Effects and Reversibility of Pre- and Post-natal Iron and Omega-3 Fatty Acid Deficiency, Alone and in Combination, on Bone Development in Rats

Both iron and omega-3 (n-3) polyunsaturated fatty acids may play an important role in bone development. The aim of this study was to investigate the effects of pre- and post-natal iron and n-3 fatty acid deficiency (FAD), alone and in combination, on bone development in rats, and to determine whether effects are reversible when a sufficient diet is provided post-weaning. Using a 2×2-factorial design, 56 female Wistar rats were allocated to one of four diets: (1) control, (2) iron deficient (ID), (3) n-3 FAD or (4) ID and n-3 FAD, and were maintained on the respective diets throughout gestation and lactation. At weaning (post-natal day [PND] 21), offspring (n = 24/group; male:female=1:1) were randomly allocated to either continue with their respective diets or to switch to the control diet until PND 42-45. Bone mineral density (BMD) and bone strength were determined using dual X-ray absorptiometry and three-point bending tests, respectively. Pre- and post-natal ID resulted in significantly lower BMD in the spine and bone strength in the left femur. Both ID and n-3 FAD resulted in lower BMD in the right femur, with an additive reduction in the combined ID and n-3 FAD group vs. controls. While negative effects of pre- and post-natal ID alone were reversed in offspring switched to a control diet post-weaning, lower BMD and bone strength persisted in offspring with combined ID and n-3 FAD during the prenatal and early post-natal period. Effects were not sex-specific. These results indicate that ID during early life may negatively influence bone development, with potential additive effects of n-3 FAD. While the effects of ID alone seem reversible, a combined ID and n-3 FAD may result in irreversible deficits in bone development.

Pilot Study: Nutritional and Preclinical Safety Investigation of Fermented Hispidin-Enriched Sanghuangporus sanghuang Mycelia: A Promising Functional Food Material to Improve Sleep

Sleep disturbances have been the hallmark of the recent coronavirus disease 2019 pandemic. Studies have shown that once sleep is disrupted, it can lead to psychological and physical health issues which can, in turn, disrupt circadian rhythm and induce further sleep disruption. As consumers are trying to establish healthy routines, nutritional and preclinical safety investigation of fermented hispidin-enriched Sanghuangporus sanghuang mycelia (GKSS) as a novel food material for spontaneous sleep in Sprague-Dawley rats is conducted for the first time. Results showed that the nutritional analysis of GKSS including moisture, ash, crude lipid, crude protein, carbohydrate, and energy were found to be 2.4 ± 0.3%, 8.0 ± 2.5%, 1.7 ± 0.3%, 22.9 ± 1.2%, 65.1 ± 3.1%, and 367.1 ± 10.2 kcal/100 g respectively. In the 28-day repeated-dose oral toxicity study, only Sprague-Dawley male rats receiving 5 g/kg showed a slight decrease in feed consumption at week 3, but no associated clinical signs of toxicity or significant weight loss were observed. Although a significant reduction of the platelet count was found in mid- and high-dose GKSS treated male groups, such changes were noted to be within the normal range and were not correlated with relative spleen weight changes. Hence, the no observed adverse effect level (NOAEL) of GKSS was identified to be higher than 5 g/kg in rats. After the safety of GKSS is confirmed, the sleep-promoting effect of GKSS ethanolic extract enriched with hispidin was further assessed. Despite 75 mg/kg of GKSS ethanolic extract does not affect wakefulness, rapid eye movement (REM) sleep and non-REM (NREM) sleep, GKSS ethanolic extract at 150 mg/kg significantly decreased wakefulness and enhanced NREM and REM sleep. Interestingly, such effects seem to be mediated through anti-inflammatory activities via NF-E2-related factor-2 (Nrf2) signaling pathway. Taken together, these findings provide the preliminary evidence to studies support the claims suggesting that GKSS contained useful phytochemical hispidin could be considered as and is safe to use as a functional food agent or nutraceutical for relieving sleep problems mediated by Nrf2 pathway, which the results are useful for future clinical pilot study.

Effects of Vitamin D and K on Interleukin-6 in COVID-19

BackgroundPathology during COVID-19 infection arises partly from an excessive inflammatory response with a key role for interleukin (IL)-6. Both vitamin D and K have been proposed as potential modulators of this process.MethodsWe assessed vitamin D and K status by measuring circulating 25-hydroxyvitamin D (25(OH)D) and desphospho-uncarboxylated Matrix Gla-Protein (dp-ucMGP), respectively in 135 hospitalized COVID-19 patients in relation to inflammatory response, elastic fiber degradation and clinical outcomes.ResultsComparing good and poor disease outcomes of COVID-19 patients, vitamin 25(OH)D levels were not significantly different. IL-6 levels, however, were significantly higher in patients with poor outcome, compared to patients with good outcome (30.3 vs. 153.0 pg/mL; p < 0.0001). Dp-ucMGP levels as biomarker of extrahepatic vitamin K status was associated with IL-6 levels (r = 0.35; p < 0.0001). In contrast, 25(OH)D levels were only borderline statistically significant correlated with IL-6 (r = −0.14; p <0.050). A significant association was also found between IL-6 and elastic fiber degradation. Contrary to vitamin K status, 25(OH)D did not correlate with elastic fiber degradation.ConclusionsDp-ucMGP associates with IL-6 as a central component of the destructive inflammatory processes in COVID-19. An intervention trial may provide insight whether vitamin K administration, either or not in combination with vitamin D, improves clinical outcome of COVID-19.

The Effect of Body Adiposity and Alcohol Consumption on Serum Uric Acid: A Quantile Regression Analysis Based on the China National Health Survey

Adiposity and alcohol consumption are reported to be associated with a higher level of serum uric acid (SUA), but whether their effect differs on SUA percentile distribution is still unclear. In this study, we aimed to investigate how alcohol intake and body fat percentage (%BF) integrated with body mass index (BMI) influence the distribution of SUA in Chinese adults. Data from the China National Health Survey (CNHS) which included adults from 10 provinces of China were used (n = 31,746, aged 20–80 years, 40% male). %BF and BMI were integrated into eight expanded body composition groups to understand how excess body adiposity affects the distribution of SUA in the populational level. Self-report alcohol intake information was collected by face-to-face questionnaire interview. Quantile regression (QR) was used to analyze the data. We found that adiposity and alcohol consumption were associated with SUA, especially at the upper percentile in both sexes. In obese men, the QR coefficients at the 75th and 95th percentiles were 74.0 (63.1–84.9) and 80.9 (52.5–109.3) μmol/L, respectively. The highest quartile of %BF in men had a 92.6 (79.3–105.9) μmol/L higher SUA levels at its 95th percentile than the 5th quartile (p < 0.001). Compared with normal or underweight with the lowest %BF group (NWBF1), the obesity-highest %BF group (OBBF4) had the strongest positive effect on SUA, especially at the higher percentile of SUA. In BMI-defined normal or underweight participants, a higher quartile of %BF had greater effect size in all SUA percentiles. In men, current alcohol drinking had the strongest effect at the 95th percentile of SUA (QR coefficient: 31.8, with 95% CI: 22.6–41.0) comparing with 14.5, 95% CI of 8.4 to 20.6 in the 5th SUA percentile. High risk of alcohol consumption had a greater effect on SUA, especially in the higher SUA percentile. The observation of stronger association at the higher percentile of SUA suggests that decreasing body adiposity and alcohol intake at the populational level may shift the upper tails of the SUA distributions to lower values, thereby reducing the incidence of hyperuricemia.

Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer's Disease: A Mini Review

Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disorder, with no curative treatment available so far. Alongside the brain deposition of β-amyloid peptide and hyperphosphorylated tau, neuroinflammation triggered by the innate immune response in the central nervous system, plays a central role in the pathogenesis of AD. Glucose usually represents the main fuel for the brain. Glucose metabolism has been related to neuroinflammation, but also with AD lesions. Hyperglycemia promotes oxidative stress and neurodegeneration. Insulinoresistance (e.g., in type 2 diabetes) or low IGF-1 levels are associated with increased β-amyloid production. However, in the absence of glucose, the brain may use another fuel: ketone bodies (KB) produced by oxidation of fatty acids. Over the last decade, ketogenic interventions i.e., ketogenic diets (KD) with very low carbohydrate intake or ketogenic supplementation (KS) based on medium-chain triglycerides (MCT) consumption, have been studied in AD animal models, as well as in AD patients. These interventional studies reported interesting clinical improvements in animals and decrease in neuroinflammation, β-amyloid and tau accumulation. In clinical studies, KS and KD were associated with better cognition, but also improved brain metabolism and AD biomarkers. This review summarizes the available evidence regarding KS/KD as therapeutic options for individuals with AD. We also discuss the current issues and potential adverse effects associated with these nutritional interventions. Finally, we propose an overview of ongoing and future registered trials in this promising field.

The Amino Acids Sensing and Utilization in Response to Dietary Aromatic Amino Acid Supplementation in LPS-Induced Inflammation Piglet Model

Dietary supplementation with aromatic amino acids (AAAs) has been demonstrated to alleviate intestinal inflammation induced by lipopolysaccharide (LPS) in the piglets. But the mechanism of AAA sensing and utilization under inflammatory conditions is not well-understood. The study was conducted with 32 weanling piglets using a 2 × 2 factorial arrangement (diet and LPS challenge) in a randomized complete block design. Piglets were fed as basal diet or the basal diet supplemented with 0.16% tryptophan (Trp), 0.41% phenylalanine (Phe), and 0.22% tyrosine (Tyr) for 21 days. The results showed that LPS treatment significantly reduced the concentrations of cholecystokinin (CCK) and total protein but increased leptin concentration, the activities of alanine transaminase, and aspartate aminotransferase in serum. Dietary supplementation with AAAs significantly increased the serum concentrations of CCK, peptide YY (PYY), and total protein but decreased the blood urea nitrogen. LPS challenge reduced the ileal threonine (Thr) digestibility, as well as serum isoleucine (Ile) and Trp concentrations, but increased the serum concentrations of Phe, Thr, histidine (His), alanine (Ala), cysteine (Cys), and serine (Ser) (P < 0.05). The serum-free amino acid concentrations of His, lysine (Lys), arginine (Arg), Trp, Tyr, Cys, and the digestibilities of His, Lys, Arg, and Cys were significantly increased by feeding AAA diets (P < 0.05). Dietary AAA supplementation significantly increased the serum concentrations of Trp in LPS-challenged piglets (P < 0.05). In the jejunal mucosa, LPS increased the contents of Ala and Cys, and the mRNA expressions of solute carrier (SLC) transporters (i.e., SLC7A11, SLC16A10, SLC38A2, and SLC3A2), but decreased Lys and glutamine (Gln) contents, and SLC1A1 mRNA expression (P < 0.05). In the ileal mucosa, LPS challenge induced increasing in SLC7A11 and SLC38A2 and decreasing in SLC38A9 and SLC36A1 mRNA expressions, AAAs supplementation significantly decreased mucosal amino acid (AA) concentrations of methionine (Met), Arg, Ala, and Tyr, etc. (P < 0.05). And the interaction between AAAs supplementation and LPS challenge significantly altered the expressions of SLC36A1 and SLC38A9 mRNA (P < 0.05). Together, these findings indicated that AAAs supplementation promoted the AAs absorption and utilization in the small intestine of piglets and increased the mRNA expressions of SLC transports to meet the high demands for specific AAs in response to inflammation and immune response.

Different Doses of Calcium Supplementation to Prevent Gestational Hypertension and Pre-Eclampsia: A Systematic Review and Network Meta-Analysis

ObjectiveCalcium supplementation can prevent gestational hypertension and pre-eclampsia. However, besides the non-consensus of existing studies, there is a lack of evidence regarding the optimal dosing of calcium.MethodEight electronic databases, namely, the Cochrane Library, PUBMED, Web of Science, EMBASE, WANGFANG, VIP, CBM, and CNKI, were searched. The studies were retrieved from inception to July 13, 2021. Two researchers independently screened the literature, extracted data, and evaluated the methodological quality based on the inclusion criteria. In particular, the calcium supplementation doses were divided into three groups, namely, the high-dose (≥1.5 g), medium-dose (1.0–1.49 g), and the low-dose group (<1.0 g). The participants were also divided into high-risk and low-risk groups, according to the risk of developing gestational hypertension and pre-eclampsia.Results and DiscussionA total of 48 studies were incorporated into the final analyses. All doses of calcium supplementation reduced the incidence of gestational hypertension in the low-risk population (low dose - three studies; medium dose- 11 studies; high dose- 28 studies), whereas the medium-dose (three studies) reduced the incidence of gestational hypertension in high-risk groups. Moreover, a medium dose of calcium supplementation had the maximum effect in reducing gestational hypertension in low-risk and high-risk populations. The medium (three studies) and high doses (13 studies) of calcium supplementation reduced the incidence of pre-eclampsia in the low-risk groups. However, a medium-dose calcium supplementation maximally prevented pre-eclampsia in the low-risk population. The authenticity and reliability of the results were reduced due to the limitations of contemporary studies in terms of experimental design, result measurement, statistics, and evidence quality. Therefore, high-quality studies with larger sample size are required to evaluate further the effect of calcium supplementation in preventing gestational hypertension and pre-eclampsia.

Genetic and Life Style Risk Factors for Recurrent Non-alcoholic Fatty Liver Disease Following Liver Transplantation

Recurrent or de novo non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) following liver transplantation (LT) is a frequent event being increasingly recognized over the last decade, but the influence of recurrent NASH on graft and patient outcomes is not yet established. Taking into consideration the long term survival of liver transplanted patients and long term complications with associated morbidity and mortality, it is important to define and minimize risk factors for recurrent NAFLD/NASH. Metabolic syndrome, obesity, dyslipidemia, diabetes mellitus are life style risk factors that can be potentially modified by various interventions and thus, decrease the risk of recurrent NAFLD/NASH. On the other hand, genetic factors like recipient and/or donor PNPLA3, TM6SF2, GCKR, MBOAT7 or ADIPOQ gene polymorphisms proved to be risk factors for recurrent NASH. Personalized interventions to influence the different metabolic disorders occurring after LT in order to minimize the risks, as well as genetic screening of donors and recipients should be performed pre-LT in order to achieve diagnosis and treatment as early as possible.

A Metagenomics Investigation of Intergenerational Effects of Non-nutritive Sweeteners on Gut Microbiome

To identify possible mechanisms by which maternal consumption of non-nutritive sweeteners increases obesity risk in offspring, we reconstructed the major alterations in the cecal microbiome of 3-week-old offspring of obese dams consuming high fat/sucrose (HFS) diet with or without aspartame (5–7 mg/kg/day) or stevia (2–3 mg/kg/day) by shotgun metagenomic sequencing (n = 36). High throughput 16S rRNA gene sequencing (n = 105) was performed for dams, 3- and 18-week-old offspring. Maternal consumption of sweeteners altered cecal microbial composition and metabolism of propionate/lactate in their offspring. Offspring daily body weight gain, liver weight and body fat were positively correlated to the relative abundance of key microbes and enzymes involved in succinate/propionate production while negatively correlated to that of lactose degradation and lactate production. The altered propionate/lactate production in the cecum of weanlings from aspartame and stevia consuming dams implicates an altered ratio of dietary carbohydrate digestion, mainly lactose, in the small intestine vs. microbial fermentation in the large intestine. The reconstructed microbiome alterations could explain increased offspring body weight and body fat. This study demonstrates that intense sweet tastants have a lasting and intergenerational effect on gut microbiota, microbial metabolites and host health.