R antagonist control group 30 min before peritoneal injecting SI. DPCPX at 1 mg/kg and DMSO at 1 mL/kg were peritoneally injected to mice in the AlR antagonist control group and the DMSO control group 30 min immediately before cerebral I/R. Rats' neurobehavioral scores were assessed after 24 h reperfusion. The volume of cerebral infarction and Bcl-2 protein expression of cerebral infarction penumbra were also detected. Results Compared with the sham-operation group, neurobehavioral scores, the volume of cerebral infarction, and Bcl-2 protein expression increased (all P <0. 05). Compared with the model group, neurobehavioral scores and the volume of cerebral infarction obviously decreased, but Bcl-2 protein expression increased in the SI group (all P <0. 05). Compared with the SI group, neurobehavioral scores increased, the volume of cerebral infarction was obviously enlarged, and Bcl-2 protein expression was obviously reduced in the A1R antagonist control group (all P <0. 05).</p><p><b>CONCLUSIONS</b>SI's neurobehavioral scores could be partially reversed in the Al R antagonist control group, the volume of cerebral infarction and Bcl-2 protein expression improved. AlR might possibly meditate neuroprotection of SI on MACO mire</p>

Central-adenosine A1 receptor involved in the thermal regulation effect of YZG-330, a N6-substituted adenosine derivative, in mice / 药学学报

Adenosine receptors (AR) play an important role in the regulation processes for body temperature and vigilance states. During our previous studies, we noticed that aminophylline (a non-selective, blood-brain-barrier penetrably AR antagonist) could attenuate the effects of YZG-330 [(2R,3S,4R,5R)-2-(hydroxymethyl-5-(6-(((R)-1-phenylpropyl)amino)-9H-purin-9-yl)tetrahydrofuran-3, 4-diol] on lowering the body temperature. Hereby, we focused ourselves on the character of thermal regulation effect of YZG-330 in mice and tried to specify the receptor subtype via giving typical adenosine receptor antagonists. The results showed that both of the magnitude and lasting time of the effect that YZG-330 played on decreasing body temperature are in a dose-dependent manner: within the next 3 hour after intragastric administration (ig) of 0.25, 1 or 4 mg . kg-1 YZG-330, the extreme values on body temperature decreasing were (1.2 ± 0.3) °C, (3.6 ± 0.4) °C (P<0.001) and (7.4±0.5) °C (P<0.001), separately; whereas the duration that body temperature below 34 °C were 0, (10±5) and (153±4) min, separately. Adenosine A1 receptor (A1R) antagonist (DPCPX) could effectively reverse YZG-330's effect on decreasing body temperature, with intraperitoneal administration of DPCPX (5 mg . kg-1) 20 min prior than YZG-330 (4 mg.kg-1, ig), the extreme value on body temperature decreasing was (3.5 ± 0.7) °C (P<0.001), the duration that body temperature below 34 °C was (8±6) min (P<0.001). However, adenosine A2a receptor antagonist, SCH-58261, did not show any influence on the effects of YZG-330 at all. Combined with the fact that 8-SPT (a non-selective, blood-brain-barrier impenetrably AR antagonist) did not reverse the effect of YZG-330, we come to the conclusion that central-adenosine A, receptor plays a significant role on the thermal regulation effect of YZG-330.

Quantitative analysis of theophylline and its metabolites in urine of Chinese healthy subjects after oral administration of theophylline sustained-release tablets / 药学学报

To study the metabolite excretion of theophylline, a rapid and specific method by liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) method for simultaneous determination of theophylline, 1, 3-dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX) and 1-methyluric acid (1-MU) in human urine was developed using theophylline-d6 and 5-fluorouracil as internal standards. Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the negative mode for mass spectrometric detection. After diluted with methanol and centrifuged, the analytes and ISs were separated on a XDB-Phenyl (150 mm x 4.6 mm, 5 microm) column with a mixture of water-methanol-formic acid (30 : 70 : 0.15) as mobile phase at a flow rate of 0.6 mL x min(-1). The linear calibration curves for theophylline, 1, 3-DMU, 3-MX and 1-MU were obtained in the concentration range of 1.0-250 microg x mL(-1), separately. The method herein described is effective and convenient, and can be used for determination of theophylline and its three metabolites. The results showed that urinary excretion ratio of theophylline, 1,3-DMU, 3-MX and 1-MU is approximately 1 : 3 : 1 : 2 in Chinese subjects, which is similar to the reported excretion pattern in Caucasian.

Effect of Tibetan medicine zuotai on the activity, protein and mRNA expression of CYP1A2 and NAT2 / 药学学报

To study the effect of Tibetan medicine Zuotai on the activity, protein and mRNA expression of CYP1A2 and NAT2, three different doses (1.2, 3.8 and 12 mg x kg(-1)) of Zuotai were administrated orally to rats once a day or once daily for twelve days, separately. Rats were administrated orally caffeine (CF) on the second day after Zuotai administration, and the urine concentration of CF metabolite 5-acetylamino-6-formylamino-3-methyl-uracil (AFMU), 1-methyluric acid (1U), 1-methylxanthine (1X), 1, 7-dimethylxanthine (17U) at 5 h after study drug administration was determined by RP-HPLC. The activity of CYP1A2 and NAT2 was evaluated by the ratio of metabolites (AFMU+1X+1U)/17U and the ratio of AFMU/(AFMU+1X+1U), respectively. The protein and mRNA expression of CYP1A2 and NAT2 were determined by ELISA and RT-PCR method, respectively. After single administration of Zuotai 3.8 mg x kg(-1) and repeated administration of Zuotai 3.8 and 12 mg x kg(-1), the activity of CYP1A2 and NAT2 decreased significantly compared with control group and there was no significant difference between other dose group and control group. The protein expression of CYP1A2 was significant lower than that in control group after repeated administration of Zuotai 12 mg x kg(-1), and the mRNA expression of CYP1A2 decreased significantly compared with that of control group after single administration of Zuotai 3.8 mg x kg(-1) and repeated admistration of Zuotai 12 mg x kg(-1), separately. The protein expression of NAT2 decreased significantly compared with that of control group after single and repeated administration of Zuotai 3.8 mg x kg(-1), respectively, and the mRNA expression of CYP1A2 decreased significantly compared with control group after single administration of Zuotai 3.8 mg x kg(-1). This study found that Tibetan medicine Zuotai had significant effect on the activity, protein and mRNA expression of CYP1A2 and NAT2.

Eventos cardiorrespiratórios adversos após vacinação primária de recém-nascidos de muito baixo peso / Adverse cardiorespiratory events following primary vaccination of very low birth weight infants

OBJETIVO: Examinar a relação entre vacinação primária de recém-nascidos pré-termo e razões de prevalência de fatores associados a eventos cardiorrespiratórios indesejados, seguindo recomendações do Comitê Consultivo de Práticas de Imunização do Centers for Disease Control and Prevention para imunização de recém-nascidos pré-termo aos 2 meses de idade cronológica. MÉTODOS: Estudo retrospectivo de 2 anos de recém-nascidos de muito baixo peso que receberam vacinação primária. Foram registrados eventos cardiorrespiratórios maiores, como apneia, bradicardia, dessaturação de SpO2, e eventos menores, como instabilidade de temperatura, comportamento inapropriado e reações locais. Foi calculada a razão de prevalência com intervalo de confiança de 95% para fatores associados entre recém-nascidos com e sem eventos cardiorrespiratórios. RESULTADOS: Foram estudados 80 recém-nascidos (mediana de peso ao nascer [:intervalo]: de 970 g [:428-1.490]:), idade gestacional de 27,4 semanas (23,3-33). Ocorreram reações adversas em 35 (44%): eventos menores em 19 (24%) pacientes, eventos maiores em 28 (35%). Recém-nascidos com eventos maiores tiveram idade gestacional significativamente menor (p = 0,008) e incidência mais alta de displasia broncopulmonar (71% versus 48%; p < 0,05). Em recém-nascidos de muito baixo peso com eventos maiores, o número de casos de dessaturação de O2 antes da vacinação foi 3,40 (1,41-8,23) vezes maior, e o tratamento com metilxantina para síndrome de apneia e bradicardia foi 8,05 (2,50-25,89) vezes maior em comparação com recém-nascidos sem eventos maiores. CONCLUSÃO: Eventos cardiorrespiratórios maiores ocorreram em mais de 1/3 de todos os recém-nascidos de muito baixo peso após a vacinação. Os fatores associados foram baixa idade gestacional, displasia broncopulmonar, tratamento com metilxantina e dessaturação de O2 persistente antes da vacinação. A vacinação primária de recém-nascidos de muito baixo peso deve ser realizada sob monitoramento contínuo de parâmetros vitais.

OBJECTIVE: To examine the relationship between primary vaccination of preterm infants and prevalence ratios of associated factors for unwanted cardiorespiratory events, following the recommendation of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices for immunization of preterm infants at 2 months of chronological age. METHODS: Two-year retrospective study of very low birth weight infants receiving their primary vaccination. Major cardiorespiratory events, such as apnea, bradycardia, SpO2 desaturation, and minor adverse events, such as temperature instability, poor handling and local reactions, were recorded. Prevalence ratio with 95% confidence interval for associated factors between infants with and without cardiorespiratory events was calculated. RESULTS: Eighty neonates were studied (median [:range]: birth weight 970 g [:428-1,490]:), gestational age of 27.4 weeks (23.3-33). Adverse reactions occurred in 35 (44%): minor events in 19 (24%) patients, major events in 28 (35%). Infants with major events had significantly lower gestational age (p = 0.008) and a higher incidence of bronchopulmonary dysplasia (71% vs. 48%; p < 0.05). In very low birth weight infants with major events, O2 desaturations before vaccination were 3.40 (1.41-8.23) times higher and treatment with methylxanthines for apnea and bradycardia syndrome was 8.05 (2.50-25.89) times higher compared to infants without major events. CONCLUSION: Major cardiorespiratory events occurred in over 1/3 of all very low birth weight infants after vaccination. Associated factors were low gestational age, bronchopulmonary dysplasia, methylxanthine treatment, and persisting O2 desaturations before vaccination. Primary vaccination of very low birth weight infants should be performed under continuous monitoring of vital parameters.

Regulation of Muscle Microcirculation in Health and Diabetes

Insulin increases microvascular perfusion and substrate exchange surface area in muscle, which is pivotal for hormone action and substrate exchange, by activating insulin signaling cascade in the endothelial cells to produce nitric oxide. This action of insulin is closely coupled with its metabolic action and type 2 diabetes is associated with both metabolic and microvascular insulin resistance. Muscle microvascular perfusion/volume can be assessed by 1-methylxanthine metabolism, contrast-enhanced ultrasound and positron emission tomography. In addition to insulin, several factors have been shown to recruit muscle microvasculature, including exercise or muscle contraction, mixed meals, glucagon-like peptide 1 and angiotensin II type 1 receptor (AT1R) blocker. On the other hand, factors that cause metabolic insulin resistance, such as inflammatory cytokines, free fatty acids, and selective activation of the AT1R, are capable of causing microvascular insulin resistance. Therapies targeting microvascular insulin resistance may help prevent or control diabetes and decrease the associated cardiovascular morbidity and mortality.

Polyphenol (-)-epigallocatechin gallate-induced cardioprotection may attenuate ischemia-reperfusion injury through adenosine receptor activation: a preliminary study / 대한마취과학회지

BACKGROUND: The activation of guanine nucleotide binding protein-coupled receptors, such as adenosine receptor (ADR) and opioid receptor (OPR), protects the heart against ischemia and reperfusion injury. We hypothesized that ADR or OPR might be involved in polyphenol (-)-epigallocatechin gallate (EGCG)-induced cardioprotection. METHODS: Langendorff perfused rat hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Hearts were treated with 10 microM of EGCG, with or without the ADR or OPR antagonist at early reperfusion. Infarct size measured with 2,3,5-triphenyltetrazolium chloride staining was chosen as end-point. RESULTS: EGCG significantly reduced infarct volume as a percentage of ischemic volume (33.5 +/- 4.1%) compared to control hearts (14.4 +/- 1.1%, P 0.05 vs. EGCG) blocked the anti-infarct effect by EGCG. The infarct reducing effect of EGCG was significantly reversed by 200 nM of the A1 ADR antagonist DPCPX (25.9 +/- 1.1%, P 0.05 vs. EGCG) and 100 nM of the A3 ADR antagonist MRS1334 (24.1 +/- 1.8%, P > 0.05). CONCLUSIONS: The infarct reducing effect of EGCG appears to involve activation of ADR, especially A1 and A2B ADR, but not OPR.

Inhibitory effect of propentofylline on chronic prostatitis pain in rats and its mechanism / 中华男科学杂志

<p><b>OBJECTIVE</b>To investigate the effects of propentofylline on the expressions of glial fibrillary acidic protein (GFAP) and TNF-alpha and its action mechanism in the rat model of chronic prostatitis pain (CPP).</p><p><b>METHODS</b>We equally randomized 30 male SD rats to groups A (sham operation), B (CPP model) and C (propentofylline intervention). After modelling, the rats in group C received intraperitoneal injection of propentofylline at 2 mg/kg, while those in groups A and B were injected intrathecally with the same dose of normal saline. At 15 days after the treatment, we examined the expressions of GFAP in the spinal cord and TNF-alpha in the prostate by immunohistochemistry.</p><p><b>RESULTS</b>The levels of GFAP and TNF-alpha were obviously lower in group A (2.56 +/- 0.16 and 1.34 +/- 0.05) than in B (16.79 +/- 0.72 and 3.46 +/- 0.05) and C (8.83 +/- 0.63 and 2.25 +/- 0.05), significantly increased in B as compared with A (P < 0.05). And the increase was markedly less in group C than in B (P < 0.05).</p><p><b>CONCLUSION</b>Propentofylline inhibits chronic prostatitis pain in the rat model by suppressing the activation of astroglia and the release of inflammatory mediators.</p>

New Therapeutic Modalities for Asthma: Biologicals from a Practical Point of View / 대한내과학회지

Asthma is a representative allergic disease of chronic airway inflammation. Dyspnea, wheezing, cough, and chest tightness are typical symptoms. Treatment consists of inhaled corticosteroid, beta2 agonist, leukotriene modifiers, and xanthines such as theophylline. Clinical practice guidelines for asthma have been developed since early 1990s. However, there are still many uncontrolled asthma patients with severe refractory symptoms, frequent exacerbations and even mortality. These patients cause high socioeconomic burden but the management of these patients are not well covered by clinical practice guidelines. High-dose steroid, methotrexate, cyclosporine, gold, IVIG, and macrolides have been suggested as therapeutic modalities for refractory asthma but with limited treatment effect and side effects. It is necessary to develop new therapeutic modalities for asthma. Biologicals, or biologics, are a variety of protein-based therapeutics, e.g. antibodies, soluble receptors, recombinant protein-based receptor antagonists and other related structures. New biologicals for the treatment of asthma are being developed. Here I will focus on three biologicals from a practical point of view: a humanized monoclonal anti-IgE antibody (omalizumab), anti-IL5, and TNF-alpha antagonist.

Sedative, hypnotic and anticonvulsive effects of an adenosine analogue WS090501 / 药学学报

This study is to examine the sedative, hypnotic and anticonvulsive effects of an adenosine analogue, WS090501. The spontaneous locomotor activity was recorded by open field equipment, and the EEG of rats was recorded by polyphysiograph. Pentylenetetrazol (PTZ)-induced seizure model was used. The spontaneous locomotor activity was decreased by WS090501 at various doses (0.06, 0.13, and 0.25 mg x kg(-1)), and the decreasing rate was 28.4%, 47.1% and 61.2% respectively. Furthermore, the effect of WS090501 on spontaneous locomotor activity of mice can be antagonized by DPCPX, a selective adenosine A1R antagonist, but cannot be antagonized by SCH58261, a selective adenosine A2AR antagonist. The NREM sleep was significantly increased by WS090501 (0.05 and 0.2 mg x kg(-1)), and the increasing rate was 27.6% and 102.8%, respectively, at 6th hour after administration. The REM sleep decreased significantly at the higher dose. PTZ induced serious convulsion in mice. The latency of convulsion was prolonged, and the number of seizure and mortality decreased after administration of WS090501. These results show that WS090501 has potent sedative, hypnotic and anticonvulsive effects, which may be mediated through adenosine A1R.

Antidipsogenic effects of central adenosine-5'-triphosphate

Besides other physiological functions, adenosine-5'-triphosphate (ATP) is also a neurotransmitter that acts on purinergic receptors. In spite of the presence of purinergic receptors in forebrain areas involved with fluid-electrolyte balance, the effect of ATP on water intake has not been investigated. Therefore, we studied the effects of intracerebroventricular (icv) injections of ATP (100, 200 and 300 nmol/µL) alone or combined with DPCPX or PPADS (P1 and P2 purinergic antagonists, respectively, 25 nmol/µL) on water intake induced by water deprivation. In addition, the effect of icv ATP was also tested on water intake induced by intragastric load of 12 percent NaCl (2 mL/rat), acute treatment with the diuretic/natriuretic furosemide (20 mg/kg), icv angiotensin II (50 ng/µL) or icv carbachol (a cholinergic agonist, 4 nmol/µL), on sodium depletion-induced 1.8 percent NaCl intake, and on food intake induced by food deprivation. Male Holtzman rats (280-320 g, N = 7-11) had cannulas implanted into the lateral ventricle. Icv ATP (300 nmol/µL) reduced water intake induced by water deprivation (13.1 ± 1.9 vs saline: 19.0 ± 1.4 mL/2 h; P < 0.05), an effect blocked by pre-treatment with PPADS, but not DPCPX. Icv ATP also reduced water intake induced by NaCl intragastric load (5.6 ± 0.9 vs saline: 10.3 ± 1.4 mL/2 h; P < 0.05), acute furosemide treatment (0.5 ± 0.2 vs saline: 2.3 ± 0.6 mL/15 min; P < 0.05), and icv angiotensin II (2.2 ± 0.8 vs saline: 10.4 ± 2.0 mL/2 h; P < 0.05), without changing icv carbachol-induced water intake, sodium depletion-induced 1.8 percent NaCl intake and food deprivation-induced food intake. These data suggest that central ATP, acting on purinergic P2 receptors, reduces water intake induced by intracellular and extracellular dehydration.

The Interaction of Gabapentin and N(6)-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA) on Mechanical Allodynia in Rats with a Spinal Nerve Ligation

We examined the antiallodynic interaction between gabapentin and adenosine A1 receptor agonist, N(6)-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), in a rat model of nerve ligation injury. Rats were prepared with ligation of left L5-6 spinal nerves and intrathecal catheter implantation for drug administration. Mechanical allodynia was measured by applying von Frey filaments. Gabapentin and R-PIA were administered to obtain the dose-response curve and the 50% effective dose (ED50). Fractions of ED50s were administered concurrently to establish the ED50 of the drug combination. The drug interaction between gabapentin and R-PIA was analyzed using the isobolographic method. Adenosine A1 receptor antagonist was administered intrathecally to examine the reversal of the antiallodynic effect. Locomotor function changes were evaluated by rotarod testing. Intrathecal gabapentin and R-PIA and their combination produced a dose-dependent antagonism against mechanical allodynia without severe side effects. Intrathecal gabapentin synergistically enhanced the antiallodynic effect of R-PIA when coadministered. There were no significant changes in rotarod performance time, except gabapentin 300 microgram. In the combination group, the maximal antiallodynic effect was reversed by A1 adenosine receptor antagonist. These results suggest that activation of adenosine A1 receptors at the spinal level is required for the synergistic interaction on the mechanical allodynia.

Advances in the study of A2B adenosine receptor antagonists / 药学学报

A2B adenosine receptor is involved in the control of mast cell degranulation, interleukin-8 synthesis and cell growth. A2B adenosine receptor antagonists may serve as novel drugs for asthma, Alzheimer' s disease, cystic fibrosis and type-II diabetes. Therefore, seeking for the highly selective A2B adenosine receptor antagonists has been one of great interest. The molecular basis, structure-activity relationship of selective A2B adenosine receptor antagonists and their interactions with A2B adenosine receptor were reviewed.