Helicobacter pylori's virulence and infection persistence define pre-eclampsia complicated by fetal growth retardation

AIM: To better understand the pathogenic role of Helicobacter pylori (H. pylori) in pre-eclampsia (PE), and whether it is associated or not with fetal growth retardation (FGR). METHODS: Maternal blood samples were collected from 62 consecutive pregnant women with a diagnosis of PE and/or FGR, and from 49 women with uneventful pregnancies (controls). Serum samples were evaluated by immunoblot assay for presence of specific antibodies against H. pylori antigens [virulence: cytotoxin-associated antigen A (CagA); ureases; heat shock protein B; flagellin A; persistence: vacuolating cytotoxin A (VacA)]. Maternal complete blood count and liver enzymes levels were assessed at delivery by an automated analyzer. RESULTS: A significantly higher percentage of H. pyloriseropositive women were found among PE cases (85.7%) compared to controls (42.9%, P < 0.001). There were no differences between pregnancies complicated by FGR without maternal hypertension (46.2%) and controls. Importantly, persistent and virulent infections (VacA/ CagA seropositive patients, intermediate leukocyte blood count and aspartate aminotransferase levels) were exclusively associated with pre-eclampsia complicated by FGR, while virulent but acute infections (CagA positive/ VacA negative patients, highest leukocyte blood count and aspartate aminotransferase levels) specifically correlated with PE without FGR. CONCLUSION: Our data strongly indicate that persistent and virulent H. pylori infections cause or contribute to PE complicated by FGR, but not to PE without feto-placental compromise.

Effect of early nutrition on intestine development of intrauterine growth retardation in rats and its correlation to leptin

AIM：To investigate the intestine and body development of intrauterine growth retardation（IUGR）rats under early different protein diet and to analyze the correlation between leptin and intestine and body development．METHODS：An IUGR rat model was established by food restriction of pregnant female rats．Fifty-six neonatal IUGR rats and 24 neonatal normal rats were randomly divided into normal control group（Cgroup），IUGR model group （scgroup），low protein diet IUGR group（SL group），and high protein diet IUGR group（SH group）．Eight rats were killed per group at wk 0，4，and 12．Serum leptin，body weight（BW），body length（BL），intestinal weight（IW），intestinal length（IL），andintestinal disaccharidase（including lactase，maltase，and saccharase） were detected．RESULTS：BW（4．50±0．41g），BL（5．96±0．40cm），IW（0．05±0．01g），and IL（15.9±2．8cm）in neonatal IUGR rats were much lower than those in Cgroup（6．01±0．55g，6．26±0．44cm，0．10±0．02g，21.8±2．7cm，P〈0．05），while intestinal lactase and maltase activities were higher than those in Cgroup．SH group showed the fastest catch up growth and their BW，BL，IW，and IL reached the Cgroup level at wk 4．SC group showed relatively slower catch up growth than SH group，and their BW，BL，IW did not reach the Cgroup level at wk 4．SL group did not show intestine and body catch up growth．Intestinal maltase [344±33μmol／（min·q）]and saccharase activities[138±32μmol／（min·g）]in SL group were both markedly lower than nose in C group [751±102，258±271μmol／（min·g），P〈0．05]．There were no significant difierences in lactase activities at wk 4 and disaccharidase activities at wk 12 among all groups（P〈0．05）．The leptin level in SL group（0．58±0．12ng／mL） was the highest in all groups，and much lower in SH group（0．21±0．03ng／mL） than that in any other IUGR groups at wk 4（P〈0．05）．Leptin was negatively related to BW （r=-0．556，P=0．001），IW（r=-0．692，P=0．001） and IL（r=-0．738，P=0．000）at wk 4，while no correlation was found at wk 12．CONCLUSION：High protein diet is a reasonable early nutritional mode to IUGR rats in promoting intestine and body catch up growth．

Dietary bile acid supplementation in weaned piglets with intrauterine growth retardation improves colonic microbiota,metabolic activity,and epithelial function

Background Intrauterine growth retardation(IUGR)is one of the major constraints in animal production.Our previ-ous study showed that piglets with IUGR are associated with abnormal bile acid(BA)metabolism.This study explored whether dietary BA supplementation could improve growth performance and colonic development,function,micro-biota,and metabolites in the normal birth weight(NBW)and IUGR piglets.A total of 48 weaned piglets(24 IUGR and 24 NBW)were allocated to four groups(12 piglets per group):(i)NBW group,(ii)NBW+BA group,(iii)IUGR group,and(iv)IUGR+BA group.Samples were collected after 28 days of feeding.Results The results showed that dietary BA supplementation increased the length and weight of the colon and colon weight to body weight ratio,while decreased the plasma diamine oxidase(DAO)concentration in the NBW pig-lets(P<0.05).Dietary BA supplementation to IUGR piglets decreased(P<0.05)the plasma concentrations of D-lactate and endotoxin and colonic DAO and endotoxin,suggesting a beneficial effect on epithelial integrity.Moreover,dietary BA supplementation to NBW and IUGR piglets increased Firmicutes abundance and decreased Bacteroidetes abundance(P<0.05),whereas Lactobacillus was the dominant genus in the colon.Metabolome analysis revealed 65 and 51 differential metabolites in the colon of piglets fed a diet with/without BA,respectively,which was associated with the colonic function of IUGR piglets.Furthermore,dietary BA supplementation to IUGR piglets upregulated the expressions of CAT,GPX,SOD,Nrf1,IL-2,and IFN-γin colonic mucosa(P<0.05).Conclusions Collectively,dietary BA supplementation could improve the colonic function of IUGR piglets,which was associated with increasing proportions of potentially beneficial bacteria and metabolites.Furthermore,BA shows a promising application prospect in improving the intestinal ecosystem and health of animals.

Antioxidant capacity and concentration of redox-active trace mineral in fully weaned intra-uterine growth retardation piglets

Background： The redox status of intra-uterine growth retardation（IUGR） piglets post-weaning has been poorly studied.Methods： Newborns from twenty-four sows were weighted, weaned at 21 d and fed a starter diet until sampling.Sampling was done at 14 d post-weaning. A piglet was defined as IUGR when its birth weight was 2 SD below the mean birth weight of the total population. At weaning, eighteen piglets with nearly equal body weight from each category（i.e. IUGR or normal birth weight（NBW） piglets） were selected and then allocated to two treatments,consisted of six replicates with each pen having three piglets.Results： Compared with NBW group, IUGR significantly decreased average daily gain（P 〈 0.001）, average daily feed intake（P = 0.003）, and feed efficiency（P 〈 0.001） of piglets during the first two weeks post-weaning. IUGR decreased the activities of total antioxidant capacity（P = 0.019）, total superoxide dismutase（T-SOD, P = 0.023）,and ceruloplasmin（P = 0.044） but increased the levels of malondialdehyde（P = 0.040） and protein carbonyl（P = 0.010） in plasma. Similarly, the decreased activities of T-SOD（P = 0.005）, copper- and zinc-containing superoxide dismutase（Cu/Zn-SOD, P = 0.002）, and catalase（P = 0.049） was observed in the liver of IUGR piglets than these of NBW piglets. IUGR decreased hepatic Cu/Zn-SOD activity（P = 0.023） per unit of Cu/Zn-SOD protein in piglets when compared with NBW piglets. In addition, IUGR piglets exhibited the decreases in accumulation of copper in both plasma（P = 0.001） and liver（P = 0.014）, as well as the concentrations of iron（P = 0.002） and zinc（P = 0.048） in liver. Compared with NBW, IUGR down-regulated m RNA expression of Cu/Zn-SOD（P = 0.021） in the liver of piglets.Conclusions： The results indicated that IUGR impaired antioxidant capacity and resulted in oxidative damage in fully weaned piglets, which might be associated with the decreased levels of redox-active trace minerals. This study highlights the importance of redox status in IUGR offspring and provides a rationale for alleviating oxidative damage by dietary interventions aiming to supplement trace minerals and to restore redox balance in the future.

Effect of Dietary Folic Acid Supplementation on Growth Performance and Hepatic Protein Metabolism in Early-Weaned Intrauterine Growth Retardation Piglets

To investigate the effects of dietary supplementation with folic acid on growth performance, hepatic protein metabolism and serum biochemical indices of early-weaned intrauterine growth retardation （IUGR） piglets, 24 male （Durocx （LandracexYorkshire）） weaned （14-d-old） IUGR piglets were randomly divided into 3 treatments with 8 replicates of 1 piglet per replicate. The piglets in each treatment were fed basal diet supplementation with either 0 （control）, 5 and 10 mg kg^-1 folic acid. The trial lasted for 21 d. Dietary folic acid supplementation reduced average daily feed intake （ADFI） （P〈0.05）. In addition, the average daily gain （ADG） in 10 mg kg^-1 folic acid group was significantly decreased （P〈0.01） and the ratio of feed：gain （F/G） increased slightly （P〉0.05）. Serum folic acid concentration increased （P〈0.01） with increasing folic acid inclusion, however, serum homocysteine concentration decreased significantly （P〈0.01）. Enhanced serum urine nitrogen （SUN） and diminished serum total protein （TP） as well as liver TP content were observed in 10 mg kg^-1 folic acid group （/＇〈0.05）. Furthermore, the relative mRNA expressions of insulin-like growth factor 1 （IGF-1） and mammalian target of rapamycin （m-TOR） in liver were respectively tended to reduce （P=0.06） and significantly downregulated （P〈0.05） in 10 mg kg1 group, in compared with 5 mg kg1 group. However, when compared with control group, folic acid supplementation had no significant effect on the mRNA abundance of IGF- 1 and m-TOR. The results indicated that supplementation with 10 mg kg-I folic acid impaired growth performance and hepatic protein metabolism of early-weaned IUGR piglets while 5 mg kg-~ folic acid enriched diet exerted limited positive effects.

Pterostilbene attenuates intrauterine growth retardation-induced colon inflamm tion in piglets by modulating endoplasmic reticulum stress and autophagy

Background:Endoplasmic reticulum(ER)stress and autophagy are implicated in the pathophysiology of intestinal inflammation;however,their roles in intrauterine growth retardation(IUGR)-induced colon inflammation are unclear.This study explored the protective effects of natural stilbene pterostilbene on colon inflammation using the IUGR piglets and the tumor necrosis factor alpha(TNF-α)-treated human colonic epithelial cells(Caco-2)by targeting ER stress and autophagy.Results:Both the IUGR colon and the TNF-α-treated Caco-2 cells exhibited inflammatory responses,ER stress,and impaired autophagic flux(P<0.05).The ER stress inducer tunicamycin and the autophagy inhibitor 3-methyladenine further augmented inflammatory responses and apoptosis in the TNF-α-treated Caco-2 cells(P<0.05).Conversely,pterostilbene inhibited ER stress and restored autophagic flux in the IUGR colon and the TNF-α-treated cells(P<0.05).Pterostilbene also prevented the release of inflammatory cytokines and nuclear translocation of nuclear factor kappa B p65,reduced intestinal permeability and cell apoptosis,and facilitated the expression of intestinal tight junction proteins in the IUGR colon and the TNF-α-treated cells(P<0.05).Importantly,treatment with tunicamycin or autophagosome-lysosome binding inhibitor chloroquine blocked the positive effects of pterostilbene on inflammatory response,cell apoptosis,and intestinal barrier function in the TNF-α-exposed Caco-2 cells(P<0.05).Conclusion:Pterostilbene mitigates ER stress and promotes autophagic flux,thereby improving colon inflammation and barrier dysfunction in the IUGR piglets and the TNF-α-treated Caco-2 cells.

Intrauterine growth retardation affects liver bile acid metabolism in growing pigs:effects associated with the changes of colonic bile acid derivatives

Background:Intrauterine growth retardation(IUGR)is associated with severely impaired nutrient metabolism and intestinal development of pigs.Our previous study found that IUGR altered intestinal microbiota and metabolites in the colon.However,the consequences of IUGR on bile acid metabolism in pigs remained unclear.The present study aimed to investigate the bile acid metabolism in the liver and the profile of bile acid derivatives in the colon of grow-ing pigs with IUGR using bile acid targeted metabolomics.Furthermore,we determined correlations between colonic microbiota composition and metabolites of IUGR and normal birth weight(NBW)pigs at different growth stages that were 7,21,and 28-day-old,and the average body weight(BW)of 25,50,and 100 kg of the NBW pigs.Results:The results showed that the plasma total bile acid concentration was higher(P<0.05)at the 25 kg BW stage and tended to increase(P=0.08)at 28-day-old in IUGR pigs.The hepatic gene expressions related to bile acid synthe-sis(CYP7A1,CYP27A1,and NTCP)were up-regulated(P<0.05),and the genes related to glucose and lipid metabolism(ATGL,HSL,and PC)were down-regulated(P<0.05)at the 25 kg BW stage in IUGR pigs when compared with the NBW group.Targeted metabolomics analysis showed that 29 bile acids and related compounds were detected in the colon of pigs.The colonic concentrations of dehydrolithocholic acid and apocholic acid were increased(P<0.05),while isodeoxycholic acid and 6,7-diketolithocholic acid were decreased(P<0.05)in IUGR pigs,when compared with the NBW pigs at the 25 kg BW stage.Moreover,Spearman’s correlation analysis revealed that colonic Unclassified_[Mogi-bacteriaceae],Lachnospira,and Slackia abundances were negatively correlated(P<0.05)with dehydrolithocholic acid,as well as the Unclassified_Clostridiaceae abundance with 6,7-diketolithocholic acid at the 25 kg BW stage.Conclusions:These findings suggest that IUGR could affect bile acid and glucolipid metabolism in growing pigs,especially at the 25 kg BW stage,these effects being paralleled by a modification of bile acid derivatives concentra-tions in the colonic content.The plausible links between these modified parameters are discussed.

Placental Isoferritin Action in Pathogenesis of Pre-eclampsia and/or Intrauterine Growth Retardation and Its Earlier Predictive Value

In order to investigate the role of placental isoferritin (PLF) in pathogenesis of pre-eclampsia and/or intrauterine growth retardation (IUGR) and its earlier predictive value, a prospective double-blinded study was performed. In 120 initial normal pregnant women at earlier third trimester (from 24 to 34 weeks), plasma placental isoferritin and nitric oxide (NO) metabolites (nitrite/nitrate) (NO 2 -/NO 3 -) were examined by using ELISA and Criess assay respectively. The outcome of pregnancies and birth weight of their infants were followed up. The receiver operating characteristic curves (ROC) and predictive values of PLF predicting the outcome of pregnancy with IUGR, pre-eclampsia were analyzed. Results showed that in 120 initial normal pregnant women, IUGR occurred in 15 pregnant women (IUGR group) and pre-eclampsia in 19 (pre-eclampsia group), and the remaining 86 had normal pregnancy (normal group). The levels of plasma placental isoferritin were significantly decreased in IUGR group (260.01±58.95) μg/ml and pre-eclampsia group (285.31±53.73) μg/ml as compared with those in normal group (775.62±89.32) μg/ml at earlier third trimester (both P<0.01). The levels of plasma NO were significantly increased in IUGR group (61.57±46.22) μmol/L and pre-eclampsia group (58.37±30.52) μmol/L as compared with those in the normal group (35.29±24.46) μmol/L (both P<0.01). There was no significant difference in plasma placental isoferritin and NO levels between IUGR group and pre-eclampsic group (both P>0 05). The plasma placental isoferritin was negatively correlated with NO levels (r=0.329,P<0 01). The areas under ROC of PLF predicting IUGR and pre-eclampsia were 0.977 and 0.905 respectively. At the cut point of 400 μg/ml PLF level, the sensitivity, specificity, positive predictive value, negative predictive value and Kappa index of PLF levels predicting the outcome of pregnancy with pre-eclampsia were 100 %, 85.15 %, 55.88 %, 100 % and 0.645 respectively. At the cut point of 390 μg/ml PLF level, the sensitivity, specificity, positive predictive value, negative predictive value and Kappa index of PLF levels predicting the outcome of pregnancy with IUGR were 100 %, 81.9 %, 44.12 %, 100 % and 0.663 respectively. It was concluded that the decrease of plasma placental isoferritin levels at earlier third trimester was associated with IUGR and/or pre-eclampsia, and the endothelial cell damage may be one of its mechanisms. The plasma PLF level can be used as an earlier predictor for screening of IUGR and/or pre-eclampsia.

EFFECTS OF EARLY NUTRITION INTERVENTION ON IGF1, IGFBP3,INTESTINAL DEVELOPMENT, AND CATCH-UP GROWTH OF INTRAUTERINE GROWTH RETARDATION RATS

To investigate the effects of early nutritional intervention on the serum insulin-like growth factor-1 (IGF1),insulin-like growth factor binding protein 3 (IGFBP3), intestinal development, and catch-up growth of intrauterine growth retardation (IUGR) rats by giving the IUGR new born rats different protein level diet. Methods IUGR rat model was built by starvation of pregnant female rats. Twenty-four IUGR pups and 8 normal pups were divided randomly into 4 groups: normal control group (C group); IUGR control group(S group), IUGR low-protein diet group (SL group), and IUGR high-protein diet group (SH group). Detected the serum IGF1, IGFBP3, body weight, body length, intestinal weight length, intestinal villi height (VH), crypt depth (CD), villi absorbing area (VSA), mucous thickness (MT), and disaccharidase at the 4th week. Results (1) The SH group showed the fastest catch-up growth, serum IGF1, IGFBP3, VH, and VSA were significantly higher than those of normal control group and IUGR control group. The intestinal weight and length, and the activities of lactase and saccharase of the SH group also reached the normal control group level. (2) The SL group kept on small size, the serum IGF1, IGFBP3, and most of intestinal histological indexes were all significantly lower than other groups. (3) IGF-1, IGFBP3 were positively correlated to intestinal VH, VSA, saccharase, body weight and length. Conclusions The serum IGF1 was a sensitive index to the catch-up growth. The early nutritional intervention of high-protein diet after birth is helpful for the catch-up growth of IUGR through promoting the intestinal development and the ab-sorption of nutrition

The Predictive Value of Plasma Fibronectin Concentration on Fetal Growth Retardation at Earlier Stage of the Third Trimester

In order to evaluate the predictive value of maternal plasma fibronectin (FN) concentration at 24-34 weeks on fetal intrauterine growth retardation (IUGR), a prospective double-blinded study was performed. The maternal plasma FN concentrations were measured by using a rate nephelometric procedure in the 130 initial normal nulliparous pregnant woman at 24-34 gestational weeks. The outcome of pregnancies and birth weight of their infants were followed up. IUGR was defined as that the birth weight was less than the 10th percentile for gestational age. The receiver operating characteristic curves and predictive values of FN predicting on outcome of pregnancy with IUGR were analyzed. The results showed that: (1) In a cohort of 130 initially normal nulliparous pregnant women, IUGR occurred in 14 cases during the follow-up; (2) The plasma FN levels in the women with IUGR (467.58±104.43 mg/L) were significantly higher than in the normal control group (299.44±105.55 mg/L, P<0.01). However, there was no significant difference in the mean maternal age, gravidity, sampling gestational ages, delivering gestational ages between the two groups (P>0.05); (3) The areas under ROC curve for predicting the outcome of pregnancy in IUGR was 0.893; (4) At the cut point of 475 mg/L FN level, the sensitivity, specificity, positive predictive value, negative predictive value and Kappa index for predicting the outcomes of pregnancy in IUGR were 57.14 %, 95.69 %, 61.54 %, 94.87 %, 0.5455 respectively. It was concluded that the maternal plasma FN might be used as an earlier predictor for screening of IUGR.

Color Doppler Monitoring of Changes ofUtero-placental-fetal Circulation in Normal Pregnancy and Intrauterine Growth Retardation

The utero-placental-fetal circulation (UPFC) of 150 subjects duringsecond and third trimester was examined by using color DOppler. Of them 89 were normal woman and 58 were patients with intrauterine growth retardation (IUGR). Our results showed that UPFC was increased gradually during normal pregnant period. In IUGR patients it was revealed that TAV and Q of UmA,UmV and UtA decreased at 20th week of gestation, especially after 30th week.PI, RI and S/D ratio of UmA were increased, but TAV, Q of UmA and UmV were markly reduced, so was UtA. Pl were increased, but the changes of RI,S/D ratio in UtA were not significant. HemodynamicaI findings of UmA,UmV and UtA were abnormal in 92. 53 % of IUGR patients,Only 81. 03% present abnormal S/D ratio of UmA (P<0. 01) and the difference was statistically significant.Maternal serum E,, HPL level in IUGR were significantly lower than that of thenormal. 6KP level was reduced, TXB,/6KP ratio was significantly increased.TXB2/6KP ratio was markedIy related with TAV, Q of UmA, UmV and UtA.Our results suggested that using color doppler ultrasound for examination of hemodynamical changes of UmA, UmV and UtA could revealed UPFC function directly. It is one of the best methods for monitoring IUGR and might be used forearly diagnosis of IUGR. The main pathophysiological changes of IUGR were UPFC obstruction and placental disfunction.

INTRAUTERINE GROWTH RETARDATION AT FULL TERM PREGNANCIES WITH ENDOCRINE FACTORS

Objective To investigate the relationship between intrauterine growth retardation (IUGR) and endocrine parameters so as to assess the effects or the main endocrine ractors on IUGR. The concentrations of growth hormone(GH), insulin, T3, T4 and TSH were measured in umbilical cord blood, amniotic fluid and maternal serum.Methods The samples were collected from 23 pregnant women who were diagnosed as the full term IUGR, 42 normal full term pregnant women with normal infants’ weight were taken as control. Growth hormone and insulin were measured by radioimmunoassay. T3, T4 and TSH were investigated by micro-radioimmunoassay. Results The concentrations of growth hormone, insulin and T4 in umbilical cord blood were lower in IUGR than that in control group(GH4. 63μ/L vs 7. o1μg/L, insulin 1o. 68μIU/ml vs 31. 44μIU/ml, T487. 39nmol/L vs 138. 1onmol/L. P <o. o5, o. o5 and o. o5, respectively). The TSH concentration in umbilical cord blood was higher in IUGR than in control group (1o. 84μmIU/L vs 5. 75μmIU/L, P <o. o1 ). The concentration of growth hormone in maternal serum and the concentration of insulin in amniotic fluid were also lower in IUGR group than in control group(GH 1. 77μg/L vs 2. 74μg/L,P <o. o1, insulin 5. 84μIU/ml vs 15. 64μIU/ml, P <o. o1). Conclusion This study confirms that full term neonates with IUGR are abnormal in endocrine factors. The inadequacy of growth hormone may be one of the causes of IUGR. The relatlve scarcity of growth hormone and insulin seems to be a factor to compromise the fetus’ metabolism. Besides, the early hypothyrosis of infants with IUGR might protect them from unfavorable environment in the uterine.

Abnormal adipose tissue-derived microbes drive metabolic disorder and exacerbate postnatal growth retardation in piglet

Postnatal growth retardation(PGR)frequently occurs during early postnatal development of piglets and induces high mortality.To date,the mechanism of PGR remains poorly understood.Adipose tissue-derived microbes have been documented to be associated with several disorders of metabolism and body growth.However,the connection between microbial disturbance of adipose tissue and pig PGR remains unclear.Here,we investigated piglets with PGR and found that the adipose tissue of PGR piglets was charac-terized by metabolism impairment,adipose abnormality,and specific enrichment of culturable bacteria from Proteobacteria.Gavage of Sphingomonas paucimobilis,a species of Sphingomonas genus from the alphaproteobacteria,induced PGR in piglets.Moreover,this bacterium could also lead to metabolic disorders and susceptibility to acute stress,resulting in weight loss in mice.Mechanistically,multi-omics analysis indicated the changes in lipid metabolism as a response of adipose tissue to abnormal microbial composition.Further experimental tests proved that one of the altered lipids phosphatidylethanolamines could rescue the metabolism disorder and growth retardation,thereby suppressing the amount of Sphingomonas in the adipose tissue.Together,these results highlight that the microbe–host crosstalk may regulate the metabolic function of adipose tissue in response to PGR.

Dietary dihydroartemisinin supplementation alleviates intestinal inflammatory injury through TLR4/NOD/NF-kB signaling pathway in weaned piglets with intrauterine growth retardation

The aim of present study was to evaluate whether diets supplemented with dihydroartemisinin(DHA)could alleviate intestinal inflammatory injury in weaned piglets with intrauterine growth retardation(IUGR).Twelve normal birth weight(NBW)piglets and 12 piglets with IUGR were fed a basal diet(NBW-CON and IUCR-CON groups),and another 12 piglets with IUGR were fed the basal diet supplemented with DHA at 80 mg/kg(IUGR-DHA group)from 21 to 49 d of age.At 49 d of age,8 piglets with similar body weight in each group were sacrificed.The jejunal and ileal samples were collected for further analysis.The results showed that IUGR impaired intestinal morphology,increased intestinal inflamma-tory response,raised enterocyte apoptosis and reduced enterocyte proliferation and activated trans-membrane toll-like receptor 4(TLR4)/nucleotide-binding and oligomerization domain(NOD)/nuclear factor-kB(NF-kB)signaling pathway.Dihydroartemisinin inclusion ameliorated intestinal morphology,indicated by increased villus height,villus height-to-crypt depth ratio,villus surface area and decreased villus width of piglets with IUGR(P<0.05).Compared with NBW piglets,IUGR piglets supplemented with DHA exhibited higher apoptosis index and caspase-3 expression,and lower proliferation index and proliferating cell nuclear antigen expression in the intestine(P<0.05).Dihydroartemisinin supple-mentation attenuated the intestinal inflammation of piglets with IUGR,indicated by increased concen-trations of intestinal inflammatory cytokines and lipopolysaccharides(P<0.05).In addition,DHA supplementation down-regulated the related mRNA expressions of TLR4/NOD/NF-kB signaling pathway and upregulated mRNA expressions of negative regulators of TLR4 and NOD signaling pathway in the intestine of piglets with IUGR(P<0.05).Piglets in the IUGR-DHA group showed lower protein ex-pressions of TLR4,phosphorylated NF-kB(pNF-kB)inhibitorα,nuclear pNF-kB,and higher protein expression of cytoplasmic pNF-kB in the intestine than those in the IUGR-CON group(P<0.05).In conclusion,DHA supplementation could improve intestinal morphology,regulate enterocyte prolifera-tion and apoptosis,and alleviate intestinal inflammation through TLR4/NOD/NF-kB signaling pathway in weaned piglets with IUGR.

Role of intergenic interactions among folate cycle genes in the development of fetal growth retardation

Objective:Metabolic disturbances in the folate cycle in mothers can lead to fetal growth retardation(FGR).This study was to analyze the role of intergenic interactions among maternal folate cycle genes in the development of FGR.Methods:This case-control study recruited 365 women in the third trimester of pregnancy,including 122 FGR patients and 243 controls.The women were genotyped for 5 polymorphisms of the 4 folate cycle genes:MTR(rs1805087),MTRR(rs1801394),serine hydroxymethyl transferase(SHMT1;rs1979277),and TYMS(rs699517 and rs2790).The SNP×SNP interactions in the two-,three-,and four-locus models were analyzed using the multifactor dimensionality reduction method and a modification of it(the model-based multifactor dimensionality reduction method).Results:Four loci of maternal folate cycle genes(rs1805087 MTR,rs2790 TYMS,rs1801394 MTRR,and rs1979277 SHMT1)were associated with FGR in 3 significant models of single nucleotide polymorphism(SNP)×SNP interactions(two-,three-,and four-locus models)(P<0.05).The highest contribution to FGR was made by polymorphic loci rs1979277 SHMT1(1.70%of entropy),rs1805087 MTR(0.96%),and interactions between rs1979277 SHMT1×rs1805087 MTR(-1.11%)and rs1801394 MTRR×rs1979277 SHMT1(-0.64%).The four-locus maternal genotype combination AG rs1801394 MTRR×AA rs1805087 MTR×CT rs1979277 SHMT1×AG rs2790 TYMS was associated with an increased risk of FGR(β=2.69,P=0.012).FGR-associated SNPs were correlated with the expression of 16 genes(MTR,MTRR,SHMT1,ALKBH5,CTD-2303H24.2,ENOSF1,FAM106A,FOXO3B,LGALS9C,LLGL1,MIEF2,NOS2P2,RP11-806L2.6,SMCR8,TOP3A,and USP32P2)in various tissues and organs related to FGR pathophysiology.Conclusion:SNP×SNP interactions of maternal folate cycle genes(MTR,MTRR,SHMT1,and TYMS)are associated with the development of FGR.

Clinical Study on Effect of Chinese Herbal Medicine for Supplementing Kidney and Qi and Activating Blood Circulation in Treating Intrauterine Growth Retardation of Fetus

Objective: To explore the therapeutic effect and the possible working mechanism in using Chinese herbal medicine (CHM) for supplementing Kidney and Qi, and activating blood circulation in treating intrauterine growth retardation of fetus (IUGR). Methods: Fifty-five cases of IUGR were divided into two groups, 30 cases in the CHM group treated with CHM and the 25 in the control group treated with amino acids. The effect of CHM treatment was observed and compared with that of the control group, normal pregnancy group and non-treated IUGR group. Results: Body weight of the newborns in the CHM was markedly higher than that in the control group. Not only the maternal fundal height (FH) and the abdominal circumference (AC), but also the fetal growth parameters, including biparietal diameter, head circumference (HC), and femur length (FL) in the CHM group increased much faster than those in the control group. After CHM treatment, the maternal serum levels of estriol (E3) and human placental lactogen (hPL) approached to those in the normal pregnancy group, but the control group,in comparison with the normal pregnancy group, was significantly different. The umbilical venous plasma concentration of essential amino acids in both treated groups improved, but the improvement in the CHM group was more significant than that in the control group. No apparent adverse effect of CHM was observed in either mother or fetus.Conclusion: CHM for supplementing Kidney and Qi and activating blood circulation was more effective in improving placental function and enhancing amino acid transportation than amino acid

Low Expression of FGF23 and Its Effect on Rats with Intrauterine Growth Retardation

Objective:To explore the levels of fibroblast growth factor 23(FGF23)during pregnancy and its relationship with intrauterine growth restriction(IUGR).Methods:Pregnant rats were classified into an ad libitum rat chow group(ad libitum rat chow,AD group,n=25)and an undernutrition group(50%of their daily food requirement,UN group,n=25).The levels of maternal serum FGF23,tissue homogenate FGF23,and bone gla protein in fetal rats,and placental FGF23 mRNA and protein expression were examined by enzyme-linked immunosorbent assay,real-time qPCR analysis respectively.Finally,the effect of recombinant FGF23 on the viability of MG-63 cells was determined by cell proliferation assay.Data were analyzed with independent two-tailed t test and one-way analysis of variance.Spearman rank-order correlation coefficients(continuous variables)was performed to determine the relationship of results.Results:The diet restriction induced IUGR in rat offsprings,and the UN group exhibited a significantly lower FGF23 level(P<0.05,n=5).The FGF23 level was increased and peaked in maternal serum on gestation day(GD)15,but peaked in fetal and placenta on GD20.Moreover,the tissue homogenate levels of FGF23 and bone gla protein in fetal rats in both groups were positively correlated(r=0.923,P<0.05;r=0.925,P<0.05,respectively,n=15),FGF23 was localized to both decidual and labyrinth zones,with remarkably higher expression on GD20,P<0.05,n=5.In vitro,recombinant human FGF23 enhanced MG-63 cell viability,P<0.05,n=5.Conclusion:Prenatal undernutrition could decrease the FGF23 expression in fetal rats caused by the mother through the placenta,and induced the IUGR and hindered the ossification.And the FGF23 levels are peaked on GD15 mother but peaked on GD20 placenta and fetuses,these might be associated with the over compensation of maternal placenta on GD20.

Study of the Effects of Glucocorticoid on Growth and Adult Final Height in Children with Primary Nephrotic Syndrome

Objective: To analyze the epidemiological characteristics of growth, as well as factors associated with growth retardation in children with primary nephrotic syndrome (PNS), and to investigate the effect of glucocorticoid (GC) use duration on growth retardation in these children. Methods: Clinical and laboratory data of 353 PNS children treated at our hospital from July 2014 to June 2015 were collected through the medical record management system. Height, weight, and GC usage were recorded. Follow-up assessments were conducted in August 2022 for the original group, recording height, weight, and GC usage. Height and weight were evaluated using standard deviation scores (SDS). Categorical data were analyzed using chi-square test while continuous measurement data were analyzed using t-test or rank-sum test. Linear regression was used to assess the association between two single independent variables, and logistic regression analysis was used to screen for risk factors related to growth retardation in children with PNS. Results: Among the 353 PNS children enrolled in this study, male-to-female ratio of 2.64:1 (256 males vs 97 females). A total of 119 children exhibited growth retardation, incidence rate of 33.71%. The duration of GC usage among those with growth retardation was significantly longer compared to those without it (762.81 ± 934.50 days vs 263.77 ± 420.49 days;p Conclusion: PNS children treated with GC have a high incidence of growth retardation, and a high proportion of short stature in adulthood, especially in children with growth retardation in childhood, most of them have short stature after grown up. Time of GC usage is a risk factor for growth retardation in children with PNS.

Perinatal Morbidity, Mortality, and Neurodevelopmental Outcomes of Neonates with Fetal Growth Restriction

Objective: This study aimed to assess perinatal morbidity, mortality rates, and neurodevelopmental outcomes in the management of fetal growth restriction (FGR) at a single tertiary institute. Methods: Among 2465 deliveries between 2013 and 2019, 109 cases of FGR were reviewed retrospectively for causes, indications for pregnancy termination, perinatal death, overall neonatal outcomes, and long-term prognosis. Results: Excluding FGR due to congenital anomalies (n = 17), the mortality rate was 3.3% (3/92). One neonate delivered at 23 weeks developed cerebral palsy (1.1%). Retinopathy of prematurity occurred in four neonates (4.3%). Neurodevelopmental disorders were present in six neonates (6.5%), all of whom were delivered at 32 - 38 weeks. Significantly lower gestational age at delivery, lower birth weight, and higher umbilical artery resistance indices were observed in neonates with neurodevelopmental disorders. Conclusions: Intact survival before 27 weeks of gestation at delivery with FGR is uncommon. Neurodevelopmental disorders may still develop after delivery at 32 - 38 weeks;consideration should be given to the timing of delivery usingfetal ductus venosus Doppler waveforms measurements to reduce neurodevelopmental disorders.

Resveratrol and its derivative pterostilbene ameliorate intestine injury in intrauterine growth-retarded weanling piglets by modulating redox status and gut microbiota

Background:Intestinal disorder is an important factor contributing to growth lag and high rates of morbidity and mortality of piglets with intrauterine growth retardation(IUGR).Resveratrol(RSV)and its derivative pterostilbene(PT)are natural stilbenes possessing various bioactivities,such as antioxidative and anti-inflammatory effects.This study compared the protective potential of RSV and PT on the intestinal redox status and gut microbiota in weanling piglets with IUGR.Methods:Eighteen male piglets of normal body weight(NBW)and 54 same-sex IUGR piglets were chosen according to their birth and weaning weights.The NBW piglets accepted a basal diet,while the IUGR piglets were allotted to one of three groups according to their body weight at weaning and received a basal diet,an RSV-supplemented diet(300 mg/kg),or a PT-supplemented diet(300 mg/kg),respectively.Results:Compared with IUGR piglets,both RSV and PT improved the IUGR-associated decrease in jejunal villus height and increases in plasma diamine oxidase activity and D-lactate level and jejunal apoptosis of piglets(P<0.05).Administering RSV and PT also enhanced jejunal superoxide dismutase activity and the mRNA and protein expression of superoxide dismutase 2 of IUGR piglets by promoting nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation(P<0.05).Comparatively,PT was more effective than RSV in elevating the villus height/crypt depth ratio and occludin mRNA and protein levels in the jejunum of IUGR piglets(P<0.05).PT was also superior to RSV in increasing Nrf2 nuclear translocation and inhibiting malondialdehyde accumulation in the jejunum of IUGR piglets(P<0.05).Additionally,RSV modulated the composition of cecal microbiota of IUGR piglets,as evidenced by increasing the prevalence of the phylum Bacteroidetes and the genera Prevotella,Faecalibacterium,and Parabacteroides and inhibiting the growth of the phylum Proteobacteria and its genera Escherichia and Actinobacillus(P<0.05).Moreover,RSV significantly increased the butyrate concentration in the cecum of IUGR piglets(P<0.05).Conclusion:PT is more potent than RSV to prevent intestinal oxidative stress,while RSV has a stronger capacity to regulate gut microbiota compared to PT.