l-Phenylalanine Restores Vascular Function in Spontaneously Hypertensive Rats Through Activation of the GCH1-GFRP Complex

Heikal, Lamia; Starr, Anna; Hussein, Dania; Prieto‐Lloret, Jesus; Aaronson, Philip I.; Dailey, Lea Ann; Nandi, Manasi

doi:10.1016/j.jacbts.2018.01.015

Cited by 22 publications

(17 citation statements)

References 63 publications

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“…Although there was no significant difference in arginine and NO synthase activity between low salt and high salt diets, the NO levels were significantly decreased in hypertensive SS rats [ 33 ], which was due to decreased BH 4 in the kidney and reduced NO production in the vasculature by uncoupling NOS. Confirming previous findings, we found that L-Phe supplementation reversed the inhibitory GCH1-BH 4 complex in both the vasculature and kidneys, thus likely contributing to the increased NO production and decreased blood pressure [ 22 , 23 ]. Furthermore, BH 4 , as an allosteric and essential cofactor for NO synthase, plays a critical role in the stabilization of the NO synthase dimer and increases the affinity of NO synthase for arginine [ 22 , 34 ].…”

Section: Discussionsupporting

confidence: 89%

“…For assessment of L-phenylalanine supplementation, all 7-week-old male SS rats were maintained on low salt diets and had free access to water. The L-Phe supplementation group was given free access to drinking water with 2.5% w/v L-Phe and low salt diets as described previously [ 23 ]. After 4 days of stable baseline blood pressure, the low salt diets were switched to a high salt diet for another 14 days (n = 7–9).…”

Section: Methodsmentioning

confidence: 99%

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L-phenylalanine attenuates high salt-induced hypertension in Dahl SS rats through activation of GCH1-BH4

et al. 2021

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Amino acid metabolism plays an important role in controlling blood pressure by regulating the production of NO and ROS. The present study examined amino acid levels in the serum of Dahl SS rats and SS.13BN rats fed a low or high salt diet. We observed that 8 of 27 amino acids responded to a high salt diet in SS rats. Thus, we hypothesized that a defect in amino acids may contribute to the development of salt-induced hypertension. L-phenylalanine was used to treat SS rats with a low or high salt diet. The results demonstrated that L-phenylalanine supplementation significantly enhanced the serum nitrite levels and attenuated the high salt-induced hypertension in SS rats. Low levels of BH4 and nitrite and the impaired vascular response to acetylcholine were rescued by L-phenylalanine supplementation. Moreover, increased GTP cyclohydrolase (GCH1) mRNA, levels of BH4 and nitrite, and reduced superoxide production were observed in the kidneys of hypertensive SS rats with L-phenylalanine. The antihypertensive effects of L-phenylalanine might be mediated by enhancing BH4 biosynthesis and decreasing superoxide production from NO synthase, thereby protecting vascular and kidney function with reduced ROS and elevated NO levels. The present study demonstrated that L-phenylalanine supplementation restored vascular function, suggesting L-phenylalanine represented a potential target to attenuate high salt-sensitive hypertension through GCH1-BH4.

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

L-phenylalanine attenuates high salt-induced hypertension in Dahl SS rats through activation of GCH1-BH4

et al. 2021

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“…52 (3) Phenylalanine can be involved in NO production, reducing superoxide species and enhancing vascular function. 53 (4) Histidine is the precursor of histamine which is synthesized by the action of the histidine decarboxylase enzyme inside mast cells and basophils. 54 As histamine is released in T1 when the patient is recovered at T2, histidine would decrease since it could be used to replenish histamine in the mast cells granules.…”

Section: Discussionmentioning

confidence: 99%

“…It is known that during anaphylaxis, mast cells, basophils and neutrophils induce hypotension, vascular hyper‐permeability and an endothelial production of nitric oxide (NO) 52 . (3) Phenylalanine can be involved in NO production, reducing superoxide species and enhancing vascular function 53 . (4) Histidine is the precursor of histamine which is synthesized by the action of the histidine decarboxylase enzyme inside mast cells and basophils 54 .…”

Section: Discussionmentioning

confidence: 99%

Characterization of anaphylaxis reveals different metabolic changes depending on severity and triggers

Perales-Chordá

Obeso

Twomey

et al. 2021

Clin Experimental Allergy

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Background Despite the increasing incidence of anaphylaxis, its underlying molecular mechanisms and biomarkers for appropriate diagnosis remain undetermined. The rapid onset and potentially fatal outcome in the absence of managed treatment prevent its study. Up today, there are still no known biomarkers that allow an unequivocal diagnosis. Therefore, the aim of this study was to explore metabolic changes in patients suffering anaphylactic reactions depending on the trigger (food and/or drug) and severity (moderate and severe) in a real‐life set‐up. Methods Eighteen episodes of anaphylaxis, one per patient, were analysed. Sera were collected during the acute phase (T1), the recovery phase (T2) and around 2–3 months after the anaphylactic reaction (T0: basal state). Reactions were classified following an exhaustive allergological evaluation for severity and trigger. Sera samples were analysed using untargeted metabolomics combining liquid chromatography coupled to mass spectrometry (LC‐MS) and proton nuclear magnetic resonance spectroscopy (1H‐NMR). Results ‘Food T1 vs T2’ and ‘moderate T1 vs T2’ anaphylaxis comparisons showed clear metabolic patterns during the onset of an anaphylactic reaction, which differed from those induced by drugs, food + drug or severe anaphylaxis. Moreover, the model of food anaphylaxis was able to distinguish the well‐characterized IgE (antibiotics) from non‐IgE‐mediated anaphylaxis (nonsteroidal anti‐inflammatory drugs), suggesting a differential metabolic pathway associated with the mechanism of action. Metabolic differences between ‘moderate vs severe’ at the acute phase T1 and at basal state T0 were studied. Among the altered metabolites, glucose, lipids, cortisol, betaine and oleamide were observed altered. Conclusions The results of this exploratory study provide the first evidence that different anaphylactic triggers or severity induce differential metabolic changes along time or at specific time‐point, respectively. Besides, the basal status T0 might identify high‐risk patients, thus opening new ways to understand, diagnose and treat anaphylaxis.

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“…Further investigations revealed that majority of the predominantly downregulated metabolites in OCC and OPC patients postchemoradiation were nitric oxide‐related precursor, modulator, and/or catalyst such as aspartic acid, phenylalanine, L‐ornithine, L‐proline, xanthine, tyrosine, and glycine 48‐52 . These findings indicate that metabolites presence in saliva reflects the microbiome communities and support the postulation of the loss of nitric oxide bioavailability in OCC and OPC patients postchemoradiation, due to the reduced abundance of oral nitrate‐reducing bacteria.…”

Section: Discussionmentioning

confidence: 59%

Chemoradiation therapy changes oral microbiome and metabolomic profiles in patients with oral cavity cancer and oropharyngeal cancer

et al. 2021

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Background Patients with oral cavity cancer (OCC) and oropharyngeal cancer (OPC) are often seen with locoregionally advanced disease requiring complex multimodality treatments. These treatments may have detrimental effects on the oral microbiome, which is critical to maintaining physiological balance and health. Methods The effects of different OCC and OPC treatment types on the oral microbiome and metabolomic profiles for 24‐month post‐treatment in patients with OCC and OPC were investigated using 16S rRNA gene amplicon next‐generation sequencing and gas chromatography–mass spectrometry (GC–MS), respectively. Results Chemoradiation resulted in oral dysbiosis with specific depletion of genera which regulate the enterosalivary nitrate–nitrite–nitric oxide pathway. These data also correlate with the oral metabolomic profiles with nitric oxide‐related precursor, modulator, or catalyst significantly downregulated in saliva samples from patients' postchemoradiation. Conclusions Together, we have shown that oral dysbiosis due to the effects of chemoradiation could potentially have an impact on OCC and OPC patient's quality of life post‐treatment.

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l-Phenylalanine Restores Vascular Function in Spontaneously Hypertensive Rats Through Activation of the GCH1-GFRP Complex

Abstract: Visual Abstract

Cited by 22 publications

References 63 publications

L-phenylalanine attenuates high salt-induced hypertension in Dahl SS rats through activation of GCH1-BH4

L-phenylalanine attenuates high salt-induced hypertension in Dahl SS rats through activation of GCH1-BH4

Characterization of anaphylaxis reveals different metabolic changes depending on severity and triggers

Chemoradiation therapy changes oral microbiome and metabolomic profiles in patients with oral cavity cancer and oropharyngeal cancer

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