ABSTRACT
Cordyceps militaris (L.) Link (C. militaris) contains various beneficial substances, including polysaccharides (galactomannan), nucleotides (adenosine and cordycepin), cordycepic acid, amino acids, and sterols (ergosterol and beta-sitosterol). It also contains other essential nutrients, such as protein, vitamins (E, K, B1, B2, and B12), and minerals (potassium, sodium, calcium, magnesium, iron, zinc, and selenium). Due to the numerous health benefits of supplements and products containing C. militaris extract, their popularity has increased. However, the immunostimulant effect of C. militaris remains unclear. Therefore, this study developed a functional beverage from the submerged fermentation of C. militaris (FCM) and aimed to investigate the potential of FCM in healthy male and female volunteers in Phayao Province, Thailand. This study provides essential information for the development of healthy drink products. Healthy men and women were provided either FCM containing 2.85 mg of cordycepin or placebo for 8 weeks (n = 10 for each gender). The immune cell markers, immunoglobulins, and safety parameters were assessed initially at baseline and at 4 and 8 weeks. The NK cell activity markedly increased in the male FCM group from baseline (p = 0.049) to 4 weeks after receiving FCM. Compared with those in the placebo group, the NK activity in women who received FCM for 8 weeks significantly increased (p = 0.023) from baseline. Within-group analysis revealed that the IL-1ß levels were markedly reduced in the male FCM group (p = 0.049). Furthermore, the IL-6 levels decreased from baseline in the female FCM group (p = 0.047). The blood sugar, lipid, and safety indices were not different between the experimental groups. FCM can potentially be developed as an immune-boosting supplement without liver, kidney, or blood component toxicity.
Subject(s)
Cordyceps , Adult , Humans , Male , Female , Cordyceps/chemistry , Deoxyadenosines/pharmacology , Adenosine/metabolism , Adjuvants, Immunologic/pharmacology , Liver , ImmunityABSTRACT
Hepatocellular carcinoma (HCC) progression is associated with dysfunctional mitochondria and bioenergetics impairment. However, no data about the relationship between mitochondrial supercomplexes (hmwSC) formation and ATP production rates in HCC are available. Our group has developed an adenosine derivative, IFC-305, which improves mitochondrial function, and it has been proposed as a therapeutic candidate for HCC. We aimed to determine the role of IFC-305 on both mitochondrial structure and bioenergetics in a sequential cirrhosis-HCC model in rats. Our results showed that IFC-305 administration decreased the number and size of liver tumors, reduced the expression of tumoral markers, and reestablished the typical architecture of the hepatic parenchyma. The livers of treated rats showed a reduction of mitochondria number, recovery of the mtDNA/nDNA ratio, and mitochondrial length. Also, IFC-305 increased cardiolipin and phosphatidylcholine levels and promoted hmwSC reorganization with changes in the expression levels of hmwSC assembly-related genes. IFC-305 in HCC modified the expression of several genes encoding elements of electron transport chain complexes and increased the ATP levels by recovering the complex I, III, and V activity. We propose that IFC-305 restores the mitochondrial bioenergetics in HCC by normalizing the quantity, morphology, and function of mitochondria, possibly as part of its hepatic restorative effect.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Rats , Animals , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Diethylnitrosamine/toxicity , Liver Neoplasms/chemically induced , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Mitochondria/metabolism , Adenosine/metabolism , Energy Metabolism , Adenosine Triphosphate/metabolismABSTRACT
Metabolic syndrome is a multifactorial disease with high prevalence worldwide. It is related to cardiovascular disease, diabetes, and obesity. Approximately 80% of patients with metabolic syndrome have some degree of fatty liver disease. An adenosine derivative (IFC-305) has been shown to exert protective effects in models of liver damage as well as on elements involved in central metabolism; therefore, here, we evaluated the effect of IFC-305 in an experimental model of metabolic syndrome in rats induced by a high-fat diet and 10% sucrose in drinking water for 18 weeks. We also determined changes in fatty acid uptake in the Huh-7 cell line. In the experimental model, increases in body mass, serum triglycerides and proinflammatory cytokines were induced in rats, and the adenosine derivative significantly prevented these changes. Interestingly, IFC-305 prevented alterations in glucose and insulin tolerance, enabling the regulation of glucose levels in the same way as in the control group. Histologically, the alterations, including mitochondrial morphological changes, observed in response to the high-fat diet were prevented by administration of the adenosine derivative. This compound exerted protective effects against metabolic syndrome, likely due to its action in metabolic regulation, such as in the regulation of glucose blood levels and hepatocyte fatty acid uptake.
Subject(s)
Metabolic Syndrome , Humans , Rats , Animals , Metabolic Syndrome/drug therapy , Metabolic Syndrome/prevention & control , Metabolic Syndrome/chemically induced , Sucrose/metabolism , Diet, High-Fat/adverse effects , Dietary Supplements , Adenosine/metabolism , Glucose/metabolism , Fatty Acids/metabolism , Liver/metabolismABSTRACT
BACKGROUND: Neutrophils consume a large amount of energy when performing their functions. Compared with other white blood cells, neutrophils contain few mitochondria and mainly rely on glycolysis and gluconeogenesis to produce ATP. The inflammatory site is hypoxic and nutrient poor. Our aim is to study the role of abnormal adenosine metabolism of neutrophils in the asthmatic airway inflammation microenvironment. METHOD: In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene-knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5'-(α, ß-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect. RESULT: PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic knockdownof CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C-C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis. CONCLUSION: Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.
Subject(s)
Asthma , Neutrophils , Animals , Mice , Neutrophils/metabolism , Aspergillus fumigatus/metabolism , Adenosine/metabolism , Asthma/therapy , Cytokines/metabolism , Inflammation , Chemokines/metabolism , Bronchoalveolar Lavage Fluid , Plant Extracts , Airway RemodelingABSTRACT
BACKGROUND: Glycolysis is the key hallmark of cancer and maintains malignant tumor initiation and progression. The role of N6-methyladenosine (m6A) modification in glycolysis is largely unknown. This study explored the biological function of m6A methyltransferase METTL16 in glycolytic metabolism and revealed a new mechanism for the progression of Colorectal cancer (CRC). METHODS: The expression and prognostic value of METTL16 was evaluated using bioinformatics and immunohistochemistry (IHC) assays. The biological functions of METTL16 in CRC progression was analyzed in vivo and in vitro. Glycolytic metabolism assays were used to verify the biological function of METTL16 and Suppressor of glucose by autophagy (SOGA1). The protein/RNA stability, RNA immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP) and RNA pull-down assays were used to explore the potential molecular mechanisms. RESULTS: SOGA1 is a direct downstream target of METTL16 and involved in METTL16 mediated glycolysis and CRC progression. METTL16 significantly enhances SOGA1 expression and mRNA stability via binding the "reader" protein insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1). Subsequently, SOGA1 promotes AMP-activated protein kinase (AMPK) complex ubiquitination, inhibits its expression and phosphorylation, thus upregulates pyruvate dehydrogenase kinase 4 (PDK4), a crucial protein controlling glucose metabolism. Moreover, Yin Yang 1 (YY1) can transcriptionally inhibit the expression of METTL16 in CRC cells by directly binding to its promoter. Clinical data showed that METTL16 expression is positively correlated to SOGA1 and PDK4, and is associated with poor prognosis of CRC patients. CONCLUSIONS: Our findings suggest that METTL16/SOGA1/PDK4 axis might be promising therapeutic targets for CRC.
Subject(s)
Adenosine , Colorectal Neoplasms , Humans , Adenosine/metabolism , Prognosis , RNA/metabolism , Colorectal Neoplasms/pathology , Glycolysis , Cell Line, Tumor , Methyltransferases/genetics , Methyltransferases/metabolismABSTRACT
Excessive drinking has been listed by the World Health Organization as the fifth major risk factor; especially the liver, as the core organ of alcohol metabolism, is prone to organic lesions. Probiotics have received attention due to their bioactivity for liver protection. The beneficial effects of probiotics on hosts are related to their physiological functions. Therefore, based on the concept of second-generation synbiotes, this study explored the protective effects of four dietary polyphenols on the stress tolerance, hydrophobicity, adhesion, and digestive characteristics of L. rhamnosus 1.0320. L. rhamnosus 1.0320 had the best synergistic effect with dihydromyricetin (DMY). Therefore, this combination was selected as a synbiotic supplement to explore the protective effect on acute alcohol exposure-induced hepatic impairment. The results showed that L. rhamnosus 1.0320 combined with DMY restored the intestinal barrier by upregulating short-chain fatty acid levels and activated the adenosine 5'-monophosphate-activated protein kinase-mediated lipid metabolism pathway to inhibit oxidative stress, inflammation, and lipid accumulation in the liver. Furthermore, 109 CFU/mouse/d L. rhamnosus 1.0320 and 50 mg/kg/d DMY by gavage were identified as the optimal doses for protection against acute alcohol expose-induced hepatic impairment. This study provides new insights into alleviating acute alcoholic hepatic impairment by targeting intestinal metabolites through the gut-liver axis.
Subject(s)
Lacticaseibacillus rhamnosus , Liver Diseases, Alcoholic , Probiotics , Mice , Animals , Lacticaseibacillus , Lipid Metabolism , Protein Kinases/metabolism , Liver/metabolism , Ethanol/metabolism , Liver Diseases, Alcoholic/drug therapy , Liver Diseases, Alcoholic/prevention & control , Liver Diseases, Alcoholic/metabolism , Fatty Acids, Volatile/metabolism , Signal Transduction , Adenosine/metabolismABSTRACT
Neutrophils (PMNs) require extracellular ATP and adenosine (ADO) to fight bacterial infections, which often have life-threatening consequences in pediatric patients. We wondered whether the ATP and ADO levels in the plasma of children change with age and if these changes influence the antimicrobial efficacy of the PMNs of these children. We measured plasma concentrations of ATP and ADO and the activities of the enzymes responsible for the breakdown of these mediators in plasma samples from healthy children and adolescents (n = 45) ranging in age from 0.2 to 15 years. In addition, using blood samples of these individuals, we compared how effective their PMNs were in the phagocytosis of bacteria. In an experimental sepsis model with young (10 days) and adolescent mice (10 weeks), we studied how age influenced the resilience of these animals to bacterial infections and whether addition of ATP could improve the antimicrobial capacity of their PMNs. We found that plasma ATP levels correlated with age and were significantly lower in infants (< 1 year) than in adolescents (12-15 years). In addition, we observed significantly higher plasma ATPase and adenosine deaminase activities in children (< 12 years) when compared to the adolescent population. The activities of these ATP and ADO breakdown processes correlated inversely with age and with the ability of PMNs to phagocytize bacteria. Similar to their human counterparts, young mice also had significantly lower plasma ATP levels when compared to adolescent animals. In addition, we found that mortality of young mice after bacterial infection was significantly higher than that of adolescent mice. Moreover, bacterial phagocytosis by PMNs of young mice was weaker when compared to that of older mice. Finally, we found that ATP supplementation could recover bacterial phagocytosis of young mice to levels similar to those of adolescent mice. Our findings suggest that rapid ATP hydrolysis in the plasma of young children lowers the antimicrobial functions of their PMNs and that this may contribute to the vulnerability of pediatric patients to bacterial infections.
Subject(s)
Anti-Infective Agents , Bacterial Infections , Adolescent , Humans , Mice , Child , Animals , Child, Preschool , Infant , Neutrophils/metabolism , Adenosine/metabolism , Adenosine Triphosphate/metabolism , Bacterial Infections/metabolism , Anti-Infective Agents/metabolism , PhagocytosisABSTRACT
We propose a new organ-conditioning strategy based on mesenchymal stromal cell (MSCs)/extracellular vesicle (EVs) delivery during hypothermic perfusion. MSCs/EVs marker CD73 is present on renal proximal tubular cells, and it protects against renal ischemia-reperfusion injury by converting adenosine monophosphate into adenosine (ADO). In this study, after checking if CD73-silenced EVs (EVsi) would impact in vitro tubular-cell proliferation, we perfused kidneys of a rat model of donation after circulatory death, with Belzer solution (BS) alone, BS supplemented with MSCs, EVs, or EVsi. The ADO and ATP levels were measured in the effluents and tissues. Global renal ischemic damage score (GRS), and tubular cell proliferation index (IPT) were evaluated in the tissue. EVsi did not induce cell proliferation in vitro. Ex vivo kidneys perfused with BS or BS + EVsi showed the worst GRS and higher effluent ADO levels than the MSC- and EV-perfused kidneys. In the EV-perfused kidneys, the tissue and effluent ATP levels and IPT were the highest, but not if CD73 was silenced. Tissue ATP content was positively correlated with tissue ADO content and negatively correlated with effluent ADO level in all groups. In conclusion, kidney conditioning with EVs protects against ischemic damage by activating the CD73/ADO system.
Subject(s)
Extracellular Vesicles , Mesenchymal Stem Cells , Adenosine/metabolism , Adenosine Monophosphate/metabolism , Adenosine Triphosphate/metabolism , Animals , Extracellular Vesicles/metabolism , Ischemia/metabolism , Kidney/metabolism , Mesenchymal Stem Cells/metabolism , RatsABSTRACT
The Chinese caterpillar mushroom, Ophiocordyceps sinensis, is rare in traditional Chinese herbal medicine. It was reported that the development of ascospores in sexual stage of Chinese Cordyceps requires certain UV irradiation, but whether light has effect on the asexual stage of O. sinensis is unclear. It is important and necessary to identify the candidate genes involved in asexual stages (mycelium period) metabolism of O. sinensis exposed to light treatment. In this study, the isolated and purified monoascospore strains from O. sinensis were treated with 10 days light (L10) and dark as control. Transcriptome sequencing (RNA-seq) was conducted to investigate the effect of light treatment on O. sinensis at the gene level and the changes in various metabolic pathways. The results showed that the colony surface was covered with villous aerial hyphae with a yellow circular mycelium ribbon in the center of the colony, and the content of polysaccharides, urea, adenosine, and cordycepin were significantly enhanced by L10 treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation analysis showed that cell structure and catalytic metabolism were the significant items classified, and crucial genes affecting the anabolic pathways of polysaccharides, urea, adenosine, and cordycepin were also identified. In addition, the important roles of photoreceptor genes CRYD, WC-1, and FRQ were verified by combined analysis of qRT-PCR and transcriptome sequencing. Collectively, this study would be helpful to better understand the influence of light on the asexual stage of Chinese Cordyceps and provide a preliminary light treatment reference for Cordyceps artificial cultivation.
Subject(s)
Cordyceps , Adenosine/metabolism , China , Mycelium/genetics , Transcriptome , UreaABSTRACT
Porcine sperm is rich in polyunsaturated fatty acids; therefore, it is highly susceptible to oxidative damage during storage. Inhibition of oxidative stress during preservation is essential for maintaining sperm motility. Astaxanthin is a potent antioxidant used in the cosmetic and pharmaceutical industries. This study aimed to explore the effect of supplementing astaxanthin as an extender of porcine semen preservation dilutions at 17°C. Various concentrations of astaxanthin were added to diluted porcine semen at 17°C. We performed computer-assisted semen analysis, evaluation of plasma membrane integrity and acrosome integrity, and measurement of total antioxidant activity, malondialdehyde (MDA) content, reactive oxygen species levels, superoxide dismutase (SOD) activity, catalase (CAT) activity, glutathione peroxidase (GSH-PX) activity and sperm motility parameters. Compared with the control group, the addition of 0.25 µg/ml astaxanthin group significantly improved sperm motility parameters stored on the fifth day; these were increased levels of sperm SOD, GSH-PX and CAT (p < .05), increased sperm adenosine trisphosphate and lactate dehydrogenase levels and decreased sperm MDA levels (p < .05). These findings suggest that adding 0.25 µg/ml of astaxanthin improves the quality of porcine semen stored at 17°C. Our findings provide theoretical support for developing new protective agents critical for preserving pig semen at 17°C.
Subject(s)
Semen Analysis , Semen Preservation , Adenosine/metabolism , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Catalase/pharmacology , Glutathione Peroxidase , Lactate Dehydrogenases/metabolism , Male , Malondialdehyde/metabolism , Reactive Oxygen Species/metabolism , Semen/physiology , Semen Analysis/veterinary , Semen Preservation/veterinary , Sperm Motility , Spermatozoa/physiology , Superoxide Dismutase/metabolism , Swine , XanthophyllsABSTRACT
In eukaryotes, N6 -methyladenosine (m6A) is the most abundant and highly conserved RNA modification. In vivo, m6A demethylase dynamically regulates the m6A level by removing the m6A marker where it plays an important role in plant growth, development and response to abiotic stress. The confirmed m6A demethylases in Arabidopsis thaliana include ALKBH9B and ALKBH10B, both belonging to the ALKB family. In this study, BvALKB family members were identified in sugar beet genome-wide database, and their conserved domains, gene structures, chromosomal locations, phylogeny, conserved motifs and expression of BvALKB genes were analyzed. Almost all BvALKB proteins contained the conserved domain of 2OG-Fe II-Oxy. Phylogenetic analysis suggested that the ten proteins were clustered into five groups, each of which had similar motifs and gene structures. Three Arabidopsis m6A demethylase-homologous proteins (BvALKBH6B, BvALKBH8B and BvALKBH10B) were of particular interest in our study. Expression profile analysis showed that almost all genes were up-regulated or down-regulated to varying degrees under salt stress. More specifically, BvALKBH10B homologous to AtALKBH10B was significantly up-regulated, suggesting that the transcriptional activity of this gene is responsive to salt stress. This study provides a theoretical basis for further screening of m6A demethylase in sugar beet, and also lays a foundation for studying the role of ALKB family proteins in growth, development and response to salinity stress.
Subject(s)
Arabidopsis , Beta vulgaris , Arabidopsis/genetics , Beta vulgaris/genetics , Phylogeny , Salt Stress/genetics , Stress, Physiological/genetics , Sugars/metabolism , Genome, Plant , Adenosine/metabolismABSTRACT
N6-methyladenosine (m6A) RNA modification confers an essential layer of gene regulation in living organisms, including plants; yet, the underlying mechanisms of its deposition on specific target mRNAs involved in key plant developmental processes are so far unknown. Here, we show that a core component of the rice m6A methyltransferase complex, OsFIP37, is recruited by an RNA-binding protein, OsFIP37-associated protein 1 (OsFAP1), to mediate m6A RNA modification on an auxin biosynthesis gene, OsYUCCA3, during microsporogenesis. This stabilizes OsYUCCA3 mRNA and promotes local auxin biosynthesis in anthers during male meiosis, which is essential for meiotic division and subsequent pollen development in rice. Loss of function of OsFAP1 causes dissociation of OsFIP37 with OsYUCCA3 and the resulting abolished m6A deposition on OsYUCCA3. Our findings reveal that OsFAP1-dependent m6A deposition on OsYUCCA3 by OsFIP37 constitutes a hitherto unknown link between RNA modification and hormonal control of male meiosis in plant reproductive development.
Subject(s)
Adenosine/analogs & derivatives , Indoleacetic Acids/metabolism , Meiosis/genetics , Adenosine/chemistry , Adenosine/metabolism , Flowers/genetics , Gene Expression/genetics , Gene Expression Regulation, Plant/genetics , Oryza/genetics , Oryza/metabolism , Plant Development/genetics , Plant Proteins/metabolism , Pollen/genetics , RNA/genetics , RNA/metabolism , RNA, Messenger/genetics , RNA-Binding Proteins/metabolismABSTRACT
The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body's metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-administration paradigm to evaluate the reinforcing and motivating effects of ethanol. Rt-PCR analyses were performed evaluating dopamine, adenosine, CB1, and Oprm gene expression. Our results showed that animals in a ketotic state displayed an overall decrease in ethanol consumption without changes in their motivation to drink. Gene expression analyses point to several alterations in the dopamine, adenosine, and cannabinoid systems. Our results suggest that nutritional interventions may be a useful complementary tool in treating alcohol-use disorders.
Subject(s)
Alcohol Drinking/prevention & control , Alcoholism/diet therapy , Diet, Ketogenic/psychology , Eating/genetics , Eating/psychology , Adenosine/metabolism , Alcohol Drinking/psychology , Alcoholism/psychology , Animals , Cannabinoids/metabolism , Disease Models, Animal , Dopamine/metabolism , Ethanol , Gene Expression/physiology , Male , Mice , Motivation/geneticsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Pain remains real and still a major problem in clinical medicine which requires new agents with improved efficacy for more therapeutic benefits. Plant sources can serve as a basis for the search for some novel drugs hence the analgesic effects of the hydroethanolic extract of Calotropis procera (CPE) which is widespread in Ghana and other tropical areas and used in folkloric medicine for painful and inflammatory conditions was evaluated. MATERIALS AND METHODS: The analgesic properties of orally administered CPE at doses of 30, 100, and 300 mg/kg were evaluated in thermal (tail immersion), chemical (acetic acid-writhing, formalin-induced paw licking, glutamate-induced nociception) and mechanical (Randall-Selitto) tests for analgesia. The involvement of tumour necrosis factor-alpha (TNF-α), interleukin 1ß (IL 1ß), bradykinin, and prostaglandin E2 (PGE2) on the analgesic effects of CPE were also evaluated in hypernociception assays measuring mechanical pain thresholds. RESULTS: The latency of tail withdrawal in the tail immersion test was significantly increased (p = 0.0001) while writhing induced by acetic acid was significantly reduced (p < 0.0001) on treatment with CPE (30-300 mg/kg). The extract also significantly inhibited both phase 1 and phase 2 nociceptive states induced by formalin comparable to morphine (p < 0.0001). Furthermore, the extract significantly attenuated hyper-nociception induced by TNF-α (p < 0.0001), interleukin 1ß (p = 0.0102), bradykinin (p < 0.0001), and prostaglandin E2 (p < 0.0001). Additionally, glutamate-induced paw licking was reduced significantly (p < 0.05). The antinociceptive effects exhibited by CPE (100 mg/kg) in the formalin test was reversed by systemic administration of naloxone (2 mg/kg) and theophylline (5 mg/kg) but not glibenclamide (8 mg/kg), granisetron (2 mg/kg), atropine (3 mg/kg), yohimbine (3 mg/kg, p.o.) nor nifedipine (10 mg/kg). CONCLUSION: Overall, the hydroethanolic leaf extract of Calotropis procera possesses analgesic properties that is mediated possibly through the glutaminergic, opioidergic, and adenosinergic pathways.
Subject(s)
Analgesics/pharmacology , Calotropis/chemistry , Pain/drug therapy , Plant Extracts/pharmacology , Adenosine/metabolism , Analgesics/administration & dosage , Analgesics/isolation & purification , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/isolation & purification , Analgesics, Opioid/pharmacology , Animals , Dose-Response Relationship, Drug , Ghana , Glutamic Acid/metabolism , Male , Mice , Mice, Inbred ICR , Pain/physiopathology , Pain Measurement , Pain Threshold/drug effects , Plant Extracts/administration & dosage , Plant LeavesABSTRACT
The endocannabinoid system (ECS) consists of endogenous cannabinoids, their receptors, and metabolic enzymes that play a critical homeostatic role in modulating polyunsaturated omega fatty acid (PUFA) signaling to maintain a balanced inflammatory and redox state. Whole food-based diets and dietary interventions linked to PUFAs of animal (fish, calamari, krill) or plant (hemp, flax, walnut, algae) origin, as well as full-spectrum hemp oils, are increasingly used to support the ECS tone, promote healthy metabolism, improve risk factors associated with cardiovascular disorders, encourage brain health and emotional well-being, and ameliorate inflammation. While hemp cannabinoids of THC and CBD groups show distinct but complementary actions through a variety of cannabinoid (CB1 and CB2), adenosine (A2A), and vanilloid (TRPV1) receptors, they also modulate PUFA metabolism within a wide variety of specialized lipid mediators that promote or resolve inflammation and oxidative stress. Clinical evidence reviewed in this study links PUFAs and cannabinoids to changes in ECS tone, immune function, metabolic and oxidative stress adaptation, and overall maintenance of a well-balanced systemic function of the body. Understanding how the body coordinates signals from the exogenous and endogenous ECS modulators is critical for discerning the underlying molecular mechanisms of the ECS tone in healthy and disease states. Nutritional and lifestyle interventions represent promising approaches to address chronic metabolic and inflammatory disorders that may overlap in the population at risk. Further investigation and validation of dietary interventions that modulate the ECS are required in order to devise clinically successful second-generation management strategies.
Subject(s)
Cannabis/metabolism , Endocannabinoids/metabolism , Fatty Acids, Unsaturated/metabolism , Plant Extracts/metabolism , Adenosine/metabolism , Animals , Cannabinoids/metabolism , Diet , Homeostasis/physiology , Humans , Inflammation/metabolism , Lipid Metabolism/physiology , Oxidative Stress/physiology , Signal Transduction/physiology , TRPV Cation Channels/metabolismABSTRACT
Acupuncture is a therapeutic treatment that is well recognized in many countries. However, the initiation mechanisms of acupuncture are not well understood. Purinergic signaling has been considered a key signaling pathway in acupuncture in recent years. Acupuncture-induced ATP is mainly produced by mast cells and fibroblasts, and ATP is gradually hydrolyzed into adenosine. ATP and adenosine further participate in the process of acupuncture information transmission to the nervous and immune systems through specific purine receptors. Acupuncture initiates analgesia via the down-regulation of the expression of P2 receptors or up-regulation of the expression of adenosine A1 receptors on nerve fibers. ATP also promotes the proliferation of immune cells through P2 receptors and A3 receptors, causing inflammation. In contrast, adenosine activates A2 receptors, promotes the production and infiltration of immunosuppressive cells, and causes an anti-inflammatory response. In summary, we described the role of purinergic signaling as a general signaling pathway in the initiation of acupuncture and the influence of purinergic signaling on the neuroimmune network to lay the foundation for future systematic research on the mechanisms of acupuncture therapeutics.
Subject(s)
Acupuncture Therapy , Purines/metabolism , Signal Transduction/genetics , Signal Transduction/physiology , Acupuncture Analgesia , Adenosine/metabolism , Adenosine Triphosphate/metabolism , Down-Regulation , Fibroblasts/metabolism , Gene Expression , Humans , Hydrolysis , Mast Cells/metabolism , Neuroimmunomodulation , Receptor, Adenosine A1/genetics , Receptor, Adenosine A1/metabolism , Receptors, Purinergic/metabolism , Receptors, Purinergic P2/genetics , Receptors, Purinergic P2/metabolism , Up-RegulationABSTRACT
Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5'-(α,ß-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.
Subject(s)
5'-Nucleotidase/antagonists & inhibitors , Phosphorous Acids/chemistry , 5'-Nucleotidase/genetics , 5'-Nucleotidase/metabolism , Adenosine/metabolism , Binding Sites , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Humans , Molecular Dynamics Simulation , Phosphorous Acids/metabolism , Structure-Activity RelationshipABSTRACT
Hyperlipidemia causes lipotoxicity which prompts an inflammatory response linked to the development of cardiovascular diseases. Natural compounds have been receiving special attention for its potential to treat diseases, inexpensiveness, and safety. Guarana (Paullinia cupana) has demonstrated notable anti-inflammatory and antioxidant effects, which may prevent chronic diseases caused by changes in lipid profile. Thus, this study aims to evaluate the effect of guarana powder (Paullinia cupana) in the purine metabolism and inflammatory profile in lymphocytes and serum of rats with Poloxamer-407-induced hyperlipidemia. Pretreatment with guarana 12.5, 25, and 50 mg/kg/day or caffeine (0.2 mg/kg/day) by gavage was applied to adult male Wistar rats for a period of 30 days. As a comparative standard, we used simvastatin (0.04 mg/kg) post-induction. Hyperlipidemia was acutely induced with intraperitoneally injection of Poloxamer-407 (500 mg/kg). Guarana powder and caffeine increased the activity of the E-NTPDase (ecto-apyrase), and all pretreatments decreased the E-ADA (ecto-adenosine deaminase) activity, reducing the inflammatory process caused by lipotoxicity. In hyperlipidemic rats, ATP levels were increased while adenosine levels were decreased, guarana and caffeine reverted these changes. Guarana powder, caffeine, and simvastatin also prevented the increase in INF-γ and potentiated the increase in IL-4 levels, promoting an anti-inflammatory profile. Guarana promoted a more robust effect than caffeine. Our results show that guarana powder and caffeine have an anti-inflammatory as seen by the shift from a proinflammatory to an anti-inflammatory profile. The effects of guarana were more pronounced, suggesting that guarana powder may be used as a complementary therapy to improve the lipotoxicity-associated inflammation.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Caffeine/pharmacology , Hyperlipidemias/drug therapy , Inflammation/prevention & control , Theobromine/pharmacology , Theophylline/pharmacology , Adenosine/metabolism , Adenosine Triphosphate/metabolism , Animals , Anti-Inflammatory Agents/administration & dosage , Caffeine/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Hyperlipidemias/physiopathology , Inflammation/etiology , Lymphocytes/drug effects , Lymphocytes/metabolism , Male , Rats , Rats, Wistar , Simvastatin/pharmacology , Theobromine/administration & dosage , Theophylline/administration & dosageABSTRACT
Cordyceps militaris (CM), a valuable edible and medicinal fungus, has been used as traditional medicine to treat health conditions, as well as hyposexuality in Asian societies for over a century. Due to the high demand, several artificial cultivation methods have been developed for their biological activities. In this study, CM was cultured on medium that contained white rice and silkworm pupae, and the levels of cordycepin and adenosine, as well as its aphrodisiac effects in diabetes-induced erectile dysfunction (DIED), were evaluated. Diabetic rats were induced by streptozotocin (STZ) injection and administered orally with CM (0.1, 0.5, and 1.0 g/kg BW/day) for 3 weeks. Diabetic rats in negative and positive control groups received vehicle and sildenafil citrate (5 mg/kg), respectively. Results showed the changes in mating behaviour in which mount latency and intromission latency were significantly increased in diabetic rats, compared with the normal control group. Diabetic rats also showed a significant reduction in intracavernosal pressure (ICP) response to cavernous nerve stimulation, sperm count, testosterone level, penile nitric oxide synthase (NOS), and testicular superoxide dismutase (SOD) activities, when compared to the normal control group. Administration of CM (0.1, 0.5, and 1.0 g/kg BW/day) reversed the effects of diabetes on the mating behaviour, and the ICP responses to electrical stimulation. Moreover, the levels of penile NOS, testicular SOD activities, testosterone, and sperm count were significantly increased, and testicular malondialdehyde (MDA) levels were significantly decreased in these treated diabetic rats. Diabetic rats treated with sildenafil showed a significant induction in intromission frequency and NOS and SOD activities, as well as a marked increase in ICP responses. These results suggest that CCM exerts its aphrodisiac effect, possibly through activating testosterone production and suppressing oxidative stress to enhance erectile function in diabetic rats.
Subject(s)
Cordyceps/chemistry , Diabetes Mellitus, Experimental/physiopathology , Penile Erection , Sexual Behavior, Animal , Adenosine/metabolism , Animals , Blood Glucose/metabolism , Blood Pressure , Deoxyadenosines/metabolism , Diabetes Mellitus, Experimental/blood , Fasting/blood , Male , Malondialdehyde/metabolism , Nitric Oxide Synthase/metabolism , Organ Size , Rats, Sprague-Dawley , Reproduction , Spermatozoa/metabolism , Streptozocin , Superoxide Dismutase/metabolism , Testis/pathology , Testosterone/bloodABSTRACT
This study aimed at exploring the potential mechanism of decreased in vivo exposure of the antiplatelet agent, ticagrelor and its active metabolite, AR-C124910XX, mediated by tea polyphenols, which was first revealed by our previous study, as well as predicting the in vivo drug-drug interaction (DDI) potential utilizing an in vitro to in vivo extrapolation (IVIVE) approach. The bidirectional transport and uptake kinetics of ticagrelor were determined using Caco-2 cells. Inhibition potency of major components of tea polyphenols, epigallocatechin gallate (EGCG) and epigallocatechin (EGC) were obtained from Caco-2 cells, human intestinal and hepatic microsomes (HIMs and HLMs) in vitro. A mean efflux ratio of 2.28 ± 0.38 and active uptake behavior of ticagrelor were observed in Caco-2 cell studies. Further investigation showed that the IC50 values of EGCG and EGC on the uptake of ticagrelor were 42.0 ± 5.1 µM (95% CI 31.9-54.8 µM) and 161 ± 13 µM (95% CI 136-191 µM), respectively. EGCG and EGC also displayed moderate to weak reversible inhibition on the formation of AR-C124910XX and the inactive metabolite, AR-C133913XX in HIMs and HLMs, while no clinically significant time-dependent inhibition was observed for either compound. IVIVE indicated a significant inhibition effect of EGCG on the uptake process of ticagrelor, while no potential DDI risk was found based on microsomal data. A 45% decrease in ticagrelor in vivo exposure was mechanistically predicted by incorporating intestinal and hepatic metabolism as well as intestinal absorption. This dual inhibition of tea polyphenols on ticagrelor revealed the underlying potential of transporter-enzyme interplay, in which the altered uptake process was more critical.