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1.
Theriogenology ; 197: 127-132, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36502590

RESUMO

The current study aimed to assess, for the first time, the effects of intramuscular injection of l-arginine (L-arg) on testicular hemodynamics, echogenicity, and plasma concentrations of testosterone, total antioxidant capacity, and nitric oxide (NO) in Ossimi rams. Twelve sexually matured heat-stressed rams were randomly assigned to one of two groups: the L-arg group (n = 6) received 5 mg/kg L-arg dissolved in 2 ml normal saline 0.9%, or the control group (n = 6) received merely 2 ml of normal saline 0.9%. Blood sampling, B-mode ultrasound assessment of the testicular parenchyma, and pulsed-wave Doppler ultrasound of the testicular artery for both right and left testis were performed immediately before 0 min and 1, 4, 24, 48, 72, and 168 h after L-arg or saline administration. In the L-arg group, resistive index (RI) and pulsatility index (PI) means were significantly lower compared to the control group at 4-168 h post-treatment. Plasma testosterone concentrations were higher (P < 0.05) at 4 h and onward in the L-arg treated compared to the control rams, the same for NO levels however its increase (P < 0.05) was observed as soon as 1 h post-treatment. In L-arg treated rams, NO concentrations were positively correlated to plasma testosterone concentrations (r = 0.7, p < .01), but negatively correlated to both RI and PI (r = -0.8 and -0.6, respectively, p < .01). In conclusion, l-arginine administration enhanced testicular blood flow and increased plasma testosterone and nitric oxide concentrations in heat-stressed rams.


Assuntos
Testículo , Testosterona , Ovinos , Animais , Masculino , Testículo/fisiologia , Óxido Nítrico , Temperatura Alta , Solução Salina , Carneiro Doméstico , Hemodinâmica , Arginina/farmacologia
2.
Tunis Med ; 100(10): 696-705, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36571754

RESUMO

OBJECTIVE: To evaluate the effect of six weeks of high intensity interval training (HIIT) and L-Arginine supplementation on interleukin-6 (IL-6) levels and body composition in Iranian adult trained males. METHODS: This experimental study was performed as an intervention with a pretest-posttest design in three experimental groups and one control group. Fortyeight young males from Qazvin province (Iran) were selected voluntarily based on convenience sampling. Participants were randomly divided into four groups (12 participants in each group): "HIIT"; "L-Arginine supplementation"; "HIIT + L-Arginine supplementation", and "HIIT + placebo". At 7 a.m., when the level of inflammation was at its lowest, a blood sample was taken from the participants, and body mass index (BMI), body fat percentage (BFP), and lean body mass (LBM) were determined. IL-6 analysis was performed using STATE FAX device and ELISA method. Training sessions were conducted for six consecutive weeks, three sessions a week. Analysis of covariance and Bonferroni post hoc test were used to analyze the data. RESULTS: i) There were no significant differences between groups in BMI, BFP, or LBM. ii) There was a significant difference in IL-6 levels between the groups (p < 0.05), so that the inflammatory levels in the "HIIT + L-Arginine supplementation" and "HIIT + placebo" groups were lesser than the "HIIT" (0.002 and <0.001, respectively) and "L-Arginine supplementation" (<0.001and <0.001, respectively) groups. HIIT "seems" to reduce the level of inflammation. CONCLUSION: HIIT had no significant effect on body composition indices. Plasma IL-6 levels decreased after six weeks of HIIT and L-Arginine supplementation. The level of IL-6 in the "HIIT + L-Arginine supplementation" and "HIIT + placebo" groups were lower than the control group (i.e.; "HIIT") and supplement control group (i.e.; "L-Arginine supplementation").


Assuntos
Treinamento Intervalado de Alta Intensidade , Interleucina-6 , Masculino , Humanos , Adulto , Treinamento Intervalado de Alta Intensidade/métodos , Irã (Geográfico) , Suplementos Nutricionais , Arginina/farmacologia , Inflamação
3.
Redox Biol ; 58: 102528, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36356464

RESUMO

Aging is considered a state of low grade inflammation, occurring in the absence of any overt infection often referred to as 'inflammaging'. Maintaining intestinal homeostasis may be a target to extend a healthier status in older adults. Here, we report that even in healthy older men low grade bacterial endotoxemia is prevalent. In addition, employing multiple mouse models, we also show that while intestinal microbiota composition changes significantly during aging, fecal microbiota transplantation to old mice does not protect against aging-associated intestinal barrier dysfunction in small intestine. Rather, intestinal NO homeostasis and arginine metabolism mediated through arginase and NO synthesis is altered in small intestine of aging mice. Treatment with the arginase inhibitor norNOHA prevented aging-associated intestinal barrier dysfunction, low grade endotoxemia and delayed the onset of senescence in peripheral tissue e.g., liver. Intestinal arginine and NO metabolisms could be a target in the prevention of aging-associated intestinal barrier dysfunction and subsequently decline and 'inflammaging'.


Assuntos
Endotoxemia , Camundongos , Animais , Arginase/metabolismo , Arginina/farmacologia , Intestinos , Envelhecimento
4.
Mar Drugs ; 20(11)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36355011

RESUMO

We successfully prepared a series of l-arginine Schiff bases acylated chitosan derivatives, aiming to improve the antioxidant activity and antimicrobial activity of chitosan by introducing a furan ring, pyridine ring, and l-arginine structure. The accuracy of the structures of ten compounds was characterized by FT-IR and 1H NMR. In terms of DPPH radical scavenging activity, except for compound CR3PCA, the scavenging rate of other compounds was higher than chitosan, especially CRCF and CRBF had strong scavenging abilities. At the same time, in the superoxide-radical scavenging activity assay, CRCF, CRBF, CR3PCA, CR2C3PCA, and CR2B3PCA were comparable to positive control at 1.60 mg/mL. Simultaneously, CRFF, CRCF, and CRBF had a certain inhibitory effect on Botrytis cinerea. Furthermore, the inhibitory effect of CRFF, CRCF, and CR3PCA on Staphylococcus aureus was very well, close to the positive control at 1.00 mg/mL. CRCF and CR2B3PCA showed better inhibitory effects on Escherichia coli than other compounds. The MTT assay was used to determine the cytotoxicity of the chitosan derivatives, which proved their safety to fibroblast cells. In summary, the study indicated that some of these compounds have the potential for further development and utilization in the preparation of antioxidants and antimicrobial agents.


Assuntos
Anti-Infecciosos , Quitosana , Bases de Schiff/farmacologia , Bases de Schiff/química , Quitosana/química , Antioxidantes/farmacologia , Antioxidantes/química , Testes de Sensibilidade Microbiana , Espectroscopia de Infravermelho com Transformada de Fourier , Antifúngicos/farmacologia , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Antibacterianos/farmacologia , Escherichia coli , Arginina/farmacologia
5.
Future Med Chem ; 14(22): 1635-1647, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36321580

RESUMO

Background: O-propyloxime-N-propoxybacteriopurpurinimide methyl ester (3) is a near-infrared photosensitizer with confirmed in vivo anticancer activity. Methods: Conjugates of 3 with arginine (1) or lysine attached at an ε-amino group (2a) or α-amino group (2b) were studied as anticancer and antibacterial photosensitizers and compared with 3. Results: The new conjugates preserve advanced spectral characteristics of 3 and high singlet oxygen quantum yield. They demonstrated tenfold higher photocytotoxicity for cancer cells, due to their enhanced intracellular accumulation and altered localization. Though they showed threefold decreased antibacterial photodynamic effect compared with 3, they kill planktonic Staphylococcus aureus bacteria, and 1 destroys bacterial biofilms. Conclusion: Conjugates 1 and 2b are near-infrared photosensitizers with high anticancer and limited antibacterial activity.


Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/farmacologia , Lisina/farmacologia , Arginina/farmacologia , Biofilmes , Antibacterianos/farmacologia
6.
Int J Mol Sci ; 23(22)2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36430764

RESUMO

Amino acids are crucial nutrients involved in several cellular and physiological processes, including fertilization and early embryo development. In particular, Leucine and Arginine have been shown to stimulate implantation, as lack of both in a blastocyst culture system is able to induce a dormant state in embryos. The aim of this work was to evaluate the effects of Leucine and Arginine withdrawal on pluripotent mouse embryonic stem cell status, notably, their growth, self-renewal, as well as glycolytic and oxidative metabolism. Our results show that the absence of both Leucine and Arginine does not affect mouse embryonic stem cell pluripotency, while reducing cell proliferation through cell-cycle arrest. Importantly, these effects are not related to Leukemia Inhibitory Factor (LIF) and are reversible when both amino acids are reconstituted in the culture media. Moreover, a lack of these amino acids is related to a reduction in glycolytic and oxidative metabolism and decreased protein translation in mouse embryonic stem cells (mESCs), while maintaining their pluripotent status.


Assuntos
Células-Tronco Embrionárias , Células-Tronco Embrionárias Murinas , Animais , Camundongos , Leucina/farmacologia , Leucina/metabolismo , Arginina/farmacologia , Arginina/metabolismo , Diferenciação Celular , Proliferação de Células
7.
Int J Mol Sci ; 23(21)2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36362379

RESUMO

Acute pancreatitis (AP) is a major, globally increasing gastrointestinal disease and a biliary origin is the most common cause. However, the effects of bile acids (BAs), given systemically, on the pancreas and on disease severity remains elusive. In this study, we have investigated the roles of different circulating BAs in animal models for AP to elucidate their impact on disease severity and the underlying pathomechanisms. BAs were incubated on isolated acini and AP was induced through repetitive injections of caerulein or L-arginine; pancreatic duct ligation (PDL); or combined biliopancreatic duct ligation (BPDL). Disease severity was assessed using biochemical and histological parameters. Serum cholecystokinin (CCK) concentrations were determined via enzyme immunoassay. The binding of the CCK1 receptor was measured using fluorescence-labeled CCK. In isolated acini, hydrophobic BAs mitigated the damaging effects of CCK. The same BAs further enhanced pancreatitis in L-arginine- and PDL-based pancreatitis, whereas they ameliorated pancreatic damage in the caerulein and BPDL models. Mechanistically, the binding affinity of the CCK1 receptor was significantly reduced by hydrophobic BAs. The hydrophobicity of BAs and the involvement of CCK seem to be relevant in the course of AP. Systemic BAs may affect the severity of AP by interfering with the CCK1 receptor.


Assuntos
Pancreatite , Camundongos , Animais , Pancreatite/patologia , Ceruletídeo/farmacologia , Ácidos e Sais Biliares/metabolismo , Doença Aguda , Colecistocinina/metabolismo , Modelos Animais de Doenças , Pâncreas/metabolismo , Arginina/farmacologia , Arginina/metabolismo , Interações Hidrofóbicas e Hidrofílicas
8.
Nutrients ; 14(19)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36235744

RESUMO

Oudemansiella raphanipies, also called "Edible Queen," is a mushroom that possesses antioxidant, anti-inflammatory, anti-bacterial, anti-tumor and immunity-enhancing properties. The present study aimed to assess the effect of O. raphanipies-derived polysaccharide (ORPS) on the progression of nonalcoholic fatty liver disease (NAFLD) in mice. We studied the structure of ORPS-1 by high-performance gel permeation chromatography (HPGPC), ion chromatography-mass spectrometry (GC-MS), and Fourier transform-infrared spectroscopy (FT-IR). ORPS-1 mainly comprised galactose, fucose, glucose, mannose, and xylose, following an 18:6:6:4:1 molar ratio. In addition, the therapeutic effect as well as a potential mechanism of ORPS-1 in the treatment of high-fat diet (HFD)-induced NAFLD were investigated. The results showed that ORPS-1 improved liver function, ameliorated liver steatosis, and reduced lipid droplet accumulation in HFD mice. A metabolomics approach with GC-MS was utilized to evaluate liver improvement by ORPS-1 treatment. Principal component analysis showed that liver metabolic profiling was significantly altered by HFD feeding or treatment with an intermediate dose of ORPS-1 in mice compared with that of control mice. By investigating the metabolic pathways with identified biomarkers, various pathways such as steroid biosynthesis, valine, leucine, and isoleucine biosynthesis, glycerol phospholipid metabolism, glyceride metabolism, and arginine and proline metabolism in HFD mice were observed to be significantly influenced by ORPS-1 treatment. The results indicate ORPS-1 metabolic effects on liver tissues, provide methods for assessing the molecular impact of ORPS-1 on NAFLD, and suggest the potential mechanism underlying its health benefits.


Assuntos
Agaricales , Transtornos do Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica , Agaricales/metabolismo , Animais , Antioxidantes/farmacologia , Arginina/farmacologia , Biomarcadores/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fucose/farmacologia , Galactose/efeitos adversos , Glucose/metabolismo , Glicerídeos/farmacologia , Glicerol/metabolismo , Isoleucina/farmacologia , Leucina/farmacologia , Metabolismo dos Lipídeos , Transtornos do Metabolismo dos Lipídeos/metabolismo , Fígado/metabolismo , Manose , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfolipídeos/metabolismo , Polissacarídeos/metabolismo , Prolina/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Esteroides/metabolismo , Valina/farmacologia , Xilose/metabolismo
9.
Nutrients ; 14(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36297080

RESUMO

Aging and menopause are associated with decreased nitric oxide bioavailability due to reduced L-arginine (L-ARG) levels contributing to endothelial dysfunction (ED). ED precedes arterial stiffness and hypertension development, a major risk factor for cardiovascular disease. This study investigated the effects of L-citrulline (L-CIT) on endothelial function, aortic stiffness, and resting brachial and aortic blood pressures (BP) in hypertensive postmenopausal women. Twenty-five postmenopausal women were randomized to 4 weeks of L-CIT (10 g) or placebo (PL). Serum L-ARG, brachial artery flow-mediated dilation (FMD), aortic stiffness (carotid-femoral pulse wave velocity, cfPWV), and resting brachial and aortic BP were assessed at 0 and 4 weeks. L-CIT supplementation increased L-ARG levels (Δ13 ± 2 vs. Δ-2 ± 2 µmol/L, p < 0.01) and FMD (Δ1.4 ± 2.0% vs. Δ-0.5 ± 1.7%, p = 0.03) compared to PL. Resting aortic diastolic BP (Δ-2 ± 4 vs. Δ2 ± 5 mmHg, p = 0.01) and mean arterial pressure (Δ-2 ± 4 vs. Δ2 ± 6 mmHg, p = 0.04) were significantly decreased after 4 weeks of L-CIT compared to PL. Although not statistically significant (p = 0.07), cfPWV decreased after L-CIT supplementation by ~0.66 m/s. These findings suggest that L-CIT supplementation improves endothelial function and aortic BP via increased L-ARG availability.


Assuntos
Hipertensão , Rigidez Vascular , Humanos , Feminino , Citrulina/farmacologia , Pressão Sanguínea , Análise de Onda de Pulso , Pós-Menopausa , Óxido Nítrico , Hipertensão/tratamento farmacológico , Arginina/farmacologia , Suplementos Nutricionais
10.
Molecules ; 27(19)2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36235174

RESUMO

Protein arginine methyltransferases 5 (PRMT5) is a clinically promising epigenetic target that is upregulated in a variety of tumors. Currently, there are several PRMT5 inhibitors under preclinical or clinical development, however the established clinical inhibitors show favorable toxicity. Thus, it remains an unmet need to discover novel and structurally diverse PRMT5 inhibitors with characterized therapeutic utility. Herein, a series of tetrahydroisoquinoline (THIQ) derivatives were designed and synthesized as PRMT5 inhibitors using GSK-3326595 as the lead compound. Among them, compound 20 (IC50: 4.2 nM) exhibits more potent PRMT5 inhibitory activity than GSK-3326595 (IC50: 9.2 nM). In addition, compound 20 shows high anti-proliferative effects on MV-4-11 and MDA-MB-468 tumor cells and low cytotoxicity on AML-12 hepatocytes. Furthermore, compound 20 possesses acceptable pharmacokinetic profiles and displays considerable in vivo antitumor efficacy in a MV-4-11 xenograft model. Taken together, compound 20 is an antitumor compound worthy of further study.


Assuntos
Neoplasias , Tetra-Hidroisoquinolinas , Arginina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Proteína-Arginina N-Metiltransferases , Tetra-Hidroisoquinolinas/farmacologia
11.
Biol Pharm Bull ; 45(10): 1537-1543, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36184513

RESUMO

Octa-arginine (R8) is a cell-permeable peptide with excellent cell adhesion properties. Surface-immobilized R8 mediates cell attachment via cell surface receptors, such as heparan sulfate proteoglycans and integrin ß1, and promotes cell spreading and proliferation. However, it is not clear how these properties are affected by specific peptide composition and if they could be improved. Here, we synthesized XR8 peptides, in which half of the original R8 arginine residues were replaced with another amino acid (X). We then aimed to investigate the effect of the substitution on cell adhesion and proliferation on XR8-conjugated agarose matrices. The XR8-matrix showed slightly better cell attachment when X was a hydrophobic or aromatic amino acid. However, hydrophobic XR8-matrices tended to promote cell proliferation to a less extent. Eventually, YR8-matrix most efficiently promoted cell adhesion, spreading, and proliferation among the XR8-matrices tested. Collectively, these observations indicate that the properties of residue X play a major role in the biological activity of XR8-matrices and shed light on the interaction between small peptides and the cell membrane. Further, YR8 is a promising cell-adhesive peptide for the development of cell culture substrates and biomaterials.


Assuntos
Proteoglicanas de Heparan Sulfato , Integrina beta1 , Sequência de Aminoácidos , Substituição de Aminoácidos , Aminoácidos Aromáticos/farmacologia , Arginina/farmacologia , Materiais Biocompatíveis/farmacologia , Adesão Celular , Proteoglicanas de Heparan Sulfato/farmacologia , Integrina beta1/farmacologia , Peptídeos/metabolismo , Peptídeos/farmacologia , Sefarose
13.
Molecules ; 27(18)2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36144655

RESUMO

An epidemic of avian type H7N9 influenza virus, which took place in China in 2013, was enhanced by a naturally occurring R294K mutation resistant against Oseltamivir at the catalytic site of the neuraminidase. To cope with such drug-resistant neuraminidase mutations, we applied the molecular docking technique to evaluate the fitness of the available drugs such as Oseltamivir, Zanamivir, Peramivir, Laninamivir, L-Arginine and Benserazide hydrochloride concerning the N9 enzyme with single (R294K, R119K, R372K), double (R119_294K, R119_372K, R294_372K) and triple (R119_294_372K) mutations in the pocket. We found that the drugs Peramivir and Zanamivir score best amongst the studied compounds, demonstrating their high binding potential towards the pockets with the considered mutations. Despite the fact that mutations changed the shape of the pocket and reduced the binding strength for all drugs, Peramivir was the only drug that formed interactions with the key residues at positions 119, 294 and 372 in the pocket of the triple N9 mutant, while Zanamivir demonstrated the lowest RMSD value (0.7 Å) with respect to the reference structure.


Assuntos
Subtipo H7N9 do Vírus da Influenza A , Influenza Humana , Ácidos Carbocíclicos , Antivirais/química , Arginina/farmacologia , Benserazida/farmacologia , Benserazida/uso terapêutico , Farmacorresistência Viral/genética , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Guanidinas/uso terapêutico , Humanos , Subtipo H7N9 do Vírus da Influenza A/genética , Subtipo H7N9 do Vírus da Influenza A/metabolismo , Influenza Humana/tratamento farmacológico , Simulação de Acoplamento Molecular , Mutação , Neuraminidase/química , Oseltamivir/farmacologia , Zanamivir/farmacologia
14.
Acta Biomater ; 153: 557-572, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36115654

RESUMO

Antimicrobial peptides (AMPs) are considered to be powerful weapons in the fight against traditional antibiotic resistance due to their unique membrane-disruptive mechanism. The combination of traditional and classical hydrophobic tryptophan (W) residues and hydrophilic charged arginine (R) residues is considered as the first choice for the minimalist design of AMPs due to its potent performance in antibacterial activity. However, some W- and R-rich AMPs that are not rationally designed and contain excessive repeats of W and R residues may cause severe cytotoxicity and hemolysis. To address this issue, we designed the (WRX)n (where X = hydrophilic uncharged amino residues; n = number of repeat units) series engineered peptides with high cell selectivity by introducing hydrophilic uncharged threonine (T), serine (S), glutamine (Q) or asparagine (N) residues into the minimalist design of W- and R-rich AMPs. The results showed that the introduction of these hydrophilic uncharged amino residues, especially T residues, significantly improved the cell selectivity of the W- and R-rich engineered peptides. Among (WRX)n series engineered peptides, T6 presents a mixture structure of ß-turn and α-helix. It has broad spectrum and potent antibacterial activity (no activity against probiotics), good biocompatibility, high selectivity index, strong tolerance (physiological salts, serum acid, alkali, and heat conditions), rapid and efficient time-kill kinetics, and no tendency of resistance. Studies on antibacterial mechanism show that T6 exert antibacterial activity mainly by disrupting bacterial cell membrane and inducing the accumulation of reactive oxygen species in bacterial cells. Furthermore, T6 exhibited potent antibacterial and antiinflammatory capabilities in vivo in a mouse peritonitis-sepsis model infected with Escherichia coli. In conclusion, our study confirms an effective strategy for the minimalist design of highly cell selective W- and R-rich AMPs by introducing hydrophilic uncharged T residues, which may trigger widespread attention to hydrophilic uncharged amino acid residues, including T residues, and provide new insights into the design of peptide-based antibacterial biomaterials. STATEMENT OF SIGNIFICANCE: We have introduced hydrophilic uncharged T, S, Q or N residues into the minimalist design of W- and R-rich engineered peptides and found that the introduction of these hydrophilic uncharged amino residues, especially the T residues, can significantly improve the cell selectivity of W- and R-rich engineered peptides. The target compound T6 showed potent antibacterial activity, high cell selectivity, strong tolerance, good in vivo efficacy and killed bacteria through multiple mechanisms mainly membrane-disruptive. These findings may spark widespread interest in hydrophilic uncharged amino acid residues, and provide new insights into the design of peptide-based antimicrobial biomaterials.


Assuntos
Anti-Infecciosos , Triptofano , Camundongos , Animais , Triptofano/farmacologia , Triptofano/química , Peptídeos Antimicrobianos , Arginina/farmacologia , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Peptídeos/química , Escherichia coli , Bactérias , Aminoácidos , Materiais Biocompatíveis , Testes de Sensibilidade Microbiana
15.
Alzheimers Res Ther ; 14(1): 134, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115980

RESUMO

BACKGROUND AND OBJECTIVES: Vascular disease is a known risk factor for Alzheimer's disease (AD). Endothelial dysfunction has been linked to reduced cerebral blood flow. Endothelial nitric oxide synthase pathway (eNOS) upregulation is known to support endothelial health. This single-center, proof-of-concept study tested whether the use of three medications known to augment the eNOS pathway activity improves cognition and cerebral blood flow (CBF). METHODS: Subjects with mild AD or mild cognitive impairment (MCI) were sequentially treated with the HMG-CoA reductase synthesis inhibitor simvastatin (weeks 0-16), L-arginine (weeks 4-16), and tetrahydrobiopterin (weeks 8-16). The primary outcome of interest was the change in CBF as measured by MRI from baseline to week 16. Secondary outcomes included standard assessments of cognition. RESULTS: A total of 11 subjects were deemed eligible and enrolled. One subject withdrew from the study after enrollment, leaving 10 subjects for data analysis. There was a significant increase in CBF from baseline to week 8 by ~13% in the limbic and ~15% in the cerebral cortex. Secondary outcomes indicated a modest but significant increase in the MMSE from baseline (24.2±3.2) to week 16 (26.0±2.7). Exploratory analysis indicated that subjects with cognitive improvement (reduction of the ADAS-cog 13) had a significant increase in their respective limbic and cortical CBF. CONCLUSIONS: Treatment of mild AD/MCI subjects with medications shown to augment the eNOS pathway was well tolerated and associated with modestly increased cerebral blood flow and cognitive improvement. TRIAL REGISTRATION: This study is registered in https://www. CLINICALTRIALS: gov ; registration identifier: NCT01439555; date of registration submitted to registry: 09/23/2011; date of first subject enrollment: 11/2011.


Assuntos
Doença de Alzheimer , Inibidores de Hidroximetilglutaril-CoA Redutases , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Arginina/farmacologia , Arginina/uso terapêutico , Biopterina/análogos & derivados , Circulação Cerebrovascular , Cognição , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Testes Neuropsicológicos , Óxido Nítrico Sintase Tipo III/farmacologia , Óxido Nítrico Sintase Tipo III/uso terapêutico , Estudo de Prova de Conceito , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
16.
ACS Appl Mater Interfaces ; 14(38): 43035-43049, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36124878

RESUMO

Antibacterial hydrogels have gradually become a powerful weapon to treat bacterially infected wounds and accelerate healing. In this paper, we designed a small-molecule self-healing antibacterial hydrogel containing 100% drug-loaded benzyl 3ß-amino-11-oxo-olean-12-en-30-oate (GN-Bn), which was governed by π-π stacking, hydrogen bonding, and van der Waals forces. Due to the carrier-free design concept, the problems of interbatch variability during sample preparation and carrier-related toxicity can be effectively avoided. Moreover, the GN-Bn hydrogel exhibited promising antibacterial activities against multidrug-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) of the GN-Bn hydrogel was 1.5625 nmol/mL, which was lower than those against clinical agents such as norfloxacin, penicillin, and tetracycline. This is attributed to its unique antibacterial mechanism that aims at killing bacteria or preventing their growth by regulating arginine biosynthesis and metabolism through both transcriptomic (RNA-seq) analysis and quantitative polymerase chain reaction (qPCR) analysis. In addition, the GN-Bn hydrogel can also inhibit proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) to promote wound healing. Collectively, the GN-Bn hydrogel elicited dual therapeutic effects on an MRSA-infected full-thickness skin wound model through its antibacterial and anti-inflammatory activities, which is attributed to the fact that the GN-Bn hydrogel has multiple advantages including sufficient mechanical stability, biocompatibility, and unique antibacterial mechanisms, making it significantly accelerate MRSA-infected full-thickness skin wound healing as a wound dressing. In a word, the GN-Bn antibacterial hydrogel dressing with an anti-inflammatory and antibacterial bifunctional material holds great potential in clinical application.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Infecção dos Ferimentos , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Arginina/farmacologia , Bandagens , Humanos , Hidrogéis/farmacologia , Interleucina-6 , Norfloxacino , Penicilinas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus , Tetraciclina/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Cicatrização , Infecção dos Ferimentos/tratamento farmacológico
17.
Andrologia ; 54(11): e14569, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36053976

RESUMO

Aluminium (Al) is a toxic metal with frequent exposure because it is a common element in nature and is found in many products used in daily life. L-arginine is a semi-essential amino acid that is involved in many biochemical pathways in the body and has antioxidant effects. The current research evaluated the possible protective effects of L-arginine against aluminium chloride (AlCl3 ) induced testicular damage. In this animal-based experimental study, 28 male Wistar Albino rats were separated into four groups: control, Al (20 mg/kg/day Al), Al + L-arginine (20 mg/kg/day Al + 50 mg/kg/day L-arginine), and L-arginine (50 mg/kg/day L-arginine). All applications were carried out intraperitoneally (i.p.) for 4 weeks. The histopathological changes caused by exposure to Al in the testicular tissue and the protective effects of L-arginine were investigated by using biochemical, histochemical, immunohistochemical [4-hydroxynonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay techniques. The testicles in the AlCl3 group showed increased 4-HNE, 8-OHdG expressions, apoptotic index, and abnormal sperm content, while serum testosterone levels, sperm motility, and sperm number were decreased (p < 0.05). Furthermore, histomorphometric examinations of testicular tissue indicated significant structural impairments such as vacuolization in the seminiferous tubule epithelium, edema, and vascular congestion in the interstitial area (p < 0.05). However, the structural alterations were largely ameliorated in the Al + L-arginine group (p < 0.05). Thus, L-arginine, which is an antioxidant, may protect against the harmful effects of Al and may help improve male fertility.


Assuntos
Motilidade Espermática , Testículo , Animais , Ratos , Masculino , Cloreto de Alumínio , Sêmen/metabolismo , Ratos Wistar , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Arginina/farmacologia , Arginina/metabolismo
18.
Bioorg Med Chem ; 72: 116970, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-36063653

RESUMO

Nitric oxide (NO) is a signalling molecule that controls a multitude of regulatory functions including neurotransmission, vascular tone, immune response, and angiogenesis. Regulating NO concentrations in cells using small molecules is an active area of research in the treatment of several pathologies such as cardiovascular disease, cancer, and inflammatory conditions. Small molecule-inhibition of critical NO regulatory enzymes, NO synthase (NOS), arginase, and dimethylarginine dimethyaminohydrolase-1 (DDAH1), has shown therapeutic benefits as well as limitations and is a focus of current research.In recent years, DDAH1 has been explored as a potential target to indirectly regulate NO in diseases characterized by excessive NO production. This review discusses the biological and pathophysiological role of the NO pathway, the existing inhibitors of NOS, arginase and DDAH1, and the conventional and structure-guided structure-activity relationship studies involved in their discovery. The key structural elements of amino acid-derived inhibitors responsible for selective inhibition of each enzyme, and the chemical features responsible for dual enzyme inhibition are also discussed. Finally, a synthetic scheme for developing both selective and dual inhibitors using common starting materials is provided, offering unique insights in the quest for the rational design of novel NO pathway inhibitors.


Assuntos
Arginase , Óxido Nítrico , Amidoidrolases , Arginina/metabolismo , Arginina/farmacologia , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase
19.
Commun Biol ; 5(1): 833, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064581

RESUMO

Cyclic guanosine 3', 5'-monophosphate (cGMP) is a second messenger that regulates a variety of physiological processes. Here, we develop a red fluorescent protein-based cGMP indicator, "Red cGull". The fluorescence intensity of Red cGull increase more than sixfold in response to cGMP. The features of this indicator include an EC50 of 0.33 µM for cGMP, an excitation and emission peak at 567 nm and 591 nm, respectively. Live-cell imaging analysis reveal the utility of Red cGull for dual-colour imaging and its ability to be used in conjunction with optogenetics tools. Using enteroendocrine cell lines, Red cGull detects an increase in cGMP following the application of L-arginine. An increase in intracellular cGMP is found to be inhibited by Ca2+, and L-arginine-mediated hormone secretion is not potentiated. We propose that Red cGull will facilitate future research in cell signalling in relation to cGMP and its interplay with other signalling molecules.


Assuntos
GMP Cíclico , Sistemas do Segundo Mensageiro , Arginina/farmacologia , GMP Cíclico/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo
20.
Int J Biol Macromol ; 222(Pt A): 818-829, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36174866

RESUMO

Polysaccharide extracted from red seaweed Bangia fusco-purpurea (BFP) is a novel sulfated galactan, differed from agarans and carrageenans in fine structure. In this study, in vitro fermentation characteristics of BFP by human gut microbiota and its protective effect on lipopolysaccharide (LPS)-induced injury in Caco-2 cells were investigated. Our results showed that BFP was mainly degraded at transverse colon for 18 h fermentation by gut microbiota with reduced molecular weight. Meanwhile, BFP fermentation was associated with increased short-chain fatty acids (SCFAs) as compared to control group, especially acetic acid was increased to 129.53 ± 0.24 from 82.14 ± 0.23 mmol/L, and butyric acid was up to 1.56 ± 0.004 from 0.62 ± 0.01 mmol/L. Furthermore, BFP promoted abundances of Bacteroidetes and Firmicutes, while decreased numbers of Proteobacteria. The up-regrated beneficial differential metabolites were SCFAs, L-proline, arginine, folic acid, pyridoxamine, thiamine, etc. (p < 0.05), and their related metabolic pathways mainly included mTOR, arginine biosynthesis, and vitamin metabolism. Notably, BFP fermentation products at transverse colon significantly restored cell viability of LPS-treated Caco-2 cells from 73.79 ± 0.48 % to 93.79-99.64 %, which might be caused by increased beneficial differential metabolites (e.g., SCFAs). Our findings suggest that BFP has prebiotic potential and can enhance gut health.


Assuntos
Microbioma Gastrointestinal , Rodófitas , Humanos , Lipopolissacarídeos/farmacologia , Fermentação , Células CACO-2 , Polissacarídeos/química , Rodófitas/metabolismo , Ácidos Graxos Voláteis/farmacologia , Arginina/farmacologia
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