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Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, 1-1 Keyakidai, Sakado 350-0295, Japan

Dr. Kazuo Ohtake

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Laboratory of Physiology, Faculty of Pharmaceutical Sciences, Josai University, 1–1 Keyakidai, Sakado, Saitama 350-0295, Japan

Dr. Kunihiro Sonoda

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Department of Food and Nutritional Environment, College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan

Nitrite and Nitric Oxide in Life

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Dear Colleagues,

In the process of biological evolution following oxygenic phototrophy, molecular oxygen has become the main electron acceptor during energy generation in the mitochondria of aerobic organisms on Earth. However, higher organisms have a backup system that uses nitrite as the electron acceptor for the generation of adenosine triphosphate and releases nitric oxide (NO). The release of NO dilates vessels and reduces mitochondrial oxygen consumption in ischemic tissues. There is evidence indicating that nitrite is the storage form of NO produced via canonical (NO synthase-mediated) and/or non-canonical (enterosalivary nitrate/nitrite NO) pathways and provides NO signaling under acidic, hypoxic, or physiological (e.g., gastric acidity and exercise) conditions in both cyclic guanosine monophosphate-dependent and -independent pathways. The local and systemic bioavailability of NO in the body may be closely involved in various physiological and pathological processes, including cardiovascular, musculoskeletal, neurotransmission, gastrointestinal, and host defense systems. In this regard, this Topic allows authors from different research areas to unite around one theme “Nitrite and Nitric Oxide in Life”, describe multidisciplinary applications, and develop new ideas. These collaborations could lead to the elucidation of the role of NO and nitrite in physiology and pathology for health promotion and the development of disease treatment. Therefore, we cordially invite authors to contribute original research articles and reviews that focus on this topic.

Prof. Dr. Jun Kobayashi
Dr. Kazuo Ohtake
Dr. Kunihiro Sonoda
Topic Editors

Keywords

nitrite
nitric oxide (NO)
NO synthase
mitochondria
enterosalivary nitrate/nitrite/NO pathway
aerobic/anaerobic respiration
ischemia/reperfusion injury

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biology biology	3.6	5.7	2012	16.4 Days	CHF 2700
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600
Current Issues in Molecular Biology cimb	2.8	2.9	1999	15.8 Days	CHF 2200
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900
Journal of Molecular Pathology jmp	-	-	2020	26.5 Days	CHF 1000
Life life	3.2	4.3	2011	17.8 Days	CHF 2600

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17 pages, 3777 KiB

Open AccessArticle

An Evaluation of the Anti-Inflammatory Effects of a Thai Traditional Polyherbal Recipe TPDM6315 in LPS-Induced RAW264.7 Macrophages and TNF-α-Induced 3T3-L1 Adipocytes

by Phetpawi Subin, Pattraporn Sabuhom, Alisa Naladta, Prathan Luecha, Somsak Nualkaew and Natsajee Nualkaew

Curr. Issues Mol. Biol. 2023, 45(6), 4891-4907; https://doi.org/10.3390/cimb45060311 - 5 Jun 2023

Cited by 4 | Viewed by 2490

Abstract

TPDM6315 is an antipyretic Thai herbal recipe that contains several herbs with anti-inflammatory and anti-obesity activities. This study aimed to investigate the anti-inflammatory effects of TPDM6315 extracts in lipopolysaccharide (LPS)-induced RAW264.7 macrophages and TNF-α-induced 3T3-L1 adipocytes, and the effects of TPDM6315 extracts on lipid accumulation in 3T3-L1 adipocytes. The results showed that the TPDM6315 extracts reduced the nitric oxide production and downregulated the iNOS, IL-6, PGE₂, and TNF-α genes regulating fever in LPS-stimulated RAW264.7 macrophages. The treatment of 3T3-L1 pre-adipocytes with TPDM6315 extracts during a differentiation to the adipocytes resulted in the decreasing of the cellular lipid accumulation in adipocytes. The ethanolic extract (10 µg/mL) increased the mRNA level of adiponectin (the anti-inflammatory adipokine) and upregulated the PPAR-γ in the TNF-α induced adipocytes. These findings provide evidence-based support for the traditional use of TPDM6315 as an anti-pyretic for fever originating from inflammation. The anti-obesity and anti-inflammatory actions of TPDM6315 in TNF-α induced adipocytes suggest that this herbal recipe could be useful for the treatment of metabolic syndrome disorders caused by obesity. Further investigations into the modes of action of TPDM6315 are needed for developing health products to prevent or regulate disorders resulting from inflammation. Full article

(This article belongs to the Topic Nitrite and Nitric Oxide in Life)

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Figure 1

Figure 1
Crude drug of the TPDM6315 recipe. Full article ">Figure 2
HPLC chromatograms of TPDM6315 extracts. (A): AE; (B): EE; and (C): a mixture of standard substances (peak 1: gallic acid; peak 2: chebulagic acid; peak 3: ellagic acid; peak 4: chebulinic acid; peak 5: 6-gingerol; and peak 6: phellopterin). Full article ">Figure 3
Effect of TPDM6315 extracts on LPS-induced-RAW264.7 macrophages. (A): Inhibition of nitric oxide production (the percentage of nitric oxide reduction from the LPS group). ** p < 0.01 compared to the LPS group, ## p < 0.01: showed the significantly different effect between aqueous extract (AE) and ethanolic extract (EE), n = 3. (B): Cell viability of LPS-induced-macrophage RAW264.7, compared to the LPS group. No significant difference appeared. Data are presented as mean ± SD. The positive control 250 µM L-NAME was used. Full article ">Figure 4
qPCR analysis of gene expression levels from the effects of TPDM6315 extracts on LPS-Induced RAW264.7 macrophages. ((A): iNOS; (B): IL-6; (C): PGE2; and (D): TNF-α. Data are presented as mean ± SD, # p < 0.05 compared to the untreated group, * p < 0.05 compared to the LPS-induced group using 500 ng/mL LPS for 24 h; n = 3), 250 µM L-NAME was used as a positive control. ** p < 0.01. Full article ">Figure 5
Effects of AE and EE on the percentage cell viability of 3T3-L1 adipocytes after incubation for 48 h. Data are presented as mean ± SD; ** p < 0.01 compared to basal group, n = 3; 20 µM TGZ and 100 nM insulin were used as positive controls. Full article ">Figure 6
Effect of TPDM6315 extracts, AE and EE, on lipid accumulation in 3T3-L1 adipocytes. The oil droplets were stained with Oil Red O and photographed using an inverted microscope (×10 magnification), ((A): 3T3-L1 preadipocyte; (B): untreated 3T3-L1 adipocyte; (C–G): treatment of AE (10, 50, 100, 200, and 400 µg/mL, respectively) during cell differentiation; (H–L): treatment of EE (10, 50, 100, 200, and 400 µg/mL, respectively) during cell differentiation; and (M): % reduction in intracellular oil with AE and EE in 3T3-L1 adipocyte compared to the untreated 3T3-L1 adipocyte; * p < 0.05 compared to the untreated 3T3-L1 adipocyte; n = 3). Full article ">Figure 7
The effect of AE and EE on relative gene expression in TNF-α-induced 3T3-L1 adipocytes. (A): adiponectin; and (B): PPAR-γ; 10 ng/mL of TNF-α was used to induce inflammation, and 20 µM troglitazone (TGZ) was a positive control. Data are presented as mean ± SD; ## p < 0.01 compared to the untreated group; * p < 0.05 and ** p < 0.01 compared to the TNF-α group; n = 3. Full article ">Figure 8
Effect of TPDM6315 on glucose uptake in TNF-α-induced 3T3-L1 adipocytes. (A): Glucose content remained in the cell culture media. (The dissimilar letter represented a significant difference between groups (p < 0.05), n = 3); (B): relative GLUT1 expression; and (C): relative GLUT4 expression. TNF-α 10 ng/mL was used to induce inflammation, and 20 µM troglitazone (TGZ) was a positive control. Data are presented as mean ± SD, * p < 0.05, ** p < 0.01, compared to the TNF-α group; n = 3. (Glucose medium was as follows: basal: 4.14; TNF-α: 4.5; TGZ: 3.5; insulin 3.6; AE100: 3.9; AE200; 4.0; EE10: 3.9; and EE50: 3.8 mg/mL). Full article ">

15 pages, 2330 KiB

Open AccessArticle

Nitric Oxide Affects Heme Oxygenase-1, Hepcidin, and Transferrin Receptor Expression in the Placenta

by Patricia Principe, George T. Mukosera, Nikia Gray-Hutto, Ashra Tugung, Ciprian P. Gheorghe and Arlin B. Blood

Int. J. Mol. Sci. 2023, 24(6), 5887; https://doi.org/10.3390/ijms24065887 - 20 Mar 2023

Viewed by 2163

Abstract

Nitric oxide (NO) is a gasotransmitter that avidly binds both free and heme-bound iron, forming relatively stable iron nitrosyl compounds (FeNOs). We have previously demonstrated that FeNOs are present in the human placenta and are elevated in preeclampsia and intrauterine growth restriction. The ability of NO to sequester iron raises the possibility of the NO-mediated disruption of iron homeostasis in the placenta. In this work, we tested whether exposure of placental syncytiotrophoblasts or villous tissue explants to sub-cytotoxic concentrations of NO would elicit the formation of FeNOs. Furthermore, we measured changes in the mRNA and protein expression levels of key iron regulatory genes in response to NO exposure. Ozone-based chemiluminescence was used to measure concentrations of NO and its metabolites. Our results showed a significant increase in FeNO levels in placental cells and explants treated with NO (p < 0.0001). The mRNA and protein levels of HO-1 were significantly increased in both cultured syncytiotrophoblasts and villous tissue explants (p < 0.01), and the mRNA levels of hepcidin and transferrin receptor were significantly increased in culture syncytiotrophoblasts and villous tissue explants, respectively, (p < 0.01), while no changes were seen in the expression levels of divalent metal transporter-1 or ferroportin. These results suggest a potential role for NO in iron homeostasis in the human placenta and could be relevant for disorders of pregnancy such as fetal growth restriction and preeclampsia. Full article

(This article belongs to the Topic Nitrite and Nitric Oxide in Life)

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Figure 1

Figure 1
Nitric Oxide (NO) concentrations and cell viability over 24 h study period. (A) NO production from different concentrations of DETA in normoxic cell culture of syncytialized BeWo cells. (B) BeWo cell viability in response to increasing DETA concentrations under normoxia. (C) NO production from different concentrations of DETA in hypoxic (2% O2) cell culture of syncytialized BeWo cells. (D) BeWo cell viability in response to increasing DETA concentrations under hypoxia, mean ± SD, **** p < 0.0001 compared to no DETA. Full article ">Figure 2
NO metabolites and FeNO formation in cultured BeWo cells and villous explants after 24 h of treatment with NO (as 500 μM DETA), nitrite (250 μM), or nitrate (250 μM). (A) Total NOx (NO, nitrite, nitrite, FeNOs, and SNOs) in normoxic cell culture media of syncytialized BeWo cells (SCTs) following 24 h of treatment with NO, nitrite or nitrate. (B) NOx (NO, nitrite, FeNOs, and SNOs but not nitrate) found in homogenized syncytialized BeWo cells following 24 h treatment with NO, nitrite, or nitrate. (C) FeNO levels found in syncytialized BeWo cells following 24 h treatment with NO, nitrite, or nitrate. (D) Total NOx in culture media of human placental explants following 24 h of treatment with NO, nitrite, or nitrate. (E) TotalNOx found in human placental explants following 24 h treatment with NO, nitrite, or nitrate. (F) FeNO levels found in placental explants following 24 h treatment with NO, nitrite, or nitrate. FeNO formation is significantly increased by the presence of NO but not nitrite or nitrate. Data are reported from at least three independent experiments as mean ± SD, * p < 0.05, ** p < 0.01, **** p < 0.0001, ns = not significant. Full article ">Figure 3
The effect of NO on iron handling genes in syncytialized BeWo cells. (A–E), qPCR results, and (E–J) protein analyses. Representative blots are shown in (K). HO-1 and HAMP mRNA levels are significantly increased in the group treated with NO compared to the untreated controls. Protein abundance of HO-1 is significantly increased in the group treated with NO compared to the untreated controls. No significant change in expression is seen in the rest of the genes studied. HO-1: heme oxygenase 1, HAMP: hepcidin antimicrobial peptide, TfR: transferrin receptor, DMT1: divalent metal transporter 1, FPN: ferroportin 1. Data are reported from at least three independent experiments as mean ± SD, ** p < 0.01, **** p < 0.0001, ns = not significant. Full article ">Figure 4
The effect of NO on iron handling gene expression in human placental villous explants. (A–E) qPCR results, (F–J) protein analyses. Representative blots are shown in (K). HO-1 and TfR mRNA levels are significantly increased in the group treated with NO compared to the untreated controls. Protein abundance of HO-1 is significantly increased in the group treated with NO compared to the untreated controls. No significant change in expression is seen in the rest of the genes studied. HO-1: heme oxygenase 1, HAMP: hepcidin antimicrobial peptide, TfR: transferrin receptor, DMT1: divalent metal transporter 1, FPN: ferroportin 1. Data are reported from at least three independent experiments as mean ± SD, *** p < 0.001, ns = not significant. Full article ">Figure 5
NO metabolism and FeNO formation in BeWo cell culture after 24 h of treatment with NO (as 500 μM DETA), nitrite (250 μM), or nitrate (250 μM) under hypoxic conditions. (A) Total NOx in hypoxia cell culture media of syncytialized BeWo cells (SCTs) following 24 h of treatment. (B) NOx found in SCTs following 24 h treatment with NO, nitrite, or nitrate under hypoxic conditions. (C) FeNO levels found in SCTs following 24 h treatment with NO, nitrite, or nitrate under hypoxic conditions. FeNO formation is significantly increased following exposure to NO but not nitrite or nitrate. Data are reported from at least three independent experiments as mean ± SD, * p < 0.05, ** p < 0.01, ns = not significant. Full article ">Figure 6
The effect of hypoxia on iron handling genes in response to NO in syncitialized BeWo cells (SCTs). (A–F) qPCR results and (G–K) protein analyses. Representative blots are shown in (K). Hypoxia alone did not significantly alter mRNA or protein levels of any of the studied iron homeostasis markers compared to normoxic controls. (A,B) The combination of hypoxia and NO resulted in a significant increase in HO-1 and HAMP mRNA levels, while NO increased HAMP mRNA levels significantly under hypoxic conditions. No significant effect of hypoxia or NO was seen in any of the other targets studied. HO-1: Heme Oxygenase 1, HAMP: Hepcidin antimicrobial peptide, TfR: Transferrin Receptor, TF: Transferrin, DMT1, Divalent metal transporter 1, FPN: Ferroportin 1. Data are reported from at least three independent experiments as mean ± SD, * p < 0.05, ns = not significant. Full article ">

12 pages, 3071 KiB

Open AccessArticle

Isodorsmanin A Prevents Inflammatory Response in LPS-Stimulated Macrophages by Inhibiting the JNK and NF-κB Signaling Pathways

by You Chul Chung, Ami Lee, Jin Ah Ryuk and Youn-Hwan Hwang

Curr. Issues Mol. Biol. 2023, 45(2), 1601-1612; https://doi.org/10.3390/cimb45020103 - 13 Feb 2023

Cited by 3 | Viewed by 1847

Abstract

Natural and synthetic chalcones exhibit anti-inflammatory, antitumoral, antibacterial, antifungal, antimalarial, and antitubercular activities. Isodorsmanin A (IDA), a chalcone, is a well-known constituent of the dried seeds of Psoralea corylifolia L. (PC). Although other constituents of PC have been widely investigated, there are no studies on the biological properties of IDA. In this study, we focused on the anti-inflammatory effects of IDA and evaluated its effects on lipopolysaccharide (LPS)-stimulated macrophages. The results showed that IDA suppressed the production of inflammatory mediators (nitric oxide [NO] and prostaglandin E₂ [PGE₂]) and proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]) without cytotoxicity. In addition, it downregulated the mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) within the treatment concentrations. In our mechanistic studies, IDA inhibited the phosphorylation of the c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK), and protected the nuclear factor of the kappa light polypeptide gene enhancer in the B-cells’ inhibitor, alpha (IκB-α), from degradation, thus preventing the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells’ (NF-κB) transcription factor. Our results suggest that IDA is a promising compound for attenuating excessive inflammatory responses. Full article

(This article belongs to the Topic Nitrite and Nitric Oxide in Life)

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17 pages, 3112 KiB

Open AccessArticle

Uric Acid Deteriorates Load-Free Cell Shortening of Cultured Adult Rat Ventricular Cardiomyocytes via Stimulation of Arginine Turnover

by Martin Weber, Rolf Schreckenberg and Klaus-Dieter Schlüter

Biology 2023, 12(1), 4; https://doi.org/10.3390/biology12010004 - 20 Dec 2022

Cited by 4 | Viewed by 2040

Abstract

Hyperuricemia is a risk factor for heart disease. Cardiomyocytes produce uric acid via xanthine oxidase. The enzymatic reaction leads to oxidative stress in uric-acid-producing cells. However, extracellular uric acid is the largest scavenger of reactive oxygen species, specifically to nitrosative stress, which can directly affect cells. Here, the effect of plasma-relevant concentrations of uric acid on adult rat ventricular cardiomyocytes is analyzed. A concentration- and time-dependent reduction of load-free cell shortening is found. This is accompanied by an increased protein expression of ornithine decarboxylase, the rate-limiting enzyme of the polyamine metabolism, suggesting a higher arginine turnover. Subsequently, the effect of uric acid was attenuated if other arginine consumers, such as nitric oxide synthase, are blocked or arginine is added. In the presence of uric acid, calcium transients are increased in cardiomyocytes irrespective of the reduced cell shortening, indicating calcium desensitization. Supplementation of extracellular calcium or stimulation of intracellular calcium release by β-adrenergic receptor stimulation attenuates the uric-acid-dependent effect. The effects of uric acid are attenuated in the presence of a protein kinase C inhibitor, suggesting that the PKC-dependent phosphorylation of troponin triggers the desensitizing effect. In conclusion, high levels of uric acid stress cardiomyocytes by accelerating the arginine metabolism via the upregulation of ornithine decarboxylase. Full article

(This article belongs to the Topic Nitrite and Nitric Oxide in Life)

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13 pages, 990 KiB

Open AccessArticle

TRPA1 Polymorphisms Modify the Hypotensive Responses to Propofol with No Change in Nitrite or Nitrate Levels

by Isabela Borges de Melo, Gustavo H. Oliveira-Paula, Letícia Perticarrara Ferezin, Graziele C. Ferreira, Lucas C. Pinheiro, Jose E. Tanus-Santos, Luis V. Garcia, Riccardo Lacchini and Waynice N. Paula-Garcia

Curr. Issues Mol. Biol. 2022, 44(12), 6333-6345; https://doi.org/10.3390/cimb44120432 - 14 Dec 2022

Cited by 1 | Viewed by 1881

Abstract

Anesthesia with propofol is frequently associated with hypotension. The TRPA1 gene contributes to the vasodilator effect of propofol. Hypotension is crucial for anesthesiologists because it is deleterious in the perioperative period. We tested whether the TRPA1 gene polymorphisms or haplotypes interfere with the hypotensive responses to propofol. PCR-determined genotypes and haplotype frequencies were estimated. Nitrite, nitrates, and NOx levels were measured. Propofol induced a more expressive lowering of the blood pressure (BP) without changing nitrite or nitrate levels in patients carrying CG+GG genotypes for the rs16937976 TRPA1 polymorphism and AG+AA genotypes for the rs13218757 TRPA1 polymorphism. The CGA haplotype presented the most remarkable drop in BP. Heart rate values were not impacted. The present exploratory analysis suggests that TRPA1 genotypes and haplotypes influence the hypotensive responses to propofol. The mechanisms involved are probably other than those related to NO bioavailability. With better genetic knowledge, planning anesthesia with fewer side effects may be possible. Full article

(This article belongs to the Topic Nitrite and Nitric Oxide in Life)

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Figure 1

Figure 1
Effects of TRPA1 genotypes on blood pressure (BP) changes in response to propofol. (A) Effects of the CC (n = 127) and TC (n = 35) genotypes for the rs920829 polymorphism on changes in systolic, mean, and diastolic BP in response to propofol. (B) Effects of the CC (n = 119) and CG+GG (n = 44) genotypes for the rs16937976 polymorphism on changes in systolic, mean, and diastolic BP in response to propofol. (C) Effects of the GG (n = 120) and AG+AA (n = 42) genotypes for the rs13218757 polymorphism on changes in systolic, mean, and diastolic BP in response to propofol. Data are shown as means ± SEMs. * p < 0.05. Full article ">Figure 2
Effects of TRPA1 haplotypes on changes in systolic, mean, and diastolic blood pressure (BP) in response to propofol. CCG (n = 240), CGA (n = 46), and TCG (n = 31). Data are shown as means ± SEMs. * p < 0.05. Full article ">Figure 3
Impact of TRPA1 genotypes on alterations in NOx, nitrite, and nitrate concentrations induced by propofol. (A) Effects of the CC (n = 127) and CG (n = 35) genotypes for the rs920829 SNP. (B) Effects of the CC (n = 119) and CG+GG (n = 44) genotypes for the rs16937976 SNP. (C) Effects of the GG (n = 120) and AG+AA (n = 42) genotypes for the rs13218757 SNP. Data are shown as means ± SDs. Full article ">

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Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biology biology	3.6	5.7	2012	16.4 Days	CHF 2700
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600
Current Issues in Molecular Biology cimb	2.8	2.9	1999	15.8 Days	CHF 2200
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900
Journal of Molecular Pathology jmp	-	-	2020	26.5 Days	CHF 1000
Life life	3.2	4.3	2011	17.8 Days	CHF 2600

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