| 1. |
- Ebert, Thomas, et al.
(author)
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Insights in the regulation of trimetylamine N-oxide production using a comparative biomimetic approach suggest a metabolic switch in hibernating bears
- 2020
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Journal article (peer-reviewed)abstract
- Experimental studies suggest involvement of trimethylamine N-oxide (TMAO) in the aetiology of cardiometabolic diseases and chronic kidney disease (CKD), in part via metabolism of ingested food. Using a comparative biomimetic approach, we have investigated circulating levels of the gut metabolites betaine, choline, and TMAO in human CKD, across animal species as well as during hibernation in two animal species. Betaine, choline, and TMAO levels were associated with renal function in humans and differed significantly across animal species. Free-ranging brown bears showed a distinct regulation pattern with an increase in betaine (422%) and choline (18%) levels during hibernation, but exhibited undetectable levels of TMAO. Free-ranging brown bears had higher betaine, lower choline, and undetectable TMAO levels compared to captive brown bears. Endogenously produced betaine may protect bears and garden dormice during the vulnerable hibernating period. Carnivorous eating habits are linked to TMAO levels in the animal kingdom. Captivity may alter the microbiota and cause a subsequent increase of TMAO production. Since free-ranging bears seems to turn on a metabolic switch that shunts choline to generate betaine instead of TMAO, characterisation and understanding of such an adaptive switch could hold clues for novel treatment options in burden of lifestyle diseases, such as CKD.
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| 2. |
- Hernandez, Leah, et al.
(author)
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Blood-brain barrier and gut barrier dysfunction in chronic kidney disease with a focus on circulating biomarkers and tight junction proteins
- 2022
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Journal article (peer-reviewed)abstract
- Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood-brain barrier (BBB). We aim to examine BBB disruption, by assessing brain-derived neurotropic factor (BDNF), neuron-specific enolase (NSE) levels, and gut-blood barrier (GBB) disruption by trimethylamine N-oxide (TMAO), in chronic kidney disease (CKD) patients. Additionally, endothelial tight-junction protein expressions and modulation via TMAO were assessed. Serum from chronic kidney disease (CKD) female and male haemodialysis (HD) patients, and controls, were used to measure BDNF and NSE by enzyme-linked immunosorbent assays, and TMAO by mass spectrometry. Immunofluorescent staining of subcutaneous fat biopsies from kidney transplant recipients, and controls, were used to measure microvascular expression of tight-junction proteins (claudin-5, occludin, JAM-1), and control microvasculature for TMAO effects. HD patients versus controls, had significantly lower and higher serum levels of BDNF and NSE, respectively. In CKD biopsies versus controls, reduced expression of claudin-5, occludin, and JAM-1 were observed. Incubation with TMAO significantly decreased expression of all tight-junction proteins in the microvasculature. Uraemia affects BBB and GBB resulting in altered levels of circulating NSE, BDNF and TMAO, respectively, and it also reduces expression of tight-junction proteins that confer BBB maintenance. TMAO serves as a potential candidate to alter BBB integrity in CKD.
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| 3. |
- Hernandez, Leah, et al.
(author)
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Gender dimension in cardio-pulmonary continuum
- 2022
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In: Frontiers in Cardiovascular Medicine. - : Frontiers Media SA. - 2297-055X. ; 9
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Research review (peer-reviewed)abstract
- Cardio-pulmonary diseases, which were once regarded as a man's illness, have been one of the leading causes of morbidity and mortality for both men and women in many countries in recent years. Both gender and sex influence the functional and structural changes in the human body and therefore play an important role in disease clinical manifestation, treatment choice, and/or response to treatment and prognosis of health outcomes. The gender dimension integrates sex and gender analysis in health sciences and medical research, however, it is still relatively overlooked suggesting the need for empowerment in the medical research community. Latest advances in the field of cardiovascular research have provided supportive evidence that the application of biological variables of sex has led to the understanding that heart disease in females may have different pathophysiology compared to males, particularly in younger adults. It has also resulted in new diagnostic techniques and a better understanding of symptomatology, while gender analysis has informed more appropriate risk stratification and prevention strategies. The existing knowledge in the pulmonary field shows the higher prevalence of pulmonary disorders among females, however, the role of gender as a socio-cultural construct has yet to be explored for the implementation of targeted interventions. The purpose of this review is to introduce the concept of gender dimension and its importance for the cardiopulmonary continuum with a focus on shared pathophysiology and disease presentation in addition to interrelation with chronic kidney disease. The review presents basic knowledge of what gender dimension means, and the application of sex and gender aspects in cardiovascular medicine with a specific focus on early pulmonary development, pulmonary hypertension, and chronic obstructive pulmonary disease (COPD). Early vascular aging and inflammation have been presented as a potential pathophysiological link, with further interactions between the cardiopulmonary continuum and chronic kidney disease. Finally, implications for potential future research have been provided to increase the impact of gender dimension on research excellence that would add value to everybody, foster toward precision medicine and ultimately improve human health.
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| 4. |
- Kublickiene, Karolina
(author)
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Regulation of vascular tone in myometrial resistance arteries in normal pregnancy and preeclampsia
- 1997
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Doctoral thesis (other academic/artistic)abstract
- Background: Normal pregnancy is characterized by the occurrence of substantial vasodilatation. Pressure responsiveness and vascular reactivity to administered vasoconstrictors undergo considerable attenuation. These circulatory changes are essential to maintain adequate oxygen and nutrient delivery to the placenta and thus to the fetus. Preeclampsia (PE) is a syndrome associated with widespread endothelial dysfunction and an increased peripheral vascular resistance, mainly affecting the renal and uteroplacental circulations. The physiology and pathophysiology underlying the vascular adaptation in human pregnancy is not fully elucidated, and improvement of our knowledge in this field is of the utmost importance. Vasoactive factors produced by vascular endothelium and alterations in vascular wall function are possible candidates as mediators of these circulatory changes. There is increasing evidence that the release of the endothelium-derived relaxing factors, nitric oxide (NO), prostacyclin (PGI2), and the constricting factor, endothelin-l (ET-I), is altered during normal pregnancy and pregnancy complicated by PE and may therefore significantly contribute to these changes. As blood flows through the lumen of a vessel, it exerts a mechanical force (i.e. shear stress) on endothelial cells. Endothelial cells can respond to shear stress by releasing endothelium-derived factors, particularly NO and PGI2 In addition to shear stress, changes in intra vascular pressure may also contribute to the regulation of vascular tone. Although myogenic in origin, pressure-induced tone may be modulated by endothelium derived factors. Objective: The purpose of the studies upon which this thesis is based was to study the effects of endothelium-derived factors, pressure and flow in the modulation of vascular tone in myometrial resistance arteries in normal pregnant women and women with PE. Owing to the putative involvement of endothelium derived factors in the regulation of vascular tone in uterine circulation, a considerable emphasis was placed on in vitro studies of myometrial resistance arteries which are directly involved in the regulation of uterine blood flow to the placenta during normal pregnancy and PE. Methods: Two different in vitro experimental approaches (i.e. isometric and isobaric) were adopted in these studies. The isometric wire-mounted artery system was used initially to evaluate vascular contractile responses to ET-I, and the interaction of ET-l with substances mediating vasodilatation, such as atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP), the Ca2+ channel blocker, is radipine, and the ETA receptor antagonist, BQ-123. The perfusion myography (isobaric) system is more representative of the in vivo situation than is the wire mounted artery system, and allows assessment of the effect of pressure and flow on vascular tone. Major findings and conclusions: ET-l is a potent vasoconstrictor of myometrial arteries in both normal and preeclamptic gravidae, and the contractile effect is mediated by ETA receptors. The ET-I induced contractile activity was attenuated to a small extent by is radipine. Both ANP and cGMP, the latter a second messenger for both ANP and NO, caused relaxation of ET-I preconstricted myometrial resistance arteries. Shear stress and pressure are important regulators of vascular tone in the uterine circulation in normal human pregnancy. Pressure-induced myogenic tone and flow-induced dilatation are modulated by endothelium-derived factors such as NO and ET-I. In preeclampsia, the pressure-induced myogenic constriction in combination with impaired endothelium-dependent dilatation, as reflected by impaired acetylcholine release and diminished shear stress mediated NO release, may contribute to the increased vascular resistance in the uteroplacental circulation. This suggests that NO may play a fundamental part in the maintenance of adequate blood supply to the fetus during human pregnancy. Significance: The functional studies in isolated myometrial artery preparations have yielded an increased knowledge of the mechanisms responsible for the regulation of uteroplacental vascular resistance in normal pregnancy and preeclampsia, specifically with respect to the effects of intraluminal pressure and flow and the part that endothelium-derived factors may play. The results may have implications for the future development of therapeutic tools for use in PE.
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| 5. |
- Larsson, Karin, et al.
(author)
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Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone
- 2019
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 176:24, s. 4625-4638
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Journal article (peer-reviewed)abstract
- Background and Purpose Microsomal PGE synthase-1 (mPGES-1), the inducible synthase that catalyses the terminal step in PGE(2) biosynthesis, is of high interest as therapeutic target to treat inflammation. Inhibition of mPGES-1 is suggested to be safer than traditional NSAIDs, and recent data demonstrate anti-constrictive effects on vascular tone, indicating new therapeutic opportunities. However, there is a lack of potent mPGES-1 inhibitors lacking interspecies differences for conducting in vivo studies in relevant preclinical disease models. Experimental Approach Potency was determined based on the reduction of PGE(2) formation in recombinant enzyme assays, cellular assay, human whole blood assay, and air pouch mouse model. Anti-inflammatory properties were assessed by acute paw swelling in a paw oedema rat model. Effect on vascular tone was determined with human ex vivo wire myography. Key Results We report five new mPGES-1 inhibitors (named 934, 117, 118, 322, and 323) that selectively inhibit recombinant human and rat mPGES-1 with IC50 values of 10-29 and 67-250 nM respectively. The compounds inhibited PGE(2) production in a cellular assay (IC50 values 0.15-0.82 mu M) and in a human whole blood assay (IC50 values 3.3-8.7 mu M). Moreover, the compounds blocked PGE(2) formation in an air pouch mouse model and reduced acute paw swelling in a paw oedema rat model. Human ex vivo wire myography analysis showed reduced adrenergic vasoconstriction after incubation with the compounds. Conclusion and Implications These mPGES-1 inhibitors can be used as refined tools in further investigations of the role of mPGES-1 in inflammation and microvascular disease.
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| 6. |
- Laucyte-Cibulskiene, Agne, et al.
(author)
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Role of GDF-15, YKL-40 and MMP 9 in patients with end-stage kidney disease : focus on sex-specific associations with vascular outcomes and all-cause mortality
- 2021
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In: Biology of Sex Differences. - : Springer Science and Business Media LLC. - 2042-6410. ; 12:1
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Journal article (peer-reviewed)abstract
- Background: Sex differences are underappreciated in the current understanding of cardiovascular disease (CVD) in association with chronic kidney disease (CKD). A hallmark of CKD is vascular aging that is characterised, amongst others, by; systemic inflammation, microbiota disbalance, oxidative stress, and vascular calcification—features linked to atherosclerosis/arteriosclerosis development. Thus, it is the necessary to introduce novel biomarkers related to athero-/arteriosclerotic damage for better assessment of vascular ageing in patients CKD. However, little is known about the relationship between uraemia and novel CVD biomarkers, such as growth differentiation factor-15 (GDF-15), cartilage glycoprotein-39 (YKL-40) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesise that there are sex-specific relationships between GDF-15, YKL-40, MMP-9 levels in end-stage kidney disease (ESKD) patients in relation to gut microbiota, vascular calcification, inflammation, comorbidities, and all-cause mortality. Methods: ESKD patients, males (n = 151) and females (n = 79), not receiving renal replacement therapy were selected from two ongoing prospective ESKD cohorts. GDF-15, YKL-40 and MMP9 were analysed using enzyme-linked immunosorbent assay kits. Biomarker levels were analysed in the context of gut microbiota-derived trimethylamine N-oxide (TMAO), vascular calcification, inflammatory response, oxidative stress, comorbidities, and all-cause mortality. Results: Increased GDF-15 correlated with higher TMAO in females only, and with higher coronary artery calcification and IL-6. In females, diabetes was associated with elevated GDF-15 and MMP-9, whilst males with diabetes only had elevated GDF-15. No associations were found between biomarkers and CVD comorbidity. Deceased males and females had higher GDF-15 concentrations (p = 0.01 and p < 0.001, respectively), meanwhile only YKL-40 was increased in deceased males (p = 0.02). Conclusions: In conclusion, in males GDF-15 and YKL-40 were related to vascular calcification, inflammation, and oxidative stress, whilst in females GDF-15 was related to TMAO. Increased levels of YKL-40 and GDF-15 in males, and only GDF-15 in females, were associated with all-cause mortality. Our findings suggest that sex-specific associations of novel CVD biomarkers have a potential to affect development of cardiovascular complications in patients with ESKD.
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| 7. |
- Massier, Lucas, et al.
(author)
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An integrated single cell and spatial transcriptomic map of human white adipose tissue
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Single-cell studies of human white adipose tissue (WAT) provide insights into the specialized cell types in the tissue. Here the authors combine publicly available and newly generated high-resolution and bulk transcriptomic results from multiple human datasets to provide a comprehensive cellular map of white adipose tissue. To date, single-cell studies of human white adipose tissue (WAT) have been based on small cohort sizes and no cellular consensus nomenclature exists. Herein, we performed a comprehensive meta-analysis of publicly available and newly generated single-cell, single-nucleus, and spatial transcriptomic results from human subcutaneous, omental, and perivascular WAT. Our high-resolution map is built on data from ten studies and allowed us to robustly identify >60 subpopulations of adipocytes, fibroblast and adipogenic progenitors, vascular, and immune cells. Using these results, we deconvolved spatial and bulk transcriptomic data from nine additional cohorts to provide spatial and clinical dimensions to the map. This identified cell-cell interactions as well as relationships between specific cell subtypes and insulin resistance, dyslipidemia, adipocyte volume, and lipolysis upon long-term weight changes. Altogether, our meta-map provides a rich resource defining the cellular and microarchitectural landscape of human WAT and describes the associations between specific cell types and metabolic states.
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| 8. |
- Risberg, Anitha, 1962-
(author)
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Hormones and fluid balance during pregnancy, labor and post partum
- 2009
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Doctoral thesis (other academic/artistic)abstract
- The aim of this thesis was to determine any association between plasma oxytocin and vasopressin concentrations and renal water and sodium excretion during normal pregnancy. In addition to investigate changes in concentrations of estradiol, progesterone, oxytocin, cortisol, and glucose in the blood before and in the nearest hours after delivery and if treatment with oxytocin affected these concentrations and the fluid balance during the different stages of labour. Oxytocin, vasopressin, estradiol, progesterone, and cortisol were analysed in blood plasma or serum by radioimmunoassay or ELISA: serum glucose, and osmolality, and sodium in plasma and urine were analysed by standard laboratory techniques. Fifty-seven women were studied during pregnancy and fifty-one during parturition and post partum. The low plasma vasopressin and increasing plasma oxytocin concentrations with unchanged water and sodium excretion indicate that oxytocin assists vasopressin in concentrating urine during pregnancy. Plasma vasopressin concentration continued to be low during parturition and post partum. Urine flow and concentration was unrelated to changes in plasma sodium concentration, indicating regulation of fluid balance during parturition was different to the non-gravid state. Women with weak myometrial contractions during parturition (slow progress of labour) reacted differently than women with normal parturition and a group of women with fast progress of labour. The group with slow labour had lower serum estradiol concentration in the latency phase and became hyponatremic. Pulsatile and continuous oxytocin infusions were both effective in the treatment of slow progress of labour. A lower amount of oxytocin was needed to affect delivery when given as pulsatile infusion. Serum cortisol and glucose concentrations were high during labour and cortisol level remained elevated after delivery and glucose concentration reached the highest levels (12 mmol/L) at the same time. Insulin resistance together with the long time of elevated cortisol concentration partly explained the high glucose concentration. In conclusion, fluid balance is not regulated according to the usual sensitive osmotic and volumetric influence on vasopressin release from the neurohypophysis during pregnancy and parturition. Parturition involves a change from one demanding condition, pregnancy, to another, lactation. Parturition and the hours directly after delivery are a turbulent period involving considerable stress.
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| 9. |
- Robertsson Grossmann, Katarina, et al.
(author)
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Kidney outcomes in early adolescence following perinatal asphyxia and hypothermia-treated hypoxic-ischaemic encephalopathy
- 2023
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In: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 0931-041X .- 1432-198X. ; 38:4, s. 1205-1214
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Journal article (peer-reviewed)abstract
- Background: Acute kidney injury (AKI) remains common among infants with hypothermia-treated hypoxic-ischaemic encephalopathy (HIE). Little is known about long-term kidney outcomes following hypothermia treatment. We recently reported that 21% of survivors of hypothermia-treated HIE had decreased estimated glomerular filtration rate (eGFR) based on plasma creatinine in early adolescence. Here, we assessed kidney functions more comprehensively in our population-based cohort of children born in Stockholm 2007–2009 with a history of hypothermia-treated HIE. Methods: At 10–12 years of age, we measured cystatin C (cyst C) to estimate GFR. Children with decreased cyst C eGFR also underwent iohexol clearance examination. We measured urine-albumin/creatinine ratio, blood pressure (BP) and kidney volume on magnetic resonance imaging. Fibroblast growth factor 23 (FGF 23) levels in plasma were assessed by enzyme-linked immunosorbent assay (ELISA). Outcomes were compared between children with and without a history of neonatal AKI. Results: Forty-seven children participated in the assessment. Two children (2/42) had decreased cyst C eGFR, for one of whom iohexol clearance confirmed mildly decreased GFR. One child (1/43) had Kidney Disease Improving Global Outcomes (KDIGO) category A2 albuminuria, and three (3/45) had elevated office BP. Subsequent ambulatory 24-h BP measurement confirmed high normal BP in one case only. No child had hypertension. Kidney volume and FGF 23 levels were normal in all children. There was no difference in any of the parameters between children with and without a history of neonatal AKI. Conclusion: Renal sequelae were rare in early adolescence following hypothermia-treated HIE regardless of presence or absence of neonatal AKI. Graphical abstract: [Figure not available: see fulltext.].
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| 10. |
- Strålberg, Towe, et al.
(author)
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Proprotein convertase subtilisin/kexin type 9 and mortality in patients starting hemodialysis
- 2019
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In: European Journal of Clinical Investigation. - : Blackwell Publishing. - 0014-2972 .- 1365-2362. ; 49:7
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cardiovascular events are the leading cause of death in end stage renal disease (ESRD), but traditional markers of dyslipidemia are not clearly associated with cardiovascular risk in this population. Proprotein Convertase Subtilsin/Kexin type 9 (PCSK-9) could be of interest as a novel cardiovascular risk marker in ESRD due to the emergence of lipid lowering therapy based on PCSK-9 inhibition. The aim of the present study was to investigate if the convertase PCSK-9 is a potential risk marker for mortality among patients starting hemodialysis treatment.MATERIALS AND METHODS: This is a cohort study of 265 patients starting hemodialysis between 1991-2009, with three years follow-up. The association between baseline PCSK-9 levels and mortality was assessed using Cox proportional hazards- and quantile regression models, with adjustment for potential confounders.RESULTS: PCSK-9 levels at initiation of hemodialysis were associated to mortality in multivariable adjusted analysis. PCSK-9 levels exhibited an U-shaped association to mortality. Inclusion of the quadratic term of PCSK-9 in regression modeling optimized model performance. At baseline, PCSK-9 levels had positive correlations to Davies comorbidity score, hemoglobin and C-reactive protein while negative correlations were found for high-density lipoprotein and total cholesterol. PCSK-9 levels were higher in statin users and patients with a history of cardiovascular disease.CONCLUSIONS: This study shows, for the first time, that the level of PCSK-9 is associated with all-cause mortality in hemodialysis patients, independently of a number of potential confounders.
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| 11. |
- Ward, Liam J., et al.
(author)
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Coronary artery calcification and aortic valve calcification in patients with kidney failure : a sex-disaggregated study
- 2023
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In: Biology of Sex Differences. - 2042-6410. ; 14:1
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Journal article (peer-reviewed)abstract
- Background: Chronic kidney disease (CKD) is linked to an increased cardiovascular disease (CVD) burden. Albeit underappreciated, sex differences are evident in CKD with females being more prone to CKD development, but males progressing more rapidly to kidney failure (KF). Cardiovascular remodelling is a hallmark of CKD with increased arterial and valvular calcification contributing to CKD. However, little is known regarding sex differences in calcific cardiovascular remodelling in KF patients. Thus, we hypothesise that sex differences are present in coronary artery calcification (CAC) and aortic valve calcification (AVC) in patients with KF. Methods: KF patients, males (n = 214) and females (n = 107), that had undergone computer tomography (CT) assessment for CAC and AVC were selected from three CKD cohorts. All patients underwent non-contrast multi-detector cardiac CT scanning, with CAC and AVC scoring based on the Agatston method. Baseline biochemical measurements were retrieved from cohort databases, including plasma analyses for inflammation markers (IL-6, TNF, hsCRP) and oxidative stress by skin autofluorescence measuring advanced glycation end-products (AGE), amongst other variables. Results: Sex-disaggregated analyses revealed that CAC score was associated with age in both males and females (both p < 0.001). Age-adjusted analyses revealed that in males CAC was associated with diabetes mellitus (DM) (p = 0.018) and CVD (p = 0.011). Additionally, for females CAC associated with IL-6 (p = 0.005) and TNF (p = 0.004). In both females and males CAC associated with AGE (p = 0.042 and p = 0.05, respectively). CAC was associated with mortality for females (p = 0.015) independent of age. AVC in females was not reviewed due to low AVC-positive samples (n = 14). In males, in multivariable regression AVC was associated with age (p < 0.001) and inflammation, as measured by IL-6 (p = 0.010). Conclusions: In female KF patients inflammatory burden and oxidative stress were associated with CAC. Whereas in male KF patients oxidative stress and inflammation were associated with CAC and AVC, respectively. Our findings suggest a sex-specific biomarker signature for cardiovascular calcification that may affect the development of cardiovascular complications in males and females with KF.
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| 12. |
- Yang, Liu L., et al.
(author)
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Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD—A Randomized Controlled Trial
- 2023
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In: Nutrients. - : MDPI AG. - 2072-6643 .- 2072-6643. ; 15:5
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Journal article (peer-reviewed)abstract
- Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota–gut–brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1β-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels.
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