Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates.

SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17ß-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.

Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates.

SLC22A10 is classified as an orphan transporter with unknown substrates and function. Here we describe the discovery of the substrate specificity and functional characteristics of SLC22A10. The human SLC22A10 tagged with green fluorescent protein was found to be absent from the plasma membrane, in contrast to the SLC22A10 orthologs found in great apes. Estradiol-17ß-glucuronide accumulated in cells expressing great ape SLC22A10 orthologs (over 4-fold, p<0.001). In contrast, human SLC22A10 displayed no uptake function. Sequence alignments revealed two amino acid differences including a proline at position 220 of the human SLC22A10 and a leucine at the same position of great ape orthologs. Site-directed mutagenesis yielding the human SLC22A10-P220L produced a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes show human-like sequences at proline 220 position, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after the divergence from the pan lineage (chimpanzees and bonobos). These findings demonstrate that human SLC22A10 is a unitary pseudogene and was inactivated by a missense mutation that is fixed in humans, whereas orthologs in great apes transport sex steroid conjugates.

Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates.

SLC22A10 is classified as an orphan transporter with unknown substrates and function. Here we describe the discovery of the substrate specificity and functional characteristics of SLC22A10. The human SLC22A10 tagged with green fluorescent protein was found to be absent from the plasma membrane, in contrast to the SLC22A10 orthologs found in great apes. Estradiol-17ß-glucuronide accumulated in cells expressing great ape SLC22A10 orthologs (over 4-fold, p<0.001). In contrast, human SLC22A10 displayed no uptake function. Sequence alignments revealed two amino acid differences including a proline at position 220 of the human SLC22A10 and a leucine at the same position of great ape orthologs. Site-directed mutagenesis yielding the human SLC22A10-P220L produced a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes show human-like sequences at proline 220 position, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after the divergence from the pan lineage (chimpanzees and bonobos). These findings demonstrate that human SLC22A10 is a unitary pseudogene and was inactivated by a missense mutation that is fixed in humans, whereas orthologs in great apes transport sex steroid conjugates.

Gingival crevicular fluid lipocalin-2 and semaphorin3A in stage III periodontitis: Non-surgical periodontal treatment effects.

BACKGROUND AND OBJECTIVE: Identification of biomarkers to assess individual risk and monitor periodontal health status is important. Research on lipocalin-2 (LCN2) and semaphorin3A (Sema3A) is lacking. This study aimed to evaluate gingival crevicular fluid (GCF) LCN2, Sema3A, and tumor necrosis factor-α (TNF-α) levels in periodontally healthy (H), gingivitis (G), and periodontitis (P) patients, and their changes following non-surgical periodontal therapy. METHODS: Sixty systemically healthy and non-smoker participants, diagnosed as periodontally healthy, gingivitis, and stage III grade C periodontitis, were recruited (n = 20/group). Clinical periodontal parameters were recorded and GCF samples were obtained at baseline from all groups; for group P, these were repeated one and three months following non-surgical periodontal treatment. GCF LCN2, Sema3A, and TNF-α levels were evaluated with enzyme-linked immunosorbent assay. RESULTS: GCF LCN2, Sema3A, and TNF-α total amounts were significantly higher in disease groups than group H (p < .001). Between P and G groups, only TNF-α levels were significantly different (p < .001). Non-surgical periodontal therapy resulted in significant improvement of all clinical parameters and significant decreases of GCF LCN2 and TNF-α levels, at both time points, compared with baseline (p < .001). Sema3A levels remained unchanged following treatment (p > .05). LCN2 and TNF-α levels were significantly positively correlated with clinical parameters. LCN2 (AUC [area under the curve] = 0.94) and TNF-α (AUC = 0.98) levels were similarly accurate in differentiating between periodontal disease (whether G or P) and healthy controls. CONCLUSIONS: LCN2 and TNF-α levels in GCF are correlated with clinical parameters and could prove useful as non-invasive screening tools for periodontitis.

Evaluation of the safety and efficacy of AdvaxTM as an adjuvant: A systematic review and meta-analysis.

PURPOSE: Developing a vaccine with improved immunogenicity is still a growing priority for many diseases. Different types of adjuvants may be beneficial to initiate and maintain the long-lasting immunogenicity of vaccines. Evidence has shown that polysaccharide adjuvants are efficient in improving immunological mechanisms with their biocompatibility and biodegradability characteristics. In this study, we aimed to investigate the safety and efficacy of AdvaxTM an adjuvant derived from delta inulin. METHODS: A systematic research was performed in Pubmed, Web of Science, and Scopus databases for the following keywords; "AdvaxTM" OR "delta inulin" until December 14th, 2020. RevMan 5.4.1 software was used for cumulative meta-analysis and bias analysis. We also used GraphPad Prism 6 software for the figures. RESULTS: In the cumulative meta-analysis, it was found that seroconversion and geometric mean titers (GMT) levels significantly increased in AdvaxTM-adjuvanted group (mean difference: 12.31, 95% Cl [4.14, 20.47], p â€‹= â€‹0.003; 17.10, 95% Cl [4.35, 29.85], p â€‹= â€‹0.009, respectively). We also observed that AdvaxTM could be effective in improving immunogenicity by inducing T-cell responses and plasmablast generation in viral vaccines. CONCLUSIONS: In this study, it was shown that AdvaxTM is a safe and well-tolerated adjuvant. AdvaxTM could be a potent adjuvant in increasing the protection and immunogenicity of different vaccines without safety issues. However, further studies are needed to verify these effects of AdvaxTM adjuvant.

Serum midkine level might be a diagnostic tool for COVID19 disease in pregnancy: From the disease severity, hospitalization and disease progression respects.

BACKGROUND: New biomarkers for diagnosis and monitoring the COVID-19 disease are the most important topics to be studied recently. We aimed to investigate the association between midkine levels and disease severity in pregnant women with COVID-19. METHODS: Totally 186 pregnant women were participated in this study. 96 of them were healthy pregnant women, 90 of them were pregnant women with COVID19. Pregnant women were evaluated according to their trimesters. Serum midkine level, biochemical profile clinical and disease severity outcomes of pregnant women were obtained. RESULTS: Our results showed that pregnant women with COVID19 have significantly increased serum midkine level compared to healthy pregnant women (1.801 ± 0.977 vs 0.815 ± 0.294 ng/dL). According to the data among each trimester, it was shown that there were significant increase in serum midkine level during all pregnancy trimesters (1st trimester Control Group: 0.714 ± 0.148, COVID-19 group 1.623 ± 0.824, p < 0.0001; 2nd trimester Control Group: 0.731 ± 0.261, COVID-19 group 2.059 ± 1.146, p < 0.0001; 3rd trimester Control Group: 1.0 ± 0.35, COVID-19 group 1.723 ± 0.907, p = 0.001). Serum midkine levels were significantly different between disease severity subgroups of pregnant women with COVID19; moderate and severe/critic groups had significantly higher serum midkine level than mild group. There was also significant correlation between serum midkine level and severity status (p:0.0001, r: 0.468). The most striking results of serum midkine levels were corelation between length of hospitalization (p: 0.01, r: 0.430) and O2 saturation (p < 0.0001, r: -0.521). ROC curve analysis showed that serum midkine level might be a tool for predicting COVID-19 in pregnant women with COVID-19 (AUC: 0.912, 95% CI: [0.871, 0.952], p < 0.0001) CONCLUSION: Our data showed that there is an obvious relation between COVID19 progression and serum midkine level for the first time which might be used for monitoring the disease process.

Maternal selenium status plays a crucial role on clinical outcomes of pregnant women with COVID-19 infection.

Adequate maternal selenium level is essential for immune response and healthy pregnancy. This study aimed to shed light on the selenium status of pregnant women with COVID-19 and the effects of potential deficiency in serum selenium levels. Totally 141 pregnant women, 71 of them were COVID-19 patients, in different trimesters were included in the study. Maternal serum selenium levels, demographic and clinical parameters were determined. Serum selenium levels of pregnant women in the second (p: .0003) and third (p: .001) trimesters with COVID-19 were significantly lower than in the healthy group. Maternal selenium level was found to be negatively correlated with gestational week (p < .0001, r: -.541), D-dimer (p: .0002, r: -.363) and interleukin-6 (IL-6) level (p: .02, r: -.243). In the second trimester, serum selenium level positively correlated with white blood cell (p: .002, r: .424), neutrophil (p: .006, r: .39), lymphocyte (p: .004, r: .410) count and hemoglobin (p: .02, r: .323), hematocrit (p: .008, r: .38) status. In the third trimester, it was found that maternal selenium level positively correlated with monocyte (p: .04, r: .353) and negatively correlated with C-reactive protein level (p: .03, r: -.384). Serum selenium level was gradually decreased during the pregnancy period, however, this natural decrease was enhanced together with COVID-19 infection. The reason might be increased selenium needs depended on the immune response against infection. The decrease in maternal selenium level was found to be related to IL-6 and D-dimer levels, which indicate selenium's role in disease progression.

The Effects of Zinc Supplementation on C-Reactive Protein and Inflammatory Cytokines: A Meta-Analysis and Systematical Review.

Zinc is known for anti-inflammatory and antioxidant roles. In this meta-analysis, we aim to evaluate the impact of zinc supplementation on inflammatory markers, acute-phase reactants, and serum zinc level during inflammatory and infectious diseases. PubMed, Scopus, and Web of Science databases were screened systematically with the terms "zinc supplementation" AND "CRP" OR "IL-1ß" OR "IL-2" OR "IL-6" OR "IL-10" OR "IL-12" OR "TNF-α" OR "TGF-ß" OR "IFN-γ" OR "WBC (clinical trial)" OR "macrophage (clinical trial)" OR "lymphocyte (clinical trial)" OR "neutrophil (clinical trial)" OR "virus (clinical trial)" OR "antiviral (clinical trial)" for all databases. A total of 2,258 publications were screened, and 73 articles had suitable data for the meta-analysis. Serum zinc level was significantly higher in supplementation group compared with controls [P = 0.0006, mean difference: 11.35 (4.84, 17.87)] (n = 37). Zinc supplementation downregulates acute-phase reactants, especially serum C-reactive protein (CRP) in adults [P < 0.00001, mean difference: -0.75 (-0.98, -0.52)] (n = 22) and pregnant women [FEM P < 0.00001, mean difference: -1.77 (-2.53, -1.00)] (n = 3) but not in children [REM P = 0.10, mean difference: -0.85 (-1.86, 0.17)] (n = 3). In subgroups analysis of chronic inflammatory diseases, serum CRP [REM P < 0.00001, mean difference: -0.57 (-0.76, -0.38)] were significantly lower in zinc-supplemented patients compared with no intervention group. Zinc supplementation (mg/day) correlated with serum interferon-gamma (IFN-γ) level (P = 0.018, r = 1,000). In the nonsupplemented group, serum zinc correlated with serum interleukin-6 (IL-6) level (P = 0.041, r = -0.829) and serum tumor necrosis factor alpha (TNF-α) level (P = 0.063, r = 0.730). Zinc intake correlated with serum zinc (P = 0.0428, r = 0.5115) and TNF-α (P = 0.0043, r = -0.9461). This meta-analysis shows that zinc supplementation improves CRP levels in adults and pregnant women. It might have modulatory effects on cytokine secretions and blood cells in inflammatory and infectious diseases. For the first time, we investigated the effects of zinc supplementation on inflammatory cytokine.

Is Zinc an Important Trace Element on Bone-Related Diseases and Complications? A Meta-analysis and Systematic Review from Serum Level, Dietary Intake, and Supplementation Aspects.

Bone-related diseases are very common problems, especially in the elderly population. Zinc takes part in the growth and maintenance of healthy bones. This meta-analysis aims to evaluate the effects of zinc supplementation or dietary zinc intake on serum zinc levels and bone turnover markers. A systematical research was performed with 2899 articles in PubMed, WoS, and Scopus for relevant articles in English which have mean/standard deviation values of serum zinc levels, dietary zinc intake/zinc supplementation (mg/day), and bone turnover markers up to February 2020. In the overall analysis, serum zinc level was significantly lower in patients with osteoporosis compared with controls (p 0.0002). Dietary zinc intake decreased in the fracture group compared with controls according to subgroup analysis patients with fracture (p 0.02). Zinc supplementation was effective on the femoral neck (p < 0.0001) and lumbar spine (p 0.05) bone mineral density (BMD). In the correlation analysis of the data obtained from all of the included studies, serum osteocalcin (p 0.0106, r - 0.9148) correlated with serum zinc level. In conclusion, serum zinc level and dietary zinc intake could have an essential role in preventing osteoporosis. Zinc supplementation might improve bone turnover markers for bone formation such as serum osteocalcin and serum alkaline phosphatase and also, BMD at the site of the femoral neck.

Transcriptomic analysis reveals responses to Cycloastragenol in Arabidopsis thaliana.

Cycloastragenol (CAG), a molecule isolated from 'Astragalus membranaceus', stimulates the telomerase activity and cell proliferation significantly. It has been proven that CAG has the ability to prevent some diseases in humans. In this study, we aimed to figure out the CAG effects on the different signaling mechanisms in plants and to broadly analyze the genome-wide transcriptional responses in order to demonstrate CAG as a new key molecule that can potentially help plants to overcome different environmental stresses. RNA-seq strategy was employed to assess the transcriptional profiles in A. thaliana calli. Our work primarily focused on an overall study on the transcriptomic responses of A. thaliana to CAG. A total of 22593 unigenes have been detected, among which 1045 unigenes associated with 213 GO terms were differentially expressed and were assigned to 118 KEGG pathways. The up-regulated genes are principally involved in cellular and metabolic processes in addition to the response to a stimulus. The data analysis revealed genes associated with defense signaling pathways such as cytochrome P450s transporter, antioxidant system genes, and stress-responsive protein families were significantly upregulated. The obtained results can potentially help in better understanding biotic and/or abiotic tolerance mechanisms in response to CAG.