Caffeine is present in products marketed for weight loss, with the purpose of increasing thermogenesis and lipid metabolism. The dosage declared by the product manufacturer, or even its presence, is not always correct...Caffeine is present in products marketed for weight loss, with the purpose of increasing thermogenesis and lipid metabolism. The dosage declared by the product manufacturer, or even its presence, is not always correctly described on the label. This work aimed to investigate the undeclared synthetic caffeine in weight loss formulations by a high-performance liquid chromatography with diode array detection(HPLC-DAD) method. From one hundred products purchased through Brazilian e-commerce, seventeen contained caffeine, either naturally or synthetically added to formulation. The caffeine-containing samples were confirmed by an ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method, and adulteration was clearly proven in five products. The content highest caffeine contained 448.8 mg per dose. Other irregularities were also found; nevertheless, the most serious was the addition of synthetic drugs without asking the consumers. Additional drugs expose the consumer to more possible side-effects as well as deleterious drug interactions. Intentional adulteration with any unlabeled substance is typically motivated by a desire to increase or alter the claimed effect of the marketed product to gain a commercial advantage.展开更多
Cross-linked pectin/high amylose mixtures were evaluated as a new excipient for matrix tablets formulations,since the mixing of polymers and cross-linking reaction represent rational tools to reach materials with modu...Cross-linked pectin/high amylose mixtures were evaluated as a new excipient for matrix tablets formulations,since the mixing of polymers and cross-linking reaction represent rational tools to reach materials with modulated and specific properties that meet specific therapeutic needs.Objective:In this work the influence of polymer ratio and cross-linking process on the swelling and the mechanism driving the drug release from swellable matrix tablets prepared with this excipient was investigated.Methods:Cross-linked samples were characterized by their micromeritic properties(size and shape,density,angle of repose and flow rate)and liquid uptake ability.Matrix tablets were evaluated according their physical properties and the drug release rates and mechanisms were also investigated.Results:Cross-linked samples demonstrated size homogeneity and irregular shape,with liquid uptake ability insensible to pH.Cross-linking process of samples allowed the control of drug release rates and the drug release mechanism was influenced by both polymer ratio and cross-linking process.The drug release of samples with minor proportion of pectin was driven by an anomalous transport and the increase of the pectin proportion contributed to the erosion of the matrix.Conclusion:The cross-linked mixtures of high amylose and pectin showed a suitable excipient for slowing the drug release rates.展开更多
Nine new sulfonamides derived from carvacrol were prepared through a reaction between 4-hydroxy-2-isopropyl-5-methyl benzene sulfonyl chloride with various amines in excellent yields (76% - 92%). The sulfonamides were...Nine new sulfonamides derived from carvacrol were prepared through a reaction between 4-hydroxy-2-isopropyl-5-methyl benzene sulfonyl chloride with various amines in excellent yields (76% - 92%). The sulfonamides were characterized using spectrometric and spectroscopic methods. Among these compounds, three derivatives showed excellent results in antibacterial activity against resistant S. aureus strains, with MIC values ranging from 3.9 to 62.50 ppm. The sulfonamide derivative of 4-methylaniline (SULF-1) had the best performance for all tested strains of bacteria (MIC = 3.9 to 15.62 ppm). Furthermore, the sulfonamide derivative of 4-fluoro aniline (SULF-3), which also presented promising results, was found to have a synergistic effect when combined with tetracycline and partial synergistic effect when combined with ampicillin, exhibiting an FIC index between 0.50 and 0.75. The sulfonamide derivative of 4-methylaniline had a synergistic effect in combination with erythromycin exhibiting an FIC index of 0.37. Carvacrol in association with the antibiotics tested did not have a synergistic effect.展开更多
Indole-3-carbinol(I3C) and diindolylmethane(DIM) are naturally derived dietary phytochemicals with promising anti-cancer properties that have been demonstrated both in vitro and in vivo. Using reversed-phase ultra-per...Indole-3-carbinol(I3C) and diindolylmethane(DIM) are naturally derived dietary phytochemicals with promising anti-cancer properties that have been demonstrated both in vitro and in vivo. Using reversed-phase ultra-performance liquid chromatography(UPLC) coupled with mass spectrometry(MS), a rapid, specific, and high throughput method was developed and validated for the quantification and identification of I3 C, DIM, and other I3 C metabolites in plasma. Samples containing I3 C or DIM and the internal standard 4-methoxy indole(IS) were extracted using a liquid-liquid extraction technique. The mean recovery was 96.21% for I3 C and 108.5% for DIM. Separation was achieved using a Waters Acquity UPLC HSS T3, 1.8 μm, 2.1 mm×150 mm column and acetonitrile–water gradient elution. The flow rate was 0.3 m L/min and the run time was 9 min. The limits of detection and quantification for I3 C and DIM were 15 ng/m L and 25 ng/m L, respectively. Calibration curves for I3 C and DIM were linear(r2>0.99) over a concentration range of 0.025–20 μg/m L. Precision, accuracy, and stability analysis fulfilled the CDER guidelines criteria. The method was successfully applied to the determination of the pharmacokinetic parameters of I3 C or DIM after oral, intravenous, or intraperitoneal administration to Sprague Dawley rats. The method described here is superior over existing analytical methods for I3 C and its metabolites in terms of sensitivity, speed, and separation.展开更多
<strong>Background and Objective:</strong> The aesthetic products’ safety should not be neglected to the detriment of the market. This study aimed to evaluate the mutagenic potential of commercial inks. I...<strong>Background and Objective:</strong> The aesthetic products’ safety should not be neglected to the detriment of the market. This study aimed to evaluate the mutagenic potential of commercial inks. It was formulated with organic (P1) and inorganic (P2) pigments for eyebrows microblading using a validated method by regulatory agencies, the <em>Salmonella</em>/microsome assay, to assure the safety of use. <strong>Methods:</strong> The assay was carried out in three steps: preliminary toxicity, medium without (-S9), and presence (+S9) of metabolic activation. The strains, auxotrophic to histidine (His-) TA97a, TA98, TA100, and TA102, were exposed to both types of inks, in triplicate, compared to negative and positive controls. Data were statistically analyzed, and values with mutagenic index ≥ 2.0 were indicative of mutagenicity. <strong>Results:</strong> The inks with organic (P1) and inorganic (P2) pigments were not toxic to TA98 and TA100 S. <em>typhimurium</em> tester strains, even at concentrations applied in humans. Both inks were not mutagenic either in the absence or presence of metabolic activation in the tested concentrations, including that applied in humans. The assay showed that P1 and P2 were not direct (-S9) or indirect (+S9) mutagens as commercially formulated. <strong>Conclusions:</strong> These results indicate that applying these inks on organisms with microsomal enzymes, including humans, is safe since no compound in the inks became more toxic to induce the bacterial reverse mutation.展开更多
Defective CD39 levels contribute to an imbalance between Tregs and Th17 effectors in inflammatory bowel disease(IBD).CD39 initiates an ATP hydrolysis cascade that culminates with the generation of adenosine,an immune ...Defective CD39 levels contribute to an imbalance between Tregs and Th17 effectors in inflammatory bowel disease(IBD).CD39 initiates an ATP hydrolysis cascade that culminates with the generation of adenosine,an immune metabolite that is key to tissue homeostasis.Human CD39 is regulated by an endogenous antisense RNA(CD39-AS)that is markedly elevated in IBD Tregs and Th17 cells.In this study,we investigated how CD39-AS affects the function of Tregs and Th17 cells in healthy subjects and IBD patients.We report that CD39-AS RNA is present in two main splice variants that are specifically expressed by Tregs or Th17 cells.Blockade of CD39-AS via self-delivering oligonucleotides targeting the splice variant expressed in Tregs results in a decrease of glucose transport and glycolysis and in enhanced Treg function and stability in IBD.In Th17 cells,silencing of CD39-AS limits oxidative responses and ameliorates mitochondrial health.These metabolic effects are also noted in a model of experimental colitis in humanized mice,along with reduced disease activity.Thus,in vivo administration of oligonucleotides targeting the Treg or Th17 cell CD39-AS variant limits disease activity,decreases the expression of GLUT1 and improves mitochondrial health in gut-derived CD4 lymphocytes.Mechanistically,activation of HIF-1αand STAT3 results in the upregulation of CD39-AS in IBD cells.In conclusion,CD39-AS is an important modulator of Treg and Th17 cell metabolism.Interference with this antisense RNA,or the factors favoring its upregulation,might contain inflammation and halt disease progression in IBD by restoring immune metabolism and Treg functional stability.展开更多
Inflammatory bowel disease(IBD),comprising Crohn’s disease and ulcerative colitis,represents the two predominant clinical entities within this spectrum of gastrointestinal disorders.Current evidence indicates that th...Inflammatory bowel disease(IBD),comprising Crohn’s disease and ulcerative colitis,represents the two predominant clinical entities within this spectrum of gastrointestinal disorders.Current evidence indicates that the etiology of IBD is multifactorial,involving a complex interplay between host genetic susceptibility and environmental determinants.In recent years,non-pharmacological strategies such as physical exercise and vagus nerve stimulation have gained increasing attention as adjunctive therapeutic approaches.Vagus nerve stimulation has emerged as a promising therapeutic modality,particularly in conditions characterized by autonomic dysfunction and diminished vagal tone.Conversely,vagotomy,by disrupting vagal control,abolishes parasympathetic reflexes and may potentiate inflammatory responses and exacerbate IBD symptomatology under stress conditions.Physical exercise has likewise been investigated as a non-pharmacological intervention in Crohn’s disease and ulcerative colitis.Although the precise mechanisms remain to be fully elucidated,accumulating evidence suggests that skeletal muscle contractions promote the secretion of myokines,with recognized anti-inflammatory properties.These myokines act on the intestinal microenvironment,conferring protection against malignant transformation and modulating the composition and function of the gut microbiota.In this review,we critically examine the interplay between physical exercise,vagus nerve stimulation,and vagotomy in the pathophysiology and management of IBD,with particular emphasis on their immunomodulatory and therapeutic potential.展开更多
Prostate cancer is the second leading cancer among men in the United States. Several studies have correlated the development of prostate cancer with diet and life-style. Therefore, a balanced diet and improved life st...Prostate cancer is the second leading cancer among men in the United States. Several studies have correlated the development of prostate cancer with diet and life-style. Therefore, a balanced diet and improved life style might inhibit prostate cancer progression. Cancer chemoprevention has emerged as an important factor in controlling cancer development through natural or synthetic compounds. Oxidative stress is among the factors contributing to prostate cancer development. The transcription factor nuclear factor(erythroid-derived 2)-like 2(Nrf2) controls detoxifying antioxidant enzymes expression by binding to the antioxidant response element(ARE) in the promoter of these genes to activate their expression. Many natural products can fight oxidative stress and protects cells from DNA damage by activating the Nrf2/ARE pathway. High consumption of fruits and vegetables can reduce disease incidence and invasive tumors. In this review, the roles of important fruit and vegetable phytochemicals in regulating prostate cancer progression and tumor growth are discussed.展开更多
文摘Caffeine is present in products marketed for weight loss, with the purpose of increasing thermogenesis and lipid metabolism. The dosage declared by the product manufacturer, or even its presence, is not always correctly described on the label. This work aimed to investigate the undeclared synthetic caffeine in weight loss formulations by a high-performance liquid chromatography with diode array detection(HPLC-DAD) method. From one hundred products purchased through Brazilian e-commerce, seventeen contained caffeine, either naturally or synthetically added to formulation. The caffeine-containing samples were confirmed by an ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method, and adulteration was clearly proven in five products. The content highest caffeine contained 448.8 mg per dose. Other irregularities were also found; nevertheless, the most serious was the addition of synthetic drugs without asking the consumers. Additional drugs expose the consumer to more possible side-effects as well as deleterious drug interactions. Intentional adulteration with any unlabeled substance is typically motivated by a desire to increase or alter the claimed effect of the marketed product to gain a commercial advantage.
基金Coordenac¸a˜o de Aperfei-c¸oamento de Pessoal de Nı´vel Superior(CAPES)and Fundac¸a˜o de Amparo a`Pesquisa do Estado de Sa˜o Paulo(FAPESP)is acknowledged.F.M.C.thanks FAPESP for a M.Sci.scholarship.
文摘Cross-linked pectin/high amylose mixtures were evaluated as a new excipient for matrix tablets formulations,since the mixing of polymers and cross-linking reaction represent rational tools to reach materials with modulated and specific properties that meet specific therapeutic needs.Objective:In this work the influence of polymer ratio and cross-linking process on the swelling and the mechanism driving the drug release from swellable matrix tablets prepared with this excipient was investigated.Methods:Cross-linked samples were characterized by their micromeritic properties(size and shape,density,angle of repose and flow rate)and liquid uptake ability.Matrix tablets were evaluated according their physical properties and the drug release rates and mechanisms were also investigated.Results:Cross-linked samples demonstrated size homogeneity and irregular shape,with liquid uptake ability insensible to pH.Cross-linking process of samples allowed the control of drug release rates and the drug release mechanism was influenced by both polymer ratio and cross-linking process.The drug release of samples with minor proportion of pectin was driven by an anomalous transport and the increase of the pectin proportion contributed to the erosion of the matrix.Conclusion:The cross-linked mixtures of high amylose and pectin showed a suitable excipient for slowing the drug release rates.
文摘Nine new sulfonamides derived from carvacrol were prepared through a reaction between 4-hydroxy-2-isopropyl-5-methyl benzene sulfonyl chloride with various amines in excellent yields (76% - 92%). The sulfonamides were characterized using spectrometric and spectroscopic methods. Among these compounds, three derivatives showed excellent results in antibacterial activity against resistant S. aureus strains, with MIC values ranging from 3.9 to 62.50 ppm. The sulfonamide derivative of 4-methylaniline (SULF-1) had the best performance for all tested strains of bacteria (MIC = 3.9 to 15.62 ppm). Furthermore, the sulfonamide derivative of 4-fluoro aniline (SULF-3), which also presented promising results, was found to have a synergistic effect when combined with tetracycline and partial synergistic effect when combined with ampicillin, exhibiting an FIC index between 0.50 and 0.75. The sulfonamide derivative of 4-methylaniline had a synergistic effect in combination with erythromycin exhibiting an FIC index of 0.37. Carvacrol in association with the antibiotics tested did not have a synergistic effect.
基金R01 CA118947R01 CA152826 from National Cancer Institute(NCI)+2 种基金R01AT007065 from the National Center for Complementary and Alternative Medicines(NCCAM)the Office of Dietary Supplements(ODS)the National Institute of Health Grant R01 CA073674
文摘Indole-3-carbinol(I3C) and diindolylmethane(DIM) are naturally derived dietary phytochemicals with promising anti-cancer properties that have been demonstrated both in vitro and in vivo. Using reversed-phase ultra-performance liquid chromatography(UPLC) coupled with mass spectrometry(MS), a rapid, specific, and high throughput method was developed and validated for the quantification and identification of I3 C, DIM, and other I3 C metabolites in plasma. Samples containing I3 C or DIM and the internal standard 4-methoxy indole(IS) were extracted using a liquid-liquid extraction technique. The mean recovery was 96.21% for I3 C and 108.5% for DIM. Separation was achieved using a Waters Acquity UPLC HSS T3, 1.8 μm, 2.1 mm×150 mm column and acetonitrile–water gradient elution. The flow rate was 0.3 m L/min and the run time was 9 min. The limits of detection and quantification for I3 C and DIM were 15 ng/m L and 25 ng/m L, respectively. Calibration curves for I3 C and DIM were linear(r2>0.99) over a concentration range of 0.025–20 μg/m L. Precision, accuracy, and stability analysis fulfilled the CDER guidelines criteria. The method was successfully applied to the determination of the pharmacokinetic parameters of I3 C or DIM after oral, intravenous, or intraperitoneal administration to Sprague Dawley rats. The method described here is superior over existing analytical methods for I3 C and its metabolites in terms of sensitivity, speed, and separation.
文摘<strong>Background and Objective:</strong> The aesthetic products’ safety should not be neglected to the detriment of the market. This study aimed to evaluate the mutagenic potential of commercial inks. It was formulated with organic (P1) and inorganic (P2) pigments for eyebrows microblading using a validated method by regulatory agencies, the <em>Salmonella</em>/microsome assay, to assure the safety of use. <strong>Methods:</strong> The assay was carried out in three steps: preliminary toxicity, medium without (-S9), and presence (+S9) of metabolic activation. The strains, auxotrophic to histidine (His-) TA97a, TA98, TA100, and TA102, were exposed to both types of inks, in triplicate, compared to negative and positive controls. Data were statistically analyzed, and values with mutagenic index ≥ 2.0 were indicative of mutagenicity. <strong>Results:</strong> The inks with organic (P1) and inorganic (P2) pigments were not toxic to TA98 and TA100 S. <em>typhimurium</em> tester strains, even at concentrations applied in humans. Both inks were not mutagenic either in the absence or presence of metabolic activation in the tested concentrations, including that applied in humans. The assay showed that P1 and P2 were not direct (-S9) or indirect (+S9) mutagens as commercially formulated. <strong>Conclusions:</strong> These results indicate that applying these inks on organisms with microsomal enzymes, including humans, is safe since no compound in the inks became more toxic to induce the bacterial reverse mutation.
基金supported by the National Institutes of Health(R01DK124408 to MSL,R01GM135377 to SKK)the Crohn’s and Colitis Foundation(Litwin IBD Pioneers Award to MSL)+1 种基金Boehringer Ingelheim Fonds MD fellowship(to DN)grant APVV-21-0370(to BG).
文摘Defective CD39 levels contribute to an imbalance between Tregs and Th17 effectors in inflammatory bowel disease(IBD).CD39 initiates an ATP hydrolysis cascade that culminates with the generation of adenosine,an immune metabolite that is key to tissue homeostasis.Human CD39 is regulated by an endogenous antisense RNA(CD39-AS)that is markedly elevated in IBD Tregs and Th17 cells.In this study,we investigated how CD39-AS affects the function of Tregs and Th17 cells in healthy subjects and IBD patients.We report that CD39-AS RNA is present in two main splice variants that are specifically expressed by Tregs or Th17 cells.Blockade of CD39-AS via self-delivering oligonucleotides targeting the splice variant expressed in Tregs results in a decrease of glucose transport and glycolysis and in enhanced Treg function and stability in IBD.In Th17 cells,silencing of CD39-AS limits oxidative responses and ameliorates mitochondrial health.These metabolic effects are also noted in a model of experimental colitis in humanized mice,along with reduced disease activity.Thus,in vivo administration of oligonucleotides targeting the Treg or Th17 cell CD39-AS variant limits disease activity,decreases the expression of GLUT1 and improves mitochondrial health in gut-derived CD4 lymphocytes.Mechanistically,activation of HIF-1αand STAT3 results in the upregulation of CD39-AS in IBD cells.In conclusion,CD39-AS is an important modulator of Treg and Th17 cell metabolism.Interference with this antisense RNA,or the factors favoring its upregulation,might contain inflammation and halt disease progression in IBD by restoring immune metabolism and Treg functional stability.
文摘Inflammatory bowel disease(IBD),comprising Crohn’s disease and ulcerative colitis,represents the two predominant clinical entities within this spectrum of gastrointestinal disorders.Current evidence indicates that the etiology of IBD is multifactorial,involving a complex interplay between host genetic susceptibility and environmental determinants.In recent years,non-pharmacological strategies such as physical exercise and vagus nerve stimulation have gained increasing attention as adjunctive therapeutic approaches.Vagus nerve stimulation has emerged as a promising therapeutic modality,particularly in conditions characterized by autonomic dysfunction and diminished vagal tone.Conversely,vagotomy,by disrupting vagal control,abolishes parasympathetic reflexes and may potentiate inflammatory responses and exacerbate IBD symptomatology under stress conditions.Physical exercise has likewise been investigated as a non-pharmacological intervention in Crohn’s disease and ulcerative colitis.Although the precise mechanisms remain to be fully elucidated,accumulating evidence suggests that skeletal muscle contractions promote the secretion of myokines,with recognized anti-inflammatory properties.These myokines act on the intestinal microenvironment,conferring protection against malignant transformation and modulating the composition and function of the gut microbiota.In this review,we critically examine the interplay between physical exercise,vagus nerve stimulation,and vagotomy in the pathophysiology and management of IBD,with particular emphasis on their immunomodulatory and therapeutic potential.
基金supported in part by Institutional Funds and from the National Cancer Institute(Grant No.R01-CA118947,R01-CA152826)the National Center for Complementary and Alt ernative Medicines and the Office of Dietary Supplements(Grant No.R01AT007065)
文摘Prostate cancer is the second leading cancer among men in the United States. Several studies have correlated the development of prostate cancer with diet and life-style. Therefore, a balanced diet and improved life style might inhibit prostate cancer progression. Cancer chemoprevention has emerged as an important factor in controlling cancer development through natural or synthetic compounds. Oxidative stress is among the factors contributing to prostate cancer development. The transcription factor nuclear factor(erythroid-derived 2)-like 2(Nrf2) controls detoxifying antioxidant enzymes expression by binding to the antioxidant response element(ARE) in the promoter of these genes to activate their expression. Many natural products can fight oxidative stress and protects cells from DNA damage by activating the Nrf2/ARE pathway. High consumption of fruits and vegetables can reduce disease incidence and invasive tumors. In this review, the roles of important fruit and vegetable phytochemicals in regulating prostate cancer progression and tumor growth are discussed.
