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Resistance exercise training (RET) is considered an excellent tool for preventing diseases with an inflammatory background. Its neuroprotective, antioxidant, and anti-inflammatory properties are responsible for positively modulating cholinergic and oxidative systems, promoting neurogenesis, and improving memory. However, the mechanisms behind these actions are largely unknown. In order to investigate the pathways related to these effects of exercise, we conducted a 12-week long-term exercise training protocol and used lipopolysaccharide (LPS) to induce damage to the cortex and hippocampus of male Wistar rats. The cholinergic system, oxidative stress, and histochemical parameters were analyzed in the cerebral cortex and hippocampus, and memory tests were also performed. It was observed that LPS: (1) caused memory loss in the novel object recognition (NOR) test; (2) increased the activity of acetylcholinesterase (AChE) and Iba1 protein density; (3) reduced the protein density of brain-derived neurotrophic factor (BDNF) and muscarinic acetylcholine receptor M1 (CHRM1); (4) elevated the levels of lipid peroxidation (TBARS) and reactive species (RS); and (5) caused inflammatory damage to the dentate gyrus. RET, on the other hand, was able to prevent all alterations induced by LPS, as well as increase per se the protein density of the alpha-7 nicotinic acetylcholine receptor (nAChRα7) and Nestin, and the levels of protein thiols (T-SH). Overall, our study elucidates some mechanisms that support resistance physical exercise as a valuable approach against LPS-induced neuroinflammation and memory loss.
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Lipopolisacáridos , Trastornos de la Memoria , Enfermedades Neuroinflamatorias , Condicionamiento Físico Animal , Ratas Wistar , Animales , Masculino , Lipopolisacáridos/toxicidad , Condicionamiento Físico Animal/fisiología , Condicionamiento Físico Animal/métodos , Ratas , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Entrenamiento de Fuerza/métodos , Corteza Cerebral/metabolismo , Corteza Cerebral/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Receptor Muscarínico M1/metabolismoRESUMEN
Tannic acid (TA) exhibits low bioavailability in the gastrointestinal tract, limiting its benefits due to small amounts reaching the CNS. Thus, the objective of this study was to develop zein capsules and fibers by electrospraying/electrospinning for encapsulation of TA. Polymeric solutions were evaluated by electrical conductivity, density, and viscosity. In zein capsules, up to 2 % TA was added, and in fibers, up to 1 % TA was added. Zein capsule and fiber with TA were evaluated by morphology, size distribution, encapsulation efficiency, thermal and thermogravimetric properties, and functional groups. Zein capsule with 1.5 % TA was evaluated in astrocyte culture for cytotoxicity and antioxidant activity. TA zein capsules and fibers exhibited high encapsulation efficiency and homogeneous morphology. TA encapsulated in zein presented higher thermal stability than free TA. TA zein capsule did not present toxicity and elicited antioxidant action in lipopolysaccharide-induced astrocyte culture. Capsules and fibers were successfully produced by electrospraying/electrospinning techniques.
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Antioxidantes , Astrocitos , Lipopolisacáridos , Polifenoles , Taninos , Zeína , Taninos/química , Taninos/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Zeína/química , Antioxidantes/farmacología , Antioxidantes/química , Lipopolisacáridos/farmacología , Animales , Escherichia coli/efectos de los fármacos , Ratas , Células Cultivadas , CápsulasRESUMEN
This study evaluated the effect of vitamin D3 (VIT D3) supplementation on the enzymatic activities and density of ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), ecto-5-nucleotidase (E-5'-NT), adenosine deaminase (ADA), as well as the density of P2 × 7R, P2Y12R, A1R, A2AR receptors, IL-1ß, and oxidative parameters in type 2 diabetic rats. Forty male Wistar rats were fed a high carbohydrate-high fat diet (HCHFD) and received an intraperitoneal injection containing a single dose of streptozotocin (STZ, 35 mg/kg). Animals were divided into four groups: 1) control; 2) control/VIT D3 12 µg/kg; 3) diabetic; and 4) diabetic/VIT D3 12 µg/kg. Results show that VIT D3 reduced blood glucose, ATP hydrolysis, ADA activity, P2Y12R density (platelets), as well as ATP, ADP, and AMP hydrolysis and ADA activity (synaptosomes). Moreover, VIT D3 increased insulin levels and AMP hydrolysis (platelets) and improved antioxidant defense. Therefore, we suggest that VIT D3 treatment modulates hyperglycemia-induced changes via purinergic enzymes and receptor expression, consequently attenuating insulin homeostasis dysregulation in the diabetic state.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Insulinas , Ratas , Masculino , Animales , Ratas Wistar , Colecalciferol/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Vitaminas , Adenosina Monofosfato/metabolismo , Adenosina Trifosfato/metabolismoRESUMEN
Chromium (Cr) is a mineral that helps animals subjected to stressful conditions. The suckling period is characterized by several stressful episodes, particularly during the first hours after birth and at weaning. There is little consumption of concentrate by calves in the first weeks of life; consequently, consuming any supplement added to feed would be negligible. Thus, the hypothesis was that the calves would take it in earlier if Cr were consumed in a milk replacer instead. Therefore, our study aimed to determine whether including organic Cr in calf feed (via milk replacer or concentrate) during the suckling phase would improve calf health and growth performance. Twenty-four male Holstein calves with an average age of 8 ± 4 days and 39.8 ± 6.9 kg average body weight were used. Calves were randomly divided into three groups: (a) Chromium-Milk (CR-M), receiving 4 mg Cr/animal/day via milk replacer during the 60 experimental days of suckling (n = 8); (b) Chromium-Concentrate (CR-C), receiving 4 mg Cr/animal/day via concentrate (n = 8); (c) Control (C), animals that did not receive Chromium (n = 8). The experiment lasted 75 days, divided into two well-defined stages: suckling (1-60 days) and weaning (61-75 days). Body weight weekly, daily feed intake, and blood samples taken every two weeks during the experiment were evaluated. At the end of the experiment, the apparent digestibility evaluation was carried out, with the results of weight and consumption carried out, and a feed efficiency analysis was carried out. It was observed that the inclusion of organic Cr (regardless of whether it was milk or concentrate) increased body weight gain (kg) for the CR-C group: 41.8 kg, CR-M: 40.4 kg compared to the C: 34.2 kg (p = 0.01). The protein digestibility was higher in the CR-M group (52%, p = 0.05). Cr consumption increased Cr concentrations in the serum of the calves and was higher in the first week in the animals in the CR-M group. This did not happen for the C group; however, with higher concentrate consumption, Cr concentrations increased and remained high until the end of the experiment. Glucose concentrations were higher in the groups that consumed Cr. Total protein concentrations were higher in the CR-M and CR-C groups than in group C. Immunoglobulin A concentrations were higher in groups CR-C and CR-M than in group C (days 40 and 60). In conclusion, the adding Cr to calf feed improves their health, indirectly favors growth performance, and increases protein digestibility.
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Physical exercise is recognized as a non-pharmacological approach to treat and protect against several neuroinflammatory conditions and thus to prevent brain disorders. However, the interest in ergogenic resources by athletes and bodybuilding practitioners is widespread and on the rise. These substances shorten the process of performance gain and improve aesthetics, having led to the prominent use and abuse of hormones in the past years. Recent evidence has shown that the purinergic system, composed of adenine nucleotides, nucleosides, enzymes, and receptors, participates in a wide range of processes within the brain, such as neuroinflammation, neuromodulation, and cellular communication. Here, we investigated the effects of the anabolic androgenic steroid (AAS) testosterone (TES) at a dose of 70 mg/kg/week in female rats and the neuroprotective effect of resistance exercise related to the purinergic system and oxidative stress parameters. Our findings showed a decrease in ATP and ADO hydrolysis in treated and trained animals. Furthermore, there was an increase in the density of purinoceptors (P2X7 and A2A) and inflammatory markers (IBA-1, NRLP3, CASP-1, IL-1ß, and IL-6) in the cerebral cortex of animals that received AAS. On the other hand, exercise reversed neuroinflammatory parameters such as IBA-1, NLRP3, CASP-1, and IL-1ß and improved antioxidant response and anti-inflammatory IL-10 cytokine levels. Overall, this study shows that the use of TES without indication or prescription disrupts brain homeostasis, as demonstrated by the increase in neuroinflammation, and that the practice of exercise can protect brain health.
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Anabolizantes , Entrenamiento de Fuerza , Humanos , Ratas , Femenino , Animales , Testosterona , Anabolizantes/farmacología , Enfermedades Neuroinflamatorias , Congéneres de la Testosterona/farmacología , EncéfaloRESUMEN
Resistance physical exercise has neuroprotective and anti-inflammatory effects on many known diseases and, therefore, it has been increasingly explored. The way in which this type of exercise exerts these actions is still under investigation. In this study, we aimed to analyze the enzymes and components of the purinergic system involved in the inflammatory process triggered by the P2X7R. Rats were divided into four groups: control, exercise (EX), lipopolysaccharide (LPS), and EX + LPS. The animals in the exercise groups were subjected to a 12-week ladder-climbing resistance physical exercise and received LPS after the last session for sepsis induction. Enzymes activities (NTPDase, 5'-nucleotidase, and adenosine deaminase), purinoceptors' density (P2X7R, A1, and A2A), and the levels of inflammatory indicators (pyrin domain-containing protein 3 (NLRP3), Caspase-1, interleukin (IL)- 6, IL-1B, and tumor necrosis factor (TNF) -α) were measured in the cortex and hippocampus of the animals. The results show that exercise prevented (in the both structures) the increase of: 1) nucleoside-triphosphatase (NTPDase) and 5'-nucleotidase activities; 2) P2X7R density; 3) NLRP3 and Caspase-1; and 4) IL-6, IL-1ß, and TNF-α It is suggested that the purinergic system and the inflammatory pathway of P2X7R are of fundamental importance and influence the effects of resistance physical exercise on LPS-induced inflammation. Thus, the modulation of the P2X7R by resistance physical exercise offers new avenues for the management of inflammatory-related illnesses.
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Lipopolisacáridos , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Lipopolisacáridos/toxicidad , 5'-Nucleotidasa/metabolismo , Enfermedades Neuroinflamatorias , Hipocampo/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Ejercicio Físico , Caspasas/metabolismo , Receptores Purinérgicos P2X7/metabolismoRESUMEN
(1) Background: This study's objective was to determine whether adding vegetable biocholine (VB) to pigs' diets would minimize the negative effects caused by daily aflatoxin (B1 + B2) intake. (2) Methods: We used seventy-two whole male pigs weaned at an average of 26 days and divided them into four groups with six replicates each (2 × 2 factorial). The treatments were identified as Afla0VB0 (negative control, without aflatoxin and without VB); Afla500VB0 (positive control, 500 µg/kg of aflatoxins; Afla0VB800 (800 mg/kg of VB); and Afla500VB800 (500 µg/kg of aflatoxin +800 mg/kg of VB). (3) Results: In the first 20 days of the experiment, only the pigs from Afla500VB0 had less weight gain and less feed consumption, different from the 30th to 40th day, when all treatments had lower performance than the negative control. In the liver, higher levels of oxygen-reactive species and lipid peroxidation were observed in Afla500VB0, associated with greater activity of the enzymes alanine aminotransferase and aspartate aminotransferase. In the jejunum, oxidative stress was associated with nitrous stress in Afla500VB0. An increase in splenic glutathione S-transferase activity in the Afla500VB800 animals was observed. (4) Conclusions: Consuming a diet contaminated with 500 µg/kg of aflatoxin influences the health and performance in the nursing phase in a silent way; however, it generates high economic losses for producers. When VB was added to the pigs' diet in the face of an aflatoxin challenge, it showed hepatoprotective potential.
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Plasma membrane anchored nucleotidases (E-ATPDases), as the E-NTPDase family, could hydrolyze and regulate the pericellular levels of nucleotides in lymphocytes. Each immune organ has a different microenvironment and display lymphocytes with different functions and phenotypes. Considering the different functions of each resident subpopulations of lymphocytes, the E-ATPDases activities in bone marrow (BML), thymus (TL) and mesenteric lymph node (MLL) lymphocytes of Wistar rats were characterized. The hydrolysis of extracellular nucleotides (eATP and eADP) showed linearity in time of reaction between 0 and 120 min, and concentration of lymphocytes expressed in proteins between 1 and 6 µg protein in the reaction medium. The optimal activity was attained at 37 °C in a pH value of 8.0. The necessity of the cofactors Ca2+ and Mg2+ for the enzymatic activity was confirmed through a curve of concentration of 0-1000 µM in the reaction medium, with both cofactors showing similar effects in the enzymatic activity. The Chevillard plot revealed that the hydrolysis of eATP and eADP occurred at the same active site of the enzyme. The analyses of E-ATPDases inhibitor and enzyme specificity showed possible involvement of E-NTPDase isoforms - 1 and - 2 in the isolated cells. Furthermore, different kinetic behavior of the nucleotide hydrolysis in each resident subpopulation lymphocyte was observed in this study, as MLL showed the higher Vmax with the lowest km values, while TL had the lowest Vmax and high km values. The kinetic values for E-NTPDase activity of each immune tissue lymphocytes can be an important therapeutic target for numeral immune-related diseases.
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Vassobia breviflora belongs to the Solanaceae family, possessing biological activity against tumor cells and is a promising alternative for therapy. The aim of this investigation was to determine the phytochemical properties V. breviflora using ESI-ToF-MS. The cytotoxic effects of this extract were examined in B16-F10 melanoma cells and the relationship if any to purinergic signaling was involved. The antioxidant activity of total phenols, (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) was analyzed, as well as production of reactive oxygen species (ROS) and nitric oxide (NO) was determined. Genotoxicity was assessed by DNA damage assay. Subsequently, the structural bioactive compounds were docked against purinoceptors P2X7 and P2Y1 receptors. The bioactive compounds found in V. breviflora were N-methyl-(2S,4 R)-trans-4-hydroxy-L-proline, calystegine B, 12-O-benzoyl- tenacigenin A and bungoside B. In vitro cytotoxicity was demonstrated at concentration ranges of 0.1-10 mg/ml, and plasmid DNA breaks only at the concentration of 10 mg/ml. V. breviflora extracts affected hydrolysis by ectoenzymes, such as ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) and ectoadenosine deaminase (E-ADA) which control levels of degradation and formation of nucleosides and nucleotides. In the presence of substrates ATP, ADP, AMP and adenosine, the activities of E-NTPDase, 5´-NT or E-ADA were significantly modulated by V. breviflora. N-methyl-(2S,4 R)-trans-4-hydroxy-L-proline presented higher binding affinity (according to receptor-ligand complex estimated binding affinity as evidenced by ∆G values) to bind to both P2X7 and P2Y1purinergic receptors.Our results suggest a putative interaction of V. breviflora bioactive compounds with growth inhibitory potential in B16-F10 melanoma and suggest that may be considered as promising compounds in melanoma and cancer treatment.
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Melanoma , Solanaceae , Humanos , Antioxidantes/farmacología , Agua , Extractos Vegetales/farmacología , Extractos Vegetales/química , Fitoquímicos/farmacología , Melanoma/tratamiento farmacológico , Proliferación CelularRESUMEN
Metastatic melanoma is a very aggressive skin cancer. Platelets are constituents of the tumor microenvironment and, when activated, contribute to cancer progression, especially metastasis and inflammation. P2Y12 is an adenosine diphosphate receptor that triggers platelet activation. Inhibition of P2Y12 by clopidogrel bisulfate (CB) decreases platelet activation, which is also controlled by the extracellular concentration and the metabolism of purines by purinergic enzymes. We evaluated the effects of CB on the viability and proliferation of cultured B16-F10 cells. We also used a metastatic melanoma model with C57BL-6 mice to evaluate cancer development and purine metabolism modulation in platelets. B16-F10 cells were administered intraperitoneally to the mice. Two days later, the animals underwent a 12-day treatment with CB (30 mg/kg by gavage). We have found that CB reduced cell viability and proliferation in B16-F10 culture in 72 h at concentrations above 30 µm. In vivo, CB decreased tumor nodule counts and lactate dehydrogenase levels and increased platelet purine metabolism. Our results showed that CB has significant effects on melanoma progression.
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Melanoma Experimental , Melanoma , Neoplasias Cutáneas , Animales , Ratones , Clopidogrel/farmacología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Melanoma Experimental/tratamiento farmacológico , Microambiente TumoralRESUMEN
OBJECTIVES: Our aim in this study was to identify predictors for diabetes among the characteristics of the glycemic curve and glycated hemoglobin (A1C) in healthy, young adults. METHODS: We used a cross-sectional study to establish predictors for diabetes based on earlier studies and evaluated occurrence of the condition in 81 healthy, young adult subjects. These volunteers underwent analysis of fasting plasma glucose, oral glucose tolerance test plasma glucose, A1C, and inflammatory markers (leukocytes, monocytes, and C-reactive protein). The nonparametric Mann-Whitney U test, Fisher's exact test, chi-square test, Kruskal-Wallis test, and multiple-comparisons test were used to analyze the data. RESULTS: We studied 2 age groups, homogeneous in terms of family history of diabetes: one group ranged in age from ≥18 to <28 years (median 20 years; body mass index [BMI] 24 kg/m2) and the other group ranged in age from ≥28 to <45 years (median 35 years; BMI 24 kg/m2). The older group had a higher incidence of predictors (p=0.0005) and was associated with the predictors 30-minute blood glucose ≥164 mg/dL (p=0.0190), 60-minute blood glucose ≥125 mg/dL (p=0.0346), and A1C ≥5.5% (p=0.0162), with a monophasic glycemic curve (p=0.007). The younger group was associated with the 2-hour plasma glucose predictor ≥140 mg/dL (p=0.014). All subjects had fasting glucose in the normal range. CONCLUSIONS: Healthy, young adults may already have predictors of diabetes, identified mainly by aspects of the glycemic curve and A1C, but at more modest levels than those with prediabetes.
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Diabetes Mellitus Tipo 2 , Estado Prediabético , Humanos , Adulto Joven , Adolescente , Persona de Mediana Edad , Hemoglobina Glucada , Diabetes Mellitus Tipo 2/epidemiología , Glucemia/análisis , Estudios Transversales , Estado Prediabético/epidemiologíaRESUMEN
Chromium is a trace element essential in metabolising carbohydrates, lipids, and proteins and is involved in other biological functions. Therefore, this study determined whether chromium propionate supplementation in dogs improves haematologic, metabolic, immune/inflammatory, and antioxidant biomarkers. A commercial product (Labex® Chromium) containing 0.4% chromium was used at 500 g/ton of food, which provided an additional calculated amount of 2 mg of chromium per kg of food. We used ten beagles divided into two treatments: the chromium group (supplemented with 0.380 mg of chromium/dog/day; T-CHR) and the control group comprised dogs fed a basal diet (no chromium supplementation). The experiment included two periods of 28 days, with an interval of 15 days, i.e. the dogs in the control group in the first period were in the chromium group in the second period (all dogs underwent all treatments in a crossover design). Dogs supplemented with chromium had higher serum mineral levels on days 14 and 28 (P ≤ 0.001). The group in the chromium group showed significantly higher numbers of total leukocytes and lymphocytes and concentrations of total protein, globulin, thio-proteins, and catalase activity in blood than the control group. Serum urea concentrations and TBARS (lipid peroxidation) were lower (P ≤ 0.05) in the chromium group. Tendencies towards lower concentrations of reactive oxygen species were observed on day 28 in the T-CHR group (P = 0.10). Chromium supplementation increased the concentration of cytokines in serum (tumour necrosis factor-alpha [TNF-α], IFN-γ, and IL-10) and C-reactive protein (P ≤ 0.05). Dogs in the chromium group had higher gamma globulin concentrations than controls (P ≤ 0.001). These findings suggest that supplementation with chromium propionate (2 mg/kg) in food positivity modulates metabolic, antioxidant, and immune indicators in dogs.
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Antioxidantes , Dieta , Perros , Animales , Antioxidantes/metabolismo , Dieta/veterinaria , Alimentación Animal/análisis , Suplementos Dietéticos , Cromo , Estrés OxidativoRESUMEN
Chagas Disease (CD) affects around eight million people worldwide. It is considered a neglected disease that presents few treatment options with efficacy only in the acute phase. Nanoparticles have many positive qualities for treating parasite infections and may be effectively and widely employed in clinical medicine. This research aimed to evaluate the nanoencapsulated benznidazole treatment in animals experimentally infected with Trypanosoma cruzi. To analyze the treatment efficacy, we evaluated survival during thirty days, parasitemia, genotoxicity, and heart and liver histopathology. Thirty-five female Swiss mice were organized into seven groups characterizing a dose curve: A - Negative control (uninfected animals), B - Positive control (infected animals), C - Benznidazole (BNZ) 100 mg/kg (infected animals), D - 5 mg/kg Benznidazole nanocapsules (NBNZ) (infected animals), E - 10 mg/kg Benznidazole nanocapsules (infected animals), F - 15 mg/kg Benznidazole nanocapsules (infected animals), G - 20 mg/kg Benznidazole nanocapsules (infected animals). The animals were infected with the Y strain of T. cruzi intraperitoneally. The treatment was administered for eight days by oral gavage. It was possible to observe that the treatment with the highest NBNZ dose presented efficacy similar to the standard benznidazole drug. The 20 mg/kg NBNZ dose was able to reduce parasitemia, increase survival, and drastically reduce heart and liver tissue damage compared to the 100 mg/kg BNZ dose. Moreover, it showed a lower DNA damage index than the BNZ treatment. In conclusion, the nanoencapsulation of BNZ promotes an improvement in parasite proliferation control with a five times smaller dose relative to the standard dose of free BNZ, thus demonstrating to be a potential innovative therapy for CD.
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Enfermedad de Chagas , Nanocápsulas , Nitroimidazoles , Tripanocidas , Trypanosoma cruzi , Ratones , Animales , Femenino , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , Enfermedad de Chagas/parasitología , Nitroimidazoles/farmacología , Nitroimidazoles/uso terapéuticoRESUMEN
The present study evaluated the effect of caffeic acid (CA) on behavioral learning and memory tasks in the diabetic state. We also evaluated the effect of this phenolic acid on the enzymatic activities of acetylcholinesterase, ecto-nucleoside triphosphate diphosphohydrolase, ecto-5-nucleotidase and adenosine deaminase as well as on the density of M1R, α7nAChR, P2×7R, A1R, A2AR, and inflammatory parameters in the cortex and hippocampus of diabetic rats. Diabetes was induced by a single intraperitoneal dose of streptozotocin (55 mg/kg). The animals were divided into six groups: control/vehicle; control/CA 10 and 50 mg/kg; diabetic/vehicle; diabetic/CA 10 and 50 mg/kg, treated by gavage. The results showed that CA improved learning and memory deficits in diabetic rats. Also, CA reversed the increase in acetylcholinesterase and adenosine deaminase activities and reduced ATP and ADP hydrolysis. Moreover, CA increased the density of M1R, α7nAChR, and A1R receptors and reversed the increase in P2×7R and A2AR density in both evaluated structures. In addition, CA treatment attenuated the increase in NLRP3, caspase 1, and interleukin 1ß density in the diabetic state; moreover, it increased the density of interleukin-10 in the diabetic/CA 10 mg/kg group. The results indicated that CA treatment positively modified the activities of cholinergic and purinergic enzymes and the density of receptors, and improved the inflammatory parameters of diabetic animals. Thus, the outcomes suggest that this phenolic acid could improve the cognitive deficit linked to cholinergic and purinergic signaling in the diabetic state.
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Disfunción Cognitiva , Diabetes Mellitus Experimental , Ratas , Animales , Ratas Wistar , Adenosina Desaminasa/metabolismo , Acetilcolinesterasa/metabolismo , Estreptozocina , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Enfermedades Neuroinflamatorias , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Transducción de Señal , Colinérgicos/uso terapéuticoRESUMEN
Several studies have indicated the vitamin D deficiency in the development of macro- and microvascular complications of diabetes mellitus (DM) including DM-related cognitive dysfunction. The purinergic system plays an important role in the modulation of a variety of mechanisms, including neuroinflammation, plasticity, and cell-cell communication. In addition, purines, their receptors, and enzymes can regulate the purinergic axis at different levels in type 1 DM (T1DM). This study evaluated the effects of vitamin D3 alone or in combination with metformin in the behavioral performance of streptozotocin-induced T1DM rats. The effects of this combination on the metabolism of ATP and ADP were also studied by NTPDase (CD39), AMP by 5'-nucleotidase (CD73), and adenosine by adenosine deaminase (E-ADA) in the brain and peripheral lymphocytes of type 1 diabetic STZ-induced rats. The results showed that anxiety and memory loss from the DM condition reverted after 30 days of vitamin D3 treatment. Furthermore, the DM state affected systemic enzymes, with no effect on the central enzymes hydrolyzing extracellular nucleotides and nucleosides. Vitamin D3 treatment positively regulated ectonucleotidase (NTPDase and 5'-nucleotidase) activity, E-ADA, and the purinergic receptors as a mechanism to prevent oxidative damage in the cerebral cortex of T1DM rats. A neuroprotector effect of vitamin D3 through adenosine signaling was also observed, by regulating A1 and A2A receptors proteins levels. The present findings suggest that purinergic signaling through vitamin D3 modulation may be a novel alternative strategy for T1DM treatment, and may compensate for the negative changes in the central nervous system.
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Diabetes Mellitus Tipo 1 , Metformina , Ratas , Animales , Colecalciferol , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , 5'-Nucleotidasa/metabolismo , Metformina/farmacología , Adenosina/farmacologíaRESUMEN
ATP and adenosine exert pivotal roles in the development, maintenance, and metastatic spreading of melanoma. The action of such key melanoma tumor microenvironment (TME) constituents might be complementary or opposed, and their effects are not exclusive to immune cells but also to other host cells and tumor cells. The effects of ATP are controlled by the axis CD39/73, resulting in adenosine, the main actor in the TME, and A2A is the crucial mediator of its effects. We evaluated ATP and adenosine signaling through A2A on B16F10 melanoma cells using istradefylline (IST) (antiparkinsonian A2A antagonist) and caffeine (CAF) treatments after exposure to ATP and adenosine. Adenosine increased melanoma cell viability and proliferation in a concentration-dependent manner. ATP increases viability only as a substrate by CD39 to produce adenosine. Both IST and CAF are toxic to B16F10 cells, but only IST potentialized paclitaxel-induced cytotoxic effects, even decreasing its IC50 value. IST positively modulated CD39 and CD73 expression. CD39 activity was increased, and E-ADA was reduced, indicating that the melanoma cells promoted compensatory feedback in the production and maintenance of adenosine levels. A2A antagonism by IST reduced the factors associated with malignancy, like migration, adhesion, colony formation, and the capacity to produce melanin. Moreover, IST significantly increases nitric oxide (NO) production, which correlates to a decline in melanoma cell viability by apoptotic events. Altogether, our results suggest that adenosine signaling through A2A is essential for B16F10 cells, and its inhibition by IST causes compensatory purinergic enzymatic modulations. Furthermore, IST is a promising therapy that provides new ways to improve current melanoma treatments.
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Cancer and infectious diseases are among the leading causes of death in the world. Despite the diverse array of treatments available, challenges posed by resistance, side effects, high costs, and inaccessibility persist. In the Solanaceae plant family, few studies with Vassobia breviflora species relating to biological activity are known, but promising results have emerged. The phytochemicals present in the ethyl acetate fraction were obtained using ESI-MS-QTOF, and the antioxidants assays 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radical capture (ABTS), plasma ferric reduction capacity (FRAP), and total antioxidant capacity (TAC). Cytotoxic activity was evaluated by MTT, Neutral Red, and lactate dehydrogenase (LDH) released. The production of reactive oxygen species, nitric oxide, and purinergic enzymes was also investigated. Antibacterial activity was measured through minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and antibiofilm activity, in addition to genotoxicity in plasmid DNA. Five major masses were identified D-glucopyranose II, allyl disulfide, γ-lactones, pharbilignoside, and one mass was not identified. V. breviflora exhibited relevant antioxidant and cytotoxic activity against the HeLa cell line and enhanced expression effect in modulation of purinergic signaling. Antibacterial activities in the assays in 7 ATCC strains and 8 multidrug-resistant clinical isolates were found. V. breviflora blocked biofilm formation in producing bacteria at the highest concentrations tested. However, there was no plasmid DNA cleavage at the concentrations tested. Data demonstrated that V. breviflora exhibited an antioxidant effect through several methods and proved to be a promising therapeutic alternative for use against tumor cells via purinergic signaling and multidrug-resistant microorganisms, presenting an anti-biofilm effect.
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Antioxidantes , Solanaceae , Acetatos , Antibacterianos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Bacterias , ADN/farmacología , Células HeLa , Humanos , Lactato Deshidrogenasas , Lactonas/farmacología , Pruebas de Sensibilidad Microbiana , Rojo Neutro/farmacología , Óxido Nítrico , Extractos Vegetales/química , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno , Ácidos SulfónicosRESUMEN
Neuroinflammation is an inflammatory process in the central nervous system (CNS), in addition to being one of the main features of Alzheimer's disease (AD) and Parkinson's disease (PD). Microglia are known for their immune functions and have multiple reactive phenotypes related to the types of stages involving neurodegenerative diseases. Depending on the state of activation of microglia in the CNS, it can be neuroprotective or neurotoxic. In this context, AD is a neurodegenerative and neuroinflammatory disease characterized by the deposition of beta-amyloid plaques, formation of fibrillar tangles of tau protein, and loss of neurons due to neurotoxic activation of microglia. However, PD is characterized by the loss of dopaminergic neurons in the substantia nigra and accumulation of alpha-synuclein in the cortical regions, spinal cord, and brain stem, which occurs by microglial activation, contributing to the neuroinflammatory process. In this aspect, the activation of microglia in both pathologies triggers high levels of inflammatory markers, such as interleukins, and causes the neuroinflammatory process of the diseases. Thus, physical exercise is pointed out as neuroprotective, as it can act to strengthen neurogenesis and reduce the inflammatory process. Therefore, the present review addresses the neuroprotective effect of microglia after different types of physical exercise protocols and evaluates the activity and effects of inflammatory and anti-inflammatory parameters and mechanisms of AD and PD. This review will discuss the anti-inflammatory effects of physical exercise through microglia activation with neuroprotective activity and the role of pro-and anti-inflammatory cytokines in AD and PD.
Asunto(s)
Enfermedad de Alzheimer , Fármacos Neuroprotectores , Enfermedad de Parkinson , Enfermedad de Alzheimer/metabolismo , Antiinflamatorios/farmacología , Citocinas/metabolismo , Neuronas Dopaminérgicas/metabolismo , Ejercicio Físico , Humanos , Mediadores de Inflamación/metabolismo , Microglía/metabolismo , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Melanoma is the most lethal form of skin cancer, and its incidence has increased considerably in the last decades. Melanoma presents difficult treatment with strong resistance of tumor cells, due to its extremely invasive nature with high capacity to metastases. Berberine (BBR), an isoquinoline alkaloid, is a molecule found in several medicinal plants, and has been studied in several diseases, demonstrating antimicrobial, antidiabetic and anti-inflammatory properties and anti-tumorigenic effects. METHODS AND RESULTS: In SK-MEL-28 cells, 50 µM BBR treatment for 24 h decreased cell viability by 50 percent. This concentration generated cell death both by early apoptosis and necrosis, with an increase in the DNA damage index. BBR increased (*p < 0.05) the proportion of cells in G1/G0 phase and decreased (###p < 0.005) the percentage of cells in S phase. The alcaloid increased (****p < 0.001) ROS production compared to untreated controls with an increase in activated caspase 3 and phosphorylated p53 protein levels. In addition, BBR significantly enhanced ERK as well as both pro- and anti-inflammatory cytokine expression compared to untreated controls. CONCLUSIONS: BBR has important antiproliferative effects and may be alone or in adjunct therapy a promising candidate for melanoma treatment, a cancer with great incidence and high lethality.
Asunto(s)
Berberina , Melanoma , Apoptosis , Berberina/farmacología , Línea Celular Tumoral , Citocinas/metabolismo , Humanos , Melanoma/tratamiento farmacológicoRESUMEN
This study aimed to determine whether butyric acid glycerides can replace conventional growth promoters, favour intestinal health, and improve performance. A total of 420 birds were used, divided into four groups with seven repetitions per group (n = 15), as follows: NC, negative control (no promoter); PC, positive control (basal diet + enramycin + salinomycin); MDT-BUT, a diet supplemented with mono-, di-, and triglycerides of butyric acid; TRI-BUT, a diet supplemented with tributyrin of butyric acid glycerides. Productive performance was measured on days 1, 21, 35, and 42. Excreta were collected for counting Escherichia coli and coliforms on days 21 and 42. Blood samples were collected at 42 days of age to analyse oxidant/antioxidant status, and the intestine was removed for intestinal morphometry. From 1 to 42 days, there was greater body weight, weight gain, and feed conversion in the PC, MDT-BUT, and TRI-BUT groups than in the NC group; the production efficiency index was 21.10% higher in all groups than in the NC group (p = 0.001). At 21 days, there were lower E. coli counts of 86.8% in the TRI-BUT and 99.7% in PC groups than in the NC and MDT-BUT groups (p < 0.001), while at 42 days, lower counts were found in the PC, MDT-BUT, and TRI-BUT groups than the NC group (p < 0.001). There were lower total protein and globulin levels in the MDT-BUT and TRI-BUT groups than in the NC group (p = 0.001). Cholesterol levels were lower in the TRI-BUT group, followed by MDT-BUT and PC groups, than in the NC group (p = 0.001), while lower triglyceride levels were found in the TRI-BUT group than in the NC and PC groups (p = 0.001). There were lower levels of lipid peroxidation and reactive oxygen species in the TRI-BUT group, followed by the PC group than the NC group (p < 0.001); on the other hand, there were higher protein thiol levels in the TRI-BUT group than the NC group (p = 0.041). The villus:crypt ratio increase was 79.4% in the TRI-BUT group, followed by the 45.1% PC and 19.8% MDT-BUT groups than the NC (p < 0.001). These findings suggest that adding butyric acid confers antimicrobial and antioxidant activity and improves birds' production efficiency, intestinal health, and metabolism. Butyric acid glycerides are an effective alternative to conventional growth promoters.