Administration Of L-arginine Research Articles

Sodium pyruvate improves the plasma amino acid profile in rats with L-arginine-induced acute pancreatitis.

Plasma amino acid levels are altered upon many pathological conditions including acute pancreatitis. It is unclear whether amino acids can be used as specific biomarker of acute pancreatitis severity or recovery. Development of acute pancreatitis is associated with mitochondrial dysfunction and decreased cytosolic ATP level. Sodium pyruvate is considered as a potential treatment of pancreatitis due to its ability to sustain mitochondrial oxidative and ATP-productive capacity in vitro. This study investigated the effect of sodium pyruvate on pancreatic morphology and plasma amino acid levels in rats with acute pancreatitis. Acute pancreatitis in rats was induced by administration of L-arginine (5g/kg) Experimental treatment group received sodium pyruvate (1g/kg) for 4days. On day 8 of the experiment, animals were killed, blood was collected and plasma amino acid concentration was determined with high-performance liquid chromatography. Histological examination showed large areas of fibrosis in the pancreas of animals treated with L-arginine irrespectively of sodium pyruvate administration. Sodium pyruvate improved the plasma amino acid levels. Rats with acute pancreatitis had significantly lower levels of most essential and non-essential amino acids and increased glutamate and aspartate in plasma. Administration of sodium pyruvate completely or partially restored the levels of methionine, phenylalanine, tryptophan, leucine, isoleucine, aspartate, asparagine and ornithine levels, while increasing glutamine and serine to levels significantly higher than control. Plasma lysine, alanine, arginine and taurine remained unaffected in all experimental groups. Sodium pyruvate may be considered for use as a maintenance therapy in acute pancreatitis.

Evaluation of Lipid Profile of High Salt fed Rats treated with L-Arginine

There is a global concern on salt consumption above the dietary guideline; salt consumption evokes physiological responses with cardiovascular risks associated with dyslipidemia other than increased blood pressure as numerous studies have pointed out. This study aimed at evaluating the effect of L-Arginine on lipid profile of rats fed high salt diet. Forty Male Albino Wister rats weighing between 70-120g were randomly selected assigned into four groups of 10 rats each. Group 1 served as the control and was given distilled water and normal rat chow. Group 2 was fed with high salt diet (8% Nacl in feed, and 1% Nacl in drinking water) Group 3 was treated as group 2 with the introduction of L-Arginine on the 43rd day of the experiment. Group 4 was treated as group 2 with the introduction of losartan administration on the 43rd day of the experiment. Administration of L-Arginine and losartan lasted for 14 days, making a total duration of feeding and drugs administration 56 days. At the end of the 56th day, the rats were fasted overnight for 12 hours and sacrificed under anaesthesia using sodium pentobarbitone. Blood samples were then collected from each animal via cardiac puncture into heparinized tubes and centrifuged at 3500rpm for a period of 15 min, and the clear supernatant plasma were collected and stored at -20°C for biochemical analyses of lipid profile. The results showed a significant increase in TG, LDL-C, TC, VLDL-C and a reduction of HDL-C in the salt fed group. Conversely, a significant reduction in TG, LDL-C, TC, VLDL-C and an increase in HDL-C was shown in the salt + L-Arginine treated group when compared to the control. The changes observed in the L-Arginine treated groups reversed the hyperlipidemia in the salt treated group which indicates L-Arginine is beneficial in treatment of salt induced dyslipidemia and cardiovascular diseases. Keywords: cardiovascular risks, dyslipidemia, L-Arginine, rats fed high salt diet

The Effect of L-Arginine Oral Supplementation on the Improvement of Cardiovascular Function and Pulmonary Artery Pressure in Patients with Major and Intermedia β-Thalassemia.

Thalassemia is the most common inherited anemia in worldwide. Heart failure is the most common cause of mortality and morbidity in patients with major and intermedia β-thalassemia. This study aimed to evaluate the effect of oral administration of L-arginine on the improvement of systolic Pulmonary Artery Pressure (PAP) and cardiac function in patients with major and intermedia β-thalassemia. This randomized clinical trial was done on 88 patients with β-thalassemia admitted to Ali Asghar Hospital, Tehran, Iran between 2020 and 2021. Echocardiography was performed for all the patients before the intervention. Afterwards, the patients were randomly divided into two groups of placebo and L-arginine. The patients underwent echocardiography after eight weeks and were compared with respect to the results. The mean blood transfusion interval was 20.21 d in the placebo group and 17.14 d in the L-arginine group (P=0.082). The results revealed no significant difference between the two groups regarding the mean levels of Hemoglobin (Hb) and ferritin, frequency of splenectomy. However, the mean PAP significantly decreased from 32.88 to 26.02 in the L-arginine group (P=0.009), but did not change in the placebo group. Nonetheless, no significant change was observed in the mean Ejection Fraction (EF) before and after L-arginine administration. L-arginine administration prevented the increase of PAP and was effective in preventing cardiovascular disorders including increased systolic PAP in patients with major and intermedia B-thalassemia. However, the results have to be confirmed in further studies with larger sample sizes.

Changes in the biochemical parameters of blood and the morphological structure of the pancreas in rats with acute pancreatitis and their correction using corvitin

Acute pancreatitis (AP) is an inflammation of the pancreas characterized by a severe course and a high mortality rate. The pathogenesis of AP is still not fully understood, so there is currently a lack of treatment. Corvitin is a water-soluble form of quercetin that retains all the properties of quercetin and has powerful antioxidant, anti-inflammatory and anti-apoptotic properties. The aim of our study was to evaluate the effect of corvitin on biochemical blood parameters and morphological features of the pancreas in rats with AP caused by intraperitoneal administration of L-arginine (200 mg/100 g). This model of AP is non-invasive, highly reproducible and causes selective, dose-dependent necrosis of acinar cells and is ideal both for studying the pathomechanisms of AP and for observing and influencing changes in the course of the disease. The legality of using this model is confirmed by the morphostructural changes in the pancreas that are characteristic of AP. In rats with AP, an increase in the blood concentration of α-amylase (twice), alanine aminotransferase (ALT) (three times), aspartate aminotransferase (AST) (one and a half times) compared to control values was observed already on the first day of the pathology development. On the second day of AP, the level of glucose and urea in the blood of rats increased by 34 and 22%, respectively, while the creatinine content did not change. Under the influence of corvitin (50 mg/kg), the levels of α-amylase, ALT and glucose decreased already after a day, while the content of AST and urea increased and remained so until the 8th day of observation. The most positive dynamics of morphological changes in the pancreas of rats was observed when corvitin was used on the first day of AP induction.

Therapeutic effects of L-arginine, L-carnitine, and mesenchymal stem cell-conditioned medium on endometriosis-induced oocyte poor quality in an experimental mouse model.

The present study aimed to explore the potential ameliorative effects of L-arginine (LA), L-carnitine (LC), and bone marrow mesenchymal stem cell-conditioned medium (BMSC-CM) on endometriosis (EMS) model in vivo and in vitro. The animals were divided into two main groups, normal and EMS-induced mice. Normal and EMS-induced groups were injected with or without LA (250 mg/kg), LC (250 mg/kg), and BMSC-CM (a final volume of 100 μL of CM/mouse). At the end of the study, the level of total antioxidant capacity (TAC), nitric oxide (NO), and total oxidative status (TOS) were measured in plasma. Furthermore, immature oocytes were collected from two groups and cultured in a maturation medium. Subsequently, the rates of in vitro maturation, in vitro fertilization (IVF), and in vitro embryonic development were evaluated. The results revealed that administration of LA, LC, and BMSC-CM ameliorated the oxidative status through maintaining TAC and alleviating TOS and NO levels. More importantly, the maturation and fertilization rates, blastocyst development, and total blastocyst cell numbers significantly increased in LA, LC, and BMSC-CM-administrated groups compared to the control group. In both the normal and EMS groups, the highest IVF, cleavage, and blastocyst percentages were associated with BMSC-CM treatment (p < 0.05). Altogether, LA, LC, and BMSC-CM have therapeutic effects on impaired oocyte quality and promote subsequent development in vitro, probably through normalization of nitro-oxidative stress, thus offering potential alternatives to conventional therapies during assisted reproductive technologies for patients with EMS-associated sub/infertility.

Effect of pancreatin on acute pancreatitis resulting from L-arginine administration in mice, a morpho-histopathological and biochemical study

Acute pancreatitis (AP) is a life-unpleasant situation with contradictory and inadequate treatments. In this regard, the present study evaluated the effect of the possible pretreatment of lipase-pancreatin on L-arginine-induced AP. Forty adult mice were selected and divided into five groups: I) control group, II and III) AP groups (i.p.) receiving L-arginine of 2×300 and 2×400 mg/100 g body weight (b.w.), IV) AP (2×300 L-arginine) group + pancreatin (mice were i.p. injected by 350 U-lipase), and V) AP (2×400 L-arginine) group + pancreatin (mice were i.p. injected by 350 U-lipase). All AP groups displayed a significant increase in serum levels of ALT, AST, TBARS, and TNF-alpha compared to the control group. Moreover, pancreatic tissue edema, inflammation, and vacuolization of acinar cells were significantly higher in the untreated L-arginine group compared to the control and pancreatin groups. Conversely, the diameter of pancreatic islets significantly declined after induction of pancreatitis compared with control and pancreatin groups. Pancreatin treatment can be used in pancreatic dysfunction, however, this medicine showed no protective effect against L-arginine-induced AP in the mouse model.

H2O2 Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling

In diabetes, the enzyme arginase is upregulated, which may compete with endothelial nitric oxide (NO) synthase (eNOS) for their common substrate L-arginine and compromise NO-mediated vasodilation. However, this eNOS uncoupling can lead to superoxide production and possibly vasodilator hydrogen peroxide (H2O2) formation to compensate for NO deficiency. This hypothesis was tested in coronary arterioles isolated from pigs with 2-week diabetes after streptozocin injection. The NO-mediated vasodilation induced by flow and VEGF was abolished by NOS inhibitor L-NAME and phosphoinositide 3-kinase (PI3K) inhibitor wortmannin but was not affected by arginase inhibitor Nω-hydroxy-nor-L-arginine (nor-NOHA) or H2O2 scavenger catalase in control pigs. With diabetes, this vasodilation was partially blunted, and the remaining vasodilation was abolished by catalase and wortmannin. Administration of L-arginine or nor-NOHA restored flow-induced vasodilation in an L-NAME sensitive manner. Diabetes did not alter vascular superoxide dismutase 1, catalase, and glutathione peroxidase mRNA levels. This study demonstrates that endothelium-dependent NO-mediated coronary arteriolar dilation is partially compromised in early type 1 diabetes by reducing eNOS substrate L-arginine via arginase activation. It appears that upregulated arginase contributes to endothelial NO deficiency in early diabetes, but production of H2O2 during PI3K-linked eNOS uncoupling likely compensates for and masks this disturbance.

A modulatory effect of L-arginine supplementation on anticancer effects of chemoimmunotherapy in colon cancer-bearing aged mice.

Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are increased in cancer-bearing aged hosts. Arginase-I in MDSCs degrades L-arginine, an amino acid required for T cell activation and proliferation. In this study, we compared the therapeutic efficacy of 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and cyclophosphamide (CP) between young and aged colon cancer-bearing mice. Therapy with 5-FU/L-OHP and CP significantly suppressed the in vivo growth of CT26 and MC38 colon carcinomas in syngeneic young mice, whereas this effect was attenuated in aged mice. L-arginine monotherapy showed no effect in aged mice. However, additional therapy with anti-programmed cell death (PD)-1 antibody and L-arginine supplementation boosted the effect of chemoimmunotherapy in aged mice, and some mice were cured. During all combination therapy, tumor-specific cytotoxic T lymphocytes (CTLs) were generated from mice with non-progressing tumor, but not from those with progressing tumor. Plasma L-arginine levels were lower in aged than young mice, and chemotherapy tended to decrease the plasma L-arginine levels in aged mice. Compared to young mice, CT26-bearing aged mice decreased arginase activity, arginase-I expression, and the proportion of monocytic MDSCs in tumor tissues, whereas contrasting results were observed in MC38-bearing aged mice. Importantly, the induction of tumor-specific CTLs was impaired at lower doses of L-arginine in vitro, and the infiltration of CTLs into CT26 tissues after chemoimmunotherapy was promoted by L-arginine administration in vivo. These results indicate that chemoimmunotherapy was less effective in cancer-bearing aged mice, but that L-arginine supplementation can modulate its therapeutic efficacy via its effect on tumor-specific CTLs.

L-Arginine is a feasible supplement to heal chronic anal fissure via reducing internal anal sphincter pressure: a randomized clinical trial study.

The hypertonicity of internal anal sphincter resting pressure is one of the main causes of chronic anal fissure. Therefore, the aim of this study was to assess the effect of oral administration of L-arginine on the improvement of the anal fissures by relaxing the internal anal sphincter. Seventy-six chronic anal fissure patients (aged 18-65years) who were referred to Rasoul-e-Akram Hospital, Tehran, Iran from February 2019 to October 2020 participated in this randomized, double-blind, placebo-controlled trial. Participants were allocated into treatment (L-arginine) and placebo groups. They took a 1000mg capsule three times a day for 1 month, and then we followed them at the end of the first and third months after the intervention. Clinical symptoms, anal sphincter resting pressure, and quality of life (QoL) were completed at baseline and the end of the study. The analysis of data showed a significant decrease in bleeding, fissure size, and pain for each group; however, in the L-arginine group was more than the control group at the end of the study (P values < 0.001). Following that, a significant increase in QoL was seen just in patients treated with L-arginine (P value = 0.006). In addition, the comparison of anal pressures at baseline and, between groups at the end of the study showed a significant reduction in sphincter pressure in patients treated with L-arginine (P value < 0.001, = 0.049; respectively). The oral administration of 3000mg L-arginine can heal chronic anal fissures by reducing internal anal sphincter pressure with more negligible side effects. However, we recommend long-term study with more extended follow-up.Clinical trial registry: IRCT20190712044182N1 at Iranian clinical trials, date: 2019-08-27.

Intramuscular administration of l-arginine boosts testicular hemodynamics, plasma concentrations of testosterone and nitric oxide in heat-stressed rams

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.

The effect of montelukast, a leukotriene receptor antagonist, on the acetic acid-induced model of colitis in rats: Involvement of NO-cGMP-KATP channels pathway.

Inflammatory bowel disease is a chronic autoimmune disorder that may involve entire gastrointestinal tract. The leukotrienes have a role as mediators in the pathophysiology of colitis. Here, we investigated the effect of a leukotriene receptor antagonist, montelukast, and also the role of the NO-cGMP-KATP channel pathway in acetic acid-induced colitis. Rectal administration of acetic acid (4%) was used for induction of colitis in rats. To investigate our hypothesis, the rats were intraperitoneally pre-treated with L-NAME (NOS inhibitor), L-arginine, sildenafil, methylene blue, glibenclamide, or diazoxide 15 min before treatment with montelukast (5–20 mg/kg, i. p.), for three consecutive days. Then, microscopic, macroscopic, and inflammatory parameters were evaluated. Montelukast reduced the microscopic and macroscopic damage induced by acetic acid. Montelukast also reduced the level of IL-1β and TNF-α. We also showed that the effects of montelukast were significantly attenuated by L-NAME, methylene blue (guanylate cyclase inhibitor), and an ATP-sensitive potassium channel blocker (glibenclamide). Also, the administration of L-arginine, sildenafil, and diazoxide before montelukast produced protective effect. In conclusion, the pathway of the NO-cGMP-KATP channel is involved in the protective effect of montelukast in acetic acid-induced colonic tissue damage.

Aspirin Ameliorates Pancreatic Inflammation and Fibrosis by Inhibiting COX-2 Expression in Experimental Chronic Pancreatitis.

AimChronic pancreatitis (CP) is a complex and intractable disease mainly manifested as chronic inflammation and fibrosis. Aspirin(acetylsalicylic acid, ASA) has been reported to be used in the treatment of acute pancreatitis (AP), but its effectiveness on CP is unclear. This study aimed to investigate the therapeutic effects of ASA in CP mice.MethodsA murine model of CP was induced by intraperitoneal injection with 20% L-arginine. After one week of L-arginine administration, mice in the ASA treatment group were administered aspirin (100mg/kg/d) by intragastric gavage. At two, four, and six weeks after the first injection of L-arginine, mice were euthanized and the pancreas was collected for histological and molecular analysis. A second model of CP (caeruelin-induced) was used as a validation experiment to test the effect of ASA.ResultsL-arginine-induced CP resulted in over-expression of the inflammatory enzyme cyclooxygenase (COX)-2. COX-2 expression decreased after ASA treatment. Pancreatic-injury inflammatory response (measured by changes in amylase, CK-19, F4/80, CD3, MCP-1, IL-6) and fibrosis degree (measured by expression of COL1A1, MMP-1 and TIMP-1) was reduce in ASA -treated mice model. The therapeutic effect of ASA was also observed in caeruelin-induced CP.ConclusionASA has an ameliorating effect in murine models of CP through inhibition of pancreatic inflammation and fibrosis, which may be a promising option for clinical treatment.

P-001 L-arginine ameliorates maternal and pre-pubertal codeine exposure-induced dysregulation of testicular cytoprotective and spermatogenic genes and improves steroidogenesis in adult rat offspring

Abstract Study question Will maternal exposure to codeine cause transgenerational effect on testicular function and what role will pre-pubertal codeine-exposure and L-arginine treatment play? Summary answer L-arginine treatment blunted maternal and pre-pubertal codeine exposure-induced downregulation of testicular cytoprotective and spermatogenic genes and distortion of steroidogenesis. What is known already Codeine, a common drug of abuse, has been reported to impair male infertility by eliciting testicular and sperm damage via oxidative stress-sensitive pathway. On the other hand, L-arginine has been shown to improve testicular perfusion and testicular redox state, thus enhancing male reproductive function. However, no study has evaluated the effect of maternal codeine exposure and concurrent pre-pubertal codeine and L-arginine administration on male reproductive health viz a viz testicular steroidogenesis, spermatogenesis, and sperm quality. Study design, size, duration This is a prospective experimental study using animal model. Forty pre-pubertal female Wistar rats of comparable age and weight were used for the study. The study lasted two generations. Participants/materials, setting, methods Forty pre-pubertal female Wistar rats were randomized into vehicle-treated or codeine-treated. After 8 weeks of administration via gavage, animals were paired with stud male Wistar rats (1: 1). Administration continued throughout pregnancy and lactation. Male offsprings were weaned at post-natal day (PND) 21 and each cohort was randomized into vehicle treated, codeine-treated, L-arginine-treated, and codeine with L-arginine-treated. Offspring intervention commenced at PND 28 and lasted for 8 weeks. Main results and the role of chance Maternal codeine exposure caused increased testicular lactate dehydrogenase activity, concentrations of lactate and uric acid, and reduced testicular sorbitol dehydrogenase activity. In addition, maternal codeine exposure reduced testicular activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glutathione and Nrf2 concentrations, but increased testicular concentrations of malondialdehyde, 8OHdG, TNF-α, IL-1β, and NFkB, MPO and caspase 3 activities, and DNA fragmentation. Furthermore, codeine exposure reduced steroidogenic markers (3β-HSD, 17β-HSD, FSH, LH, and testosterone), indices of spermatogenesis, and sperm quality. This was associated with reduced expression of regulatory genes for spermatogenesis (mRNA of Ndrg4, Kit, Rhcg, Lrrc34, and Lgals1), and cytoprotection (mRNA SOD, mRNA GPx, and mRNA Nrf2), and increased mRNA TNF-α, mRNA NFkB, and mRNA caspase 3. The observed codeine-induced perturbations were worsened by pre-pubertal codeine exposure in offsprings damned by mothers with codeine exposure but blunted by L-arginine treatment. Limitations, reasons for caution This study is an animal model; therefore, findings should be extrapolated to human with care. Thus, human studies are recommended. Wider implications of the findings This study demonstrates for the first time the transgenerational effect of maternal codeine exposure, and the impact of concomitant pre-pubertal codeine use and L-arginine treatment. The present findings add to the available literature by providing further molecular mechanisms through which codeine impairs male reproductive function. Trial registration number not applicable

Mechanistic pathways of fibromyalgia induced by intermittent cold stress in mice is sex-dependently

Fibromyalgia results from a complex interplay of biochemical and neurobiological elements mediated sensitization of nociceptive pathways. Despite the symptoms of fibromyalgia negatively affect the quality of life of patients, the pathophysiology of this disease remains inconclusive, which difficult the development of an appropriate treatment. The present study investigated the involvement of the serotonergic receptors, the N-methyl-D-aspartate (NMDA)/ nitric oxide (NO)/ cyclic guanosine monophosphate (cGMP) pathway and the oxidative stress in an animal model of fibromyalgia induced by intermittent cold stress (ICS), considering the specificities of male and female Swiss mice. The ICS exposure increased mechanical and thermal sensitivities, and decreased muscle strength in mice of both sexes. Female mice exhibited a longer-lasting mechanical sensitivity than male mice exposed to ICS along with an enhancement of the Na+, K+-ATPase activity in the spinal cord and cerebral cortex. Conversely, an inhibition in the Na+, K+-ATPase and glutathione peroxidase activities accompanied by an increase in the reactive species levels in the cerebral cortex of male mice were observed. The treatment with different serotonergic antagonists (pindolol, ketanserin and ondasetron) reversed the mechanical sensitivity in mice of both sexes, after the ICS exposure. The administration of MK-801, L-arginine and methylene blue also blocked the mechanical sensitivity in female mice exposed to ICS. Except L-arginine, MK-801 and methylene blue also attenuated this nociceptive signal in male mice, after ICS exposure. In conclusion, the modulation of serotonergic receptors, the NMDA/NO/cGMP pathway, and the oxidative stress seems contribute to nociceptive behaviors induced by ICS exposure sex-dependent.

Electroacupuncture at BL15 attenuates chronic fatigue syndrome by downregulating iNOS/NO signaling in C57BL/6 mice.

Chronic fatigue syndrome (CFS) has a high incidence due to the increased pressure of daily life and work in modern society. Our previous clinical studies have found the effects of electroacupuncture (EA) on CFS patients, however, the mechanism of EA on CFS is still unknown. In this study, we investigated the effects of EA on cardiac function in a CFS mouse model to explore its underlying mechanism. The mice were randomly divided into three groups: control, CFS, and CFS mice receiving EA (CFS + EA). After behavioral assessments and echocardiographic measurement, blood and heart tissue of the mice were collected for biochemical tests, and then we evaluated the effects of EA on the CFS mouse model when nitric oxide (NO) levels were enhanced by l-arginine. The results showed that EA ameliorated the injured motor and cardiac function. Meanwhile, EA also inhibited increased expression of inducible nitric oxide synthase (iNOS) at heart tissue and the serum NO levels in mice subjected to sustained forced swimming stress. Furthermore, the NO level in serum increased with l-arginine administration, which blocked the effects of EA on CFS mice. This study suggested that EA could improve the motor function and cardiac function in CFS mice and its effects may be associated with the down-regulation of iNOS/NO signaling.

L-arginine supplementation improved neonatal outcomes in pregnancies with hypertensive disorder or intrauterine growth restriction: A systematic review and meta-analysis of randomized controlled trials

Previous research established that the availability of l-arginine affects placental vascular development and fetal growth. However, practical details associated with the effects of l-arginine supplementation on the neonatal outcomes of hypertensive disorder (HD) and intrauterine growth restriction (IUGR) pregnancies are limited. The PubMed, ScienceDirect, and Web of Science databases were searched for peer-reviewed literature published by September 30, 2021 to investigate the operational details of l-arginine supplementation in improving neonatal outcomes in complicated pregnancies. Standardized mean difference (SMD) and weighted mean difference (WMD) of continuous variables, as well as the risk ratio (RR) for categorical variables were pooled by random-effects models. The results indicated that l-arginine supplementation increased the plasma nitric oxide (NO) concentrations in IUGR pregnancies (SMD: 0.71; 95% CI: 0.45, 0.97; I2=0%), but decreased the risk of preeclampsia in HD mothers (RR: 0.49; 95% CI: 0.31, 0.76; I2=0%). Administration with l-arginine elevated birth weights both in hypertensive and IUGR pregnant women, with WMDs of 194.70g (95% CI: 58.21, 331.20; I2=44.2%) and 134.00g (95% CI: 43.53, 224.46; I2=42.4%), respectively. However, the intervention had no effect on gestational age except in HD pregnancies (WMD: 7.05d; 95% CI: 3.16, 10.95; I2=36.5%). l-arginine administration during pregnancy significantly reduced the small for gestational age (SGA) risk of fetus both in HD (RR: 0.51; 95% CI: 0.31, 0.83; I2=0.0%) and IUGR mothers (RR: 0.46; 95% CI: 0.25, 0.88; I2=0.0%). Subgroup analyses revealed that l-arginine supplementation at <4g/d dosage or for ≥1-month duration or in the third trimester had a greater effect on birth weights in HD women without proteinuria, but a higher l-arginine dosage was more beneficial for extending gestational age and reducing the risk of SGA in older pregnancies. Additionally, intravenous infusion of l-arginine, but not oral administration, significantly increased birth weight in IUGR pregnancies with elevated NO concentrations, although the recommended amount should be confined to <4g/d. These findings provide practical guidelines for l-arginine supplementation to improve the birth outcomes of complicated pregnancies. CRD42021246290 (https://www.crd.york.ac.uk/PROSPERO).

Arginine-mediated gut microbiome remodeling promotes host pulmonary immune defense against nontuberculous mycobacterial infection

ABSTRACT Nontuberculous mycobacterial pulmonary diseases (NTM-PDs) are emerging as global health threats with issues of antibiotic resistance. Accumulating evidence suggests that the gut–lung axis may provide novel candidates for host-directed therapeutics against various infectious diseases. However, little is known about the gut–lung axis in the context of host protective immunity to identify new therapeutics for NTM-PDs. This study was performed to identify gut microbes and metabolites capable of conferring pulmonary immunity to NTM-PDs. Using metabolomics analysis of sera from NTM-PD patients and mouse models, we showed that the levels of l-arginine were decreased in sera from NTM-PD patients and NTM-infected mice. Oral administration of l-arginine significantly enhanced pulmonary antimicrobial activities with the expansion of IFN-γ-producing effector T cells and a shift to microbicidal (M1) macrophages in the lungs of NTM-PD model mice. Mice that received fecal microbiota transplants from l-arginine-treated mice showed increased protective host defense in the lungs against NTM-PD, whereas l-arginine-induced pulmonary host defense was attenuated in mice treated with antibiotics. Using 16S rRNA sequencing, we further showed that l-arginine administration resulted in enrichment of the gut microbiota composition with Bifidobacterium species. Notably, oral treatment with either Bifidobacterium pseudolongum or inosine enhanced antimicrobial pulmonary immune defense against NTM infection, even with multidrug-resistant clinical NTM strains. Our findings indicate that l-arginine-induced gut microbiota remodeling with enrichment of B. pseudolongum boosts pulmonary immune defense against NTM infection by driving the protective gut–lung axis in vivo.

TREM-2 mediates dendritic cell-induced NO to suppress Th17 activation and ameliorate chronic kidney diseases.

Chronic kidney disease (CKD) is a global public health issue. CKD is caused by the infiltration of various myeloid cell types into renal tissue, resulting in renal fibrosis and tubular atrophy. Unilateral ureteral obstruction (UUO) surgery in mice is a model of CKD and characterized by high expression of the anti-inflammatory receptor, Triggering receptor expressed on myeloid cells 2 (TREM-2), on myeloid cells in affected kidneys. Here, we show that iNOS expression and nitric oxide (NO) induction were decreased in Trem-2-/- bone marrow-derived DCs (BMDCs) and in Trem-2 knockdown DC2.4 cells stimulated in vitro with LPS. The nitration of RORγt was decreased in T cells co-cultured with LPS-stimulated Trem-2-/- BMDCs, enhancing IL-17 production. UUO-treated Trem-2-/- mice displayed aggravated renal pathogenesis accompanied by greater neutrophil infiltration and enhanced Th17 cells differentiation, phenotypes that could be rescued by the administration of L-arginine (a biological precursor of NO). Our data identify a key mechanism underlying TREM-2-mediated NO to modulate the cellular crosstalk between dendritic cells, Th17, and neutrophils. Furthermore, we also reveal TREM-2 as a potential novel target for the development of anti-inflammatory drugs in CKD treatment. KEY MESSAGES: The expression of TREM-2 is increased in nephritis TREM-2+ DCs maintain NO production to negatively regulate Th17 differentiation The severe pathologies of nephritis can be rescued by L-arginine supplementation.

Investigations of the vascular endothelial factor levels’ changes in experimental diabetic retinopathy

Introduction: The paper presents the results of the vascular endothelial growth factor of rats with experimental diabetic retinopathy (DR). Material and methods: Experimental studies were performed on white Wistar rats, which were divided into 7 groups: 1st group – intact animals; 2nd group – 60 animals with modelling of DR without correction (control pathology); 3rd group –60 animals with modelling of DR with correction of hyperglycemia; 4th group – 60 animals with modelling of DR with correction of hyperglycemia, administration of aflibercept and L-arginine solution; 5th group – 60 animals with modelling of DR with correction of hyperglycemia, administration of aflibercept and bromfenak; 6th group – 60 animals with modelling of DR with correction of hyperglycemia, administration of aflibercept, L-carnitine solution and bromfenak; 7th group – 60 animals with modelling of DR with correction of hyperglycemia, administration of aflibercept, L-arginine solution and citicoline. Results: The results of the analysis of the VEGF in the 2nd group confirm the development of DR, a particularly pronounced increase in the marker was detected on the 180th day of the development of the pathological process. The results of the 4th group indicate that the involvement of a nitric oxide donor and aflibercept in the correction of DR has positive effect on the reduction of the VEGF level, more pronounced compared to the 3rd group, but it does not reach normative values. It is observed that the correction of the simulated pathological condition by reducing hyperglycemia, administration of aflibercept and bromfenac (group No. 5) gives positive results, but less pronounced, compared to the data of the 4th group. It was found that in rats with DR with subsequent correction of hyperglycemia, administration of aflibercept, L-carnitine and bromfenac (group No. 6) at the first stage, there is a pronounced effectiveness of the proposed method of correction in comparison with the previously considered methods. The most pronounced positive effect of normalizing the VEGF level is observed when using a hypoglycemic drug in combination with the administration of aflibercept, a solution of L-arginine and citicoline (group No. 7). Conclusions: The obtained data confirm the development of diabetic retinopathy, a particularly marked increase in the marker was detected on the 180th day of the development of the pathological process (p&lt;0.001). Aflibercept has a positive effect on the normalization of this condition, but a more pronounced effect is observed in combination with long-term administration of L-arginine. The relationship between the normalization of the vascular growth factor and the correction of hypoxia was also revealed.

L-Arginine prevents 4-hydroxy-2-nonenal accumulation and depresses inflammation via inhibiting NF-κB activation.

4-Hydroxy-2-nonenal (HNE) is an inducer of inflammation. The aim of this study was to elicit the link between the inhibition of HNE accumulation and the depression of inflammation whether dependent onl-arginine availability in growing rats. Male Wistar rats were fed with different levels of l-arginine at 250, 500, and 1000 mg/kg body weight for 14 days. The control group was fed with commercial pellets. After 14 days of oral administration, l-arginine significantly reduced hepatic accumulation of HNE and depressed inflammation in rats as compared with the control group. Compared to the control group, the anti-inflammatory action of l-arginine is reflected by upregulation of hepatic interleukin-10 (IL-10) and the suppression of hepatic cyclooxygenase-2, tumor necrotic factorα, IL-1β,and IL-6expressions in growing rats. With l-arginine administration, the activation of nuclear factor-κB (NF-κB) was efficaciously inhibited through the upregulation of inhibitory κBα, and the depression of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). In conclusion, this study demonstrated that l-arginine could reduce hepatic HNE levels and depress inflammation in growing rats, revealing a link between the inhibition of HNE accumulation with the depression of inflammation, which was attributed to the availability of l-arginine. A significant finding of this study was that the anti-inflammatory mechanism exerted by l-arginine was to inhibit NF-κB activation via downregulating PI3K/Akt.