Preparation and in vitro evaluation of polylactic acid nanoparticles containing arginine and glucose oxidase / 药学学报

Hydrogen peroxide (H2O2) and nitric oxide (NO) has a short half-life, low bioavailability, poor tumor targeting and systemic adverse reactions in the physiological environment. In this study, phacoemulsification and nano-precipitation were used to synthesize didecyl dimethyl ammonium bromide (DDAB)/polylactic acid nanoparticles (PLA), then L-arginine (L-Arg) and glucose oxidase (GOx)-loaded nanoparticles (GADP) were prepared, and the in vitro antitumor activity was investigated．The particle size, potential, embedding rate and the ability to produce H2O2/NO of the nanoparticles were investigated. Meanwhile, in vitro cell cytotoxicity against human hepatoma cells (HepG2) was evaluated．The results showed that the prepared L-Arg-DDAB/PLA (ADP) nanoparticles were spherical particles. And the particle size and zeta potential were (225.7 ± 6.33) nm and (+23.5 ± 0.12) mV, respectively. The adsorption rate of GOx was 87.23% ± 0.02%. The drug loading of L-Arg was 15.6% ± 0.22%. The pH value of glucose solution and the amount of H2O2 showed that GADP had good catalytic activity. In vitro cytotoxicity experiments showed that blank nanoparticles were nontoxic, while the drug-loaded nanoparticles presented enhanced antitumor effect on HepG2 cells. And can inhibit tumor cell migration. The low dose nano-scale NO delivery system GADP can effectively inhibit the migration of tumor cells and kill tumor cells, thus producing therapeutic benefits.

Effect of dual blockade of renin-angiotensin system on renal nephrin and vascular endothelial growth factor – A expression in diabetic-hypertensive rats

Objectives: The effects of early renin-angiotensin system (RAS) blockade using angiotensin-converting enzyme (ACE) inhibitor lisinopril and/or angiotensin receptor blocker valsartan on renal nephrin and vascular endothelial growth factor (VEGF)-A gene expression were investigated in diabetic-hypertensive rats. Materials and Methods: Diabetes and hypertension were induced in adult Wistar rats using streptozotocin (45 mg/kg, i.p.) and N?-nitro-L-arginine methyl ester (60 mg/kg/12 h) for 4 consecutive days. Experimental animals were allocated into six groups (n = 6): normal control, diabetic control, diabetic-hypertensive control and lisinopril-, valsartan- and combination-treated diabetic-hypertensive groups (5 mg/kg/drug/day, p.o., for 21 days). Blood glucose, blood pressure, body weight, kidney weight to body weight ratio, serum albumin, creatinine, total protein and urea were measured and recorded every week. Nephrin and VEGF-A gene expression were measured using real-time polymerase chain reaction. Renal nephrin protein was measured using ELISA as well as nephrin immunostaining. Results: Blood pressure was significantly decreased by all treatments (P ? 0.05). All treatments normalised serum albumin and urea. Serum creatinine significantly decreased, while total protein significantly increased (P ? 0.05). Nephrin gene expression had a non-significant decrease in diabetic-hypertensive rats, yet it was statistically increased with individual treatments (P ? 0.05) and normalised with combined treatment. Renal nephrin protein significantly decreased in diabetic-hypertensive rats, normalised by lisinopril and significantly increased by valsartan and combined treatments (P ? 0.05). VEGF-A expression significantly increased in diabetic-hypertensive rats and significantly decreased with lisinopril and valsartan monotherapy and normalised with combined treatment (P ? 0.05). Immunostaining of nephrin also showed an obvious increase in the case of combined treatment. Conclusion: Early dual blockade of RAS in diabetic-hypertensive rats protected against renal damage and improved renal nephrin and VEGF-A gene expression as well as renal nephrin protein expression.

Effect of add-on L-arginine on blood pressure in hypertensive patients on antihypertensive treatment

Background: The prevalence of hypertension is rapidly increasing among both rural and urban populations and is a matter of concern in India. L-Arginine serves as a principle substrate for nitric oxide production which is a potent vasodilator. Aims and Objectives: This study was designed to determine the effects of oral L-arginine on blood pressure in hypertensive patients on antihypertensive drugs. Materials and Methods: This was a randomized clinical trial, registration in Clinical Trial Registry of India (CTRI) Registration number: CTRI/2019/03/018026. All patients with hypertension visiting the medicine outpatient department of Dr. Vitthalrao Vikhe Patil Pravara Rural Hospital, Loni, were included in the study. Study participants were randomized into intervention group (I group) and control group (C group). The I group includes 74 participants and the C group includes 75 participants. The I group received antihypertensive therapy along with add-on L-arginine oral supplementation for 14 days. The C group received only standard antihypertensive therapy and had followed up similar to that of the participants of the I group. Results: The baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the I group and C group was statistically non-significant as analyzed by unpaired t-test, whereas in the I group, there was a significant decrease in SBP and DBP on the 1st, 2nd, and 3rd follow-up visits compared to the C group (Friedman test). Conclusion: The findings of the present study showed that add-on L-arginine supplementation at a dose of 3 g/d (L-arginine 5 g sachet) for 2 weeks in patients of hypertension resulted in significant decrease in the SBP and DBP.

Administration of L-citrulline prevents Plasmodium growth by inhibiting/ modulating T-regulatory cells during malaria pathogenesis

Background & objectives: Malaria affects around 228 million people all over the globe. Malaria causing parasite Plasmodium infection leads to activation of immune responses. The growth of parasite and immune activation requires semi essential amino acids like L-arginine. Malaria infection leads to condition of hyperargininemia and low availability of nitric oxide. However, the effect of L-arginine supplementation in malaria infected mice has not been explored in in-vivo studies. In this study we have compared the effect of oral supplementation of nitric oxide donor, L-arginine and L-citrulline, in malaria infected mice Methods: To examine the effect of oral supplementation of L-arginine and L-citrulline, Plasmodium berghei infected mice were divided in different groups and respective groups were fed with L- arginine and L-citrulline, parasitemia was measured on different days. Mice was sacrificed and immunophenotyping was done on 10 days post infection. Results: our results show that supplementation of L-arginine induces conducive environment for Plasmodium growth due to which the infected mice dies earlier than control wild type infected mice whereas L-citrulline supplementation inhibits parasite growth and mice survives for longer period of time. Flow cytometric analysis shows that supplementation of L-arginine increases cTLA-4 on T cell population, increases Treg cells leading to immunosuppression while supplementation of L-citrulline does not have effect on T cells population and number of Treg cell decrease compared to P. berghei infected mice. Interpretation & conclusion: our results show that L-citrulline can be a better alternative than L-arginine because of lower expression of inhibitory molecules and lower parasitemia as well as increased survival of infected mice.

Synthesis and protective effect of carboxymethylcysteine L-arginate in bronchial epithelial cells / 中国药科大学学报

@#Carboxymethylcysteine (CMC) is a common drug for the clinical treatment of chronic obstructive pulmonary disease, yet its long-term use can cause severe irritation to the gastrointestinal tract.As the substrate of nitric oxide (NO) synthase (NOS), L-arginine can be converted in the body into NO beneficial to the cardiovascular system, the gastrointestinal tract and so on.As a basic amino acid, L-arginine can be salified with some compounds containing acidic groups to improve the water solubility of the parent drug and may enhance the activity and alleviate side effects due to NO release.In this study, we designed and synthesized carboxymethylcysteine L-arginate (CMCA), and tested its physico-chemical properties, and the abilities to scavenge reactive oxygen species (ROS), inhibit apoptosis and release NO in cigarette smoke-induced injury model of human bronchial epithelial cells.The results revealed that CMCA is superior to CMC or L-arginine in that it could capture ROS, release NO and suppress apoptosis, suggesting that CMCA is worthy of further research and development.

Effect of 8% arginine toothpaste on Streptococcus mutans in patients undergoing fixed orthodontic treatment: randomized controlled trial

ABSTRACT Objective: To assess the effect of toothpaste containing 8% arginine on Streptococcus mutans (S. mutans) in dental plaque around orthodontic brackets, and to draw a comparison with a regular fluoride toothpaste. Trial design: A single-center, parallel-arm, triple-blind, randomized controlled trial was conducted. Methods: The clinical trial was conducted at the Orthodontic Clinic, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran. Seventy-two patients (age range: 15-30 years) who required fixed orthodontic treatment were recruited and randomly assigned to arginine and fluoride groups. Randomization was performed using RANDOM.ORG online software, and the participants were divided into two parallel groups, with a 1:1 allocation ratio. Patients were requested to brush their teeth twice daily for 30 days with an experimental toothpaste. Plaque sampling was performed at two intervals, namely at the beginning of the study (T0) and 30 days later (T1). Real-time PCR was used to assess plaque samples in terms of the number of S. mutans surrounding stainless steel brackets in orthodontic patients. A triple-blind design was employed. Results: The baseline characteristics (age, sex, and the relative number of S. mutans) between the groups were similar (p>0.05). Only the arginine group showed a significant decrease in the relative number of bacteria between T0 and T1 (p=0.02). Conclusion: Arginine is an important prebiotic agent in maintaining healthy oral biofilms, and prevent dental caries during fixed orthodontic treatments. Trial registration: The trial was registered at the Iranian Registry of Clinical Trials (IRCT20181121041713N2), https://en.irct.ir/user/trial/42409/view.

RESUMO Objetivo: Avaliar o efeito de um dentifrício contendo arginina a 8% no Streptococcus mutans (S. mutans) da placa bacteriana ao redor de braquetes ortodônticos, e compará-lo a um dentifrício fluoretado convencional. Desenho do estudo: Foi conduzido um estudo unicêntrico, com braços paralelos, triplo-cego, controlado e randomizado. Métodos: O ensaio clínico foi conduzido na Clínica de Ortodontia da Faculdade de Odontologia da Universidade de Ciências Médicas de Shiraz, no Irã. Setenta e dois pacientes (com idades variando de 15 a 30 anos) que necessitavam de tratamento ortodôntico com aparelho fixo foram recrutados e alocados aleatoriamente nos grupos arginina ou flúor. A randomização foi feita usando o programa on-line RANDOM.ORG, e os participantes foram divididos em dois grupos paralelos, com proporção de alocação de 1:1. Solicitou-se aos pacientes que escovassem os dentes duas vezes ao dia com a pasta experimental, durante 30 dias. Amostras da placa bacteriana foram coletadas em dois intervalos: ao começo do estudo (T0) e após 30 dias (T1). Um PCR em tempo real foi usado para avaliar as amostras de placa, em termos de números de S. mutans ao redor dos braquetes de aço inoxidável nos pacientes ortodônticos. Um desenho de estudo triplo-cego foi usado. Resultados: As características iniciais (idade, sexo e quantidade relativa de S. mutans) foram semelhantes entre os grupos (p>0,05). Apenas o grupo arginina mostrou uma redução significativa na quantidade de bactérias entre T0 e T1 (p=0,02). Conclusão: A arginina é um agente prebiótico importante na manutenção de biofilmes bucais saudáveis, e previne as cáries dentárias durante o tratamento ortodôntico com aparelho fixo. Registro do ensaio: O ensaio foi registrado no Iranian Registry of Clinical Trials (IRCT20181121041713N2), https://en.irct.ir/user/trial/42409/view.

Suppression of L-arginine-induced acute necrotizing pancreatitis in rats by metformin associated with the inhibition of myeloperoxidase and activation of interleukin-10 / Supresión de la pancreatitis necrotizante aguda inducida por L-arginina en ratas por metformina asociada con la inhibición de mieloperoxidasa y activación de interleucina-10

SUMMARY: Acute pancreatitis is a frequent life-threatening inflammatory disease of the pancreas characterized by severe abdominal pain that lasts for days to weeks. We sought to determine whether the antidiabetic and anti-inflammatory drug, metformin can substantially protect against acute pancreatitis in an animal model of L-arginine-induced acute pancreatitis, and whether this is associated with the augmentation of the anti-inflammatory cytokine interleukin-10 (IL-10) and inhibition of the enzyme that promotes tissue damage, myeloperoxidase (MPO). Rats were either injected with two doses of the amino acid L-arginine (2.5 gm/kg; i.p., at one-hour intervals) before being sacrificed after 48 hours (model group) or were pretreated with metformin (50 mg/kg) daily for two weeks prior to L- arginine injections and continued receiving metformin until the end of the experiment (protective group). Using microscopic examination of the pancreas and blood chemistry, we observed that L-arginine induced acute pancreatic injury. This is demonstrated by an enlarged pancreas with patchy areas of haemorrhage, vacuolated cytoplasm and pyknotic nuclei in the acini, disorganized lobular architecture with infiltration of inflammatory cells within the interlobular connective tissue (CT) septa, and the presence of congested blood vessels that were substantially ameliorated by metformin. Metformin also significantly (p<0.05) inhibited L-arginine-induced MPO, lactate dehydrogenase (LDH), and the inflammatory biomarker tumor necrosis factor alpha (TNF-α). Whereas, metformin significantly (p<0.05) increased IL-10 levels that were inhibited by pancreatitis induction. We further demonstrated a significant (p<0.001) correlation between the scoring of the degree of pancreatic lobules damage tissue damage and the blood levels of TNF-α, IL-10, LDH, and MPO. Thus, metformin effectively protects against L-arginine-induced acute pancreatitis, which is associated with the inhibition of MPO and augmentation of IL-10.

RESUMEN: La pancreatitis aguda es una enfermedad inflamatoria del páncreas que amenaza la vida y se caracteriza por un dolor abdominal intenso que dura de días a semanas. Buscamos determinar si la metformina, fármaco antidiabético y antiinflamatorio, puede proteger contra la pancreatitis aguda en un modelo animal de pancreatitis aguda inducida por L-arginina. Además se estudió la asociación con el aumento de la citocina antiinflamatoria interleucina-10. (IL-10) e inhibición de la enzima que promueve el daño tisular, mieloperoxidasa (MPO). Las ratas se inyectaron con dos dosis del aminoácido L-arginina (2,5 g / kg; ip, a intervalos de una hora) antes de ser sacrificadas des- pués de 48 horas (grupo modelo) o se pre trataron con metformina (50 mg / kg) durante dos semanas antes del tratamiento de L- arginina y continuaron recibiendo metformina hasta el final del experimento (grupo protector). Mediante el examen microscópico del páncreas y la química sanguínea, se observó que la L- arginina inducía una lesión pancreática aguda. Se observó un aumento significativo de tamaño del páncreas con áreas hemorrágicas, citoplasma vacuolado y núcleos picnóticos en los acinos, arquitectura desorganizada con infiltración de células inflamatorias dentro de los tabiques del tejido conjuntivo interlobulillar (TC) y la presencia de vasos sanguíneos congestionados mejorados por metformina. Se observó que la metformina inhibió significativamente (p <0,05) la MPO inducida por L- arginina, la lactato deshidrogenasa (LDH) y el factor de necrosis tumoral alfa (TNF-α). Además, demostramos una correlación significativa (p <0,001) entre la puntuación del grado de daño tisular de los lóbulos pancreáticos y los niveles sanguíneos de TNF-α, IL-10, LDH y MPO. Por tanto, la metformina protege eficazmente contra la pancreatitis aguda inducida por L-arginina, que se asocia con la inhibición de MPO y el aumento de IL-10.

Effect of cassia seed aqueous extract on blood pressure level in n-nitro-l-arginine-methyl ester induced hypertensive rats / 中国组织工程研究

BACKGROUND: The concept of modern diagnosis and treatment of hypertension is to protect target organs, improve clinical symptoms and minimize clinical events through antihypertensive treatment. Cassia seed has an antihypertensive effect that has been confirmed in animal experiment and clinical practice, but whether it can improve the vascular dysfunction, oxidative stress and end organ damage of hypertension remains to be further studied. OBJECTIVE: To evaluate the antihypertensive effect of cassia seed water extract on hypertensive rats induced by N-nitro-L-arginine methyl ester. METHODS: A rat model of hypertension was established by intragastric administration of N-nitro-L-arginine methyl ester to observe the changes of blood pressure and heart rate after the intervention of cassia seed aqueous extract (500 mg/kg per day), once a day, for 4 continuous weeks. Blood pressure and heart rate were measured once a week. At 24 hours after the final administration, serum levels of aspartate aminotransferase, alanine aminotransferase, urea and serum creatinine, and lipid mass spectrometry were detected by an automatic biochemical analyzer. Malondialdehyde, nitric oxide, reduced glutathione levels and angiotensin converting enzyme activity in rat liver and kidney were determined by corresponding assay kits. The expression levels of endothelial nitric oxide synthase and inducible nitric oxide synthase protein and gene in rat kidney tissues were examined by immunohistochemistry as well as real-time quantitative PCR. RESULTS AND CONCLUSION: Compared with the model group, cassia seed aqueous extract treatment significantly reduced mean arterial pressure, diastolic pressure and systolic pressure (P < 0.05) in hypertensive rats, and improved liver and renal markers, lipid distribution and oxidative status. In addition, cassia seed aqueous extract significantly reduced the activity of angiotensin-converting enzyme in the liver and kidney of hypertensive rats (P < 0.05). The protein and mRNA expression levels of endothelial nitric oxide synthase in the kidney of rats treated with cassia seed aqueous extract were significantly higher than those of the model group. In conclusion, cassia seed water extract has shown considerable potential for antihypertension, and its anti-hypertension mechanism includes up-regulation of endothelial nitric oxide synthase expression, antioxidants and inhibition of angiotensin-converting enzymes.

Morin attenuates L-arginine induced acute pancreatitis in rats by downregulating myeloperoxidase and lipid peroxidation

Objective:To explore the therapeutic role of morin against L-arginine-induced acute pancreatitis in rats. Methods:The group 1 received two intraperitoneal injections of normal saline, and groups 2-4 were given two intraperitoneal injections of L-arginine (250 mg/100 g body weight) at 1 h interval to induce acute pancreatitis. Subsequently, group 2 received no further treatment while groups 3 and 4 were treated with morin (30 mg/kg) and diclofenac sodium (30 mg/kg), respectively. Blood glucose and serum levels of insulin, α-amylase, malondialdehyde, myeloperoxidase, alanine aminotransferase, aspartate aminotransferase and cholesterol were measured. Moreover, histopathological study was carried out to investigate the effect of morin treatment on physiology of the pancreas. Results:L-arginine significantly altered the level of blood glucose and serum levels of insulin, α-amylase, malondialdehyde, myeloperoxidase, alanine aminotransferase, aspartate aminotransferase and cholesterol. Treatment with morin or diclofenac sodium significantly improved the levels of these biomarkers. Furthermore, morin showed more significant effect than diclofenac sodium. Histopathological analysis verified that morin protected the pancreas from deleterious effects of L-arginine. Conclusions:Morin plays a protective role against L-arginine-induced acute pancreatitis via reducing lipid peroxidation and tissue inflammation, and attenuating acute pancreatitis-associated alteration in insulin secretion and glucose metabolism.

L-arginine promotes the survival of extended dorsal perforator skin flap through activating L-arginine-nitric oxide pathway / 中国组织工程研究

BACKGROUND: Studies have shown that nitric oxide(NO) can effectively improve blood supply and promote flap survival, but the specific mechanism is still unclear. OBJECTIVE: To explore the effects of L-arginine(L-Arg) on the survival of extended dorsal perforator skin flap in rats by activating L-Arg-NO pathway. METHODS: Animal models of extended dorsal perforator skin flap were successfully established in 81 male Sprague Dawley rats, which were then divided into a L-Arg group, a blank group and a L-NAME group. L-Arg(400 mg/kg per day) and nitro-amino-methyl-L-arginine(L-NAME; 40 mg/kg per day) were injected intraperitoneally in the L-Arg group and L-NAME group immediately and 1-7 days after operation, respectively, while the same volume of isotonic sodium chloride solution was injected intraperitoneally in the blank group at the same time points. Flap survival rate was measured. Angiography was performed to observe appearance and distribution of blood vessels at 7 days after operation. NO concentration of choke II zone was detected immediately, 1, 3, 5, and 7 days after operation. Tissue samples were harvested from the choke II zone for detecting density and caliber of new blood vessels using hematoxylin-eosin staining and the expression of vascular endothelial growth factor and matrix metalloproteinase was detected by western blot, respectively. The study protocol was approved by the Animal Ethics Committee of the 94 th Hospital of the PLA Joint Logistics Support Force(approval No. 2015 KYLL046). RESULTS AND CONCLUSION: The highest survival rate of flap appeared in the L-Arg group, (89.47±3.17)%, which was significantly higher than that in the other groups(F=49.908, P < 0.001). At 7 days after operation, the vascular structure in the choke II zone of the L-Arg group was relatively complete with clear trajectory. The vessels that had expanded to achieve true anastomosis extended along the longitudinal axis of the flap to the end of the flap. In the blank group and L-NAME group, the vascular structure and vascular trajectory in the choke II zone were disordered. Moreover, the vascular structure at the end of flap in L-NAME group disappeared. NO concentration in L-Arg group was increased after surgery, peaked at 3 days after operation, and then decreased gradually. Microvessel density and caliber in the L-Arg group were significantly higher than those in the other groups at 7 days after operation(P < 0.001). Western blot showed that the expression of vascular endothelial growth factor and matrix metalloproteinase-2 were significantly higher in the L-Arg group than the other groups at 3 after operation(P < 0.05), while at 7 days after operation, the expression of vascular endothelial growth factor in the L-Arg group was significantly higher than that in the other groups(P < 0.05), but the expression of matrix metalloproteinase-2 showed no significant difference among the three groups. To conclude, NO could promote microvascular growth and dilatation in the choke II zone of extended dorsal three-vascular perforator flaps in rats; L-Arg could increase the NO concentration in tissue by activating the L-Arg-NO pathway, which is beneficial to the survival of skin flap.

Effects of L-Arginine and α / 中国医学科学院学报

Kidney is one of the important organs of the body.With both excretory and endocrine functions,it plays a vital role in regulating the normal physiological state.As a precursor of the nitric oxide(NO)synthesis

Improvement of impaired endothelial progenitor cell functions by in vitro drug interference in DOCA-salt hypertensive mice / 药学实践杂志

Objective To investigate the effect of tetrahydrobiopterin (BH4), superoxide dismutase-polyethylene glycol (PEG-SOD) and N(G)-nitro-L-arginine (L-NNA) on impaired endothelial progenitor cell (EPC) functions in DOCA-salt hypertensive mice. Methods DOCA-salt hypertension was created and systolic blood pressure was measured by tail-cuff methods. EPC was isolated from bone marrow of mice and characterized by flow cytometry and fluorescence microscopy. EPC of DOCA-salt mice was incubated with BH4, PEG-SOD, and L-NNA for 24 h, then in vitro EPC function assays were performed. Results Compared with control group, systolic blood pressure was significantly increased in DOCA-salt mice. Both EPC adhesion and angiogenesis functions were impaired in DOCA-salt mice compared to control animals, which were reversed by incubation with BH4, PEG-SOD and L-NNA. Conclusion BH4, PEG-SOD and L-NNA rescued the impairments from EPC functions in DOCA-salt hypertensive mice.

Effects of l-arginine supplementation on glycemic profile: Evidence from a systematic review and meta-analysis of clinical trials / 中西医结合学报

BACKGROUND@#The effects of l-arginine supplementation on indices of glycemic control and the role of many factors influencing this intervention have been controversial in clinical trials.@*OBJECTIVE@#This meta-analysis was performed to assess the effects of l-arginine supplementation on indices of glycemic control, including fasting blood glucose (FBG), hemoglobin A1c (HbA1c), serum insulin and homeostatic model assessment of insulin resistance (HOMA-IR) levels in randomized controlled trials (RCTs).@*SEARCH STRATEGY@#This study conducted a systematic review of RCTs published in PubMed, Scopus, Web of Science, Cochrane Library and Embase, up to 5 May, 2018.@*INCLUSION CRITERIA@#Studies were included in this meta-analysis if they were RCTs with parallel design and reported sufficient data on participants before and after intervention, and outcomes of glycemic profile parameters in both the arginine supplementation and control groups.@*DATA EXTRACTION AND ANALYSIS@#The screening of titles and abstracts was performed independently by two reviewers. Selected articles were considered if they met the study's inclusion criteria. The quality of included studies was assessed by using the Cochrane Collaboration modified tool. From 710 articles retrieved in the initial search, only 10 trials were suitable for pooling the effects of arginine supplementation on serum glucose, insulin, HOMA-IR and HbA1c levels, with effect sizes of nine, eight, five and five, respectively.@*RESULTS@#Pooled random-effect analysis revealed that l-arginine supplementation could significantly decrease FBG level (weighted mean difference [WMD]: 3.35 mg/dL; 95% confidence interval [CI] = [-6.55, -0.16]; P = 0.04) and serum insulin level (WMD: -2.19 μIU/mL; 95% CI = [-3.70, -0.67]; P = 0.005). However, the effects of l-arginine supplementation on HOMA-IR and HbA1c were not significant. Results of subgroup analysis showed that supplementation with l-arginine could significantly decrease serum insulin levels when the dosage of l-arginine is > 6.5 g/d (WMD: -3.49 μIU/mL; 95% CI = [-5.59, -1.38]; P = 0.001), when the duration of supplementation is ≤ 12.8 weeks (WMD: -3.76; 95% CI = [-6.50, -0.98]; P = 0.008), when the participants are not diabetic patients (WMD: -2.54 μIU/mL; 95% CI = [-4.50, -0.50]; P = 0.01) and when the baseline serum level of insulin was > 20 μIU/mL (WMD: -3.98; 95% CI = [-6.31, -1.65]; P = 0.001).@*CONCLUSION@#Although the results of this study confirmed that supplementation with l-arginine could have significant effects on some glycemic profile indices of participants in clinical trials, the clinical importance of this reduction may not be meaningful.

Ameliorating Effect of Melatonin on L- Arginine Induced Acute Pancreatitis in Rats

The present study was aimed to evaluate the ameliorative potential of melatonin against L-arginine induced acute pancreatitis in rats. Male Sprague Dawley rats (150–240 g) were divided into 3 groups, viz. group I (control group), group II (acute pancreatitis control group) and group III (treatment control) which were further subdivided into 3 subgroups according to time points of 24 hours, 3 days and 7 days. Rats from groups II and III received two injections of L-arginine (2 g/kg i.p.) at 1 h intervals for induction of acute pancreatitis. Melatonin was administered to group III daily at a single dose of 10 mg/kg i.p. On 6 hours, 24 hours, 3 days and 7 days, blood samples were obtained from each group and subjected for the assays of oxidative stress and serum biochemical parameters. Erythrocytic lipid peroxides contents in acute pancreatitis group were significantly higher, while reduced glutathione contents were significantly lower in comparison with the normal controls. The activities of other antioxidant enzymes were also significantly low in these rats. Moreover, significantly increased activities of serum amylase and serum lipase were found in these rats. Administration of melatonin significantly reduced the over production of malonaldialdehyde levels. Other antioxidant enzymes viz. reduced glutathione, superoxide dismutase and catalase activities were improved significantly in melatonin treated rats. Melatonin had also considerably ameliorated the altered serum amylase and serum lipase levels towards normalcy. Thus, it can be concluded that melatonin may possess therapeutic efficacy against L-arginine induced acute pancreatitis in rats

Efficacy of oral L-arginine on amniotic fluid index in pregnant women with oligohydramnios attending antenatal clinic in a tertiary care hospital in Telangana, India

Background: Oligohydramnios leads to feto-maternal morbidity and mortality. Though there is no specific treatment for oligohydramnios, use of L-arginine seems to be promising. As a nitric oxide donor, it causes vasodilatation, increases placental perfusion and finally increases amniotic fluid. However, data on the use of L-arginine for oligohydramnios is scarce. Hence, this study was aimed to evaluate the efficacy of oral L-arginine on Amniotic Fluid Index (AFI) and to document the pregnancy outcomes in women with oligohydramnios.Methods: This was a prospective observational study conducted on pregnant women attending antenatal clinic (ANC) at Mediciti Institute of Medical Sciences (MIMS), Ghanpur, Telangana, India from 1st January 2018 to 30th June 2018.Results: A total of 50 participants were enrolled and 4 participants among them were lost to follow- up. Mean age (SD) of the women enrolled was 23.3 (3.49) years. Mean gestational age (SD) at the time of diagnosis was 34.61 (1.53) weeks. Mean AFI (SD) at the time of diagnosis and after treatment with L-arginine were 6.8 (1.3) cm and 9.4 (2.82) cm respectively. After a mean treatment duration (SD) of 3.23 (1.38) weeks, a mean (SD) increase of AFI by 2.6 (1.57) cm (P <0.0001) was observed. An increase of AFI was noted in 84.78% of cases (P <0.0001). Mean (SD) Gestational age at the time of delivery was 38.25 (1.48) weeks. Only 37% of participants required operational deliveries. Mean (SD) birth weight of the new borns was 2.54 (0.47) kg. Neonatal Intensive Care Unit (NICU) admissions were required in 32.6% of new borns.Conclusions: L-arginine is efficacious in improving AFI in oligohydramnios. AFI improvement could possibly lead to better neonatal outcomes by reducing preterm deliveries and operative interventions.

A study on perioperative lung protection by way of l-arginine aerosolized inhalation of pulmonary arterial hypertension patients after pulmonary lobectomy / 中华胸心血管外科杂志

Objective To study l-arginine aerosolized inhalation's protective effect on pulmonary ventilation of the pulmonary-arterial-hypertension patients during the early stage after pulmonary lobectomy,and its preventive effect on reducing postoperative complications.Methods 54 cases of pulmonary lobectomy patients with preoperative plumonary arterial hypertension were divided into two groups randomly-Group A was given L-arginine aerosolized inhalation within 4 h after the operation;Group B was given the same dose of aerosolized inhalation of physiological saline as contrast(other postoperative medication being the same with Group A).Compare the two groups of patients in terms of oxygenation index(PaO2/FiO2),alveolararterial oxygen difference(PA-aO2),nitric oxide(NO) concentration,ultrasonic cardiogram,mechanical ventilation duration,ICU duration,occurances of hemodvnamic disturbance and arrhythmia,and differences in postoperative hospital stay.Results The oxgenation index and the content of NO in plasma of Group A were higher than that of Group B(P ＜0.001);the alveolar-arterial oxygen difference and the postoperative pulmonary arterial pressure detected by UCG of Group A were lower than that of Group B(P ＜ 0.001);the postoperative mechanical ventilation duration,ICU duration,occurances of hemodynamic disturbance and arrhythmia of Group A were all lower than that of Croup B(P ＜ 0.05).Conclusion The postoperative l-arginine aerosolized inhalation during the early stage after pulmonary lobectomy has positive effect on the lung protection of the pulmonary-arterial-hypertension patients and it can reduce the perioperative complications and postoperative hospital stay of such patients.

Effect of alpha-lipoic acid supplementation on blood pressure, renal oxidant-antioxidant status and renal damage in spontaneously hypertensive rats

Objective: To investigate the effect of alpha-lipoic acid (ALA) supplementation on systolic blood pressure (SBP), renal oxidant-antioxidant status and renal damage in spontaneously hypertensive rats (SHR) and SHR administered with Nω-nitro-L-arginine methyl ester (L-NAME). Methods: Male rats were divided into four groups (SHR, SHR+ALA, SHR+L-NAME, SHR+ALA+L-NAME). The respective group of rats was administered with ALA (100 mg/kg/day) from age 4 weeks to 28 weeks and L-NAME (25 mg/kg/day) from age 16 weeks to 28 weeks. SBP was measured every two weeks and twenty four hour urine was collected at 4 weeks, 16 weeks and 28 weeks for estimation of protein, creatinine and N-acetyl-β-D-glucosaminidase. At the end of 28 weeks, rats were sacrificed and blood and kidneys collected for assessment of blood creatinine, kidney thiobarbituric acid reactive substances, protein carbonyls, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, glutathione disulfide, glutathione, total antioxidant status and nitric oxide as well as histopathological examination. Results: ALA supplementation significantly reduced SBP of SHR and SHR+L-NAME rats when compared to their respective non-supplemented groups. Renal oxidant status markers including thiobarbituric acid reactive substances and protein carbonyls were significantly reduced on SHR and SHR+L-NAME rats supplemented with ALA at 28 weeks as well as ALA supplementation significantly increased renal antioxidants including superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, glutathione and glutathione/glutathione disulfide ratio at 28 weeks. No significant change in nitric oxide levels was observed between the ALA supplemented and non-supplemented groups. Renal dysfunction was ameliorated on ALA supplementation as evidenced by significant reduction in urine protein levels, N-acetyl-β-D-glucosaminidase activity and significant increase of creatinine clearance in SHR and SHR+L-NAME at 28 weeks. Renal histopathological examination showed that ALA supplementation prevented vascular damage in SHR and ameliorated glomerular damage in SHR+L-NAME at 28 weeks. Conclusions: ALA has hypotensive and renoprotective effects on both SHR and SHR+L-NAME, which could be due to its ability to ameliorate oxidative stress in the kidneys.

Effect of ASPP2 on regulating GRP78 in apoptosis of placental trophoblast cells induced by L-NAME / 中国药理学通报

Aim: To explore the role of apoptosis stimulating protein 2 of p53 (ASPP2) on L-NAME induced apoptosis of placental trophoblast cells by regulating glucose-regulated protein78(GRP78), and provide a theoretical basis for the study of clinical pregnancy-induced hypertension. Methods: The HTR-8/SVneo human placental trophoblast cells were cultured in vitro, and in the absence (control group) or presence of 100 μmol · L-1 L-NAME (L-NAME group) for 48 h. The effects of L-NAME on placental trophoblast cell apoptosis were tested using flow cytometry and AO/EB assay. The expressions of caspase-12, GRP78 and ASPP2 were detected by Western blot. The ASPP2 interference with adenovirus was used to transfect the cells, and the mRNA expression level of ASPP2 and the protein expression level of GRP78 were detected by qRT-PCR and Western blot, respectively. After treated with 100 (xrnol · L-1 L-NAME for 48 h, the protein expression of caspase-12 and GRP78 was detected by Western blot and immunofluorescence. Results: Compared with control group, the placental trophoblast cell apoptosis significantly increased in L-NAME group (P < 0. 05). AO/EB staining showed that compared with control group, the majority of cells in L-NAME group showed bright orange and the number of late apoptotic cells increased significantly. At the same time, caspase-12, GRP78 and ASPP2 protein expression increased (P < 0. 05, P < 0. 01). After interfering with ASPP2, caspase-12 and GRP78 protein expressions decreased (P < 0. 05). Conclusions: Down-regulation of ASPP2 could decrease GRP78 expression and inhibit L-NAME-induced apoptosis in placental trophoblast cells.

Risk Assessment of "Other Substances" –L-arginine and Arginine Alpha-ketoglutarate

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. The risk assessments are the scientific basis for NFSA in its efforts to regulate the use of "other substances". "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of the amino acid L-arginine and L-arginine alpha-ketoglutarate (AAKG), a salt of arginine. It is based on published articles retrieved from a literature search and previous risk assessments of L-arginine. According to information from NFSA, L-arginine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of L-arginine, which according to the information provided by NFSA is found in food supplements in the doses 3000, 3500, 4000, 4500, 5000, 5500, 6000 and 6800 mg/day. Arginine alpha-ketoglutarate is found in food supplements in doses of 1000 and 2000 mg/day. Arginine is a constituent of all food proteins. Dairy products, beef, pork, poultry, wild game and seafood, as well as plant sources such as wheat germ and flour, oatmeal and nuts are good sources of arginine. Arginine is a conditionally essential amino acid, meaning that under most circumstances endogenous synthesis by the human body is sufficient. However, the biosynthetic pathway may under certain conditions produce insufficient amounts. In such cases a dietary supply is needed. Individuals with poor nutrition or certain physical conditions are examples of vulnerable groups. Under normal conditions, endogenous production of arginine is 15-20 g/day. The requirements for L-arginine in adults are 117 mg/kg body weight (bw) per day (WHO, 2007), i.e. for a 70 kg adult person, the requirement is 8.2 g per day. The mean daily dietary intake for all life stage and gender groups of arginine is approximately 4.2 g/day (1988–1994 NHANES III, USA). Arginine is physiologically active in the L-form, which is synthesised by endothelial cells and excreted with urine. The major part of body L-arginine is found in proteins. However, L-arginine is also substrate of nitric-oxide, a potent vasodilator, which may play a major role in regulating blood pressure and improve vascular function. Arginine, supplied as alpha-ketoglutarate, has been observed to increase nitric-oxide production and is mostly studied in athletes because of its claimed enhancing effect on physical performance. Due to the lack of adequate scientific information, a no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL) of arginine has not been identified, thus a tolerable upper intake level for arginine has not been established. Most studies of arginine supplements have been of relatively short duration. The two most relevant randomised placebo-controlled trials for the current risk assessment are those published by Monti et al. (2012) and Lucotti et al. (2009). Both provided a daily dose of 6.4 g arginine, for a duration of 6 and 18 months, respectively. In both studies, adverse events did not differ between arginine and placebo groups. Thus, based on the studies reviewed as well as previous reports, VKM will use the value 6.4 g/day as value for comparison in the risk characterisation of L-arginine. The dose 6.4 g/day of arginine corresponds to 91 mg/kg bw per day in a 70 kg person. AAKG is one of several compounds that have been used as a source of arginine in food supplements. It has been studied in healthy athletic men without serious adverse side effects. However, studies of AAKG supplementation are too scarce to draw conclusions for this specific arginine compound. No data are available indicating whether children or adolescents have different tolerance levels than adults for L-arginine. No tolerance level is set for L-arginine specifically for children or adolescents. The conclusions are therefore based on the assumption of similar tolerance for children and adolescents, per kg body weight, as for adults. VKM concludes that: In adults (≥18 years), the specified doses of 3000, 3500, 4000, 4500, 5000, 5500 and 6000 mg/day of L-arginine in food supplement are considered unlikely to cause adverse health effects. The dose 6800 mg/day may represent a risk of adverse health effects. In adolescents (14 to <18 years), the specified doses 3000, 3500, 4000, 4500, 5000, 5500 mg/day L-arginine in food are considered unlikely to cause adverse health effects, whereas the doses 6000 and 6800 mg/day may represent a risk of adverse health effects. In children (10 to <14 years), the specified doses 3000 and 3500 mg/day L-arginine in food supplements are considered unlikely to cause adverse health effects, whereas the doses 4000, 4500, 5000, 5500, 6000 and 6800 mg/day may represent a risk of adverse health effects. Children below 10 years were not included in the terms of reference. No dosage of arginine alpha-ketoglutarate in food supplements can be evaluated, due to lack of data. In terms of the arginine content of AAKG, a dose of 1000 mg AAKG contains 544 mg arginine and 450 mg alpha-ketoglutarate (based on the molecular weight of 174.2 g/mol for arginine and 144.1 g/mol for alpha-ketoglutarate). A dose of 2000 mg AAKG, the highest dose found in food supplements sold in Norway, contains 1088 mg arginine and 900 mg alpha-ketoglutarate. This amount of arginine is well below the lowest specified dose of 3000 mg/day L-arginine found in food supplements.

Effects of aqueous leaf extract of Tridax procumbens on contractile activity of corpus cavernosum in N-nitro-l-arginine methyl ester-induced hypertensive male rats / 中西医结合学报

<p><b>OBJECTIVE</b>This study investigated the effects of aqueous leaf extract of Tridax procumbens (ALETP) on contractile activity of corpus cavernosum in N-nitro-l-arginine methyl ester (l-NAME)-induced hypertensive male rats.</p><p><b>METHODS</b>Twenty normal, adult male rats (130-150 g) were divided into four groups of five rats each. Group I (control) was given normal saline (0.6 mL/kg) and group II was given l-NAME (40 mg/kg) for 6 weeks. Groups III and IV also received l-NAME (40 mg/kg) for 6 weeks but were further co-treated with 100 and 200 mg/kg of ALETP, respectively, from week 4 to week 6. All treatments were given orally. Strips of corpus cavernosum from each of the four groups were exposed to increasing concentrations of acetylcholine (ACh) and sodium nitroprusside (SNP) (10-10mol/L) after contraction with phenylephrine (10 mol/L) to test for a dose-response effect. Response to potassium and calcium was also measured after cumulatively adding potassium and calcium (10-50 mmol/L) to potassium- and calcium-free organ chamber. Isometric contractions were recorded through an Ugo Basile data capsule acquisition system.</p><p><b>RESULTS</b>Mean arterial blood pressure was significantly reduced in the ALETP co-treated group compared to the control and l-NAME-only groups (P < 0.05). Cavernosa strips from ALETP co-treated rats exhibited significant inhibition of contraction in response to phenylephrine, potassium chloride, and calcium chloride (P < 0.05). Relaxation in response to Ach and SNP was also significantly impaired in cavernosa strips from the l-NAME-only treated group (P < 0.05), while ALETP co-treated groups showed enhanced percentage relaxation.</p><p><b>CONCLUSION</b>ALETP treatment of l-NAME-induced hypertensive rats promotes a relaxant effect on isolated cavernosa strips. ALETP shows potential in correcting erectile dysfunction in hypertension.</p>