Biologic therapy in large and small vessels vasculitis, and Behçet's disease: Evidence- and practice-based guidance.

OBJECTIVE: Vasculitis are a very heterogenous group of systemic autoimmune diseases, affecting large vessels (LVV), small vessels or presenting as a multisystemic variable vessel vasculitis. We aimed to define evidence and practice-based recommendations for the use of biologics in large and small vessels vasculitis, and Behçet's disease (BD). METHODS: Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice on autoimmune diseases management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2022. Preliminary recommendations were drafted by working groups for each disease and voted in two rounds, in June and September 2021. Recommendations with at least 75% agreement were approved. RESULTS: A total of 32 final recommendations (10 for LVV treatment, 7 for small vessels vasculitis and 15 for BD) were approved by the experts and several biologic drugs were considered with different supporting evidence. Among LVV treatment options, tocilizumab presents the higher level of supporting evidence. Rituximab is recommended for treatment of severe/refractory cryoglobulinemic vasculitis. Infliximab and adalimumab are most recommended in treatment of severe/refractory BD manifestations. Other biologic drugs can be considered is specific presentations. CONCLUSION: These evidence and practice-based recommendations are a contribute to treatment decision and may, ultimately, improve the outcome of patients living with these conditions.

Biological therapy in systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren's syndrome: evidence- and practice-based guidance.

Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and Sjögren's syndrome (SS) are heterogeneous autoimmune diseases. Severe manifestations and refractory/intolerance to conventional immunosuppressants demand other options, namely biological drugs, and small molecules. We aimed to define evidence and practice-based guidance for the off-label use of biologics in SLE, APS, and SS. Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice in autoimmune disease management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2021. Preliminary recommendations were drafted by working groups for each disease. A revision meeting with all experts anticipated the consensus meeting held in June 2021. All experts voted (agree, disagree, neither agree nor disagree) during two rounds, and recommendations with at least 75% agreement were approved. A total of 32 final recommendations (20 for SLE treatment, 5 for APS, and 7 for SS) were approved by the experts. These recommendations consider organ involvement, manifestations, severity, and response to previous treatments. In these three autoimmune diseases, most recommendations refer to rituximab, which aligns with the higher number of studies and clinical experience with this biological agent. Belimumab sequential treatment after rituximab may also be used in severe cases of SLE and SS. Second-line therapy with baricitinib, bortezomib, eculizumab, secukinumab, or tocilizumab can be considered in SLE-specific manifestations. These evidence and practice-based recommendations may support treatment decision and, ultimately, improve the outcome of patients living with SLE, APS, or SS.

Cancer-Related Fatigue - Clinical Evaluation Scales and Interventions: A Systematic Review.

Background: Cancer-related fatigue (CRF) is one of the most frequent and prevalent symptoms expressed by cancer patients and cancer survivors. It is a multifactorial phenomenon that causes a direct detrimental impact on quality of life. Objectives: This systematic review aims to identify different clinical evaluation scales and interventions available for fatigue associated with cancer. Materials and Methods: A methodology of the systematic literature review was carried out. Two separate databases PubMed and Google Scholar searches were performed using different MeSH terms. Results: A total of 2611 research articles were screened and identified 10 unidimensional scales (four with one item scales and six with numerous item scales) and 13 multidimensional scales which are available for the screening and clinical evaluation of fatigue. Reviews have also revealed non-pharmacological interventions such as exercise, complementary therapies, nutritional and psychoeducational interventions, sleep therapy, energy therapy, bright white light, restorative therapies upcoming anthroposophical medicine, and various pharmacological agents effective in managing CRF. Conclusion: Clinical evaluation of fatigue and its management is crucial for improving the quality of life. Yet, more rigorous research studies with higher statistical power need to be conducted on these interventions to generate adequate evidences for managing the CRF.

Cellular target of isoquercetin from Passiflora ligularis Juss for glucose uptake in rat soleus muscle.

Quercetin 3-O-beta-d-glucopyranoside (isoquercetin) is one of the most frequent metabolites of the Passiflora ligularis Juss. The purpose of this study was to investigate the effect of the aqueous extract and ethanol fraction from P. ligularis Juss leaves on glycaemia and the mechanism of action of isoquercetin on glucose uptake. In the glucose tolerance test, the aqueous extract and ethanol fraction from P. ligularis Juss (125 mg/kg to 500 mg/kg o. g.) reduced glycaemia and increased the hepatic and muscular glycogen content. Phytochemical analysis evidenced the dominant presence of isoquercetin in the extract and fraction from leaves of P. ligularis Juss. Isoquercetin mediates the stimulatory effect on glucose uptake independent of insulin receptor activation but, involve PI3K, MAPK, MEK/ERK pathways and de novo protein synthesis to GLUT-4 translocation. Overall findings revealed that isoquercetin and aqueous extract and ethanol fraction of P. ligularis Juss leaves might be a promising functional food or medicine for the treatment or prevention of diabetes.

Rehabilitation of Neonatal Brachial Plexus Palsy: Integrative Literature Review.

This integrative literature review has been carried out with the aim of analyzing the scientific literature aimed at identifying and describing existing rehabilitation treatments/therapies for neonatal brachial plexus palsy (NBPP). NBPP is a frequent consequence of difficult birthing, and it impairs the function of the brachial plexus in newborns. This is why knowledge on rehabilitation strategies deserves special attention. The data collection was carried out in January 2019, in the EBSCOhost and BVS (Biblioteca Virtual em Saúde) platforms, in the CINAHL Complete, MEDLINE Complete, LILACS and PubMed databases. Thirteen articles were included in this integrative literature review, based on a literature search spanning title, abstract and full text, and considering the inclusion criteria. Two main treatments/therapies for NBPP rehabilitation were identified: conservative treatment and surgical treatment. Conservative treatment includes teamwork done by physiatrists, physiotherapists and occupational therapists. These professionals use rehabilitation techniques and resources in a complementary way, such as electrostimulation, botulinum toxin injection, immobilizing splints, and constraint induced movement therapy of the non-injured limb. Professionals and family members work jointly. Surgical treatment includes primary surgeries, indicated for children who do not present any type of spontaneous rehabilitation in the first three months of life; and secondary surgeries, recommended in children who after primary surgery have some limitation of injured limb function, or in children who have had some spontaneous recovery, yet still have significant functional deficits. Treatment options for NBPP are defined by clinical evaluation/type of injury, but regardless of the type of injury, it is unanimous that conservative treatment is always started as early as possible. It should be noted that there was no evidence in the literature of other types of rehabilitation and techniques used in clinical practice, such as preventive positioning of contractures and deformities, hydrotherapy/aquatic therapy, among others, so we consider there is a need for further studies at this level in this area.

Astragalin augments basal calcium influx and insulin secretion in rat pancreatic islets.

Astragalin is a flavonol glycoside with several biological activities, including antidiabetic properties. The objective of this study was to investigate the effects of astragalin on glycaemia and insulin secretion, in vivo, and on calcium influx and insulin secretion in isolated rat pancreatic islets, ex vivo. Astragalin (1 and 10 mg / kg) was administered by oral gavage to fasted Wistar rats and serum glucose and plasma insulin were measured. Isolated pancreatic islets were used to measure basal insulin secretion and calcium influx. Astragalin (10 mg/ kg) decreased glycaemia and increased insulin secretion significantly at 15-180 min, respectively, in the glucose tolerance test. In isolated pancreatic cells, astragalin (100 µM) stimulated calcium influx through a mechanism involving ATP-dependent potassium channels, L-type voltage-dependent calcium channels, the sarcoendoplasmic reticulum calcium transport ATPase (SERCA), PKC and PKA. These findings highlight the dietary coadjuvant, astragalin, as a potential insulin secretagogue that may contribute to glucose homeostasis.

Ameliorative potential of standardized fruit extract of Pterodon pubescens Benth on neuropathic pain in mice: Evidence for the mechanisms of action.

ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal plant Pterodon pubescens Benth has been traditionally used for a long time to treat rheumatic diseases due to its anti-inflammatory and analgesic activities. The present study aims to evaluate the antinociceptive effect of ethanolic extract from P. pubescens fruits (EEPp) in a model of neuropathic pain in mice. MATERIALS AND METHODS: The phytochemical analysis of EEPp was performed through GC-MS, HPLC and colorimetric analysis. The antinociceptive effects of EEPp (30-300 mg/kg, i.g.) were evaluated on mechanical and thermal (cold or heat) hyperalgesia in neuropathic pain induced by partial sciatic nerve ligation (PSNL) in mice. We also investigated the effects of EEPp on the nociceptive response induced by intrathecal injection (i.t.) of ionotropic (AMPA, NMDA and kainate) and metabotropic (trans-ACPD) glutamate receptor agonists, proinflammatory cytokines such as IL-1ß and TNF-α, as well as TRPV1 and TRPA1 agonists. In addition, we also investigated the safety profile of prolonged treatment with EEPp in mice. RESULTS: The phytochemical analysis showed a higher amount terpenes, being nine sesquiterpenes and seven diterpenes with vouacapan skeletons, as well as a small amount of phenols and flavonoids. The exact mechanism by which EEPp promotes its antinociceptive effect is not yet fully understood, but its oral administration causes significant inhibition of glutamate-, kainate-, NMDA-, trans-ACPD-induced biting responses, as well as of proinflammatory cytokines (TNF-α and IL-1ß) and TRPV1 and TRPA1 channels activators (capsaicin and cinnamaldehyde, respectively). These results may indicate, at least in part, some of the mechanisms that are involved in this effect. In particular, EEPp decreases neuropathic pain and clearly shows, for the first time, a thermal and mechanical hyperalgesia reduction in the model of partial sciatic nerve ligation (PSNL), without inducing tolerance. Furthermore, the prolonged treatment with EEPp (300 mg/kg, i.g.) showed a cumulative effect over 24h, in the 15th day, after last treatment. In addition, the open-field test showed that doses up to 300 mg/kg in both treatments, acute and/or prolonged, did not affect the motor activity of mice. Also, EEPp showed no toxicity according to the serum levels of the renal and hepatic injury indicators or observed macroscopic organs, after PSNL. CONCLUSIONS: Taken together, these results provide the first experimental evidence of the significant antinociceptive effect of EEPp on neuropathic pain without causing side effects, such as sedation or locomotor dysfunction. Moreover, these results appear to be mediated, at least in part, by the inhibition of glutamatergic receptors, TRPV1 and TRPA1 channels and proinflammatory cytokines. Thus, this study adds new scientific evidence and highlights the therapeutic potential of the medicinal plant P. pubescens in the development of phytomedicines for the management of neuropathic pain.

Determinação da atividade antioxidante e do teor total de polifenol em amostras de chá de ervas comercializadas em sachets / Determination of total antioxidant activity and total content of polyphenols in samples of tea leaves marketed in bags

OBJETIVO: Os chás de ervas são tradicionalmente utilizados na medicina popular em muitas regiões do Brasil. Os chás contêm compostos antioxidantes que combatem o stress oxidativo e seu consumo tem sido associado à diminuição dos níveis de colesterol, pressão arterial e até de doenças cardiovasculares. O objetivo deste estudo foi determinar a capacidade antioxidante total, o teor total de polifenóis, o consumo (scavenging) de H2O2 e a presença de outros grupos de compostos antioxidantes em 43 amostras de chás em sachets. MÉTODOS: O método CUPRAC (cupric ion reducing antioxidant capacity) foi utilizado para determinar a capacidade antioxidante total. O teor total de polifenóis foi obtido com o uso do reagente de Folin-Ciocalteu; o ensaio de scavenging baseou-se no consumo de solução de H2O2 após adição do chá; e a presença de flavonóides, carotenos e catequinas foi investigada por cromatografia em papel. RESULTADOS: A capacidade antioxidante total nas amostras analisadas seguiu a ordem: camomila > hortelã > carqueja >cidreira > boldo > verde > mate > preto > branco > erva doce. O teor total de polifenóis obedeceu à sequência: branco > hortelã > preto > mate > boldo > verde > camomila > carqueja > cidreira > erva doce. As divergências encontradas entre as amostras de um mesmo grupo de chá podem ser atribuídas à época da colheita, ao tipo de solo, local de plantio, variações climáticas e partes da planta utilizadas na elaboração dos sachets. CONCLUSÃO: Conclui-se que todas as amostras analisadas apresentaram capacidade antioxidante e consumo de H2O2. Em apenas uma delas não foi possível detectar flavonóides, carotenos ou catequinas.

OBJECTIVE: Tea leaves are traditionally used in folk medicine in many regions of Brazil. They contain antioxidant compounds that can protect against oxidative stress and their regular intake have been associated with decreased of cholesterol levels, blood pressure and, thereby, with the lowered risk of coronary heart disease. The objective of this study was to determine the total antioxidant capacity, the total polyphenols content,scavenging of H2O2 and presence of other groups of antioxidant compounds in 43 tea samples packed in bags. METHODS: The CUPRAC method (cupric ion reducing antioxidant capacity) was used to quantify the total antioxidant capacity. The polyphenols content was performed using the Folin-Ciocalteu reagent. The scavenging assay was based on the consumption of H2O2 after addition of tea; the presence of flavonoids, carotenes and catechins was evaluated by paper chromatography. RESULTS:The total antioxidant capacity found in tea samples followed the order: chamomile > mint > carqueja > balm > boldo > green > mate > black > white > fennel. For total polyphenol content the order was: white > mint > black > matte > boldo > green > chamomile > carqueja > balm > fennel. The differences found in the samples from the same kind of tea can be attributed to the harvest season, soil type, planting location, climate differencesand from the parts of the vegetal material used in the preparation of the tea bags. CONCLUSION: All samples analyzed presented antioxidant activity and ability to scavenge H2O2. It was not possible to detect flavonoids, carotenes and catechins in only one sample.

The role of calcium in intracellular pathways of rutin in rat pancreatic islets: potential insulin secretagogue effect.

Rutin is a flavonol glycoside with multiple biological activities and it has been demonstrated that rutin modulates glucose homeostasis. In pancreatic ß-cell, an increase in intracellular calcium concentration triggers exocytosis and thus insulin secretion. The aim of the study reported herein was to investigate the effect of rutin associated intracellular pathways on Ca(2+) uptake in isolated rat pancreatic islets. We focused on the acute effects of rutin on in vivo insulin secretion and the in vitro cellular signaling of pancreatic islets related to this effect. The results show that rutin significantly increased glucose-induced insulin secretion in an in vivo treatment. Moreover, it was demonstrated that rutin stimulated Ca(2+) uptake after 10 min of incubation compared with the respective control group. The involvement of L-type voltage-dependent Ca(2+) channels (L-VDCCs) was evidenced using nifedipine, while the use of glibenclamide and diazoxide demonstrated that the ATP-sensitive potassium (KATP) channels are not involved in the rutin action in pancreatic islets. In conclusion, rutin diminish glycemia, potentiate insulin secretion in vivo and significantly stimulates Ca(2+) uptake in rat pancreatic islets. A novel cellular mechanism of action of rutin in Ca(2+) uptake on pancreatic ß-cells was elucidated. Rutin modulates Ca(2+) uptake in pancreatic islets by opening L-VDCCs, alter intracellular Ca(2+), PLC and PKC signaling pathways, characterizing KATP channel-independent pathways. These findings highlight rutin, a dietary adjuvant, as a potential insulin secretagogue contributing to glucose homeostasis.

Anti-hyperglycemic action of apigenin-6-C-ß-fucopyranoside from Averrhoa carambola.

A stimulatory effect of apigenin-6-C-ß-fucopyranoside (1) on glucose uptake was observed when rat soleus muscle was incubated with 1, 10 and 100 µM of this flavonoid glycoside. The presence of specific insulin signaling inhibitors, such as wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), RO318220, an inhibitor of protein kinase C (PKC), PD98059, an inhibitor of mitogen-activated protein kinase (MEK), and HNMPA(AM)3, an insulin receptor tyrosine kinase activity inhibitor showed that apigenin-6-C-ß-fucopyranoside triggers different metabolic pathways in skeletal muscle. The oral administration of crude extract, fractions and isolated flavonoids (apigenin-6-C-ß-fucopyranoside (1) and apigenin-6-C-(2″-O-α-rhamnopyranosyl)-ß-fucopyranoside (2)) from Averrhoa carambola leaves exhibited a potential hypoglycemic activity in hyperglycemic normal rats. Additionally, both flavonoids significantly increased the muscle and liver glycogen content after an acute treatment. The results indicate that A. carambola can be regarded as a potent antihyperglycemic agent with insulin secretagogue and insulin mimetic properties.

Short and long-term effects of Baccharis articulata on glucose homeostasis.

In this study, the in vivo effect of the crude extract and n-butanol and aqueous residual fractions of Baccharis articulata (Lam.) Pers. on serum glucose levels, insulin secretion and liver and muscle glycogen content, as well as in vitro action on serum intestinal disaccharidase activity and albumin glycation were investigated. Oral administration of the extract and fractions reduced glycemia in hyperglycemic rats. Additionally, the n-butanol fraction, which has high flavonoids content, stimulated insulin secretion, exhibiting an insulinogenic index similar to that of glipizide. Also, the n-butanol fraction treatment significantly increased glycogen content in both liver and muscle tissue. In vitro incubation with the crude extract and n-butanol and aqueous residual fractions inhibited maltase activity and the formation of advanced glycation end-products (AGEs). Thus, the results demonstrated that B. articulata exhibits a significant antihyperglycemic and insulin-secretagogue role. These effects on the regulation of glucose homeostasis observed for B. articulata indicate potential anti-diabetic properties.

1α,25-dihydroxyvitamin D(3) mechanism of action: modulation of L-type calcium channels leading to calcium uptake and intermediate filament phosphorylation in cerebral cortex of young rats.

The involvement of calcium-mediated signaling pathways in the mechanism of action of 1α,25-dihydroxyvitamin D(3) (1,25D) is currently demonstrated. In this study we found that 1,25D induces nongenomic effects mediated by membrane vitamin D receptor (VDRm) by modulating intermediate filament (IF) phosphorylation and calcium uptake through L-type voltage-dependent calcium channels (L-VDCC) in cerebral cortex of 10 day-old rats. Results showed that the mechanism of action of 1,25D involves intra- and extracellular calcium levels, as well as the modulation of chloride and potassium channels. The effects of L-VDCCs on membrane voltage occur over a broad potential range and could involve depolarizing or hyperpolarizing coupling modes, supporting a cross-talk among Ca(2+) uptake and potassium and chloride channels. Also, the Na(+)/K(+)-ATPase inactivation by ouabain mimicked the 1,25D action on (45)Ca(2+) uptake. The Na(+)/K(+)-ATPase inhibition observed herein might lead to intracellular Na(+) accumulation with subsequent L-VDCC opening and consequently increased (45)Ca(2+) (calcium, isotope of mass 45) uptake. Moreover, the 1,25D effect is dependent on the activation of the following protein kinases: cAMP-dependent protein kinase (PKA), Ca(2+)/calmodulin-dependent protein kinase (PKCaMII), phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase p38 (p38(MAPK)). The modulation of calcium entry into neural cells by the 1,25D we are highlighting, might take a role in the regulation of a plethora of intracellular processes. Considering that vitamin D deficiency can lead to brain illness, 1,25D may be a possible candidate to be used, at least as an adjuvant, in the pharmacological therapy of neuropathological conditions.

Potential insulin secretagogue effects of isovitexin and swertisin isolated from Wilbrandia ebracteata roots in non-diabetic rats.

The antihyperglycemic effect and mechanism of action of extracts, fractions and compounds from Wilbrandia ebracteata was studied. The crude extract reduced the glycemia, increased glycogen content and serum insulin in hyperglycemic rats. Also, a significant effect was observed with the n-butanol and metanol subfraction. However, the antihyperglycemic effect of the n-butanol fraction was not observed in diabetic rats. The C-glycosylflavones isovitexin and swertisin showed a strong antihyperglycemic action compared with the extracts and fractions. These results show that the extracts, fractions, and isolated C-glycosylflavones have an antihyperglycemic action that was reinforced by the stimulation on in vivo insulin secretion.

Stimulatory effect of apigenin-6-C-beta-L-fucopyranoside on insulin secretion and glycogen synthesis.

In vivo and in vitro treatments were carried out to investigate the effects of apigenin-6-C-beta-L-fucopyranoside (1), isolated from Averrhoa carambola L. (Oxalidaceae), on serum glucose and insulin levels in hyperglycemic rats as well as its effect on glycogen synthesis in normal rat soleus muscle. Apigenin-6-C-beta-L-fucopyranoside showed an acute effect on blood glucose lowering in hyperglycemic rats and stimulated glucose-induced insulin secretion. A stimulatory effect of 1 on glycogen synthesis was observed when muscles were incubated with this flavonoid and also its effect was completely nullified by pre-treatment with insulin signal transduction inhibitors. Taking this into account, the MAPK-PP1 and PI3K-GSK3 pathways are involved in the apigenin-6-C-beta-L-fucopyranoside-induced increase in glycogen synthesis in muscle. This study provides evidence for dual effects of apigenin-6-C-beta-L-fucopyranoside as an antihyperglycemic (insulin secretion) as well as an insulinomimetic (glycogen synthesis) agent.

Insulinomimetic effect of kaempferol 3-neohesperidoside on the rat soleus muscle.

A stimulatory effect of kaempferol 3-neohesperidoside ( 1) on glucose uptake (35% and 21%) was observed when the rat soleus muscle was incubated with 1 and 100 nM of this flavonoid glycoside, respectively. The concentration-response curve of insulin showed a stimulatory effect at 3.5 and 7.0 nM (42% and 50%) on glucose uptake when compared with the control group. The effect of 1 on glucose uptake was completely nullified by pretreatment with LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), and RO318220, an inhibitor of protein kinase C (PKC). However, no significant change occurred on glucose uptake stimulated by 1 when muscles were pretreated with PD98059, an inhibitor of mitogen-activated protein kinase (MEK), and cycloheximide, an inhibitor of protein synthesis. Compound 1 and insulin (7 nM) did not show a synergistic effect on glucose uptake. Additionally, 100 mg/kg of 1 by oral gavage was able to increase glycogen content in the muscle. These results suggest that 1 stimulates glucose uptake in the rat soleus muscle via the PI3K and PKC pathways and, at least in part, independently of MEK pathways and the synthesis of new glucose transporters.

Influence of chalcone analogues on serum glucose levels in hyperglycemic rats.

A series of chalcone derivatives from 3,4-methylenedioxybenzaldehyde and substituted acetophenones have been synthesized and investigated as antihyperglycemic agents in a glucose loaded animal model. Chalcones with biological activity were compared with lispro, regular insulin and tolbutamide effects on serum glucose levels. Compound 01, without substituent in the A-ring was not able to change glycemic levels. On the other hand, compounds 03, 04, 05, 09 and 10 with substitutions at position 3' and/or 4' in the A-ring caused significant reduction in serum glucose levels. Concerning the antihyperglycemic effect, compounds 03 and 05 (methoxy substituent) inhibited the hyperglycemia induced by glucose around 96% similar to that demonstrated for lispro insulin and tolbutamide at 60 min. A rapid and lasting antihyperglycemic effect was found with compound 09 and 10 (nitro substituent). In conclusion, besides the nature of the functional groups electron-donor substituent, as methoxy and hydroxyl or electron-acceptor, as nitro groups, the position of the group may be mandatory for biological activity.

Effect of crude extract and fractions from Vitex megapotamica leaves on hyperglycemia in alloxan-diabetic rats.

The effect of the crude extract, ethyl acetate and n-butanol fractions from Vitex megapotamica (Spreng) Moldenke on glycemia was investigated in diabetic rats. Oral administration of crude extract significantly reduced serum glucose levels in both normal and diabetic animals. In normal rats, serum glucose lowering was observed with 400 and 800 mg/kg at 2 and 2-3h, respectively after oral crude extract treatment. Nevertheless, the hypoglycemic effect of Vitex megapotamica in diabetic rats was evident at 1 and 2h and from 1 to 3h after treatment with 400 and 800 mg/kg, respectively. The ethyl acetate as well as n-butanol fractions were able to diminish glycemia in diabetic animals. The ethyl acetate fraction (400 and 800 mg/kg) produced the maximum hypoglycemic effect (28 and 20%, respectively) in diabetic rats and the same dose of the n-butanol fraction reduced the hyperglycemia only by 11% at 1h after treatment. Additionally, in hyperglycemic normal rats neither crude extract nor ethyl acetate fraction modified the glucose tolerance and the known tolbutamide effect on insulin release was clearly observed in this group. Thus, this study shows that Vitex megapotamica has an anti-hyperglycemic action, is able to ameliorate the diabetic state and, probably, is a source of hypoglycemic compounds.

Genomic-independent action of thyroid hormones on NTPDase activities in Sertoli cell cultures from congenital hypothyroid rats.

The Sertoli cells play an essential role in the maintenance and control of spermatogenesis. The ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and 5'-nucleotidase activities can modulate the extracellular adenine nucleotide levels, controlling nucleotide-mediated signaling events in Sertoli cells. Since thyroid hormones (TH) and adenine nucleotides and nucleosides play important modulatory roles in Sertoli cell proliferation and differentiation, the aim of our study was to investigate the effect of hypothyroidism upon the NTPDase and 5'-nucleotidase activities in Sertoli cell cultures, as well as to verify whether these effects may be reversed by short and long-term supplementation with TH. Congenital hypothyroidism was induced by adding 0.02% methimazole in the drinking water from day 9 of gestation and continually until 18 days of age. Hypothyroidism significantly decreased the extracellular ATP and ADP hydrolysis and this effect was significantly reversed when cell cultures were supplemented with 1 microM T3 or 0.1 microM T4 for 30 min. In contrast, AMP hydrolysis was not altered by hypothyroidism, but was increased by T4 supplementation for 24 h. The presence of the enzymes NTPDase 1, 2 and 3 was detected by RT-PCR in Sertoli cell cultures, however, hypothyroidism was not able to alter the expression of these enzymes. These findings demonstrate that TH modify NTPDase activities in hypothyroid Sertoli cells, probably via nongenomic mechanisms and, consequently, may influence the reproductive function throughout development.

Hypoglycemic effect and antioxidant potential of kaempferol-3,7-O-(alpha)-dirhamnoside from Bauhinia forficata leaves.

In vivo and in vitro treatments were carried out to investigate the effects of kaempferol-3,7-O-(alpha)-dirhamnoside (kaempferitrin), a major flavonoid compound of the n-butanol fraction from Bauhiniaforficata leaves, on serum glucose levels, as well as its antioxidant potential. Oral administration of kaempferitrin led to a significant hypoglycemic effect in normal and in alloxan-induced diabetic rats. In normal rats, blood glucose lowering was observed only with the higher dose of kaempferitrin (200 mg/kg) at 1 h after treatment. However, the hypoglycemic effect of kaempferitrin in diabetic rats was evident at all doses tested (50, 100, and 200 mg/kg), and this profile was maintained throughout the period studied for both higher doses. Additionally, in glucose-fed hyperglycemic normal rats, the kaempferitrin failed to decrease blood glucose levels. In vitro antioxidant properties or action against reactive oxygen species of this compound was also evaluated. The compound showed high reactivity with 1,1-diphenyl-2-picryl hydrazyl (DPPH), IC(50) of 84.0 +/- 7.8 microM, inhibited myeloperoxidase activity with K(0.5) = 86 +/- 9.9 microM, and decreased lipid peroxidation, induced by ascorbyl radical either in microsomes or in asolectin and phosphatidylcholine liposomes, with IC(50)'s of 320 +/- 14.1, 223 +/- 8.3, and 112 +/- 8.8 microM, respectively.

Acute effect of Bauhinia forficata on serum glucose levels in normal and alloxan-induced diabetic rats.

Experimental diabetes was used to study the acute effect of the n-butanol fraction of Bauhinia forficata Link (Leguminosae) (BF) leaves on the serum glucose levels of rats. Body weight was measured on the day of diabetes induction and on the day of the experiment. Levels of glucose were determined at different doses and times following treatment with BF or with vehicle in normal, diabetic and hyperglycemic normal rats. Oral administration of n-BuOH fraction led to a significant blood glucose-lowering effect in normal and diabetic rats. However, in glucose-fed hyperglycemic normal rats, the maximum dose of this fraction failed to decrease blood glucose levels. The hypoglycemic effect was observed at doses of 500 and 600 mg/kg after 1 and 2 h treatment respectively, in normal rats. The maximum effect of BF was detected at 1 h with 800 mg/kg in diabetic animals and this profile was maintained for the next 3 h. Treatment of normal and alloxan-induced diabetic rats with BF decreased glucose levels, while this fraction was devoid of hypoglycemic effect in glucose-fed hyperglycemic normal rats.