Absorption Pathways Research Articles

Development of lipophilic ester prodrugs of dolutegravir for intestinal lymphatic transport

The establishment of latent cellular and anatomical viral reservoirs is a major obstacle to achieving a cure for people infected by HIV. Mesenteric lymph nodes (MLNs) are one of the most important anatomical reservoirs of HIV. Suboptimal levels of antiretroviral (ARVs) drugs in these difficult-to-penetrate viral reservoirs is one of the limitations of current antiretroviral therapy (ART) regimens. This study aimed to design and assess highly lipophilic ester prodrugs of dolutegravir (DTG) formulated with long-chain triglyceride (LCT) for delivery of DTG to the viral reservoir in mesenteric lymph and MLNs. A number of alkyl ester prodrugs of DTG were designed based on the predicted affinity to chylomicrons (CM), and the six most promising prodrugs were selected and synthesised. The synthesised prodrugs were further assessed for their intestinal lymphatic transport potential and biotransformation in biorelevant media in vitro and ex vivo. DTG and the most promising prodrug (prodrug 5) were then assessed in pharmacokinetic and biodistribution studies in rats. Although oral administration of 5 mg/kg of unmodified DTG (an allometrically scaled dose from humans) with or without lipids achieved concentrations above protein binding-adjusted IC90 (PA-IC90) (64 ng/mL) in most tissues, the drug was not selectively targeted to MLNs. The combination of lipophilic ester prodrug and LCT-based formulation approach improved the targeting selectivity of DTG to MLNs 4.8-fold compared to unmodified DTG. However, systemic exposure to DTG was limited, most likely due to poor intestinal absorption of the prodrug following oral administration. In vitro lipolysis showed a good correlation between micellar solubilisation of the prodrug and systemic exposure to DTG in rats in vivo. Thus, it is prudent to include in vitro lipolysis in the early assessment of orally administered drugs and prodrugs in lipidic formulations, even when intestinal lymphatic transport is involved in the absorption pathway. Further studies are needed to clarify the underlying mechanisms of low systemic bioavailability of DTG following oral administration of the prodrug and potential ways to overcome this limitation.

Population Pharmacokinetic Analysis Supports Initiation Treatment and Bridging from Sublingual Buprenorphine to Subcutaneous Administration of a Buprenorphine Depot (CAM2038) in the Treatment of Opioid Use Disorder.

In treating opioid use disorder (OUD), subcutaneous (SC) extended-release buprenorphine (BPN) depots, e.g.,CAM2038, have been shown to provide smaller and less frequent fluctuations in BPN plasma concentrations and pharmacodynamic responses, improve outcomes, reduce treatment burden, and lower risks of misuse and diversion compared to daily sublingual (SL) BPN. This analysis characterized the pharmacokinetics (PK) of BPN following intravenous and SL administration, and administration of SC CAM2038 weekly and monthly. Pharmacokinetic data from two Phase 1 and two Phase 2 trials in healthy participants and participants with OUD, respectively, were used to develop a population PK model using non-linear mixed effects modelling. The analysis included data from 252 participants and 10,658 BPN observations. The disposition of BPN was best described by a three-compartment model with first-order elimination, and absorption of SL BPN and SC CAM2038 weekly and monthly by dual parallel absorption pathways. Model diagnostics indicated good predictive performance of BPN concentrations. Buprenorphine plasma concentration-time profiles were simulated for treatment initiation, switching from SL BPN to CAM2038 weekly and monthly, and tapering after interrupting treatment with CAM2038. Simulations predicted CAM2038 weekly and monthly doses that provided BPN plasma maximum concentration (Cmax) and trough concentration (Ctrough) values at steady state within those observed following SL BPN administration. This population PK model supports the use of CAM2038 doses as individualized treatment for OUD across different treatment stages, including initiation, switching from SL BPN according to established dose conversion schedules, and tapering. ISRCTN41550730 (05/19/2014), ISRCTN24987553 (07/29/2014), NCT02611752 (11/23/2015), NCT02710526 (03/16/2016).

Integration of transcriptomics and metabolomics reveals the responses of the maternal circulation and maternal-fetal interface to LPS-induced preterm birth in mice.

Term birth (TB) and preterm birth (PTB) are characterized by uterine contractions, rupture of the chorioamniotic membrane, decidual activation, and other physiological and pathological changes. In this study, we hypothesize that inflammation can cause changes in mRNA expression and metabolic stability in the placenta, decidua, chorioamniotic membrane, uterus and peripheral blood, ultimately leading to PTB. To comprehensively assess the effects of inflammation on mRNA expression and metabolite production in different tissues of pregnancy, we used a mouse PTB model by intraperitoneally injecting lipopolysaccharide (LPS) and integrated transcriptomics and metabolomics studies. Our analysis identified 152 common differentially expressed genes (DEGs) and 8 common differentially expressed metabolites (DEMs) in the placenta, decidua, chorioamniotic membrane, uterus, and peripheral blood, or placenta and uterus after LPS injection, respectively. Our bioinformatics analysis revealed significant enrichment of the NOD-like receptor signaling pathway (mmu04621), TNF signaling pathway (mmu04668), IL-17 signaling pathway (mmu04657), and NF-kappa B signaling pathway in the transcriptomics of different tissues, and Hormone synthesis, Lysosome, NOD-like receptor signaling pathway, and Protein digest and absorption pathway in metabolomics. Moreover, we found that several upstream regulators and master regulators, including STAT1, STAT3, and NFKB1, were altered after exposure to inflammation in the different tissues. Interaction network analysis of transcriptomics and metabolomics DEGs and DEMs also revealed functional changes in mice intraperitoneally injected with LPS. Overall, our study identified significant and biologically relevant alterations in the placenta, decidua, chorioamniotic membrane, uterus, peripheral blood transcriptome and the placenta and uterus metabolome in mice exposed to LPS. Thus, a comprehensive analysis of different pregnancy tissues in mice intraperitoneally injected with LPS by combining transcriptomics and metabolomics may help to systematically understand the local and systemic changes associated with PTB caused by inflammation.

SNP rs11185644 in RXRA gene and SNP rs2235544 in DIO1 gene predict dosage requirements in a cross-sectional sample of hypothyroid patients

Background and purposePrimary hypothyroidism due to abnormality in the thyroid gland is the most common endocrine disease The recommended starting dose of levothyroxine replacement therapy is 1.6 µg/kg. This dose however is not optimal for every patient and dose adjustments are frequently done. Genetic polymorphisms in the absorption and metabolism pathway of levothyroxine are likely to influence its dose requirements. This study aimed to study the influence of genetic polymorphisms on levothyroxine replacement requirements.MethodsThis was a cross-sectional study. Participants were recruited through a private nutrition clinic and through announcements distributed in the University of Petra in Amman, Jordan between September 2020 and February 2021. Hypothyroid patients had already been on stable doses of levothyroxine for the previous 3 months. A questionnaire was distributed to collect demographic and clinical information and a blood sample was taken for DNA extraction and clinical biochemistry analysis. rs11249460, rs2235544, rs225014, rs225015, rs3806596, rs11185644, rs4588, rs602662 were analyzed using Applied Biosystems TaqMan™ SNP Genotyping Assays on Rotor-Gene® Q and rs3064744 by direct sequencing. SPSS and Excel were used to perform analysis.Results76 patients were studied. The equation we calculated to find predicted daily dose of levothyroxine (mcg/kg) is 3.22+ (0.348 for CT genotype of rs11185644, 0 for other genotypes) + 0.027*disease duration (years) − 0.014*age (years) − 0.434*T3 (pmol/L) levels+ (0.296 for CC genotype of rs2235544, 0 for other genotypes).ConclusionSNP rs11185644 in RXRA gene and SNP rs2235544 in DIO1 affect dose requirement in hypothyroid patients and if confirmed in larger trials they can be used to individualize thyroxine starting doses.

Proteomic and transcriptomic analysis of large yellow croaker (Larimichthys crocea) during early development under hypoxia and acidification stress

In recent years, aquatic ecosystems have been exposed to various stressors such as hypoxia and acidification, which has become an issue of significant concern. Many studies in fish have investigated the regulatory mechanisms of the response to hypoxia and acidification stress at the molecular level. However, molecular studies on hypoxia acidification dual stress conditions in rhubarb fish are less. For this study, the juvenile large yellow croaker was used as the study object. Four experimental groups were established, including the control group (normal group, N107; DO = 7.0 mg/L, pH = 8.1), hypoxia group (H107; DO = 3.5 mg/L, pH = 8.1), acidification group (A107; DO = 7.0 mg/L, pH = 7.3), and hypoxia–acidification group (dual stress group, D107; DO = 3.5 mg/L, pH = 7.3). Study of its response mechanism under hypoxia acidification conditions by transcriptome and proteome analysis. The present study revealed that the number of quantifiable proteins was 6303. Five pairwise comparisons between experimental groups demonstrated that a total of 265 DEGs/DEPs showed associations between the transcriptome and proteome at the level of quantitative and differential expression. Comparative proteomic and transcriptomic analyses were performed to identify differentially expressed genes/proteins in juvenile Larimichthys crocea under hypoxia and acidification stress. The GO term enrichment analysis showed that hypoxia had a greater effect on the organism. The KEGG pathway enrichment analysis showed that pathways associated with the extracellular matrix ECM–receptor interaction and protein digestion and absorption pathways were notably affected by hypoxia and acidification stress. Among these, the protein digestion and absorption pathway was significantly affected in all five pairwise comparisons between experimental groups. The ECM–receptor interaction pathway was significantly enriched under dual stress, indicating that dual stress had a greater detrimental effect on fish growth than single stressors. The study provides valuable insights into the potential combined effects of decreased pH and DO in Sciaenidae and elucidates the mechanism underlying the response of L. crocea to simultaneous hypoxia–acidification stress during early development.

Catalytic absorption pathway with kinetically favorable dissolution of nitric oxide in aqueous absorbents

AbstractNitrogen capture is a crucial strategy for coping with the environmental crisis arising from continually industrial NO emissions, while it suffers from the generally inefficient aquatic absorbent. This work developed a novel absorbent with favorable gas affinity via using sterically hindered imidazole to regulate the gas–liquid interface of typical K2S2O8 solution, initially achieving an efficiently catalytic absorption of poorly soluble NO. The best catalytic absorption efficiencies increased from 17.83% to 91.90% as compared to traditional one. Moreover, an established absorption kinetic model indicated that both capacity and rate of NO dissolution were increased. The imidazole molecules spontaneously migrated to gas–liquid interface of solution and imparted an additional dissolution impetus to NO. This catalytic absorption method overcoming the conventional NO dissolution limitation in water not only improves commercial NO capture, but also provides a new design of aquatic absorbent for heterogeneous reactions requiring transporting poorly soluble gases in aqueous solvents.

The Absolute Bioavailability and Absorption, Metabolism, and Excretion of Ipatasertib, a Potent and Highly Selective Protein Kinase B (Akt) Inhibitor.

Ipatasertib (GDC-0068) is a potent, highly selective, small-molecule inhibitor of protein kinase B (Akt) being developed by Genentech/Roche as a single agent and in combination with other therapies for the treatment of cancers. To fully understand the absorption, metabolism, and excretion of ipatasertib in humans, an open-label study using 14C-radiolabeled ipatasertib was completed to characterize the absolute bioavailability (period 1) and mass balance and metabolite profiling (period 2). In period 1, subjects were administered a 200 mg oral dose of ipatasertib followed by an 80 μg (800 nCi) intravenous dose of [14C]-ipatasertib. In period 2, subjects received a single oral dose containing approximately 200 mg (100 μCi) [14C]-ipatasertib. In an integrated analytical strategy, accelerator mass spectrometry was applied to measure the 14C microtracer intravenous pharmacokinetics in period 1 and fully profile plasma radioactivity in period 2. The systemic plasma clearance and steady-state volume of distribution were 98.8 L/h and 2530 L, respectively. The terminal half-lives after oral and intravenous administrations were similar (26.7 and 27.4 hours, respectively) and absolute bioavailability of ipatasertib was 34.0%. After a single oral dose of [14C]-ipatasertib, 88.3% of the administered radioactivity was recovered with approximately 69.0% and 19.3% in feces and urine, respectively. Radioactivity in feces and urine was predominantly metabolites with 24.4% and 8.26% of dose as unchanged parent, respectively; indicating that ipatasertib had been extensively absorbed and hepatic metabolism was the major route of clearance. The major metabolic pathway was N-dealkylation mediated by CYP3A, and minor pathways were oxidative by cytochromes P450 and aldehyde oxidase. SIGNIFICANCE STATEMENT: The study provided definitive information regarding the absolute bioavailability and the absorption, metabolism, and excretion pathways of ipatasertib, a potent, novel, and highly selective small-molecule inhibitor of protein kinase B (Akt). An ultrasensitive radioactive counting method, accelerator mass spectrometry was successfully applied for 14C-microtracer absolute bioavailability determination and plasma metabolite profiling.

Knockdown of SDC-1 Gene Alleviates the Metabolic Pathway for the Development of MODS

This study aims to reveal the metabolic differences between SDC-1 knockout mice and wild-type mice and the metabolic differences caused by shock in SDC-1 knockout mice by integrating transcriptomics and metabolomics. A total of 1009 differential metabolites were differentially expressed based on untargeted metabolomics and high-resolution mass spectrometry detection techniques. According to Kyoto Encyclopedia of Genes and Genomes enrichment, SDC-1 knockout significantly altered fat digestion and absorption, GnRH signaling pathway, fructose and mannose metabolism, and some other amino-related metabolic pathways and significantly modulated positively regulated longevity regulatory pathways, longevity regulatory pathways-worm, nicotinamide and niacinamide metabolism, and vitamin digestion and absorption pathways after its shock. Our findings indicate that SDC-1 knockout may have potential therapeutic effects in hemorrhagic shock by increasing nicotinamide metabolism.

Knowledge absorption pathways for eco-innovation: an empirical analysis of small and medium-sized enterprises in the European Union

PurposeThis study contributes to the literature on eco-innovation (EI) and the circular economy (CE) by providing insights into the factors of external knowledge absorption that facilitate the adoption of a subset of EIss called proactive-EIs. Proactive-EIs involve collaborations among multiple stakeholders, the use of technical knowledge and a greater level of investment than other innovations. In this study, the environmental actions taken by small and medium-sized enterprises (SMEs) in resource-intensive sectors in the European Union (EU) were observed, and elements related to the national context were compared.Design/methodology/approachThe national innovation system (NIS) perspective was adopted using a multilevel framework to assess the determinants of proactive-EIs among SMEs in the EU. The framework involves three levels: micro- (environmental awareness), meso- (external collaboration and intra-industry agglomeration) and macro- (economic complexity, trade openness and government research and development [R&D]). The survey data of 6,188 SMEs in resource-intensive sectors were analysed using a binary logistic regression.FindingsThe results showed that public awareness, economic complexity and public sector R&D positively influenced SMEs' adoption of proactive-EIs, whereas external collaboration and sectoral agglomeration negatively influenced adoption.Originality/valueAmong the existing empirical studies on EI, areas related to external knowledge-based innovations and systematic assessments of heterogeneity among EU member states remain underexplored. This study contributed to the literature by assessing the conditions surrounding external knowledge absorption. The findings contribute to the green entrepreneurship literature in the context of developed economies and offer insights for managers and policymakers seeking to promote EIs.

Cyanocobalamin-Modified Colistin-Hyaluronan Conjugates: Synthesis and Bioactivity.

Polymeric drug delivery systems enhance the biopharmaceutical properties of antibiotics by increasing their bioavailability, providing programmable and controlled-release properties, and reducing toxicity. In addition, drug delivery systems are a promising strategy to improve the intestinal permeability of various antimicrobial agents, including colistin (CT). This study describes the modification of conjugates based on CT and hyaluronic acid (HA) with cyanocobalamin (vitamin B12). Vitamin B12 was chosen as a targeting ligand because it has its own absorption pathway in the small intestine. The resulting polysaccharide conjugates contained 95 μg/mg vitamin B12 and the CT content was 335 μg/mg; they consisted of particles of two sizes, 98 and 702 nm, with a ζ-potential of approximately -25 mV. An in vitro release test at pH 7.4 and pH 5.2 showed an ultra-slow release of colistin of approximately 1% after 10 h. The modified B12 conjugates retained their antimicrobial activity at the level of pure CT (minimum inhibitory concentration was 2 μg/mL). The resulting delivery systems also reduced the nephrotoxicity of CT by 30-40% (HEK 293 cell line). In addition, the modification of B12 improved the intestinal permeability of CT, and the apparent permeability coefficient of HA-CT-B12 conjugates was 3.5 × 10-6 cm/s, corresponding to an in vivo intestinal absorption of 50-100%. Thus, vitamin-B12-modified conjugates based on CT and HA may be promising oral delivery systems with improved biopharmaceutical properties.

Identification of survival-associated biomarkers based on three datasets by bioinformatics analysis in gastric cancer.

Gastric cancer (GC) is one of the most common malignant tumors with poor prognosis in terms of advanced stage. However, the survival-associated biomarkers for GC remains unclear. To investigate the potential biomarkers of the prognosis of patients with GC, so as to provide new methods and strategies for the treatment of GC. RNA sequencing data from The Cancer Genome Atlas (TCGA) database of STAD tumors, and microarray data from Gene Expression Omnibus (GEO) database (GSE19826, GSE79973 and GSE29998) were obtained. The differentially expressed genes (DEGs) between GC patients and health people were picked out using R software (x64 4.1.3). The intersections were underwent between the above obtained co-expression of differential genes (co-DEGs) and the DEGs of GC from Gene Expression Profiling Interactive Analysis database, and Gene Ontology (GO) analysis, Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA), Protein-protein Interaction (PPI) analysis and Kaplan-Meier Plotter survival analysis were performed on these DEGs. Using Immunohistochemistry (IHC) database of Human Protein Atlas (HPA), we verified the candidate Hub genes. With DEGs analysis, there were 334 co-DEGs, including 133 up-regulated genes and 201 down-regulated genes. GO enrichment analysis showed that the co-DEGs were involved in biological process, cell composition and molecular function pathways. KEGG enrichment analysis suggested the co-DEGs pathways were mainly enriched in ECM-receptor interaction, protein digestion and absorption pathways, etc. GSEA pathway analysis showed that co-DEGs mainly concentrated in cell cycle progression, mitotic cell cycle and cell cycle pathways, etc. PPI analysis showed 84 nodes and 654 edges for the co-DEGs. The survival analysis illustrated 11 Hub genes with notable significance for prognosis of patients were screened. Furtherly, using IHC database of HPA, we confirmed the above candidate Hub genes, and 10 Hub genes that associated with prognosis of GC were identified, namely BGN, CEP55, COL1A2, COL4A1, FZD2, MAOA, PDGFRB, SPARC, TIMP1 and VCAN. The 10 Hub genes may be the potential biomarkers for predicting the prognosis of GC, which can provide new strategies and methods for the diagnosis and treatment of GC.

Comparative analysis of quantitative phosphoproteomics between two tilapias (Oreochromis niloticus and Oreochromis aureus) under low-temperature stress.

As an important farmed fish, tilapia has poor tolerance to low-temperatures. At the same time, different tilapia strains have apparent differences in low-temperature tolerance. In this study, using the iTRAQ method, the phosphorylated proteomics of two tilapia strains (Oreochromis niloticus and Oreochromis aureus) with different tolerances to low-temperature stress were quantitatively and comparatively analyzed, to clarify the physiological mechanism of tilapia's response to low-temperature stress. Through the GO and IPR analyses of differentially phosphorylated proteins, a number of similarities in physiological activities and regulatory effects were found between the two tilapias in response to low-temperature stress. Many differentially phosphorylated proteins are mainly involved in lipid metabolism, cell proliferation and apoptosis. However, the difference in endurance of low temperature of these two tilapias might be related to the differences in categories, expression and modification level of genetic products which were involved in the aforementioned physiological processes. And meanwhile, the enrichment results of KEGG showed the changes of multiple immune-related and growth-related phosphorylated proteins in the cytokine-cytokine receptor interaction pathway in O. aureus are more prominent. Furthermore, the significantly enriched pathway of carbohydrate digestion and absorption in O. niloticus may indicate that low-temperature stress exerts a more severe impact on energy metabolism. The relative results would help elucidating the molecular mechanism by which tilapia responds to low-temperature stress, and developing culture of tilapia species.

Comparative transcriptomic analysis reveals the underlying molecular mechanism in high-fat diet-induced islet dysfunction.

Obesity, characterized by accumulation of adipose, is usually accompanied by hyperlipidemia and abnormal glucose metabolism, which destroys the function and structure of islet β cells. However, the exact mechanism of islet deterioration caused by obesity has not yet been fully elucidated. Here, we fed C57BL/6 mice with a high-fat diet (HFD) for 2 (2M group) and 6 months (6M group) to construct obesity mouse models. Then, RNA-based sequencing was used to identify the molecular mechanisms in HFD-induced islet dysfunction. Compared with the control diet, a total of 262 and 428 differentially expressed genes (DEGs) were identified from islets of the 2M and 6M groups, respectively. GO and KEGG enrichment analysis revealed that the DEGs up-regulated in both the 2M and 6M groups are mainly enriched in response to endoplasmic reticulum stress and the pancreatic secretion pathway. DEGs down-regulated in both the 2M and 6M groups are mainly enriched in the neuronal cell body and protein digestion and absorption pathway. Notably, along with the HFD feeding, mRNA expression of islet cell markers was significantly down-regulated, such as Ins1, Pdx1, MafA (β cell), Gcg, Arx (α cell), Sst (δcell), and Ppy (PP cell). In contrast, mRNA expression of acinar cell markers was remarkably up-regulated, such as Amy1, Prss2, and Pnlip. Besides, a large number of collagen genes were down-regulated, such as Col1a1, Col6a6, and Col9a2. Overall, our study provides a full-scale DEG map regarding HFD-induced islet dysfunction, which was helpful to understand the underlying molecular mechanism of islet deterioration further.

Affecting mechanism of Chlorella sorokiniana meal replacing fish meal on growth and immunity of Litopenaeus vannamei based on transcriptome analysis

The purpose of this study was to analyze the affecting mechanism of Chlorella sorokiniana meal replacing fish meal on the growth performance and immune function of Pacific white shrimp, Litopenaeus vannamei by transcriptomics analysis. In a control diet containing 560 g % /kg fish meal, chlorella was used to replace 0 %, 20 %, 40 %, 60 %, 80 % and 100 % of dietary fish meal to form six iso-nitrogenous and iso-lipidic diets (C0, C20, C40, C60, C80, C100). The six diets were fed to white shrimp (1.37 ± 0.02 g) for 8 weeks. Compared to the control group, the final body weight (FBW), specific growth rate (SGR) and feed efficiency (FE) of the C20 group were significantly improved (P < 0.05). There was no significant difference in growth performance between the C40 group and the C0 group (P > 0.05). When the replacement level of fish meal by chlorella was ≥ 60 %, the FBW, SGR and FE of shrimp were significantly decreased (P < 0.05). In the analysis of the hepatopancreatic transcriptome, the amount of differentially expressed genes (DEGs) in C20, C40, C60, C80 and C100 groups were 322 (176 up and 146 down), 482 (246 up and 236 down), 804 (487 up and 317 down), 1080 (684 up and 396 down) and 1262 (827 up and 435 down), respectively, when compared to the C0 group. GO Term and KEGG pathway enrichment analysis of DEGs showed that DEGs between the C20 and C0 groups were significantly enriched in chitin binding and inositol metabolism processes. Several immune-related signaling pathways were also enriched, including the C-type lectin receptor pathway, complement and coagulation cascades, the B-cell receptor pathway, and most of these genes were up-regulated in the C20 group. Compared to the C0 group, DEGs in C40, C60, C80 and C100 groups were significantly enriched in lysosomal, protein digestion, and absorption pathways. In addition, in the C80 and C100 groups, the DEGs were also significantly enriched in lipid catabolism process. The high replacement of fish meal with chlorella meal affected the absorption and utilization of nutrients by regulating the signaling pathways related to protein digestion and absorption, and aggravated lipid catabolism of the body, thereby affecting the growth of shrimp. The high replacement of fish meal might also affect the homeostasis of shrimp cells and reduce immunity through the lysosomal signaling pathway. In summary, the low replacement of fish meal (20 %) with chlorella meal significantly improved the growth performance of Litopenaeus vannamei, which might be realized through activating the C-type lectin receptor signaling pathway to regulate immune function of the body, but the high substitution of fish meal (≥ 60 %) reduced the growth performance and immunity by affecting the lysosomal signaling pathway.

Ecological Risk Assessment of Inorganic Arsenic and Mercuric Fungicides Through Biological Tools

This review discusses the use, mode of action, biomarkers, and bioindicators of inorganic arsenic and mercuric fungicides, as well as their effects on the environment and human health. The most prevalent indicator of exposure to arsenic is the measurement of total arsenic in urine. Biomarkers of exposure for arsenic and inorganic fungicides incudes the analysis of hair, urine, blooda and nails. Bio indicators are species or group of species that are used to indicate adverse effect of contamination. Freshwater fish species act as a very good bio indicator for inorganic arsenic. Tree bark, rice fields and sea birds could be a valuable indicator of inorganic arsenic contamination. Black Piranha, fish and earthworms are an ideal bio indicator of inorganic mercury. Inorganic arsenic compounds are known to be highly carcinogenic and toxic compounds. Mercuric fungicide is very toxic when inhaled by humans or animals it causes severe health issues and when absorbed by plants it retards their growth. To estimate the daily dose of arsenic exposure to humans through absorption, ingestion and other pathways, Average daily dose is implemented by using two equations from the US EPA. To determine the ecological risk assessment a simplified equation was proposed by FDA i.e. HQ = E/RfD. Overall, the review emphasizes the need for heightened awareness, regulation, and alternative approaches to fungicide use, with a focus on minimizing the use of inorganic arsenic and mercuric fungicides to safeguard the environment and promote sustainable agricultural practices.

Particulate matter 10 exposure affects intestinal functionality in both inflamed 2D intestinal epithelial cell and 3D intestinal organoid models.

A growing body of evidence suggests that particulate matter (PM10) enters the gastrointestinal (GI) tract directly, causing the GI epithelial cells to function less efficiently, leading to inflammation and an imbalance in the gut microbiome. PM10 may, however, act as an exacerbation factor in patients with inflamed intestinal epithelium, which is associated with inflammatory bowel disease. The purpose of this study was to dissect the pathology mechanism of PM10 exposure in inflamed intestines. In this study, we established chronically inflamed intestinal epithelium models utilizing two-dimensional (2D) human intestinal epithelial cells (hIECs) and 3D human intestinal organoids (hIOs), which mimic in vivo cellular diversity and function, in order to examine the deleterious effects of PM10 in human intestine-like in vitro models. Inflamed 2D hIECs and 3D hIOs exhibited pathological features, such as inflammation, decreased intestinal markers, and defective epithelial barrier function. In addition, we found that PM10 exposure induced a more severe disturbance of peptide uptake in inflamed 2D hIECs and 3D hIOs than in control cells. This was due to the fact that it interferes with calcium signaling, protein digestion, and absorption pathways. The findings demonstrate that PM10-induced epithelial alterations contribute to the exacerbation of inflammatory disorders caused by the intestine. According to our findings, 2D hIEC and 3D hIO models could be powerful in vitro platforms for the evaluation of the causal relationship between PM exposure and abnormal human intestinal functions.

Identification of SNPs Associated with Goose Meat Quality Traits Using a Genome-Wide Association Study Approach.

(1) Background: Goose meat is highly valued for its economic significance and vast market potential due to its desirable qualities, including a rich nutritional profile, tender texture, relatively low-fat content, and high levels of beneficial unsaturated fatty acids. However, there is an urgent need to improve goose breeding by identifying molecular markers associated with meat quality. (2) Methods: We evaluated meat quality traits, such as meat color, shear force (SF), cooking loss rate (CLR), and crude fat content (CFC), in a population of 215 male Sichuan white geese at 70 days of age. A GWAS was performed to identify potential molecular markers associated with goose meat quality. Furthermore, the selected SNPs linked to meat quality traits were genotyped using the MALDI-TOP MS method. (3) Results: A dataset of 2601.19 Gb of WGS data was obtained from 215 individuals, with an average sequencing depth of 10.89×. The GWAS revealed the identification of 43 potentially significant SNP markers associated with meat quality traits in the Sichuan white goose population. Additionally, 28 genes were identified as important candidate genes for meat quality. The gene enrichment analysis indicated a substantial enrichment of genes within a 1Mb vicinity of SNPs in both the protein digestion and absorption pathway and the Glycerolipid metabolism pathway. (4) Conclusion: This study provides valuable insights into the genetic and molecular mechanisms underlying goose meat quality traits, offering crucial references for molecular breeding in this field.

A novel oral biomimetic delivery system enhancing both the mucosal and systemic immunity of influenza virus vaccine

Oral vaccines hold great promise for preventing major infectious diseases, but their development is limited by various gastrointestinal tract (GIT) barriers and the low proportion of intestinal microfold (M) cells. Here, inspired by the specific absorption pathway of dietary fat, a novel bionic intestinal lymphatic delivery system based on large mesoporous silica nanoparticles (LMSN) was developed for oral delivery of H1N1 influenza split vaccine (SV). Encouragingly, LMSN with triglyceride biomimetic structure and encapsulated by double-end palmitic acid esterified PEG (PEG-DP), namely TGLMSN@PEG-DP, exhibited high intestinal epithelium permeability and excellent lymphatic targeting ability. Additionally, TGLMSN, which acting as both antigen carrier and adjuvant, significantly enhanced the ability of SV to stimulate dendritic cells maturation. The results demonstrated that TGLMSN@PEG-DP vigorously augmented SV-induced antigen-specific systemic and mucosal immunity, compared to oral SV alone. To our knowledge, this is the first study to customize mesoporous silica nanocarriers to load SV and deliver vaccines to mesenteric lymph nodes (MLNs) mainly through the intestinal epithelium cells (IECs) pathway rather than M cells route alone. This work will not only improve the existing influenza vaccination methods, but also open up a new avenue for the design of vaccines against pathogens infected via mucosal route.

Concentrations and health risk appraisal of heavy metals and volatile organic compounds in soils of automobile mechanic villages in Ogun State, Nigeria.

This report presents the findings of the concentrations, distributions and health risks assessment of heavy metals (HMs) and volatile organic compounds (VOCs) in topsoils of two typical automobile mechanic villages (MVs) situated within Ogun State, Nigeria. One of the MVs is located in basement complex terrain (Abeokuta), while the second is in the sedimentary formation (Sagamu). Ten composite samples were collected at depth of 0-30cm with the aid of soil auger from spent oil-contaminated spots within the two MVs. The chemical parameters of interest were Pb, Cd, benzene, ethylbenzene, toluene, total petroleum hydrocarbon (TPH) as well as oil and grease (O&G). In addition, soil pH, cation exchange capacity (CEC), electrical conductivity (EC) and particle size distribution were also evaluated in order to find out their impacts on assessed soil pollutants. Results revealed that the soils in both MVs are of sandy loam texture, slight acidic to neutral pH, mean CEC < 15 cmol/kg and mean EC > 100 μS/cm. The mean concentration of each of analyzed HMs and VOCs in soils from the two MVs was < 5mg/kg, while the mean values of TPH and O&G content were > 50mg/kg. The mean Cd values in soils of both MVs were higher than the national soil screening level of 0.8mg/kg, but lower than the Canadian and Italian guidelines. There is no significant correlation between each of HMs/VOCs and any of assessed soil physicochemical variables. The non-cancer risk expressed in terms of hazard index (HI) was > 1 via oral ingestion route for adults and children at the two MVs, indicating adverse non-carcinogenic health risk. The HI > 1 value was obtained for adults only through the dermal absorption pathway in Abeokuta MV. However, HI values for the two age groups at the two MVs via inhalation route were < 1, indicating no likelihood of any non-carcinogenic effects via the breathing exposure. The potential of non-cancer risk via oral ingestion route in both MVs was derived from the contributive ratios of HMs and VOCs in the order: Cd > benzene > Pb > toluene. The carcinogenic risk (CR) values due to ingested Cd, benzene and Pb for both age groups at the two MVs exceed the safe limit range of 10-6 to 10-4. Cadmium, benzene and lead made considerable contributions to the estimation of CR through dermal exposure for adults only in Abeokuta MV. The CR values via inhalation pathway for adults and children in both MVs were within the threshold range. Artisans and children should circumvent accidental ingestion of contaminated soils in addition to wearing of protective clothes during routine vehicle maintenance activities.

RNA sequencing to characterize pathways in EGFR-mutated non-small cell lung cancer.

e21019 Background: The purpose of our study is to explore patterns in gene expression for patients with EGFR-mutated non-small cell lung cancer (NSCLC). Methods: 287 patients with EGFR-mutated lung cancer were identified using the Tempus Lens database. Raw RNA sequence expression data was requested from TEMPUS XT RNA analysis. Sequences were processed through the EdgeR analysis in the R programming environment. Differential abundance analysis was done to further filter out genes and Benjamini-Hochberg correction selected genes with a corrected p-value of &lt; 0.05 for further pathway analysis. Pathway analysis was performed using GSEA (Gene Set Enrichment Analysis). Enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GSEA Molecular Signatures Database (MsigDB) was performed for overexpressed and under-expressed genes in patients. Results: Pathway analysis run against the KEGG reference database and GSEA MSigDB helped to illustrate genes shared in activated and suppressed pathways in our patient cohort. For example, using the KEGG reference database, enriched pathways meeting p value significance threshold of &lt; 0.005 included the nicotine addiction, olfactory transduction, and cortisol synthesis and secretion pathways, amongst others. Suppressed pathways using the KEGG reference database meeting p value significance threshold of &lt; 0.005 included fat digestion and absorption, vitamin digestion and absorption, PPAR signaling pathway, and drug metabolism by cytochrome P450 and other enzymes. Using the GSEA MSigDB, enriched pathways included G protein-coupled receptor activity, sensory perception, synaptic signaling and trans-synaptic signaling, meanwhile suppressed pathways included cytolysis by host of symbiont cells, negative regulation of very-low-density lipoprotein particle remodeling, and oxidoreductase activity. Conclusions: Patterns in gene and pathway expression were observed in our cohort of patients with EGFR-mutated NSCLC. Analyzing RNA sequencing pathways showed differential up and down regulation of multiple pathways. For example, suppression of the fat and vitamin digestion and absorption pathways may shed light on processes involved in cancer cachexia and metabolism. Though further work needs to be done, RNA sequencing results for patients with EGFR-mutated lung cancer may lead to information on cancer development and additional therapeutic targets.