bluuebunny/crossref_metadata_2025 huggingface dataset:
A reduction of myeloperoxidase and interleukin‐10 expressions in mesenteric lymph nodes of the rats fed a cholic acid‐supplemented diet
Authors: JOE GA‐HYUN , Hori Shota , Shimizu Hidehisa , Hara Hiroshi , Ishizuka Satoshi
Published: November 2023

Background

Bile acids (BAs) are synthesized from cholesterol in hepatocytes and contribute to absorption of hydrophobic nutrients such as lipids and hydrophobic vitamins. Ingestion of high‐fat diet promotes BA secretion. Aging increases the ratio of cholic acid (CA) against chenodeoxycholic acid in the primary BAs. To mimic these conditions, we fed a diet supplemented CA and found attenuation of intestinal permeability, suggesting a possibility that immune system is involved in subsequent development of disorders. To investigate the effect of CA on immune functions, we analyzed gene expressions of immune responses in mesenteric lymph nodes of the CA‐fed rats.

Material and method

WKAH/HkmSlc male rats (three weeks old) were fed an AIN‐93G‐based diet with or without a CA supplementation for 13 weeks. Also, BA metabolism was evaluated by using feces and some tissues. Mesenteric lymph nodes were collected at 13 weeks to analyze immune‐related gene expressions with PCR array and RT‐qPCR.

Result

The CA supplementation significantly decreased the myeloperoxidase (Mpo) and interleukin‐10 (Il10) expressions. Mpo is an enzyme found in neutrophils and monocytes that catalyze radical production and modulate macrophage functions. Il10 is one of the key cytokines to down‐regulate a variety of inflammatory responses and expressed in M2 macrophages. Also, CA‐ingestion had no effect on tumor necrosis factor and interleukin‐1β expressions known as pro‐inflammatory cytokines.

Conclusion

The CA supplementation might modulate function of immune cells as well as neutrophils, macrophages and dendritic cells. Also, the decreases of Mpo and Il10 expressions can participate in disease developments observed in the CA‐fed rats.
Relationship Between Vitamin D Status and Plasma Aminothiol Redox in Critically Ill Children
Authors: Alvarez Jessica A , Grunwell Jocelyn R , Gillespie Scott E , Tangpricha Vin , Hebbar Kiran
Published: November 2023

Background

Critically ill populations incur high levels of oxidative stress. Vitamin D deficiency, which is common in children presenting to the pediatric intensive care unit (PICU), has been shown to correlate with plasma aminothiol redox imbalance, as well as systemic inflammation. The purpose of this study was to investigate the relationship between vitamin D status and plasma markers of aminothiol redox and inflammation in critically ill children.

Methods

This was a cross‐sectional study of n = 50 PICU patients. Blood was drawn within 24 hr of admission to the PICU. Plasma glutathione (GSH), glutathione disulfide (GSSG), cystine (Cys), and cysteine (CySS) were measured with high‐performance liquid chromatography, and their associated redox potentials determined (EhGSSG and Eh CySS, respectively). Plasma 25‐hydroxyvitamin D [25(OH)D] was measured using a chemiluminescent assay. Vitamin D insufficiency was defined as 25(OH)D levels < 30 ng/mL. Plasma markers of inflammation were assayed with a multiplex platform and ELISA.

Results

Mean age (± SD) was 11.8 ± 5.2 yrs, and 56% of patients were male. 74% of patients had vitamin D insufficiency.. Proportionally fewer patients in the vitamin D insufficient group required mechanical ventilation (p=0.009). Plasma Cys and CySS did not differ by vitamin D status, although Eh CySS was lower (more reduced; p−=0.005) in the vitamin D sufficient group. Plasma GSH and GSSG were lower in the vitamin D sufficient group (p=0.017 and 0.011, respectively), with a trend towards lower EhGSSG in the vitamin D insufficient group (p=0.076). Plasma glutamine levels were lower in the vitamin D sufficient group (p=0.005). Plasma LL‐37 was higher in the vitamin D sufficient group (p=0.025), although there were no differences in other markers of inflammation. Adjustment for age, sex, race, weight, and ventilation status attenuated the difference in plasma Eh CySS (p=0.08). In linear regression analyses, serum 25(OH)D was inversely associated with plasma Eh CySS p=0.006), although adjustment for age, sex, race, weight, and ventilation status attenuated the relationship (p=0.09).

Conclusion

In critically ill children, vitamin D sufficiency was associated with less oxidized plasma EhCySS, the redox state of the primary extracellular redox couple (Cys and CySS), and with higher plasma LL‐37, an indicator of innate immune function. Lower plasma GSH, GSSG, and glutamine in vitamin D sufficient patients may suggest vitamin D‐regulated mechanisms to preserve extracellular and/or the intracellular redox states during critical illness, although further study is needed.

Support or Funding Information

This study was supported by the Children's Healthcare of Atlanta Friends (grant number 38234), the National Institutes of Health (UL1 TR000454 and K01 DK102851), the Emory+Children's Statistical Core, and the Emory+Children's Biomarkers Core.
Undernutrition, Nutrient Intake and Acute Phase Response of Anemic Children
Authors: Agdeppa Imelda Angeles , Capanzana Mario V
Published: November 2023

Background

Undernutrition in the Philippines is alarmingly high and this increases the risk to infection.

Objective

This study aimed to assess the acute phase response, iron and physical growth and nutrient intake of anemic schoolchildren aged 6 to 9 years old.

Methods

Screening for haemoglobin (hb) was done among 2423 children. The anemia rate was 10 % (246) with mean hb of 11.0 g/dl. Only 228 children were included in the analysis. All Mean age of children was 7.3 years. The average household size is 6 members. Mean monthly income tended to cluster around approximately P14,000.00 with an average daily food expenditure of P260.00 or U$5.5. Major occupation of breadwinner are production and service related. Weight and height were measured using standard techniques. Serum Ferritin (SF), transferrin receptors (TfR), C‐reactive protein (CRP) and α1 – acid glycoprotein (AGP) and retinol – binding proteins (RBP) were measured using sandwich ELISA method. The presence of infection is defined as values higher than the cut‐offs for CRP (>10mg/L) or AGP (>1g/L). Food intake was collected using 24h recall.

Results

Among the anemic children, mean weight was 19.7 kg, mean height was 115.4 cm. Stunting prevalence among anemic children was 27.6 %, underweight 24.1 % and wasting 10.5 %. Mean levels SF was 69.2ug/L, TfR 6.9 mg/L and RBP 0.99 umol/L. Mean intakes of energy was 1325 kcal, protein 42.8g, carbohydrates 189.3g, fats 44.2g, iron 7.7mg, vitamin A 526 IU, and vitamin C 29.2 mg. Among anemic children, 15% are with infections of which 28.6% was underweight, stunted (25.7%), and wasted (20.0%). Among anemic children with infections the mean SF level was 94.5 ug/L, TfR 7.0 mg/L, and mean food intake was 1299 kcal. The presence of infection puts children to undernutrition by 20%.

Conclusion

Anemic children with high CRP or high AGP are more likely to be vitamin A deficient.

Recommendation

Policies addressing reduction of malnutrition must integrate policies to reduce infection to improve health outcomes.
Serum retinol and selenium levels correlate negatively with hemolysis markers in sickle cell disease adult patients
Authors: Citelli Marta , Delesderrier Emília , Cordovil Karen , Omena Juliana , Santos‐Rodrigues Claudia Cople
Published: November 2023

Sickle cell disease (SCD) is the most prevalent inherited hemoglobinopathy in the world. It is a hemolytic disease characterized by the presence of chronic inflammation and production of reactive species of oxygen and nitrogen. Very little is known about the adequate diet therapy for people with SCD, but it is seems that foods rich in antioxidants components should benefit these individuals. Thus, we hypothesized that insufficient quantities of selenium, retinol, alpha‐tocopherol and zinc could reduce the body's ability to regulate free radicals insults, leading to oxidative stress condition which could affect hemolysis in patients with SCD. We then conducted a study with 55 patients aged over 40 years and assessed the possible associations between serum levels of these nutrients and the indices of oxidative damage, inflammation and hemolysis markers. Reduced serum concentrations of retinol and selenium correlated negatively with hemolysis and inflammation markers values. In parallel, selenium and zinc were inversely correlated to to the concentrations of serum malondialdehyde. Therefore, our data point to the necessity for an adequate dietary intake of these nutrients.

Support or Funding Information

Brasil Ministry of Health and FAPERJ
Synergistic effects of glutamine, citrulline, and antioxidant vitamin C and E on modulating splenocytic immune responses in rats with intestinal ischemia and reperfusion
Authors: Lo Hui‐Chen , Chiu Yu‐Wen , Lee Chien‐Hsing
Published: November 2023

Intestinal ischemia and reperfusion (IIR) is a common event in patients with acute mesenteric ischemia, intestinal obstruction, organ transplantation, and hemorrhagic and septic shock. It has been demonstrated that IIR‐induced intestinal mucosa damage may cause systemic inflammation and multiple organ failure and further lead to death. Our previous study showed that oral glutamine/citrulline and antioxidant vitamins C/E have additive effects on attenuating intestinal damage and systemic inflammation in IIR rats. Herein, we investigated the effects of these supplements on IIR‐induced immune alterations. Male Wistar rats were divided into normal rats and IIR rats that underwent intestinal ischemia for 60 min and fed with placebo, glutamine/citrulline (AA), vitamins C/E (CE), or glutamine/citrulline plus vitamins C/E (AV) at 15 minutes before and 3, 9 and 21 hr after reperfusion. After 24 hr reperfusion, IIR‐increased plasma nitrate/nitrite was significantly reversed in rats with AA and CE and IIR‐increased interleukin‐6 was reversed in rats with AA, CE, and AV. The results of two‐way ANOVA showed that CE was a main factor to reverse IIR‐altered T‐helper leukocytes, B‐leukocytes, and monocytes and to increase tumor necrosis‐factor (TNF)‐alpha production in lipopolysaccharide‐stimulated leukocytes; and AA and CE were main factors to increase granulocytes in the circulation. In concanavalin A‐ and lipopolysaccharide‐stimulated splenocytes, AA was a main factor to increase TNF‐alpha and interleukin‐4 productions, CE was a main factor to increase interleukin‐4 productions, and AA and CE have significant interactions in TNF‐alpha and IL‐4 productions as shown in the significant increases in IIR rats with AV, not with AA or CE alone. In conclusion, oral glutamine/citrulline and vitamins C/E may have synergistic effects on modulating splenocytic immune responses in intestinal ischemia and reperfusion injury. The alleviated intestinal damage and systemic inflammation and the elevated splenocytic activity reveal that oral, combined administration of glutamine, citrulline, and antioxidant vitamins C and E may have beneficial effects in patients with intestinal ischemia and reperfusion.

Support or Funding Information

NSC 98‐2320‐B‐030‐003‐MY3
Vitamin D attenuates MED28‐mediated cell growth and migration in human colon cancer cells
Authors: Hsieh Nien‐Tsu , Huang Chun‐Yin , Weng Yu‐Ting , Lee Ming‐Fen
Published: November 2023

Increasing lines of evidence indicate that vitamin D can prevent cancer progression by reducing cell proliferation and increasing cell differentiation. MED28 is both a Mediator subunit for transcriptional activation and an interactor with Grb2, Src kinases, actin cytoskeleton, and merlin. Our laboratory previously reported that MED28 regulates cell growth and migration in human breast cancer cells, indicating a role of MED28 in cancer development. Recently we have also found that MED28 mediates Wnt/β‐catenin signaling in human colon cancer cells. This study was to investigate the effect of vitamin D on MED28 in colorectal cancer. Our data indicated that MED28 not only upregulated Wnt/β‐catenin signaling but also increased the expression of fibronectin, a mesenchymal marker, and reduced the expression of E‐cadherin, an epithelial marker, in human colon cancer cells. Moreover, MED28 suppressed the expression of microRNA‐22 (miR‐22) which has been shown involved in suppressing tumor growth, migration, and invasion in colorectal cancer cells. However, vitamin D reversed these MED28‐mediated effects by downregulating the expression of MED28 at both mRNA and protein levels. Taken together, vitamin D suppresses cell growth and migration, at least partially, by targeting MED28‐regulated miR‐22 and Wnt/β‐catenin signaling in colorectal cancer.

Support or Funding Information

This work was supported by the grant NSC102‐2320‐B‐309‐001‐MY3 to M‐F Lee.
Association of Vitamin D Status with Dual Task Physical Performance in Older Adults
Authors: Lopez Johanna , Campa Adriana , Lewis John E. , Ercanli‐Huffman Fatma G. , Liuzzi Juan P. , Li Tan , Martinez Ana H. , Ferris Serena M
Published: November 2023

Objective

To evaluate the association of vitamin D status with age‐related changes in mobility and higher order cognitive function using a single and dual task physical performance test.

Methods

After consenting, participants completed the baseline assessments that included serum levels of vitamin D, vitals, anthropometrics and body composition, as well as completing surveys to evaluate physical activity, depressive symptoms and fear of falling. Participants performed in random order the physical performance tests, which included 1) walking (single gait task); 2) counting backwards from 50 by 1 (single cognitive task); and 3) walking while counting backwards from 50 by 1 (dual task). The dual task physical performance variables measured were: 1) dual task gait velocity; 2) single task gait velocity; 3) difference in dual and single task gait velocity; 4) dual task counting rate; 5) single task counting rate; 6) difference in dual and single counting rate. Paired t‐tests were used to compare single and dual task variables within the whole population and each vitamin D status group. Spearman's correlations, independent t‐tests, repeated measures ANOVAs and multiple logistic regressions were used to examine the relationship between vitamin D insufficiency (25OHD<30ng/mL) and sufficiency (25OHD≥30ng/mL) and dual task physical performance variables. The significance level was set at α≤0.05, and statistical analyzes were performed using SPSS 21.

Results

The mean +/− SD of serum vitamin D levels were 30.73 +/− 8.73 ng/ml and 46% of the participants were vitamin D insufficient. Dual and single task counting rate were significantly lower in the vitamin D insufficient group compared to the sufficient group (mean difference: −0.14, P=0.018 and mean difference: −0.06, P=0.028, respectively). Using Spearman correlations, a slower single (r=0.258, P=0.011) and dual counting rate (r=0.278, P=0.006) were significantly associated with vitamin D insufficiency.

Conclusions

Cognitive performance for dual or single tasking were worse in the vitamin D insufficient group. Since counting backward is a mental tracking task, which is a component of executive function, our results support a relationship between vitamin D insufficiency and executive dysfunction.
Assessing Dietary Intake of Minerals in the Form of Mineral Ratios may be more Informative for Evaluating their Status than by their Individual Intake
Authors: Kelly Owen Joseph , Gilman Jenifer C , Ilich Jasminka Z
Published: November 2023

Conventionally, evaluating dietary intakes of minerals in relation to their recommendations are considered on an individual basis. However, minerals are consumed in food together, and not one at a time. The objective was to analyze NHANES data from 2011–2012 and assess mineral intakes of middle‐age population, calculate the mineral ratios and compare them to the DRIs. Summarized NHANES data were accessed from the “What We Eat in America” website, and values for K, Na, Ca, P, Mg, Zn, Fe, Cu and Se are reported here. All values for minerals were converted to mg. Subsequently, the ratio of minerals within the DRI was compared to NHANES data. According to the DRIs, males and females (aged 51–70 years) should consume 8,340mg and 8,437mg of the reported minerals/d, respectively. NHANES data showed that males consumed 10,343mg while females consumed 7,866mg of those minerals, from food, in one day. According to the DRI ratios, for every 1,000mg Ca males should consume 4,700mg K, 1,500mg Na, 700mg P, 420mg Mg and 8mg Fe. However, NHANES analysis showed that males consumed 2,900mg K, 3,724mg Na, 1,460mg P, 310mg Mg and 15mg Fe for every 1,000mg Ca. Because the DRI for Ca for older females is higher, they consumed 2,910mg K, 3,362mg Na, 1,350mg P, 320mg Mg and 15mg Fe for every 1,000mg Ca. Based on the calculated ratios, the most obvious difference was between the recommended 3‐to‐1 for K/Na ratio compared to the 0.8‐to‐1 ratio actually consumed (for both males and females). This indicates that looking at deficiencies in relation to excesses, in other words, at the mineral ratios, may provide more information regarding mineral status, and may take mineral‐mineral interactions into account which might be more important than just individual values.

Support or Funding Information

No funding source.
Assessing Dietary Intake of Vitamins in the Form of Vitamin Ratios may be more Informative for Evaluating their Status than by their Individual Intake
Authors: Kelly Owen J , Gilman Jenifer C , Ilich Jasminka Z
Published: November 2023

Conventionally, dietary vitamin intakes and their DRIs are considered on a one by one basis. However, vitamins in food are consumed together, and not one at a time. Therefore, the objective was to analyze NHANES data from 2011–2012 to assess vitamin intakes of middle‐age population, calculate the vitamin ratios and compare them to the DRIs. Summarized NHANES data were accessed from the “What We Eat In America” website, for vitamins C, niacin, E, B6, riboflavin, thiamine, A, folate, K, D3 and B12. According to the DRIs males should consume 127 mg of reported vitamins/d, and females 109mg of the same vitamins/d. NHANES, for 50–59 year olds, showed that males consumed 139mg of vitamins/d and females 136mg/d, from food. Setting D3=1, the male DRI ratio suggests for every 1mg D3; 60mg A, 1,000mg E and 8mg K should be consumed. In contrast, NHANES data showed that males consumed 117mg A, 1,470mg E and 22mg K for every 1mg D3. For females, for every 1mg D3; 54mg A, 1,163mg E and 7mg K should be consumed, per DRI. However NHANES showed consumption of 164mg A, 2,055mg E and 32mg K for every 1mg D3. This suggests that the ratio of all vitamins may be more important than focusing on individual vitamin intakes. In addition, mega doses of one vitamin may have unintentional negative consequences on the actions of others.

Support or Funding Information

No funding source.
Association between Serum Levels of 25‐Hydroxyvitamin and Triglycerides in Patients with Metabolic Syndrome
Authors: Pedrosa Lucia Fatima Campos , Pereira Hermilla Torres , Cunha Aline Tuane Oliveira , Aquino Sephora Louyse Silva , Lima Severina Carla Vieira Cunha , Fayh Ana Paula Trussardi , Lima Josivan Gomes , Sena‐Evangelista Karine Cavalcante Maurício
Published: November 2023

Objective

To evaluate the association between serum levels of 25‐hydroxyvitaminD [25(OH)D] and metabolic, nutritional, sociodemographic, and environmental factors in patients with metabolic syndrome (MS).

Methods

Across‐sectional study included 103 patients (82% women) with MS seen at the endocrinology outpatient clinic of the Onofre Lopes University Hospital, Natal, Northeast Brazil. Biochemical, nutritional, sociodemographic, dietary, sun exposure, and lifestyle variables were measured. Multivariable line arregression was performed to assess associations between serum levels of 25(OH)D and covariates.

Results

The mean age of patients was 50.2 (SD=13.0) years. The mean 25(OH)D levels were 28.6 (SD=10.4) ng/ml. Approximately 40% and 20 % of patients respectively had insufficient (>20 and<30ng/ml)and deficient (<20ng/ml) levels of 25(OH)D. In the multivariate model(adjusted for age, gender, waist circumference, vitamin D intake, sun exposure, skin phototype, physical activity) 25(OH)D levels were inversely associated with triglycerides (p=0.043). This finding suggests that the increase of 1 mg/dl of triglycerides can reduce 25(OH)D levels by −0.016 ng/ml (95% CI: −0.0307, −0.0004).

Conclusion

Our results highlight the inverse association between vitamin D and triglycerides independently of the various factors evaluated.

Support or Funding Information

National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico) – CNPq, Brazil; grant 471761/2013‐3
Absorption of Iron in Caco‐2 Cells Evaluated by Ferritin Upregulation from Five Dietary Supplement Iron Sources
Authors: Morgan Shane , Hartle Jennifer W
Published: November 2023

The purpose of this study was to use ferritin response of various commercially available dietary supplement iron sources as an indicator of iron absorption in a Caco‐2 cell model. Five iron sources were modeled: ferrous bisglycinate (FBG), ferrous asparto‐glycinate (FDG), ferrous sulfate (FS), ferric glycinate (FG), and iron polysaccharide (FP). Cells were grown in T‐25 culture flasks in a DMEM/10% FBS until maturity. Prior to treatment with the iron sources, the cell media was exchanged for a serum free MEM for 24 hours. Iron test materials were diluted to 50 μM in serum free MEM solutions at pH 7.4. Three milliliters of the test solution was added to each flask and the cultures were incubated for 3 hours. The cells were aspirated and rinsed with cold DPBS. Two milliliters RIPA buffer was added to each culture and they were incubated for four hours. Ferritin response was quantified using a commercial human ELISA kit (Abcam). It was found that the ferrous sources of iron had significantly more ferritin response than the ferric sources (p<0.05). Among the ferrous sources of iron, FBG had the highest ferritin response (120.85 ±4.71 ng), followed by FDG (113.20 ±6.54 ng) and FS (110.98 ±10.49 ng). Among the ferric sources of iron, FP had the highest ferritin response (33.91 ±4.60 ng), but it was not significantly different from the negative control (20.81 ±4.71 ng). Although it has been reported that Caco‐2 cells have iron reductase activity, it was not significantly upregulated in this trial. Alternative conditions may increase the uptake of ferric compounds for evaluation of absorption. This study did not measure the export of iron outside of the cell, and can provide indications of bioavailability potential of compounds. These results indicate that FBG had the highest total absorption of all iron sources and may be indicative of the highest bioavailability of all the tested iron sources.

Support or Funding Information

Albion
Acute effects of aerobic exercise on zinc status – a systematic review and meta‐analysis
Authors: Chu Anna , Petocz Peter , Samman Samir
Published: November 2023

Zinc is involved in numerous metabolic roles, including energy metabolism, immunity and anti‐oxidative effects. Zinc depletion leads to reductions in cardiorespiratory function and muscle endurance. Zinc losses during exercise, especially through sweat, are well documented. However, conflicting results have been reported for changes in circulating and tissue zinc concentrations following exercise. The present systematic review aims to quantify the acute effects of aerobic exercise on markers of zinc status in humans. We conducted a systematic review of peer‐reviewed papers published up to December 2014 for studies that investigated the acute effects of exercise on zinc biomarkers. Meta‐analyses were conducted to determine the changes in serum zinc concentration following exercise. Forty‐five studies were included in the systematic review. Sufficient data were available from 34 studies (46 comparisons) to quantify the change in serum zinc following exercise. Serum zinc concentration significantly increased immediately after exercise (0.45 ± 0.12 μmol/L, P < 0.001; mean ± SE). Serum zinc level was higher after exercising maximally (0.77 ± 0.20 μmol/L, P<0.001), running (0.71 ± 0.26 μmol/L, P = 0.006) and in untrained individuals (0.65 ± 0.19 μmol/L, P = 0.001). During exercise recovery, serum zinc concentration was lower than pre‐exercise values (−1.31 ± 0.22 μmol/L, P < 0.001). This systematic review and meta‐analysis indicated significant changes in serum zinc concentration following aerobic exercise, suggesting acute perturbations in zinc homeostasis. Greater disturbances in serum zinc levels are observed following high intensity exercise in previously inactive individuals. Further research is required to ascertain the clinical implications for exercise prescription and dietary management in chronic disease, where suboptimal zinc status may co‐exist.
Zip14 (Slc39A14) is critical to modulate inflammatory responses in murine skeletal muscle
Authors: Kim Jinhee , Aydemir Tolunay Beker , Cousins Robert J.
Published: November 2023

Skeletal muscle has primarily a contractile function that is accompanied with secretion of molecules that act through autocrine, paracrine, and endocrine modes of action. Some of these muscle‐derived factors are induced during inflammation. The cytokine IL‐6 is produced in muscle and responds to inflammation and endotoxemia induced by LPS (endotoxin). Zinc metabolism is altered during endotoxemia. In this context, specific zinc transporters respond to endotoxemia. Using LPS administration to mice, we identified that expression of a relatively few zinc transporter genes were up‐regulated in skeletal muscle after LPS. At the transcript level, Zip14, a transporter associated with cellular zinc uptake, was the most highly upregulated of all 24 zinc transporter mRNAs in response to LPS administration. LPS also altered the zinc concentration in skeletal muscle. We hypothesized that Zip14 plays an important role in muscle during inflammation such as IL‐6 production. To determine the potential role of muscle Zip14 during inflammation, we used female wild type (WT) and Zip14 KO mice administered LPS by intraperitoneal injection. Interestingly, TNFα and IL‐6 mRNA expression in skeletal muscle of Zip14 KO mice over time was greater than in WT mice. The increased IL‐6 production and concurrent activation of the NF‐kB pathway, which was greater in the Zip14 KO mice, is suggestive of a regulatory role of Zip14 in skeletal muscle during inflammation. Hence, Zip14 may be an important factor to control zinc homeostasis and metabolic signaling in skeletal muscle during inflammation, suggesting a strong correlation between Zip14 and cytokines with the innate immune system, host defense, chronic disease and aging.

Support or Funding Information

Supported by grant DK94244 from the National Institutes of Health.
Zinc Supplementation and Antioxidant Activity in Adult Women in Rural Southern Ethiopia
Authors: Bogale Alemtsehay , Stoecker Barbara J.
Published: November 2023

Accumulating evidence suggests that zinc plays a significant role in antioxidant defense mechanisms and protects cellular components from oxidation. This study evaluated effects of 20 mg zinc supplementation for 23 days on antioxidant activity and oxidative stress biomarkers in blood and urine of women from resource limited households. Adult women (n=48) participated in this randomized double blind, placebo‐controlled trial. Participants were randomly assigned to placebo or zinc groups. Socio‐demographic and dietary diversity data were collected at baseline. Blood and urine samples were collected at baseline and end of the study. Enzyme‐linked immunosorbent assay kits were used to measure several antioxidant activity and oxidative stress biomarkers in plasma, erythrocytes and urine. Mean ± SD age of participants was 33 ± 5 and household size was 7 ± 3. Dietary diversity score was 4.5 ± 1 out of 12 food groups. Mean tropical livestock units per household was 2 ± 1. None of the participants reported consuming meat, fish or egg in the 24 h prior to the survey. Ferric reducing ability of plasma (FRAP), 8‐hydroxydeoxyguanosine (8‐OHdG), malondialdehyde (MDA), superoxide dismutase (SOD), urinary 8‐isoprostane and the other biomarkers measured were not changed significantly in response to zinc supplementation. However, increases representing oxidative damage were observed in 8‐OHdG (p = 0.013) and 8‐isoprostane (p = 0.002) in the placebo group. Although antioxidant activity biomarkers did not differ significantly between baseline and endpoint within the zinc‐supplemented group, they tended to remain higher while some oxidative stress markers tended to remain lower in that group than in the placebo group. Thus, the findings warrant further investigation of these biomarkers

Support or Funding Information

Supported by Oklahoma State University and W3002 Multistate Project
Functional Diversity of Novel Disease Mutations in the Unfolded Protein Response regulator, ATF6
Authors: Chiang Wei‐Chieh , Chan Priscilla , Lin Jonathan H.
Published: November 2023

The endoplasmic reticulum (ER) is essential for secretory and membrane protein synthesis, folding, and assembly. Increase of protein misfolding creates ER stress, activating the Unfolded Protein Response (UPR). In response to ER stress, a key regulator of UPR, ATF6, undergoes regulated intra membrane proteolysis to release its cytosolic bZIP transcriptional activator domain to transcriptionally upregulate genes encoding chaperone and enzymes required for ER protein folding and ER homeostasis, such as Grp78/BiP. We recently identified novel mutations in Atf6 gene associated with a human disease, achromatopsia, characterized by loss of cone photoreceptor function and progressive cone photoreceptor cells death. These mutations are found through out Atf6 gene, producing splice variants, truncated protein, or missense mutant protein. In response to ER stress, some of the Atf6 mutations attenuate ATF6 transcriptional activity. However, other Atf6 mutations create constitutively active protein. The functional diversity of ATF6 mutants suggests that multiple mechanisms can contribute to the pathology of achromatopsia caused by mutations in Atf6 gene.
Rip3 Forms Different Complexes Leading to Apoptosis or Necrosis
Authors: Li Wenjuan
Published: November 2023

We have previously reported (Chen X, Cell Res, 2014 Jan; 24(1):105–210) that MLKL oligomerization leads to translocation of MLKL to lipid rafts of the plasma membrane, and that the plasma membrane MLKL complex acts either by itself or via other proteins to increase sodium influx, which increases osmotic pressure, eventually leading to membrane rupture. Recently, we find that MLKL functions not only as the downstream substrate of Rip3, but also as a regulator of Rip3 status, which would form different complex structures leading to cell survival, apoptosis or necrosis. We also identified some components that block Rip3‐dependent necrosis; these component acts quite differently from GSK872, a kinase inhibitor of Rip3. These compounds effect the interaction between Rip3 and MLKL, leaving Rip3 in a transition state, which delays Rip3‐dependent necrosis and does not induce Rip3‐dependent apoptosis.

Support or Funding Information

This work was supported by the National Basic Research Program of China (973 Program; 2013CB944903 and 2014CB541804), the National Natural Science Foundation of China (31330047, 91029304 and 31221065), the Hi‐Tech Research and Development Program of China (863 program; 2012AA02A201), the 111 Project (B12001), and the Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2012KF003).
Gingival cell smoke exposure disrupts skeletal muscle metabolic function
Authors: Laub Samantha G. , Taylor Oliver J. , Reynolds Paul R. , Bikman Benjamin T.
Published: November 2023

Cigarette smoke exposure compromises health through damaging multiple physiological systems, including disrupting skeletal muscle metabolic function. The purpose of this study was to determine the role of oral gingiva in mediating the deleterious metabolic effects of cigarette smoke exposure on skeletal muscle metabolic function. Using an in vitro conditioned‐medium cell model, skeletal muscle cells were incubated with medium from gingival cells treated with normal medium or medium containing suspended cigarette smoke extract (CSE). Following incubation of muscle cells with gingival cell conditioned medium, muscle cell mitochondrial respiration and insulin signaling and action were determined as an indication of overall muscle metabolic health. Skeletal muscle cells incubated with conditioned medium of CSE‐treated gingival cells had a profound reduction in mitochondrial respiration and respiratory control. Furthermore, skeletal muscle cells had a greatly reduced response in insulin‐stimulated Akt phosphorylation and glycogen synthesis. Altogether, these results provide a novel perspective on the mechanism whereby cigarette smoke affects systemic metabolic function. In conclusion, we found that oral gingival cells treated with CSE create an altered milieu that is sufficient to both disrupt skeletal muscle cell mitochondrial function and insulin sensitivity.
Celiac disease: role of intestinal compartments in the mucosal immune response
Authors: Iaquinto Gaetano , Aufiero Vera Rotondi , Iacomino Giuseppe , Mazzarella Giuseppe , Schettino Michele , Masucci Armando
Published: November 2023

Background

Different approaches have been used to study the pattern of cytokines in celiac disease (CD). Laser capture microdissection (LCM) is a powerful tool for the isolation of specific tissue compartments. We aimed to investigate the mucosal immune response that takes place in different intestinal compartments of CD patients, dissected by LCM, analyzing cytokine expression profile

Methods

Frozen section of jejunum were obtained from 15 untreated CD and 15 control. Surface epithelium and lamina propria compartment were isolated by LCM. RNA from each LCM sample was extracted and, after a retrotranscription step, messenger RNA (mRNA) levels for MxA, IL‐15, TNF‐α, IFN‐γ, IL‐17α, IL‐21, IL‐10 and TGF‐β were determined by quantitative reverse transcriptase‐PCR.

Results

Increased gene expression levels of MxA, IL‐15, TNF‐α, IL‐10 and TGF‐β in the surface epithelium of untreated CD with respect to control. Furthermore, all the cytokines investigated were upregulated in the lamina propria of untreated CD as compared to control. Within the untreated CD group the expression of IL‐15 was higher, in the surface epithelium than in the lamina propria, whereas the expression of IL‐17 and IL‐21 were higher in the lamina propria than in the surface epithelium. Finally, high levels of IL‐10 and TGF‐β were detected in both compartments of untreated CD biopsies.

Conclusion

In CD, surface epithelium and lamina propria compartments, play a prominent role in determining innate and adaptive immunity, respectively. Conversely, surface epithelium and lamina propria produce high levels of anti‐inflammatory cytokines, suggesting that both compartments are involved in the immunoregulatory response.
Echinacea Purpurea Down Regulates LPS‐induced Expression of Pro‐inflammatory and Angiogenic Factors in An Ex Vivo Model of Equine Placentitis
Authors: Sloboda Cole , Chico Sarah , Gordon Jacob , Bailey Scott , Zwetsloot Kevin A. , Mowa Chishimba
Published: November 2023

Equine placentitis is a hard‐to‐diagnose infectious condition, which affects 3–7% of pregnancies. It represents the most common cause of late‐term abortion and neonatal disease. Current treatment protocols include antibiotic, as well as anti‐inflammatory therapeutics to mitigate the effects of uterine infection, but are largely empirical and have shown inconsistent effectiveness. In the current study, we tested the ability of Echinacea purpurea whole leaf extract to inhibit LPS‐induced up‐regulation of tumor necrosis factor 1 alpha (TNF) and vascular endothelial growth factor (VEGF) in ex‐vivo cultured equine placenta. Chorioallantois was harvested during c‐section of 2 mares and cultured ex vivo for 1 hour. Tissue samples of approximately 1g each were subsequently exposed to the following treatments for 6 hours in triplicate: a) negative control, RPMI media only; b) positive control, Lipopolysaccharide (LPS, 1,000 ng/well) only; c) Echinacea only (10 mg/well); d) LPS (1000ng/well) + Echinacea: low (1 mg), medium (10 mg) and high (20 mg). Tissues were incubated in treatment‐solutions at 370C and 8% CO2 for 6 hours, fixed in 10% Formalin, embedded in paraffin and sectioned for confocal immunofluorescence studies using antibodies of VEGF and TNF. Addition of Echinacea blocked the up regulation of VEGF and TNF alpha by LPS dose‐dependently. We conclude that Echinacea could potentially be used to develop therapy for equine placentitis.

Support or Funding Information

Appalachian State University, Office of Student Research.
The attenuating effects of 1,2,3,4,6 Penta‐o‐Galloyl‐β‐D‐Glucose on the inflammatory cytokines release from activated BV‐2 microglial cells
Authors: Mendonca Patricia , Bauer David , Taka Equar , Soliman Karam F.
Published: November 2023

Inflammation is a critical pathogenic mechanism involved in neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's diseases. One of the hallmarks of AD is the abnormal extracellular deposition of neurotoxic amyloid‐β (Aβ) peptides which are toxic to neurons. An inflammatory process and the activation of glial cells by a variety of factors appear to have an important role in the pathway leading to neuronal cell death. Many natural compounds derived from plants have showed antiinflammatory activity, such as 1,2,3,4,6 Penta‐O‐Galloyl‐β‐D‐Glucose (PGG), which is a polyphenolic compound isolated from Rhus chinensis Mill that exhibits multiple pharmacological activities. Moreover, PGG is a potent inhibitor of IAPP (islet amyloid polypeptide, amylin) aggregation, which can slow or possibly prevent the toxic effects of IAPP oligometic intermediates. In this study, we investigated the protective effect of PGG in BV2 microglia cells activated by LPS/IFNγ. In this experiment, BV2‐immortalized murine microglial cells were used and cytokine antibody arrays were used to assess the effect of PGG in the release of proinflammatory cytokines, and ELISA experiments were performed to validate the results from the arrays. The results obtained from the cytokine arrays showed that PGG decreased the expression of monocyte chemotactic protein‐5 (MCP‐5) and matrix metallopeptidase 9 (MMP‐9). Both of these cytokines are up regulated during the inflammatory process. The results obtained demonstrate the ability of PGG to inhibit MCP‐5 and MMP‐9 synthesis in activated BV2 microglia cell. Up‐regulation of MMP‐9 and MCP‐5 has a great effect upon brain injury, inflammation, and neurodegeneration. Therefore, PGG inhibition effects on the release of these cytokines may provide novel therapeutic agent to treat brain inflammation and may be useful in delaying the onset of microglia‐mediated neurodegenerative disorders

Support or Funding Information

NIH Grants G12 MD007582 and P20 MD 006738
Upregulation of Chemokine Ligands and Receptors in the Spinal Cord of Type 2 Diabetic Monkeys
Authors: Kiguchi Norikazu , Ding Huiping , Peters Christopher M. , Kock Nancy D. , Kishioka Shiroh , Wagner Janice D. , Cline J. Mark , Ko Mei‐Chuan
Published: November 2023

Chemokines are a family of small chemoattractant cytokines that have an important role in controlling leukocyte migration and neuron‐glia interactions. Rodent studies have demonstrated that, like other cytokines, chemokine ligands and their cognate receptors in the spinal dorsal horn (SDH) can regulate both acute and chronic/neuropathic pain. Given the high prevalence of pain in patients with type 2 diabetes, it is pivotal to know if chemokine ligand‐receptor systems are upregulated in diabetic primates. Therefore, the aim of this study was to determine and compare the mRNA expression levels of chemokines in the spinal cord of monkeys that had 3–6 years of spontaneously occurring type 2 diabetes (n=7) and age‐matched nondiabetic monkeys (n=6). Chemokine mRNA expressions were analyzed by real‐time RT‐PCR in the SDH of these cynomolgus monkeys. CC‐chemokine ligands, CCL2 (MCP‐1) and CCL3 (MIP‐1alpha), mRNA expression levels were upregulated in the SDH of diabetic monkeys. In addition, their cognate receptors, CC‐chemokine receptors CCR1, CCR2, and CCR5, mRNA levels were upregulated in the SDH. Expression levels of these ligands and receptors mRNA were also higher in the spinal ventral horn of diabetic monkeys. Among numerous chemokines examined, CX3CL1 (Fractalkine) and CX3CR1 are the most highly expressed genes in the spinal cord. However, their expression levels did not differ between diabetic and nondiabetic monkeys. These results indicate that at least two chemokine ligand‐receptor systems (i.e., CCL2‐CCR2 and CCL3‐CCR1/CCR5) were upregulated in the spinal cord of type 2 diabetic monkeys, which is widely regarded as a clinically relevant model. This first‐in‐primate study opens a new avenue to study the functional roles of chemokines and their cognate receptor antagonists for modulating pain in diabetic primates.

Support or Funding Information

Supported by US‐PHS grants AR‐059193 and DA‐032568
Granzyme B Disrupts Epithelial Barrier Function
Authors: Santacruz Stephanie , Parkinson Leigh , Granville David
Published: November 2023

The epithelium functions as a barrier to the external environment, which is maintained in large part by cell junctions. Age‐related and chronic inflammatory conditions of the skin result in a loss of epithelial barrier integrity through the degradation of cell adhesion proteins. Granzyme B (GzmB) is a serine protease that accumulates in the extracellular milieu in a number of autoimmune skin conditions. As such, GzmB may contribute to the progressive loss of epithelial barrier function. We hypothesized that GzmB disrupts epithelial barrier function through the proteolytic cleavage of cell junction proteins. Human keratinocytes were treated with exogenous GzmB, in the presence or absence of a GzmB inhibitor. Subsequently, epithelial barrier function was assessed by Electric Cell‐substrate Impedance Sensing (ECIS) and immunofluorescence (confocal) microscopy was used to visualize E‐cadherin. GzmB treatment resulted in a loss of E‐cadherin staining on the cell membrane which was further supported by western blot analysis of cell supernatants and biochemical cleavage assays, where we observed a dose‐dependent increase in E‐cadherin fragmentation. E‐cadherin cleavage was markedly decreased when treated with a GzmB inhibitor. Moreover, ECIS analysis showed a noticeable decline in barrier function after GzmB treatment. In summary, GzmB contributes to a decline in epithelial barrier function in part through the proteolytic cleavage of E‐cadherin.

Support or Funding Information

BC Lung Association
Wound Healing in a Model of Systemic Lupus Erythematosus may be Delayed by a Lack of Interleukin‐2
Authors: Doersch Karen Melissa , Newell‐Rogers M Karen
Published: November 2023

Objective

The purpose of this study is to examine the mechanism of delayed wound closure in a mouse model of Systemic Lupus Erythematosus (SLE).

Background

SLE is a common and devastating autoimmune disease with symptoms that include skin changes and poor wound healing. SLE patients are frequently deficient in Interleukin‐2. Quercetin is known to alter the apoptosis‐verses‐proliferation balance and also to decrease Interleukin‐2 production by immune cells. This study uses quercetin to perturb wound healing in a mouse model of SLE and seeks to examine the Interleukin‐2‐dependent mechanism by which wounds in SLE patients fail to heal appropriately.

Hypothesis

Decreased Interleukin‐2 delays and perturbs wound healing in SLE.

Methods

Fas‐deficient (LPR), and Fas‐Ligand mutant (GLD) mice served as the SLE model. These mice were wounded with an 8 mm biopsy punch, treated daily with intraperitoneal injections of quercetin and compared to wild‐type quercetin‐treated mice. Wounds were measured with calipers and lymphocyte frequencies and Interleukin‐2 receptor expression were measured by flow cytometry.

Results

Quercetin administration to LPR and GLD mice delayed wound healing compared with wild‐type mice. At day 10 post‐wounding, LPR and GLD mice had decreased percentages of both T‐helper and cytotoxic T lymphocytes in the draining lymph nodes of the wounds compared to wild‐type. This decrease in T‐cells may prevent adequate cytokine production at the wound site. Furthermore, CD4‐CD8‐ lymphocytes accumulate in LPR and GLD mice and express high levels of Interleukin‐2 receptor that can remove Interleukin‐2 from the wound environment. These cells appear to modulate the impaired wound closure.

Conclusions

Quercetin impairs wound healing in SLE‐model mice, possibly in an Interleukin‐2 dependent manner. This study describes a novel model for understanding delayed wound healing in SLE and identifies Interleukin‐2 as a treatment target for wound healing in patients with SLE.

Support or Funding Information

Scott and White Foundation, Texas A&M Health Science Center College of Medicine
Soluble VE‐cadherin contributes to loss of VE‐cadherin‐mediated adhesion and endothelial barrier function
Authors: Flemming Sven , Burkard Natalie , Renschler Melanie , Vielmuth Franziska , Meir Michael , Schick Martin , Wunder Christian , Germer Christop‐Thomas , Spindler Volker , Waschke Jens , Schegel Nicolas
Published: November 2023

Endothelial barrier breakdown in systemic inflammation and sepsis is a hallmark preceding organ failure and death in patients. Vascular endothelial (VE)‐cadherin‐mediated adhesion represents a crucial determinant of endothelial barrier integrity. Previously we demonstrated that under inflammatory conditions the disintegrin and metalloproteinase 10 (ADAM10) caused shedding of VE‐cadherin which resulted in the formation of soluble VE‐cadherin (sVE‐cadherin) in close temporal correlation of inflammation‐induced endothelial barrier disruption. Here we further characterized ADAM10‐induced VE‐cadherin shedding and tested whether recombinant sVE‐cadherin inferes VE‐cadherin mediated adhesion.

First we identified possible cleavages sites of VE‐cadherin by mass spectrometry (MSM). Therefore, digestion of recombinant VE‐cadherin (rVE‐cadherin) with recombinant ADAM10 was performed. This led to the formation of sVE‐cadherin at 90 and 110kDa, as shown by coomassie stained gel an western blot, which correlated with several cleavage sites of the extracellular domain of VE‐cadherin. MSM showed only peptides up to 452 amino acids (aa) and one peptide at 503–530 aa, which also corresponds to the extracellular domains 1–5 of human VE‐cadherin. Additionally two other cleavage sites at 80–127aa and 160–175aa were observed. In the next step we performed atomic force microscopy measurements in a cell free sytem to test whether sVe‐cadherin blocked VE‐cadherin‐mediated adhesion. In these experiments both, sVE‐cadherin and rVE‐cadherin blocked VE‐cadherin‐mediated adhesion. Accordingly, application of rVE‐cadherin on Human dermal microvascular endothelial cells (HDMECs) resulted in a dose‐dependent loss of endothelial barrier functions as revealed by measurements of transendothelial electrical resistance (TER). In immunostaining of endothelial monolayers incubation with rVE‐cadherin led to intercellular gap formation.

In summary our data demonstrate specific cleavage sites of VE‐cadherin by ADAM10. The resulting sVE‐cadherin fragments interfere VE‐cadherin mediated adhesion and thereby contribute to loss of endothelial barrier disruption. This may play a novel role in inflammation‐induced endothelial barrier breakdown.

Support or Funding Information

The present study was supported by grants from the German Research Foundation (DFG) to N.S. (Grant numbers: SCHL1962/2‐1 and SCHL 1962/4‐1).