ArticlePDF Available

Association between NAD+ levels and anaemia among women in community‐based study

Wiley
Journal of Cellular and Molecular Medicine
Authors:

Abstract and Figures

Nicotinamide adenine dinucleotide (NAD+) level is the protective factor of cardiovascular diseases (CVDs). In addition, anaemia is a risk factor of adverse cardiovascular outcomes in women. However, there are limited data about the association between NAD+ and anaemia. The aim of this study was to evaluate association of NAD+ with anaemia among women. A total of 727 females from Jidong community were included in the current analysis. NAD+ levels were tested by the cycling assay and HPLC assay using whole blood samples. Anaemia was determined by haemoglobin (Hb) concentration, and the subtypes of anaemia were further defined according to mean corpuscular volume (MCV) in blood. Multivariable logistic analysis was used to analyse the association between NAD+ levels and anaemia or its subtypes. The mean age of recruited subjects was 42.7 years. The proportion of anaemia by NAD+ levels quartiles were 19.7% (35/178), 4.8% (9/189), 3.4% (6/178) and 2.7% (5/182). Haematological parameters including haemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC) and red blood count (RBC) increased over NAD+ quartiles. Red cell volume distribution width (RDW) decreased over NAD+ quartiles. Compared with the lowest quartile of NAD+ levels (<27.6μM), the adjusted odds ratios with 95% confidence intervals of the top quartile were 0.15 (0.06–0.41) for anaemia, 0.05 (0.01–0.36) for microcytic anaemia and 0.37 (0.10–1.36) for normocytic anaemia respectively. Higher NAD+ levels were significantly associated with lower prevalence of anaemia among women, especially microcytic anaemia and normocytic anaemia. Haematological parameters might serve as a predictor of the blood NAD+ levels.
This content is subject to copyright. Terms and conditions apply.
2698
|
J Cell Mol Med. 2022;26:2698–2705.wileyonlinelibrary.com/journal/jcmm
Received: 30 November 2021 
|
Revised: 12 February 2022 
|
Accepted: 3 March 20 22
DOI : 10.1111/j cmm .1728 1
ORIGINAL ARTICLE
Association between NAD+ levels and anaemia among women
in community- based study
Fan Yang1| Xuguang Zhang2| Feifei Hu3| Ye Yu4| Lei Luo1| Xuan Deng3|
Yuzheng Zhao5| Bo Pan6| Jinping Zheng7| Yugang Qiu8| Jun Guo1| Feng Xiao1|
Xiaomei Xie9| Zhenyu Ju1| Yong Zhou3
1Institute of Aging and Regenerat ive Medi cine, The Firs t Affiliated Ho spital of Jinan University, Jinan Un iversi ty, Guangzhou, China
2Science a nd Technology Centre, By- Health C o. Ltd., Guangzhou, China
3Clinical Resea rch Institute, Shanghai General Hospital, Shanghai Jiao Tong Universit y School of Medicine, Shanghai, China
4Adminis trati ve Offi ce, Total Qualit y Management Office, Total Quality Mana gement Ins titute, Shanghai Gener al Hospit al, Shan ghai Jiao Tong University
School of Medicine, Shan ghai, China
5State Key Laboratory of Bioreac tor Engineering, Shanghai Collabor ative Innovatio n Center for Biomanufac turin g Technolog y, Optogenetics & Syntheti c
Biolog y Interd isciplinary Research Center, Research Unit of Chinese Aca demy of Medical Sciences, East C hina Universit y of Science and Technology, Sha nghai,
China
6Depar tment of Auricular Reconstruction , Plastic Surgery Hospital, Peking Union Med ical Co llege and Chinese Academy of Medical Science, Beijing, China
7Depar tment of Public Health and Preventive Medicine, Changzh i Medic al College, Chan gzhi, C hina
8School of Rehabilitatio n Medicine, Weifa ng Medical Universit y, Weifang, C hina
9Tangshan Gem Flower Hospital, Tangshan, China
This is an op en access arti cle under the ter ms of the Creative Commons Attribution L icense, which pe rmits use, dis tribu tion and reprod uction in any med ium,
provide d the original wor k is properly cited.
© 2022 The Author s. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and M olecular Medi cine and J ohn Wil ey & Sons Ltd .
Fan Yang, Xugu ang Zhang, Feif ei Hu, and Ye Yu contribu ted equa lly to this paper.
Correspondence
Yong Zhou, Clinical Researc h Institute,
Shanghai General Hospital, Shanghai
Jiao Tong University School of Medicine,
Shanghai, 200080, China.
Email: yongzhou78214@163.com
Zhenyu Ju, Key Laborator y of
Regener ative Me dicine of M inistry of
Education, Guangzhou Regenerative
Medicine and Health Guangdong
Labor atory, Institute of Aging and
Regener ative Me dicine, Jinan University,
Guangzhou 510632, China.
Email: zh enyuju@16 3.co m
Funding information
Nutrit ional Science Research Foundation
of BY- HEALTH Co. Ltd; National Key R&D
Program of China, Grant /Award Number:
2018YFC2000705 and 2021YFC2500500;
Nationa l Natural Scien ce Foundation of
China, G rant/Award Numbe r: 81973112,
92049302 and 92049304
Abstract
Nicotinamide adenine dinucleotide (NAD+) level is the protective factor of cardiovas-
cular diseases (CVDs). In addition, anaemia is a risk factor of adverse cardiovascular
outcomes in women. However, there are limited data about the association between
NAD+ and anaemia. The aim of this study was to evaluate association of NAD+ with
anaemia among women. A total of 727 females from Jidong community were included
in the current analysis. NAD+ levels were tested by the cycling assay and HPLC assay
using whole blood samples. Anaemia was determined by haemoglobin (Hb) concen-
tration, and the subtypes of anaemia were further defined according to mean corpus-
cular volume (MCV) in blood. Multivariable logistic analysis was used to analyse the
association between NAD+ levels and anaemia or its subtypes. The mean age of re-
cruited subjects was 42.7 years. The proportion of anaemia by NAD+ levels quartiles
were 19.7% (35/178), 4.8% (9/189), 3.4% (6/178) and 2.7% (5/182). Haematological
parameters including haemoglobin (Hb), mean corpuscular volume (MCV), mean cor-
puscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC)
and red blood count (RBC) increased over NAD+ quartiles. Red cell volume distribu-
tion width (RDW) decreased over NAD+ quartiles. Compared with the lowest quartile
   
|
2699
YANG et Al.
1 | INTRODUCTION
Nicotinamide adenine dinucleotide (NAD+) is a pivotal metabolite
with a wide range of roles in cell survival, mitochondrial homeosta-
sis, cellular bioenergetics, adaptive stress responses and genomic
stability.1 NAD+ is involved in over 500 enzymatic reactions in reg-
ulating almost all major biological processes.2 Meanwhile, NAD+ is
also a co- substrate of regulatory enzymes, including sirtuins (SIRTs),
poly (ADP- ribose) polymerases (PARPs) and cyclic ADPR (cADPR)
synthetases.3 The association of NAD
+ levels with cardiovascular
diseases (CVDs) including endothelial, atherosclerosis and heart
failure has been reported by a few studies.4 – 7 Loss of NAD+ con-
tents are implicated in the pathogenesis of multiple types of CVDs,
and boosting NAD+ levels seems to be a strongly protective role of
CVDs.8 Moreover, NAD precursors have been suggested to delay
the process of vascular aging and increase the span of cardiovascular
health.9
Anaemia is a worldwide health problem in the world,10– 1 3 particu-
larly so in developing countries with children and women as the most
affected population groups.14 Approximately 1.9 billion individuals
worldwide suffer from anaemia, which is nearly one- quarter of the
global population in 2013.15 The World Health Organization (WHO)
estimated that 32.4 million pregnant women and 496.3 million non-
pregnant women were anaemic across the world in 2011.16 In ad-
dition, severe anaemia in pregnant and postnatal women strongly
and independently contributes to maternal death.17 Managing
anaemia is one of the global health goals.13 In China, whose pop-
ulation accounts for more than 18% of the world, the prevalence
of anaemia is about 15.0% according to the fifth Chinese National
Nutrition and Health Sur vey (CNNHS 2010– 2012) and the anaemia
prevalence for Chinese rural reproductive age women was 24.8%
in 2012.18, 19Anaemia was defined by WHO as a lower haemoglobin
(Hb) content than normal in whole blood.20 In addition, lower Hb is
significantly and independently associated with adverse cardiovas-
cular outcomes in women.21 Anaemia is significantly correlated with
severe complications of CVDs including stroke, arrhythmias and
thromboembolics in the general population. It is also an indepen-
dent predictor of cardiovascular mortalities.2 2– 24 NAD+ levels and
anaemia are the protective factor and risk factor of CVDs respec-
tively. However, the research on the associations between NAD+
contents in whole blood and subtypes of anaemia is still in scarcity.
We assumed that NAD+ levels would be negatively correlated with
anaemia. In our current study, we sought to understand the relation-
ship of NAD+ levels with the anaemia and explore the associations
of different types of anaemia with NAD+ levels.
2 | METHOD
2.1  | Study design and population
The population in this community- bas ed stud y was from Jido ng com-
mu nit y in Tan gsh a n Cit y, Heb e i Pro vin c e, Ch ina . Fr om 20 19 to 20 2 0, a
total of 1723 participants were originally recruited into the study. We
excluded 802 males and 191 participants with incomplete informa-
tio n. Final ly, 727 fe ma le s were included in the final analysis (Figure 1).
All participants gave written informed consent, and the study was
conducted according to the guidelines of the Helsinki Declaration.
2.2  | Data collection
In this study, basic info rmati on of subject s was obt ained fro m st an d-
ardized questionnaires, laboratory tests and clinical examinations.25
Face- to- face interviews were performed by well- trained examiners.
Information on demographic characteristics including age, income
and education level was collected by standardized questionnaires.
The average monthly income was divided into ‘≤¥3000’, or ‘>¥3000’.
Ed u cat ion leve l s wer e ca te gor ize d as ‘Mi d d le sc h o ol or be l ow’ or ‘co l -
legeor above’. Body mass index (BMI) was categorized as ‘<18.5 kg/
m2’, ‘18.5– 23.9 kg/m2’, ‘24.0– 27.9 kg/m2’ and ‘>28.0 kg/m2’. Previous
history of hyperlipidaemia, hypertension and diabetes mellitus was
recorded directly by self- reports of par ticipants.
2.3  | Measurement of NAD+ levels
Blood samples were collected from the large antecubital veins after
overnight fasting. All blood samples were stored in vacuum tubes
containing EDTA (ethylene diamine tetraacetic acid), and NAD+ lev els
of NAD+ levels (<27. 6 μM), the adjusted odds ratios with 95% confidence intervals of
the top quartile were 0.15 (0.06– 0.41) for anaemia, 0.05 (0.01– 0.36) for microcytic
anaemia and 0.37 (0.10– 1.36) for normocy tic anaemia respectively. Higher NAD+ lev-
els were significantly associated with lower prevalence of anaemia among women,
especially microcytic anaemia and normocytic anaemia. Haematological parameters
might serve as a predictor of the blood NAD+ levels.
KEYWORDS
cardiovascular diseases, hemoglobin, Nicotinamide adenine dinucleotide
2700 
|
    YANG e t Al.
were determined by the cycling assay and LC- MS/MS analysis in the
laboratories.26 – 29 (see Supplementary Material 1 and Figure S1).
NAD+ levels were stratified into 4 categories: Q1 (<27.6), Q2
(27.6– 31.0), Q3 (31.0– 34.5) and Q4 (≥34.5), which were based on
the quartiles of NAD+ levels. In addition, the participant s in Q2, Q3
and Q4 were grouped into Q2- 4, whose NAD+ level was in 2th- 4th
NAD+ quartile (25th percentile- 100th percentile).
2.4  | Determination of haematology parameters
Haematology parameters including haemoglobin (Hb), mean corpus-
cular volume (MCV), mean corpuscular haemoglobin (MCH), mean
corpuscular haemoglobin concentration (MCHC), red cell distribu-
tion width (RDW) and red blood count (RBC) were measured by
autoanalyzer (Hitachi 747; Hitachi,) in the central laboratory of the
Staff Hospital of the Jidong Oilfield.
2.5  | Diagnosis of anaemia
According to World Health Organization (WHO), anaemia was de-
fined as Hb concentration lower than 120 mg/dl for women.20
According to MCV, anaemia was fur ther classified into three t ypes:
microcytic anaemia if MCV was lower than 80 fl, normocy tic anae-
mia if MCV was from 80 to 100 fl, and macrocytic anaemia if MCV
was higher than 100 fl.30
2.6  | Statistical analysis
The normality distributions of continuous variables were evaluated
by the Kolmogorov– Smirnov test. Continuous variables are ex-
pressed as the mean ± standard deviation (SD) and were compared
using one- way ANOVA or t- test, as appropriate. Categorical variables
are presented as proportions and frequencies and were compared by
chi- squared tests. Multivariable logistic regression models were used
to assess the associati on betwee n NAD+ quartiles and anaemia or its
different types. We adjusted 4 covariates which were thought to be
potential confounder of the risk factors for anaemia: age, BMI, UA
and RBC. All statistical tests were 2- sided, and p values of less than
0.05 we re consid er ed to be sign if ic ant. Sta ti st ic al ana ly se s were co n-
ducted with SAS sof tware, version 9.4 (SAS Institute Inc.,).
3 | RESULTS
3.1  | Baseline Characteristics in eligible
participants
Baseline characteristics of par ticipants according to NAD+ quartiles
are summarized in Table 1. Of 727 females finally included, the mean
age was 42.7 years and there were only 6 smokers and 5 drinkers.
BMI distributions were different among the quartiles of NAD+. The
levels of UA increased along with the levels of NAD+. Analysis of
haematological parameters in different NAD+ quartiles is also pre-
sented in Table 1. The levels of Hb, MCV, MCH, MCHC and RBC
increased along with the qua rtiles of NAD+, while the levels of RDW
dec rease d along wit h the quartiles of NAD+. Age, income, education
level, history of smoke, history of drink, salt intake, eGFR, history of
hyperlipidaemia, hypertension and diabetes were not significantly
different among the quartiles. Baseline characteristics of male and
females has been provided. (see Table S2).
3.2  | Association between NAD+
levels and anaemia
The anaemia occurred in 19.7%, 4.8%, 3.4% and 2.7% in each NAD+
quartile respectively (Figure 2). Crude and adjusted odds ratios (OR)
with 95% confiden ce inter vals (CI ) of NAD + level s fo r anaemia sta tu s
are shown in Table 2. In general, lower NAD+ levels were associated
FIGURE 1 Flow chart of this study
   
|
2701
YANG et Al.
with higher prevalence of anaemia. Compared with the first quartile
of NAD+, propor tion rates of anaemia in the 2th- 4th NAD+ quartile
(25th percentile- 100th percentile) was also much lower. The NAD+
levels between anaemic and non- anaemic group have been pro-
vided. (see Table S3).
3.3  | Association between quartiles of NAD+
levels and types of anaemia
Rates of types of anaemia according to quartiles of NAD+ levels
are presented in Table 3. The proportion of microcytic anaemia
and normocytic anaemia was 4.1% and 3.5%. Both of them de-
creased by NAD+ quartiles. The proportion of macrocytic anaemia
was just 0.1% (N = 2), so macroc ytic anaemia was not further ana-
lys ed in the logi st ic regression model due to few eve nt s. As shown
in Table 4, the prevalence decreased with the higher NAD+ lev-
els in microcytic anaemia and normocytic anaemia respectively;
compared with the first quartiles of NAD+, the adjusted ORs and
95% CI of the fourth NAD+ quartile were 0.05 (0.01– 0.36) for mi-
crocytic anaemia and 0.37 (0.10– 1.36) for normocytic anaemia,
and the adjusted ORs and 95% CI of the 2th~4th NAD+ quartile
(25th percentile- 100th percentile) were 0.16 (0.07– 0.36) for mi-
crocytic anaemia and 0.20 (0.070.56) for normocytic anaemia.
TAB LE 1  Baseline characteristics of participants according to NAD+ quartiles
Characteristics
Overall
(n = 727)
Q1 (<27. 6)
(n = 178)
Q2 (27.6– 31.0)
(n = 189)
Q3 (31.0– 34.5)
(n = 178)
Q4 (≥34.5)
(n = 182) p value
Age (years) 42.7 ± 11. 3 41.4 ± 9.3 43.5 ± 12.4 42.9 ± 11.5 42.9 ± 11.7 0.33
Income,¥/month (n,%) 0.33
≤¥3000 52 (7.8) 8 (5.0) 13 (7.7) 17 (10.6) 14 (8.1)
>¥3000 613 (92.2) 152 (95.0) 157 (92.4) 177 (89.4) 160 (92.0)
Education level (n,%) 0.57
Middle school or below 254 (34.9) 63 (35.4) 73 (38.6) 60 (33.7) 58 (31.9)
College or above 473 (65.1) 115 (64.6) 116 (61.4) 118 (66.3) 124 (68.1)
Body mass index (k g/m2)<0.05
<18.5 99 (13.6) 23 (12.9) 25 (13.2) 29 (16.3) 22 (12.1)
18 . 5– 2 3 .9 395 (54.3) 97 (54.5) 108 (57.1) 98 (55.1) 92 (50.6)
24 . 0 – 2 7.9 178 (24.5) 53 (29.8) 4 3 (22.8) 31 (17.4) 51 (28.0)
≥28.0 55 (7.6) 5 (2.8) 13 (6.9) 20 (11.2) 17 (9.3)
Smoking (n,%) 6 (0.9) 0 (0.0) 3 (1.8) 2 (1.2) 1 (0.6) 0.43
Drinking (n,%) 5 (0.8) 2 (1.3) 0 (0.0) 2 (1.2) 1 (0.6) 0.46
Salt intake (n,%) 0.49
Low 218 (32.8) 55 (34.4) 53 (31.2) 49 (30.4) 61 (35.1)
Medium 370 (55.6) 81 (50.6) 101 (59.4) 96 (59.6) 92 (52.9)
High 77 (11.6) 24 (15.0) 16 (9.4) 16 (9.9) 21 (12.1)
Hyperlipidaemia (n,%) 256 (38.4) 56 (35.0) 59 (34.7) 60 (37.0) 81 (46 .6) 0.08
Hyper tesion (n,%) 107 (16.1) 19 (11.9) 26 (15.3) 26 (16.1) 36 (20.7) 0.18
Diabetes (n,%) 35 (5.3) 7 (4.4) 6 (3.5) 8 (4.9) 14 (8.1) 0.26
eGFR (mL/min/1.73m2)121.4 ± 24.3 121.0 ± 23.3 124.1 ± 24.4 118.7 ± 24 .4 121.9 ± 24.7 0.28
UA (μmol/L) 2 89. 9 ± 66.2 281.9 ± 61. 4 283.1 ± 61 .7 296.1 ± 68.8 298.6 ± 71.2 <0.05
Haematological parameters
Hb (g/L) 136.0 ± 1 2.1 130.1 ± 15.6 135.6 ± 11.0 138.4 ± 9.4 1 39. 8 ± 9.2 <0.0001
MCV (fL) 91.9 ± 6.4 89.9 ± 8.7 91.6 ± 6.5 93 .1 ± 4.7 93.1 ± 4.2 <0.0001
MCH (pg) 30.9 ± 2.5 30.1 ± 3.4 30.6±2.5 31.4 ± 1.7 31.4 ± 1.5 <0.0001
MCHC (g/L) 335.6 ± 8.8 334.2 ± 10.1 33 4.1 ± 8.4 337. 0 ± 7.5 33 7.2 ± 8.4 <0.0001
RDW (%) 12.2 ± 1.5 12.6 ± 2.1 12.2 ± 1.6 12.0 ± 1.1 12.0 ± 1.0 <0.01
RBC (10^12/L) 4.4 ± 0.3 4.3 ± 0.4 4.4 ± 0.3 4.4 ± 0.3 4.5 ± 0.3 <0.01
PLT (10^9/L) 22 9.7 ± 5 7. 8 235.6 ± 61. 5 235.6 ± 58.9 2 19. 5 ± 50.1 2 27. 8 ± 59.1 <0.05
WBC (10^9/L) 6.3 ± 1.5 6.3 ± 1.6 6. 3 ± 1.5 6.3 ± 1.5 6.4 ± 1.6 0.77
Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; UA, uric acid; NAD+, nicotinamide adenine dinucleotide; Hb,
haemoglobin; MC V, mean corpuscular volume; MCH, mean corpuscular; MCHC, mean corpuscular haemoglobin concentration; RDW, red cell volume
distribution width; RBC, red blood cell; PLT, platelet count; WBC, white blood cell.
2702 
|
    YANG e t Al.
The haematological parameters in each type of anaemia have been
provided. (see Table S1).
4 | DISCUSSION
In this community- based study, individuals with the low NAD+
quartile were associated with high risk of anaemia among women.
Anaemia subtype analysis in our study showed that this associa-
tion was also evident in microcytic anaemia and normocytic anae-
mia among women. Besides, we observed a positive association
between NAD+ levels and haematological parameters including Hb,
MCV, MCH, MCHC and RBC. Our results provide evidence for the
relationship between NAD+ levels and anaemia among women.
Most of the existing studies focused on the association be-
tween NAD+ contents in RBCs and sickle cell disease (SCD).
Stu di es about th e as so ci at io n between SCD and NAD+ contents in
RBCs are controversial. Sickle RBCs had an increased NAD+ con-
tent , and this incr ease in NAD + may be th e reaso n of a dve rse met-
abolic consequences in sickle RBCs.31 However, a study reported
that the levels of NAD+ in sickle RBC s were similar to the levels in
normal RBCs.32 As reported, among patients with anaemia, 50%–
80% are iron deficiency anaemia (IDA) which is highly prevalent
among women throughout their lives.33 A study in rhesus mon-
key found that the NAD metabolites were similar between IDA
and control groups, and NAD pathway components nearly dou-
bled after the treatment of IDA.34 Another study in male chicks
found that iron deficiency reduced the utilization of tryptophan
with which de novo biosynthesis of NAD star ts.35,36 Haemolytic
anae mi a co uld be ind uc ed by m ed ic ation s along with oth er ca uses,
whose late diagnosis could be fatal.37 Nicotinamide mononucle-
otide ad enylylt ra nsfer as e 3 (Nm na t3 ) is consid er ed a NA D s yn th e-
sis enz yme involved in de novo and salvage pathways. Deficienc y
of Nmnat3 in mice can cause haemoly tic anaemia.38 In our study,
the anaemia subtypes distinguished by pathogeny like IDA and
haemolytic anaemia could not be judged and anaemia was clas-
sified into three subtypes by MCV. NAD+ levels were detected
in whole blood instead of just in RBCs. We found that low NAD+
quartile was associated with high risk of anaemia among women.
The prevalence of microcytic anaemia and normocytic anaemia
decreased with increase of NAD+ level. The specific impact of
NAD+ levels on anaemia warrants further research.
Elevated Hb was related to Sirtuin 1 (SIRT1) levels, which was the
activation of NAD- dependent deacetylase.39 A study in mice found
that replenishing NAD had a positive effect on the most primitive
blood stem cells and protected patients from haematological fail-
ure.40 These findings indicated that NAD+ might be a prote ct ive fac-
tor of anaemia and also provided a possible theoretical suppor t for
our findings. In our study, there were positive associations between
NAD+ levels and haematological parameters including Hb, MCV,
MCH, MCHC and RBC. Our result implied that, NAD+ might be a
new indicator for anaemia among women, especially in microcytic
anaemia and normocytic anaemia.
The study has several potential limitations. First, we were un-
able to determine subtype of anaemia according to the pathogeny
due to the lim ite d data. Thus, the asso ciations of anaemia su bt ypes
accord in g to th e pat ho ge ny wi th NA D+ level s ne ed to be fur ther in-
ve sti gat ed in a su bse que nt stu d y. S eco nd, th e cro ss- s e c tio nal st udy
FIGURE 2 Proportions of anaemia status according to NAD+
quartiles
Q1 Q2 Q3 Q4
0
5
10
15
20
25
19.7%
4.8%
3.4% 2.7%
Percent of participants %
TAB LE 2  Association between quartiles of NAD+ levels and anaemia among women
NAD+ Quartiles
Subjec ts with anaemia
(n,%) Unadjusted OR (95% CI) Adjusted OR (95% CI)
Q1 35 (4.8) 1 (Reference) 1 (Reference)
0.00.5 1.01.5
Q2 9 (1.2) 0.20 (0.10– 0.44) 0.25 (0.110.55)
Q3 6 (0.8) 0.14 (0.06– 0.35) 0.17 (0.070.43)
Q4 5 (0.7) 0.12 (0.04– 0.30) 0.15 (0.06– 0.41)
Q 2 - 4 20 (2.8) 0.15 (0.090.28) 0.19 (0.10– 0.35)
Note: Covariates included age, BMI, UA and RBC .
Abbreviations: CI, confidence interval; OR, odds ratio.
   
|
2703
YANG et Al.
made it difficult to infer the causal effect relationship between
anaemia and NAD+ contents. Third, the participants were mainly
from an urb an ci ty in North Chin a; ther ef or e, th e fin din gs migh t not
be generalized to other ethnics and male. Finally, given the charac-
teristics of obser vational study, there might be some unmeasured
or residual confounding effects that could not be adjusted.
The study aim was to investigate the association between NAD+
level and the prevalence of anaemia subtypes distinguished by MCV
and the cor re lation of NAD + with haematological parameters among
wo men . Due to the li mit ed dat a , the as soc i ati o n bet wee n NAD + level
and specific anaemia subtypes according to the pathogeny could not
be analysis. Whether NAD+ is involved in the occurrence and de-
velopment of anaemia, has core effect or just was accompanied by
appearance, still need to be studied in future research.
In summary, the high NAD+ level in whole blood was associated
with a low prevalence of anaemia among women, especially micro-
cytic anaemia. Besides, haematological parameters including Hb,
MCV, MCH, MCHC and RBC were positively associated with NAD+
contents. Haematological parameters might serve as a predictor for
lack of NAD+ in whole blood among women.
ACKNOWLEDGMENTS
This work is supported by the National Key R&D Program of China
(2018YFC2000705 and 2021YFC2500500), National Natural
Science Foundation of China (81973112, 92049302, 9204930 4) and
Nutritional Science Research Foundation of BY- HEALTH Co. Ltd. We
thank members of the Ju group for their technical assistance for de-
tecting NAD+ levels. We thank many volunteers in this study.
CONFLICT OF INTEREST
The authors declare no competing interests.
AUTHOR CONTRIBUTIONS
Yong Zhou: Funding acquisition (equal); Project administration
(lead). Fan Yang: Data curation (lead); Formal analysis (equal);
Methodology (supporting); Writing original draft (supporting);
Writing review & editing (supporting). Xuguang Zhang: Data
curation (supporting); Formal analysis (supporting); Methodology
(supporting); Project administration (supporting); Writing re-
view & editing (supporting). Feifei Hu: Data curation (equal);
Formal analysis (equal); Methodology (supporting); Project
Type of anaemia
Unadjusted OR
(95% CI) Adjusted OR (95% CI)
Microcytic anaemia
0.00.5 1.01.5
Q2 VS Q1 0. 31
(0.13– 0.76)
0.28
(0.11– 0.71)
Q3 VS Q1 0.14
(0.04– 0.48)
0.14
(0.04– 0.50)
Q4 VS Q1 0.05
(0.010.34)
0.05
(0.010.36)
Q2- 4 VS Q1 0.17
(0.08– 0.36)
0.16
(0.070.36)
Normocytic anaemia
Q2 VS Q1 0.11
(0.02– 0.47)
0.13
(0.03– 0.67)
Q3 VS Q1 0.17
(0.05– 0.59)
0.15
(0.03– 0.69)
Q4 VS Q1 0. 22
(0.070.66)
0.37
( 0 . 1 0 1 . 3 6 )
Q2- 4 VS Q1 0.16
(0.070.38)
0.20
(0.070.56)
Note: Covariates included age, BMI, UA and RBC .
Abbreviations: CI, confidence interval; OR, odds ratio.
TAB LE 4  Association between
quartiles of NAD+ levels and t ypes of
anaemia among women
NAD+ Quartiles, μM
Type of anaemia Overall
Q1
(<27. 6)
Q2
(27.6– 31.0)
Q3
(31.0– 34.5)
Q4
(≥34 .5) p value
microcytic
anaemia
29 (4.1) 18 (2.6) 7 (1.0) 3 (0.4) 1 (0.1) <0.0001
normocytic
anaemia
24 (3.5) 15 (2.2) 2 (0.3) 3 (0.4) 4 (0.6) <0.001
TAB LE 3  Rates of t ypes of anaemia
according to quartiles of NAD+ levels
among women
2704 
|
    YANG e t Al.
adm inistr ation (su pp or ting ); Writing – or iginal draft (le ad); Writ in g
review & editing (lead). Ye Yu: Data curation (equal); Writing
review & editing (equal). Lei Luo: Data curation (supporting);
Formal analysis (supporting); Methodology (supporting); Project
administration (supporting). Xuan Deng: Data curation (support-
ing); Methodology (supporting); Project administration (support-
ing). Yuzheng Zhao: Data curation (supporting); Methodology
(supporting); Project administration (supporting). Bo Pan: Data
curation (supporting); Methodology (supporting); Project admin-
istration (supporting). Jin- ping Zheng: Data curation (supporting);
Methodology (supporting); Project administration (supporting).
Yugang Qiu: Data curation (supporting); Methodology (support-
ing); Project administration (supporting). Feng Xiao: Dat a curation
(supporting); Funding acquisition (supporting); Methodology (sup-
porting); Project administration (supporting). Zhenyu Ju: Data cu-
ration (equal); Formal analysis (equal); Funding acquisition (equal);
Methodology (equal); Project administration (equal); Writing
review & editing (equal). Jun Guo: Methodology (supporting);
Validation (supporting). Xiaomei Xie: Data curation (supporting);
Investigation (supporting).
ORCID
Yong Zhou https://orcid.org/0000-0001-5221-8026
REFERENCES
1. Lautrup S, Sinclair DA, Mattson MP, Fang EF. NAD(+) in brain aging
and neurodegenerative disorders. Cell Metab. 2019;30:630 - 655.
2. Biefer HRC, Elkhal A, Cesarovic N, Emmert MY. NAD+ the
disregarded molecule in cardiac metabolism. Eur Heart J.
2020;41:983- 986.
3. Zou Y, Wang A, Huang L, et al. Illuminating NAD(+) metabolism in
live cells and in vivo using a genetically encoded fluorescent sensor.
Dev Cell. 2020;53:240- 252.
4. Matasic DS, Brenner C, London B. Emerging potential benef its of
modulating NAD(+) metabolism in cardiovascular disease. Am J
Physiol Heart Circ Physiol. 2018;314:H839- H852.
5. Song P, Zou MH. Regulation of NAD(P)H oxidases by AMPK in car-
diovascular systems. Free Radic Biol Med. 2012;52:1607- 1619.
6. Borradaile NM, Pickering JG. NAD(+), sirtuins, and cardiovascular
disease. Curr Pharm Des. 20 09;15:110 - 117.
7. Alefishat E, A lexander SP, Ralevic V. Effects of NAD at purine re-
ceptors in isolated blood vessels. Purinergic Signal. 2015;11:47- 57.
8. Kane AE, Sinclair DA. Sirtuins and NAD(+) in the development
and treatment of metabolic and cardiovascular diseases. Circ Res.
2018;123:868- 885.
9. Csiszar A, Tarantini S, Yabluchanskiy A, et al. Role of endothelial
NAD(+) deficiency in age- related vascular dysfunction. Am J Physiol
Heart Circ Physiol. 2019;316:H1253- H1266.
10. Eisele L, Dürig J, Broecker- Preuss M, et al. Prevalence and incidence
of anemia in the german heinz nixdorf recall study. Ann Hematol.
2013;92:731- 737.
11. Mugisha JO, Baisley K, Asiki G, Seeley J, Kuper H. Prevalence,
types, risk fac tors and clinical correlates of anaemia in older people
in a rural Ugandan population. PLoS O ne. 2013;8:e78394.
12. Alsaeed AH. An analysis of hematological parameters to assess the
prevalence of anemia in elderly subjects from Saudi Arabia. Genet
Test Mol Biom. 2011;15:697- 700.
13. Jalambo MO, Karim NA, Naser IA, Sharif R. Prevalence and risk fac-
tor analysis of iron deficiency and iron- deficiency anaemia among
female adole scents in the Gaza Strip, Pales tine. Public Health Nutr.
2018;21:2793- 2802.
14. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic
analysis of global anemia burden from 1990 to 2010. Blood.
2014;123:615- 624.
15. Kassebaum NJ. The global burden of anemia. Hematol Oncol Clin
North Am. 2016;30:247- 308.
16. Elmardi KA, Adam I, Malik EM, et al. Prevalence and determi-
nants of anaemia in women of reproductive age in Sudan: anal-
ysis of a cross- sectional household survey. BMC Public Health.
2020;20:1125.
17. Dar u J, Zamora J, Fernandez- Felix BM, et al. Risk of maternal mor-
tal it y in wo men wit h seve re ana emia d uri ng preg nanc y an d post par-
tum: a multilevel analysis. Lancet Glob Health. 2018;6:e548- e554.
18. Ma QY, Zhang SK, Liu J, et al. [Anemia status of Chinese rural
women of reproductive age in 2012]. Zhonghua Yi Xue Za Zhi.
2018 ;98 :211 5- 2119.
19. Hu Y, Li M, Wu J, et al. Prevalence and risk factors for anemia in
non- pregnant childbearing women from the chinese fifth na-
tional health and nutrition survey. Int J Environ Res Public Health.
2019;16(7):1290.
20. McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Wor ldwide
prevalence of anaemia, WHO vitamin and miner al nutrition infor-
mation system, 1993– 2005. Public Health Nutr. 2009;12:444 - 454.
21. Ar ant C, Wessel T, Olson M, et al. Hemoglobin level is an indepen-
dent predictor for adverse c ardiovascular outcomes in women un-
dergoing evaluation for chest pain: results from the national heart,
lung, and bloo d institute women's ischemia syndrome evaluation
stud y. J Am Coll Cardiol. 2004;43:2009- 2014.
22. Sarnak MJ, Tighiouart H, Manjunath G, et al. Anemia as a risk factor
for cardiovascular disease in the atherosclerosis risk in communi-
ties (ARIC) study. J Am Coll Ca rdiol. 2002;40:27- 33.
23. Kuhn V, Diederich L, Keller TCS. Red blood cell function and
dysfunction: redox regulation, nitric oxide metabolism, anemia.
Antioxid Redox Signal. 2017;26:718- 742.
24. Honda Y, Wat anabe T, Otaki Y, et al. Gender differences in the
impact of anemia on subclinical myocardial damage and cardiovas-
cular mortality in the general population: the yamagata (Takahata)
stud y. Int J Cardiol. 2018;252:207- 212.
25. Zhang Q, Zhou Y, Gao X, et al. Ide al cardiovascular health metrics
and the risks of ischemic and intracerebral hemorrhagic stroke.
Stroke. 2013;44: 2451- 2456 .
26. Kanamori K, de Oliveira G, Auxiliadora- Martins M, Schoon R, Reid
J, Chini E. Two dif ferent methods of quantification of oxidized nic-
otinamide adenine dinucleotide (NAD) and reduced nicotinamide
adenine dinucleotide (NADH) intracellular levels: enzymatic cou-
pled cycling assay and ultra- performance liquid chromatography
(UPLC)- mass spectrometry. Bio Protoc. 2018;8:undefined.
27. Liu L, Cui Z, Deng Y, Dean B, Hop CEC A, Liang X. Analytical tech-
nologies in the biomedical and sciences l. Surrogate analyte ap-
proach for quantitation of endogenous NAD(+) in human acidified
blood samples using liquid chromatography coupled with electro-
spray ionization tandem mass spectrometry. J Chromatogr B Analy t
Technol Biomed Life Sci. 2016;1011:69- 76.
28. Trammell S, Schmidt M, Weidemann B, et al. Nicotinamide ribo-
side is uniquely and orally bioavailable in mice and humans. Nat
Commun. 2016 ;7:12948.
29. Ying W, Sevigny M, Chen Y, Swanson R A. Poly (ADP- ribose) glyco-
hydrolase mediates oxidative and excitotoxic neuronal death. Proc
Natl Acad Sci U S A. 2001;98:12227- 12232.
30. Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J.
Variable hematologic presentation of autoimmune gastritis: age-
related progression from iron deficiency to cobalamin depletion.
Blood. 2006;107:1673- 1679.
31. Zerez CR, Lachant NA, Lee SJ, Tanaka K R. Decreased er yth-
rocyte nicotinamide adenine dinucleotide redox potential and
   
|
2705
YANG et Al.
abnormal pyridine nucleotide content in sickle cell disease. Blood.
198 8;71:51 2- 51 5.
32. Det terich JA, Liu H, Suriany S, et al. Erythrocyte and plasma oxida-
tive stre ss appears to be compensated in patients with sickle cell
disease during a period of relative health , despite the presence of
known oxidative agents. Free Radic Biol Med. 2019;141:40 8- 415.
33. Mir za F, Abdul- Kadir R, Breymann C, Fraser Ian S, Taher Ali. Impact
and management of iron deficiency and iron deficiency anemia in
women’s health. Expert Rev Hematol. 2018;11:727- 736.
34. Sandri BJ, Lubach GR, Lock EF, et al. Correcting iron deficiency ane-
mia with iron dextr an alters the serum metabolomic profile of the
infant Rhesus Monkey. Am J Clin Nutr. 2021;113:915- 923.
35. Oduho GW, , Han Y, Baker DH. Iron deficienc y reduces the efficacy
of tryptophan as a niacin precursor. J Nutr. 1994;124:444- 450.
36. Tannous C, Booz G, Altara R, et al. Nicotinamide adenine dinucle-
otide: biosynthesis, consumption and therapeutic role in cardiac
diseases. Acta Physiol. 2021;231:e13551.
37. Afra F, Mehri M , Namazi S. Bosentan- induced immune hemo-
lytic anemia in 17 years old man. a case report. DARU J Pharm Sci.
2021;29:211- 215.
38. Hikosaka K, Ikutani M, Shito M, et al. Deficiency of nicotinamide
mononucleotide adenylyltransferase 3 (Nmnat3) causes hemolytic
anemia by altering the glycolytic flow in mature er ythrocy tes. J Biol
Chem. 2014;289:147 96- 148 11.
39. Esmayel IM, Hussein S, Gohar EA , Ebian HF, Mousa MM. Plasma
levels of sirtuin- 1 in patients with cerebrovascular stroke. Neurol
Sci. 2021;42(9):3843- 3850.
40. Vannini N, Campos V, Girotra M, et al. The NAD- booster nicotin-
amide riboside potently stimulates hematopoiesis through increased
mitochondrial clearance. Cell Stem Cell. 2019;24(3):405- 418.
SUPPORTING INFORMATION
Additional supporting information may be found in the online
version of the article at the publisher ’s website.
How to cite this article: Yang F, Zhang X, Hu F, et al.
Association bet ween NAD+ levels and anaemia among
women in community- based study. J Cell Mol Med.
2022;26:2698– 2705. doi:10.1111/jcmm.17281
... These complexities necessitate thorough optimization of LC/MS methods to produce reliable results for plasma eNAD + quantification (54). Yet, it is important to note that while LC/MS has been a robust and validated technique for NAD + measurements in whole blood, correlating well with enzymatic assays (55)(56)(57), such an equivalence has yet to be established for blood plasma. Nevertheless, the data is novel, and the inclusion of healthy volunteers has ruled out surrogate parameters of age or disease, which is the case for many other studies. ...
Article
Full-text available
Nicotinamide adenine dinucleotide (NAD +), a coenzyme for more than 500 enzymes, plays a central role in energy production, metabolism, cellular signaling, and DNA repair. Until recently, NAD + was primarily considered to be an intracellular molecule (iNAD +), however, its extracellular species (eNAD +) has recently been discovered and has since been associated with a multitude of pathological conditions. Therefore, accurate quantification of eNAD + in bodily fluids such as plasma is paramount to answer important research questions. In order to create a clinically meaningful and reliable quantitation method, we analyzed the relationship of cell lysis, routine clinical laboratory parameters, blood collection techniques, and pre-analytical processing steps with measured plasma eNAD + concentrations. Initially, NAD + levels were assessed both intracellularly and extracellularly. Intriguingly, the concentration of eNAD + in plasma was found to be approximately 500 times lower than iNAD + in peripheral blood mononuclear cells (0.253 ± 0.02 μM vs. 131.8 ± 27.4 μM, p = 0.007, respectively). This stark contrast suggests that cellular damage or cell lysis could potentially affect the levels of eNAD + in plasma. However, systemic lactate dehydrogenase in patient plasma, a marker of cell damage, did not significantly correlate with eNAD + (n = 33; r = −0.397; p = 0.102). Furthermore, eNAD + was negatively correlated with increasing c-reactive protein (CRP, n = 33; r = −0.451; p = 0.020), while eNAD + was positively correlated with increasing hemoglobin (n = 33; r = 0.482; p = 0.005). Next, variations in blood drawing, sample handling and pre-analytical processes were examined. Sample storage durations at 4°C (0-120 min), temperature (0° to 25°C), cannula sizes for blood collection and tourniquet times (0-120 s) had no statistically significant effect on eNAD + (p > 0.05). On the other hand, prolonged centrifugation (> 5 min) and a faster braking mode of the centrifuge rotor (< 4 min) resulted in a significant decrease in eNAD + levels (p < 0.05). Taken together, CRP and hemoglobin appeared to be mildly correlated with eNAD + levels whereas cell damage was not correlated significantly to eNAD + levels. The blood drawing trial did not show any influence on eNAD + , in contrast, the preanalytical steps need to be standardized for accurate eNAD + measurement. (2024) Optimized protocol for quantification of extracellular nicotinamide adenine dinucleotide: evaluating clinical parameters and pre-analytical factors for translational research.
... 1,6,7,8). Recent study also suggests that administration of NR [130] and NAD [131] may improve anemia, which is a common complication in patients with CKD [18]. The mechanisms may be associated with increased activation of sirtuins that antagonize HIF-1α, NF-kB, and AHR activity but promote HIF-2α responses [17,25,79] (Figs. 1, 6, 7, 8). ...
Article
Full-text available
Early-stage detection of chronic kidney diseases (CKD) is important to treatment that may slow and occasionally halt CKD progression. CKD of diverse etiologies share similar histologic patterns of glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Macro-vascular disease and micro-vascular disease promote tissue ischemia, contributing to injury. Tissue ischemia promotes hypoxia, and this in turn activates the hypoxia-inducible transcription factors (HIFs). HIF-1α and HIF-2α, share a dimer partner, HIF-1β, with the aryl hydrocarbon receptor (AHR) and are each activated in CKD and associated with kidney cellular nicotinamide adenine dinucleotide (NAD) depletion. The Preiss-Handler, salvage, and de novo pathways regulate NAD biosynthesis and gap-junctions regulate NAD cellular retention. In the Preiss-Handler pathway, niacin forms NAD. Niacin also exhibits crosstalk with HIF and AHR cell signals in the regulation of insulin sensitivity, which is a complication in CKD. Dysregulated enzyme activity in the NAD de novo pathway increases the levels of circulating tryptophan metabolites that activate AHR, resulting in poly-ADP ribose polymerase activation, thrombosis, endothelial dysfunction, and immunosuppression. Therapeutically, metabolites from the NAD salvage pathway increase NAD production and subsequent sirtuin deacetylase activity, resulting in reduced activation of retinoic acid-inducible gene I, p53, NF-κB and SMAD2 but increased activation of FOXO1, PGC-1α, and DNA methyltransferase-1. These post-translational responses may also be initiated through non-coding RNAs (ncRNAs), which are additionally altered in CKD. Nanoparticles traverse biological systems and can penetrate almost all tissues as disease biomarkers and drug delivery carriers. Targeted delivery of non-coding RNAs or NAD metabolites with nanoparticles may enable the development of more effective diagnostics and therapies to treat CKD.
... Previously, RDW has been used for the diagnosis and differential diagnosis of different types of anemia (2). Red blood cell distribution width values are often seen in cases of nutrient deficiency, hemolysis, and anemia, and have been used to diagnose and classify anemia from various causes (3)(4)(5). An increase in RDW values is usually associated with an increase in the rate of erythrocyte proliferation. ...
Article
Full-text available
Background Although red cell distribution width (RDW) is widely observed in clinical practice, only a few studies have looked at all-cause mortality in unselected critically ill patients, and there are even fewer studies on long-term mortality. The goal of our study was to explore the prediction and inference of mortality in unselected critically ill patients by assessing RDW levels. Methods We obtained demographic information, laboratory results, prevalence data, and vital signs from the unselected critically ill patients using the publicly available MIMIC-III database. We then used this information to analyze the association between baseline RDW levels and unselected critically ill patients using Cox proportional risk analysis, smoothed curve fitting, subgroup analysis, and Kaplan–Meier survival curves for short, intermediate, and long-term all-cause mortality in unselected critically ill patients. Results A total of 26,818 patients were included in our study for the final data analysis after screening in accordance with acceptable conditions. Our study investigated the relationship between RDW levels and all-cause mortality in a non-selected population by a smoothed curve fit plots and COX proportional risk regression models integrating cubic spline functions reported results about a non-linear relationship. In the fully adjusted model, we found that RDW values were positively associated with 30-day, 90-day, 365-day, and 4-year all-cause mortality in 26,818 non-selected adult patients with HRs of 1.10 95%CIs (1.08, 1.12); 1.11 95%CIs (1.10, 1.13); 1.13 95%CIs (1.12, 1.14); 1.13 95%CIs (1.12, 1.14). Conclusion In unselected critically ill patients, RDW levels were positively associated with all-cause mortality, with elevated RDW levels increasing all-cause mortality.
Article
Full-text available
The importance of nicotinamide adenine dinucleotide (NAD+) in human physiology is well recognized. As the NAD+ concentration in human skin, blood, liver, muscle and brain are thought to decrease with age, finding ways to increase NAD+ status could possibly influence the ageing process and associated metabolic sequelae. Nicotinamide mononucleotide (NMN) is a precursor for NAD+ biosynthesis, and in vitro/in vivo studies have demonstrated that NMN supplementation increases NAD+ concentration and could mitigate ageing-related disorders such as oxidative stress, DNA damage, neurodegeneration and inflammatory responses. The promotion of NMN as an anti-ageing health supplement has gained popularity due to such findings; however, since most studies evaluating the effects of NMN have been conducted in cell or animal models, a concern remains regarding the safety and physiological effects of NMN supplementation in the human population. Nonetheless, a dozen human clinical trials with NMN supplementation are currently underway. This review summarizes the current progress of these trials and NMN/NAD+ biology to clarify the potential effects of NMN supplementation and to shed light on future study directions.
Article
Full-text available
Background: Anaemia is a global health problem and women in reproductive age (WRA) are amongst the most affected population. Its consequences include low birth weight and maternal mortality. This study aimed to assess the prevalence of anaemia and to identify its determinants in Sudanese women in reproductive age. Methods: A population-based cross-sectional study was conducted in Sudan in 2016. A multi-stage stratified cluster sampling design was executed with consideration of rural population, urban population, and internally displaced persons/refugees camps residents. All women in reproductive age (15-49 years), classified by pregnancy status, in the targeted households were surveyed and personal characteristic data were collected. Their haemoglobin level and malaria infection (using rapid diagnostic test, RDT) were assessed. The World Health Organization (WHO) haemoglobin level cut-off for defining anaemia and severe anaemia in pregnant and non-pregnant women was used. Logistic regression analyses were performed. Results: A total of 4271 women (WRA) of which 421 (9.9%) pregnant women (PW) were included in the study. The overall anaemia prevalence in WRA was 35.6%. It was 36.0 and 35.5% in PW and non-pregnant women (NPW), respectively. The average haemoglobin level was found to be 113.9 g/L (SD 16.3) and 123.2 g/L (SD 15.7) for PW and NPW respectively. Severe anaemia prevalence was 1.2% in each group. In the logistic regression model, anaemia was associated with malaria infection in PW (aOR 4.100, 95%CI 1.523-11.039, p = 0.003), NPW (aOR 2.776, 95%CI 1.889-4.080, p < 0.001), and WRA (aOR 2.885, 95%CI 2.021-4.119, p < 0.001). Other identified determinants of anaemia in NPW was living in camps (aOR 1.499, 95%CI 1.115-2.017, p = 0.007) and in WRA was being in the poorest economic class (aOR 1.436, 95%CI 1.065-1.936, p = 0.018). Conclusions: Anaemia is a public health problem in Sudan. The study supported the association between malaria infection and anaemia, but not with low and moderate malaria transmission areas. Resources need to be allocated for all anaemic populations with special attention for the populations in most need and interventions need to be implemented based on local variations. Malaria control interventions, specifically case management, may have a major impact in reducing anaemia prevalence in low to moderate malaria transmission areas.
Article
Full-text available
Understanding of NAD⁺ metabolism provides many critical insights into health and diseases, yet highly sensitive and specific detection of NAD⁺ metabolism in live cells and in vivo remains difficult. Here, we present ratiometric, highly responsive genetically encoded fluorescent indicators, FiNad, for monitoring NAD⁺ dynamics in living cells and animals. FiNad sensors cover physiologically relevant NAD⁺ concentrations and sensitively respond to increases and decreases in NAD⁺. Utilizing FiNad, we performed a head-to-head comparison study of common NAD⁺ precursors in various organisms and mapped their biochemical roles in enhancing NAD⁺ levels. Moreover, we showed that increased NAD⁺ synthesis controls morphofunctional changes of activated macrophages, and directly imaged NAD⁺ declines during aging in situ. The broad utility of the FiNad sensors will expand our mechanistic understanding of numerous NAD⁺-associated physiological and pathological processes and facilitate screening for drug or gene candidates that affect uptake, efflux, and metabolism of this important cofactor.
Article
Full-text available
It has been recently shown that increased oxidative phosphorylation, as reflected by increased mitochondrial activity, together with impairment of the mitochondrial stress response, can severely compromise hematopoietic stem cell (HSC) regeneration. Here we show that the NAD+^{+}-boosting agent nicotinamide riboside (NR) reduces mitochondrial activity within HSCs through increased mitochondrial clearance, leading to increased asymmetric HSC divisions. NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80%, and accelerates blood recovery after murine lethal irradiation and limiting-HSC transplantation. In immune-deficient mice, NR increased the production of human leucocytes from hCD34+ progenitors. Our work demonstrates for the first time a positive effect of NAD+^{+}-boosting strategies on the most primitive blood stem cells, establishing a link between HSC mitochondrial stress, mitophagy, and stem-cell fate decision, and unveiling the potential of NR to improve recovery of patients suffering from hematological failure including post chemo- and radiotherapy.
Article
Background: The effects of infantile iron deficiency anemia (IDA) extend beyond hematological indices and include short- and long-term adverse effects on multiple cells and tissues. IDA is associated with an abnormal serum metabolomic profile, characterized by altered hepatic metabolism, lowered NAD flux, increased nucleoside levels, and a reduction in circulating dopamine levels. Objectives: The objective of this study was to determine whether the serum metabolomic profile is normalized after rapid correction of IDA using iron dextran injections. Methods: Blood was collected from iron-sufficient (IS; n = 10) and IDA (n = 12) rhesus infants at 6 months of age. IDA infants were then administered iron dextran and vitamin B via intramuscular injections at weekly intervals for 2 to 8 weeks. Their hematological and metabolomic statuses were evaluated following treatment and compared with baseline and a separate group of age-matched IS infants (n = 5). Results: Serum metabolomic profiles assessed at baseline and after treatment via HPLC/MS using isobaric standards identified 654 quantifiable metabolites. At baseline, 53 metabolites differed between IS and IDA infants. Iron treatment restored traditional hematological indices, including hemoglobin and mean corpuscular volume, into the normal range, but the metabolite profile in the IDA group after iron treatment was markedly altered, with 323 metabolites differentially expressed when compared with an infant's own baseline profile. Conclusions: Rapid correction of IDA with iron dextran resulted in extensive metabolic changes across biochemical pathways indexing the liver function, bile acid release, essential fatty acid production, nucleoside release, and several neurologically important metabolites. The results highlight the importance of a cautious approach when developing a route and regimen of iron repletion to treat infantile IDA.
Article
Hemolytic anemia is a very important immune-mediated reaction, which its late diagnosis can be fatal. Medications along with other causes can induce hemolytic anemia. Drug induced immune hemolytic anemia (DIIHA) is caused by the development of autoantibodies. Accordingly, DIIHA is rare and there is not enough data for its prevalence. Number of drugs that can cause DIIHA have increased in recent decades. A 17-year-old man who had congenital single ventricle heart (CHB) and pulmonary artery hypertension (PAH) was admitted at Imam Khomeini hospital complex affiliated to Tehran University of Medical Sciences, with chief complaint of jaundice and icter. Bosentan and Tadalafil were in the list of the drugs used by this patient. Although both drugs were recommended to be discontinued in the patient, in the course of hospitalization, the patient accidentally continued to take his Tadalafil. However, the patient’s recovery continued. Given that the patient’s Coombs test was positive, his hemolytic anemia mechanism was drug-induced immune-mediated hemolytic anemia. As a result, according to Naranjo score = 6, Bosentan was considered as the main possible culprit to induce DIIHA in this patient. Following the discontinuation of Bosentan and receiving Prednisolone, the patient’s clinical symptoms and laboratory parameters resolved and the patient was then discharged.
Article
Background: Worldwide, stroke is the second cause of death and a main cause of morbidity. In Egypt, circulatory system disease is responsible for one-third of the annual deaths. Stroke comes 3rd after heart disease and liver diseases. Stroke includes two types; ischemic and hemorrhagic. The sirtuins (SIRTs) are a family of histone deacetylases that are nicotinamide adenine dinucleotide (NAD‏)+ dependent. They are activated under conditions of decreased cellular energy stores and are involved in the control of several physiological processes. They modulate energy metabolism, DNA repair, and oxidative stress responses. They protect against age-related disorders such as cardiovascular diseases (CVD), cancer, diabetes mellitus, and neurodegenerative diseases. Objectives: to measure plasma levels of SIRT1 in acute cerebrovascular stroke and assess its potential role as a candidate biomarker to predict the risk of acute cerebrovascular stroke and to compare its levels between the two groups of stroke patients and to evaluate the association between its levels and the severity of stroke. Also to assess the correlations between the plasma SIRT1 levels and variables that might play a role in the severity of acute cerebrovascular stroke. Methods: This is a case-control study carried out on one hundred and eight participants. The participants were divided into two groups: Group A (control group) included fifty-four individuals. Group B (acute cerebrovascular stroke group) included fifty-four stroke patients of two subgroups; B1: twenty-eight patients suffering from acute ischemic stroke. B2: twenty-six patients suffering from acute hemorrhagic stroke. Results: Regarding SIRT1 levels, acute stroke groups were significantly lower than the control group with no significant difference between ischemic and hemorrhagic groups. There were positive correlations between SIRT1 and hemoglobin level, serum potassium level. There were negative correlations between SIRT1 and triglycerides (TG) and stroke score. Conclusion: Plasma levels of SIRT1 are lower in patients with acute cerebrovascular stroke than in control and it acts as a candidate biomarker for predicting the risk of acute stroke
Article
Nicotinamide adenine dinucleotide (NAD) is an abundant cofactor that plays crucial roles in several cellular processes. NAD can be synthesized de novo starting with tryptophan, or from salvage pathways starting with NAD precursors like nicotinic acid (NA), nicotinamide (NAM), or nicotinamide riboside (NR), referred to as niacin/B3 vitamins, arising from dietary supply or from cellular NAD catabolism. Given the interconversion between its oxidized (NAD+) and reduced form (NADH), NAD participates in a wide range of reactions: regulation of cellular redox status, energy metabolism, and mitochondrial biogenesis. Plus, NAD acts as a signaling molecule, being a co‐substrate for several enzymes such as sirtuins, poly‐ADP‐ribose‐polymerases (PARPs), and some ectoenzymes like CD38, regulating critical biological processes like gene expression, DNA repair, calcium signaling, and circadian rhythms. Given the large number of mitochondria present in cardiac tissue, the heart has the highest NAD levels and is one of the most metabolically demanding organs. In several models of heart failure, myocardial NAD levels are depressed and this depression is caused by mitochondrial dysfunction, metabolic remodeling, and inflammation. Emerging evidence suggests that regulating NAD homeostasis by NAD precursor supplementation has therapeutic efficiency in improving myocardial bioenergetics and function. This review provides an overview of the latest understanding of the different NAD biosynthesis pathways, as well as its role as a signaling molecule particularly in cardiac tissue. We highlight the significance of preserving NAD equilibrium in various models of heart disease and shed light on the potential pharmacological interventions aiming to use NAD boosters as therapeutic agents.