Absorption Pathways Research Articles

Pickering high internal phase emulsions stabilized by soy protein isolate/κ-carrageenan complex for enhanced stability, bioavailability, and absorption mechanisms of nobiletin

Nobiletin (NOB), a lipid-soluble polymethoxyflavone with potent antioxidant, antimicrobial, and anti-inflammatory properties, suffers from poor stability and pH sensitivity, limiting its bioavailability. In this study, Pickering high internal phase emulsions (HIPEs) stabilized by soy protein isolate (SPI) and κ-carrageenan (KC) were developed to encapsulate and protect NOB. The emulsions, containing a 75 % medium-chain triglyceride (MCT) volume fraction, were optimized by investigating the effects of pH and KC concentration on the key properties such as the creaming index, particle size, zeta potential, microstructure, and rheology. Results showed that under optimal conditions (pH 7 and 1.0 % KC), the SPI/KC HIPEs exhibited improved physicochemical properties. Furthermore, encapsulation of NOB in HIPEs significantly improved its stability against UV exposure, heat, and storage conditions. Additionally, simulated gastrointestinal digestion studies revealed that the SPI/KC HIPEs improved the digestion stability and bioaccessibility of NOB, with controlled release in the intestinal phase. Moreover, the SPI/KC HIPEs facilitated increased cellular uptake and bioavailability of NOB, with clathrin-mediated endocytosis and macropinocytosis as primary absorption pathways. The encapsulated NOB also showed enhanced inhibition of inflammatory markers, including NO, IL-6, and TNF-α. These findings suggested that SPI/KC HIPEs provided a promising delivery system for improving the bioavailability and bioactivity of hydrophobic compounds.

Effects of temperature to the liver transcriptome in the hybrid puffer fish (Takifugu rubripes ♀ × Takifugu obscurus ♂)

Water temperature exerts a crucial impact on the growth and development of fish. Hybrids may integrate the superior traits of their parents, thereby leading to higher economic benefits. Takifugu rubripes and T. obscurus are two important economic species in Asia. Here, to investigated the effect of temperature on the hybrid puffer larvae (T. rubripes ♀ × T. obscurus ♂), the larvae (0.79 ± 0.02 cm in body length) were treated to three temperatures: 15 °C (T15), 20 °C (T20), and 25 °C (T25) for 45 days. At the end of the study, the body length and weight were measured, the survival rate was calculated, and liver transcriptome analysis was performed on liver tissues. The hybrid puffer larvae in the T25 group showed a significant increase in average body length and body weight compared to the T15 and T20 groups (P < 0.05). 1292, 329, and 1927 differentially expressed genes (DEGs) were identified in T15 vs. T20, T20 vs. T25, and T15 vs. T25 groups, respectively. KEGG enrichment analyses showed that DEGs were primarily involved in the citrate cycle (TCA cycle), PPAR signaling, glycine, serine and threonine metabolism, and protein digestion and absorption pathways. These results indicated that temperature affects metabolism, signal transduction and protein digestion and absorption in hybrid puffer fish. In addition, twelve DEGs were randomly selected for RNA-seq validation, and the transcriptome results were consistent with the qPCR validation results, illustrating the accuracy of transcriptome sequencing. These findings deepen our understanding of the complex molecular mechanism of the response of hybrid puffer fish to temperature changes and contribute to the development of hybrid puffer fish breeding.

Optimisation of a novel series of ENaC inhibitors, leading to the selection of the long-acting inhaled clinical candidate ETD001, a potential new treatment for cystic fibrosis

Cystic Fibrosis (CF) results from the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel of key importance in the airway epithelia. CFTR helps control optimal hydration of the airways, a crucial requirement for healthy lungs. CFTR modulators have recently been approved as an effective treatment option for many genetic variants of CF. The epithelial sodium channel (ENaC), unlike CFTR which is secretory, is an absorptive pathway, and therefore its inhibition is an alternative and potentially complementary approach to aid hydration of the airways. Due to the adverse effect of ENaC inhibition in the kidney we, as have several others, focused on the design and synthesis of novel ENaC inhibitors for direct delivery to the airways via inhalation. A new series of ENaC inhibitors is described, wherein the well-established pyrazine core of first-generation inhibitors was replaced with a pyrrolopyrazine. Aiming for high retention at the surface of the lung following inhalation, optimisation of this template focused on significantly increasing polarity to minimize passive cellular permeability. The resulting optimized clinical candidate ETD001 demonstrates potent inhibition of ENaC (59 nM) prolonged retention in the airways of rats (13 % of the delivered dose retained after 6h) following intratracheal administration and a potent and long-acting effect in a sheep model of mucociliary clearance following inhalation (ED100 (4–6h) = 9 μg/kg). ETD001 entered a phase II study in CF patients in July 2024.

Multi-Omics Reveal the Improvements of Nutrient Digestion, Absorption, and Metabolism and Intestinal Function via GABA Supplementation in Weanling Piglets.

The nonprotein amino acid γ-aminobutyric acid (GABA) can enhance intestinal function in piglets; however, the mechanisms involved are not yet fully understood. To explore the effects of GABA and its underlying mechanisms, weanling piglets were randomly assigned to three groups, receiving either a basal diet or a basal diet supplemented with GABA (80 mg/kg or 120 mg/kg). The results demonstrated that dietary GABA improved growth performance and reduced diarrhea incidence (p < 0.05). Additionally, GABA supplementation decreased the serum and intestinal levels of pro-inflammatory cytokines (p < 0.05), and improved intestinal morphology. Multi-omics analyses were employed to explore the alterations caused by GABA supplementation and elucidate the related mechanisms. Microbiota profiling revealed improved beta-diversity and changes in the composition of ileal bacteria and fungi. Amino acid metabolism, lipid metabolism, and digestive processes were primarily enriched in the GABA group according to metabolomics analysis. A transcriptome analysis showed significant enrichment in ion transmembrane transport and nutrition absorption and digestion pathways in the ileum. Furthermore, increased lipase and trypsin activity, along with the elevated expression of tight junction proteins confirmed the beneficial effects of GABA on intestinal nutrient metabolism and barrier function. In conclusion, dietary 80 mg/kg GABA supplementation improved nutrient digestion and absorption and intestinal function in weanling piglets.

Eriocalyxin B ameliorated experimental autoimmune prostatitis via modulation of macrophage polarization through gut microbiota-mediated vitamin D3 alteration

BackgroundChronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a often heterogeneous condition in urology. Accumulating evidence suggests that the autoimmune response against prostate antigens is related to CP/CPPS. The gut microbiota may be a possible cause of a number of autoimmune diseases. Eriocalyxin B (EriB) is used as an anti-inflammatory treatment for autoimmune disorders. The underlying mechanism of fecal metabolome involved in CP/CPPS treatment by EriB remains unclear. MethodsThe experimental autoimmune prostatitis (EAP) mouse model was generated by subcutaneous immunization. Macrophages, inflammatory cytokines, intestinal microbiota, and fecal metabolome of the mice were analyzed. The alteration of the fecal metabolome was investigated in detail in EriB-treated EAP mice and confirmed by in vitro experiments. ResultsEriB ameliorated significantly decreased prostate inflammation in EAP mice and promoted macrophage phenotype polarizing from M1 to M2. The gut microbiome was altered, and intestinal barrier damage was improved by EriB treatment. Furthermore, the enrichment of vitamin digestion and absorption pathways in the fecal metabolome revealed that vitamin D3 was altered by EriB. In vitro experiments confirmed that macrophage polarization from M1 to M2 was promoted by vitamin D3. Finally, fecal transplantation from EriB-treated mice markedly reduced inflammatory indicators and the macrophage M1/M2 ratio in pseudogerm-free EAP mice. In our study, the immune state of macrophage regulated by gut microbiota-mediated vitamin D3 alteration was first time revealed in EAP treatment. ConclusionsEriB ameliorated in mice with EAP, the gut microbiota mediates vitamin D3 alterations to modulate macrophage phenotype polarizing from M1 to M2.

The Critical Role of Folate in Prenatal Health and a Proposed Shift from Folic Acid to 5-Methyltetrahydrofolate Supplementation

Folate, or vitamin B9, is a water-soluble vitamin essential in periconceptional nutrition. In its active form, tetrahydrofolate, it plays a vital role in DNA methylation and homocysteine breakdown. Maintenance of normal serum folate levels is crucial during pregnancy; deviation from these levels, either in dearth or excess, can lead to various pregnancy and infant complications. This article analyzes existing literature on folate’s absorption pathway in human physiology and reviews the evidence surrounding prenatal supplementation guidelines for folic acid. Prior research supports these guidelines because, in the absence of folate during pregnancy, research has shown an increased incidence of neurodevelopmental defects, food allergies, ophthalmic deficits, and other adverse effects for both mother and child. This significant body of evidence has driven most developed countries to implement folic acid supplementation initiatives, with the World Health Organization recommending a daily 400-µg folic acid supplementation for periconceptional women. As progress continues on a global scale, further efforts should be made to improve folic acid levels in pregnant populations among demographic subgroups. Research supports the use of 5-methyltetrahydrofolate in place of traditional folic acid prenatal supplements based on the increased bioavailability, resistance to genetic polymorphisms, and avoidance of several potential risks associated with folic acid supplements. More research and product development should be done to drive and support this shift in prenatal supplementation trends.

Exploring the Role of Cuprotosis-Associated Genes in Cancer Progression and Therapy Resistance: A Comprehensive Analysis across Multiple Cancer Types

This review presents a comprehensive overview of the role of cuprotosis-associated genes in various cancer types, highlighting their significance in tumor progression and therapy resistance. In breast cancer and colorectal cancer (CRC), dysregulation of genes involved in mitochondrial function and copper metabolism, such as FDX1, LIAS, LIPT1, DLD, DLAT, and PDHA1/PDHB, promotes metabolic reprogramming and enhances cancer cell survival. Ovarian cancer exhibits unique dysregulations in genes like ATP7B, CCS, and COMMD1, influencing copper metabolism and redox signaling pathways, thereby contributing to chemoresistance and tumor growth. Head and neck cancer involves upregulation of MT1X, ATP7A, and CCS, potentially aiding cancer cell survival under oxidative stress conditions. Lung cancer is characterized by distinct dysregulation of genes like SLC31A1, ATOX1, and COMMD1, modulating copper homeostasis and redox signaling to support tumor proliferation. Liver cancer and kidney cancer each present unique sets of dysregulated cuprotosis-associated genes, such as SLC39A4, SCO2, and ATP7A, suggesting novel therapeutic targets specific to these cancer types. Pathway analysis reveals enrichment in mineral absorption pathways, emphasizing the importance of these genes in maintaining cellular mineral homeostasis. Understanding the intricate interplay between cuprotosis-associated genes and cancer biology offers insights into potential therapeutic strategies targeting copper metabolism for improved treatment outcomes across various cancer types.

Fermented Palm Kernel Cake Improves the Rumen Microbiota and Metabolome of Beef Cattle.

In this study, we utilised palm kernel cake as a substrate and fermented it with a composite of bacteria (Pediococcus pentosaceus CGMCC No. 27203 and Lactobacillus plantarum CGMCC No. 27202) and enzymes. We conducted a trial with twenty-four cattle, randomly divided into two groups of twelve cattle each. The control group (CON) was fed the standard farm diet, whereas the treatment group (PKC) received a diet with 3% of soyabean replaced by fermented palm kernel cake. The trial lasted for six weeks. The results showed no significant differences in growth performance between the PKC and CON groups. The abundance of Firmicutes, Bacteroidetes, Proteobacteria, and Spirochaetes was significantly higher in the PKC group than in the CON group. At the genus level, the abundances of Anaeroplasma, norank_f__Bacteroidales_UCG-001, norank_f__Absconditabacteriales_SR1, norank_f__p-251-o5, Prevotellaceae_NK3B31_group, Prevotellaceae_UCG-001, Prevotellaceae_UCG-004, and Treponema significantly increased in the PKC group. Lipid digestion and absorption pathways were significantly enriched in the PKC group. The results indicate that adding fermented palm kernel cake to the diet can increase the abundance of Bacteroidetes and Fibrobacteres in the rumen of beef cattle, enhancing the ability of the PKC group to degrade protein, carbohydrates, and fibrous materials in the feed, thereby improving the feed utilisation efficiency in beef cattle. Adding fermented palm kernel cake to the diet improved carbohydrate metabolism, metabolism of cofactors and vitamins, and nucleotide metabolism. Correlation analysis between the rumen microbiota and metabolic pathways showed that Prevotellaceae_UCG-001 and Prevotellaceae_UCG-003 were positively correlated with amino acid metabolism, Rikenellaceae_RC9_gut_group and Succiniclasticum were positively correlated with metabolism of cofactors and vitamins, and Prevotella and Ruminococcus were positively correlated with nucleotide metabolism. These findings elucidate the differences in rumen microbiota when fermented palm kernel cake is added to the diet, providing a theoretical basis for the application of fermented palm kernel cake in the diet of beef cattle.

Enabling oral novel Taxanes-based Chemotherapy with Lipophilic prodrug Self-nanoemulsifying drug delivery system

Larotaxel (LTX) and SB-T-1214 (SBT), two new synthetic experimental toxoids, have shown broad-spectrum antitumor activity, especially against tumors that are resistant to other drugs. However, their poor solubility, membrane permeability, and first-pass effect limits their use in oral administration. We designed and synthesized two long-chain triglyceride-mimic prodrugs of LTX (LTXSSTG) and SBT (SBTSSTG), which are bridged by disulfide bonds and efficiently incorporated them into Self-nanoemulsifying drug delivery system (SNEDDS). These prodrugs can bypass hepatic metabolism by entering the blood through intestinal lymphatic transport, following a similar oral absorption pathway to dietary lipids. It was found that LTXSSTG and SBTSSTG significantly improved oral bioavailability (about 4.5-fold for LTX and 3.4-fold for SBT) compared to their solution forms. Moreover, with LTXSSTG and SBTSSTG incorporating reduction stimulus-responsive spacer were much more effective in suppressing tumor growth in vivo with eliminated adverse effects than solution form. To sum up, this strategy provides a new avenue to enhance oral delivery of new toxoids.

Accumulation of nanoplastics by wheat seedling roots: Both passive and energy-consuming processes

Nanoplastics can transfer from the environment to plants and potentially harm organisms. However, the mechanisms on how crop root systems absorb and transport nanoplastics are still unclear. Here, original and fluorescent labeled polystyrene and polyvinyl chloride nanoparticles (PS-NPs, PVC-NPs; 30 nm; 10 mg L−1) were employed to study the distribution and internalization pathways in wheat seedling roots. In the study, nanoplastics accumulated more in the root tip and surface, with PVC-NPs more prevalent than PS-NPs. After being treated with inhibitors (Na3VO4, chlorpromazine and amiloride), the nanoplastics mean fluorescence intensities were reduced by 4.0–51.1 %. During the uptake, both passive and energy-consuming pathways occurred. For the energy-consuming uptake pathway, macropinocytosis contributed more to cytoplasm than clathrin-mediated endocytosis. H+ influx was observed during nanoplastic transport into the cytoplasm, and the reduction in plasma membrane ATPase activity led to a decrease in nanoplastic internalization. These results elucidate the pathways of nanoplastics absorption and transport in wheat roots, provide crucial evidence for assessing nanoplastics' ecological risks and support the development of technologies to block nanoplastics absorption by crop roots, ensuring agricultural and ecosystem safety.

Identifying the Genetic Associations Between Diabetes Mellitus and the Risk of Vitiligo.

While increasing observational studies have suggested an association between diabetes mellitus (DM) and vitiligo, the causal relationship and possible mechanism remain unclear. Publicly accessible genome-wide association study (GWAS) was utilized to conduct a bidirectional two-sample Mendelian randomization (MR) analysis. GWAS data for diabetes and vitiligo were obtained from the UK Biobank Consortium (20203 cases and 388756 controls) and the current GWAS data with largest cases (GCST004785, 4680 cases and 39586 controls) for preliminary analysis, respectively. Inverse variance weighting (IVW) was used as the main analysis method. Several sensitivity analyses were utilized to test the pleiotropy or heterogeneity. To explore the possible mechanism of gene-generating effects represented by the final instrumental variables in the analysis, enrichment analysis was conducted using the DAVID and STRING database. IVW method showed a significant genetic causal association between DM and vitiligo (OR = 1.20, 95% CI: 1.08-1.33, PIVW = 0.0009). Diabetes subtype analysis showed that T2D (type 2 diabetes) were associated with an increased risk of vitiligo (OR = 1.13, 95% CI: 1.00-1.27, PIVW = 0.0432). Sensitivity analysis further confirmed the robustness of the results. The enrichment analysis revealed that the genetic inducing effects of diabetes mellitus on vitiligo were primarily about pancreatic secretion and protein digestion and absorption pathway. Our findings provide genetic evidence that there is a notable association between T2D and an elevated risk of vitiligo in European populations. This result may explain why the co-presentation of T2D and vitiligo is often seen in observational studies, and emphasize the significance of vigilant monitoring and clinical evaluations for vitiligo in individuals diagnosed with T2D. The aberrant glucose and lipid metabolism and the primary nutrient absorption disorder of vitiligo brought on by diabetes may be the potential mechanisms behind this association.

Hygroscopic and hydrothermal aging behaviors and performance deterioration mechanisms of jute yarn wound composites

The gyratory jute yarn wound composites (JYWCs) manufactured by the filament winding process show significant potential as eco-friendly alternatives to plastic pipes commonly used in outdoor settings. Ensuring the long-term service performance and durability of the JYWCs in hot and humid environments becomes critical. This study investigated the hygroscopic and hydrothermal aging behaviors of the JYWCs to elucidate their performance deterioration mechanisms. Compared with hygroscopic aging, long-term hydrothermal aging posed a more serious threat to the overall performance of the JYWCs. The jute yarns in the JYWCs experienced swelling, shrinkage, and degradation due to hygroscopic and hydrothermal aging, leading to a 47.4 % and 161.5 % increase in the void volume fraction of the JYWCs, respectively. The deterioration in the mechanical properties of the JYWCs was attributed to the attenuation of jute yarn properties, debonding of the fiber-resin matrix interface, and an increase in voids within the composites. Improving the manufacturing process to minimize voids in the JYWCs and control the pathways for moisture absorption is a highly effective strategy to enhance their long-term performance and durability.

Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers.

In the small intestine, sodium (Na) absorption occurs primarily via two apical transporters, Na-hydrogen exchanger 3 (NHE3) and Na-glucose cotransporter 1 (SGLT1). The two primary Na-absorptive pathways were previously shown to compensatorily regulate each other in rabbit and rat intestinal epithelial cells. However, whether NHE3 and SGLT1 regulate one another in normal human enterocytes is unknown, mainly due to a lack of appropriate experimental models. To investigate this, we generated 2D enterocyte monolayers from human jejunal 3D organoids and used small interfering RNAs (siRNAs) to knock down NHE3 or SGLT1. Molecular and uptake studies were performed to determine the effects on NHE3 and SGLT1 expression and activity. Knockdown of NHE3 by siRNA in enterocyte monolayers was verified by qPCR and Western blot analysis and resulted in reduced NHE3 activity. However, in NHE3 siRNA-transfected cells, SGLT1 activity was significantly increased. siRNA knockdown of SGLT1 was confirmed by qPCR and Western blot analysis and resulted in reduced SGLT1 activity. However, in SGLT1 siRNA-transfected cells, NHE3 activity was significantly increased. These results demonstrate for the first time the functionality of siRNA in patient-derived organoid monolayers. Furthermore, they show that the two primary Na absorptive pathways in human enterocytes reciprocally regulate one another.

Virtual screening study for biological activity assessment and metabolism pathway of a fuel dye in airborne exposure scenario.

The utilization of synthetic dyes increases the risk to human health. Despite the progress of information on azo dyes, very little attention has been reported on toxicity assessment of anthraquinone dyes. Solvent Blue 35 (SB35) is one of the anthraquinone dyes likely to be encountered because of its increasing use in various industries. Whereas the design of laboratory tests is very expensive, in silico screening was used to predict the metabolic profile and toxicity effect of SB35. MetaTox software was used to predict the metabolites of phase I and II in two layers. Since airborne exposure has been considered, the pathways of inhalation and dermal absorption of SB35 were investigated through the SwissADME model based on the modified Lipinski's rule of five. To predict the biological effect and toxicity of SB35 and each of the metabolites, PASS online software was used. Chemical activity was considered according to the probability of activation values (Pa) higher than the probability of inactivation values (Pi). N- dealkylation of SB35 was predicted in the first layer, while seven active compounds were obtained in the second layer from phases I and II reactions. Investigating the physicochemical properties of SB35 confirmed inhalation absorption for occupational exposure scenarios. All metabolites are absorbed from intestinal routes based on the RO5 rules. SB35 and their metabolites have an effective substrate role for the sub-type of CYP 450 enzymes. The toxicity effect of carcinogenicity for SB35 and mutagenicity for metabolites are predicted while confirmed with some biological effects. However, reproductive disorders are pointed with SB35 by probability higher than 70%. Virtual screening methods are efficient tools for creating cost-effective predictions in the hazard's evaluation of SB35. However, a perspective view is suggested before decision-making for laboratory designing tests.

Biology of calcium homeostasis regulation in intestine and kidney.

Calcium (Ca2+) is an essential divalent cation involved in many bodily functions including bone composition, cell growth and division, blood clotting, and muscle contraction. The bone, intestine, and kidneys are important to the maintenance of Ca2+ homeostasis. Ninety-nine percent of body Ca2+ is stored in the skeleton as hydroxyapatite. The small, and to a lesser extent the large intestine absorbs Ca2+ from the diet. Once in the circulation, Ca2+ is filtered by the glomerulus and the majority, >95%, is reabsorbed along the nephron. The remainder is excreted in the urine. Two general (re)absorptive pathways contribute to the vectorial transport of Ca2+ across renal and intestinal epithelia: 1) a paracellular pathway, which is reliant on claudins in the tight junction of epithelium and the electrochemical gradient and 2) a transcellular pathway, which requires different influx, intracellular buffering/shuttling and basolateral efflux mechanisms, to actively transport Ca2+ across the epithelial cell. Blood Ca2+ levels are maintained by hormones including parathyroid hormone, 1,25-dihydroxyvitamin D3, fibroblast growth factor 23 and through effects of Ca2+-sensing receptor (CaSR) signaling. Disruption of Ca2+ homeostasis can result in altered blood Ca2+ levels and/or hypercalciuria, the latter is a phenomenon closely linked to the formation of kidney stones. Genetic alterations affecting renal Ca2+ handling can cause hypercalciuria, an area of expanding investigation. This review explores the molecular mechanisms governing Ca2+ homeostasis by the intestine and kidneys and discusses clinical aspects of genetic disorders associated with Ca2+-based kidney stone disease.

Absorption and transport mechanism of colloidal nanoparticles (CNPs) in lamb soup based on Caco-2 cell

Soup is an important presence in diet, but its absorption and transport mechanism by the human body remains unclear. In this study, Caco-2 intact cell and monolayer cell models were constructed to simulate small intestine absorption on colloidal nanoparticles (CNPs) isolated from lamb soup. The intracellular localization of CNPs was viewed by laser confocal microscopy (LSCM). CNPs uptake and release pathways were explored by differences in CNPs concentrations in 5 endocytosis inhibitor models and 4 exocytosis inhibitor models. Results indicated that CNPs endocytosis by Caco-2 cells was restrained by Nystatin and Cytochalasin D, with exocytosis being inhibited by Nocodazole and Monensin. Therefore, the major absorption pathways for CNPs were caveolin-dependent endocytosis, macropinocytosis and phagocytosis. The major transport pathways were microtubule-vesicle-mediated protein transport to the membrane and transportation between the Golgi apparatus and membrane. This study may provide theoretical support for the transport mechanism of soup products in the small intestine.

Predicting Human Subcutaneous Bioavailability of Therapeutic Monoclonal Antibodies from Systemic Clearance and Volume of Distribution.

Subcutaneous delivery of monoclonal antibody therapeutics is often preferred to intravenous delivery due to better patient compliance and overall lower cost to the healthcare system. However, the systemic absorption of biologics dosed subcutaneously is often incomplete. The aim of this work was to describe a human bioavailability prediction method for monoclonal antibodies delivered subcutaneously that utilizes intravenous pharmacokinetic parameters as input. A two-compartment pharmacokinetic model featuring a parallel-competitive absorption pathway and a presystemic metabolism pathway was employed. A training data set comprised 19 monoclonal antibodies (geometric mean bioavailability of 68%), with previously reported human pharmacokinetic parameters, while a validation set included data compiled from 5 commercial drug products (geometric mean bioavailability of 69%). A single fitted absorption rate constant, paired with compound-specific estimates of presystemic metabolism rate proportional to compound-specific systemic clearance parameters, resulted in calculations of human subcutaneous bioavailability closely mimicking clinical data in the training data set with a root-mean-square error of 5.5%. Application of the same approach to the validation data set resulted in predictions characterized by 12.6% root-mean-square error. Factors that may have impacted the prediction accuracy include a limited number of validation data set compounds and an uncertainty in the absorption rate, which were subsequently discussed. The predictive method described herein provides an initial estimate of the subcutaneous bioavailability based exclusively on pharmacokinetic parameters available from intravenous dosing.

Comprehensive Serum Proteomic and Metabolomic Profiles of Pediatric Patients with Moyamoya Disease Reveal Core Pathways.

Moyamoya disease (MMD) signifies a cerebrovascular disorder with obscure origin and a more rapid and severe progression in children than adults. This investigation aims to uncover age-associated distinctions through proteomic and metabolomic profiling to gain insights into the underlying mechanisms of MMD. Twelve MMD patients-six children and six adults-along with six healthy controls (HC), participated, each providing a 10 mL blood sample. Serum proteomic and metabolomic analyses were conducted using ultra-performance liquid chromatography and high-resolution mass spectrometry, complemented by bioinformatics to identify differential biomolecules and their interactions. Pathway implications were ascertained using GO and KEGG enrichment analysis. Notable proteomic and metabolomic discrepancies were observed between pediatric and adult MMD subjects. A total of 235 and 216 proteins varied in adult and pediatric cases compared to HCs, with 73 proteins shared. In addition, 129 and 74 anionic, plus 96 and 104 cationic metabolites, were differentially expressed in the pediatric and adult groups, respectively, with 34 anionic and 28 cationic metabolites in common. Age-specific biomolecules further characterized these distinctions. Enrichment analysis pinpointed immunity and inflammation pathways, with vitamin digestion and absorption highlighted as pivotal in pediatric MMD. This study unveils distinct metabolic and proteomic patterns within pediatric and adult MMD patients. The critical role of the vitamin digestion and absorption pathway in the pathogenesis of pediatric MMD offers novel insight into disease mechanisms.

A Semi-Mechanistic Physiologically Based Biopharmaceutics Model to Describe Complex and Saturable Absorption of Metformin: Justification of Dissolution Specifications for Extended Release Formulation.

Physiologically based pharmacokinetic (PBPK) or physiologically based biopharmaceutics models (PBBM) demonstrated plethora of applications in both new drugs and generic product development. Justification of dissolution specifications and establishment of dissolution safe space is an important application of such modeling approaches. In case of molecules exhibiting saturable absorption behavior, justification of dissolution specifications requires development of a model that incorporates effects of transporters is critical to simulate in vivo scenario. In the present case, we have developed a semi-mechanistic PBBM to describe the non-linearity of BCS class III molecule metformin for justification of dissolution specifications of extended release formulation at strengths 500mg and 1000mg. Semi-mechanistic PBBM was built using physicochemical properties, dissolution and non-linearity was accounted through incorporation of multiple transporter kinetics at absorption level. The model was extensively validated using literature reported intravenous, oral (immediate & extended release) formulations and further validated using in-house bioequivalence data in fasting and fed conditions. Virtual dissolution profiles at lower and upper specifications were generated to justify the dissolution specifications. The model predicted literature as well as in-house clinical study data with acceptable prediction errors. Further, virtual bioequivalence trials predicted the bioequivalence outcome that matched with clinical study data. The model predicted bioequivalence when lower and upper specifications were compared against pivotal test formulations thereby justifying dissolution specifications. Overall, complex and saturable absorption pathway of metformin was successfully simulated and this work resulted in regulatory acceptance of dissolution specifications which has ability to reduce multiple dissolution testing.

Migration and accumulation of microplastics in soil-plant systems mediated by symbiotic microorganisms and their ecological effects

The coexistence of microorganisms in complex soil environments greatly affects the environmental behavior and ecological effects of microplastics (MPs). However, relevant studies are sparse, and internal mechanisms remain unclear. Herein, arbuscular mycorrhizal fungi (AMF), a common symbiotic microorganism in the soil–plant system, was proved to significantly affect MPs absorption and migration with a “size effect”. Specifically, the existence of AMF accelerated small-sized MPs (0.5 μm) uptake but slowed large-sized MPs (2 μm) uptake in lettuce. The content of 0.5 μm MPs absorbed by plants with AMF was 1.26 times that of the non-AMF group, while the content of 2 μm MPs was only 77.62 % that of non-AMF group. Additionally, the different effects of microorganisms on the intake content of MPs with different particle sizes in plants also led to different toxic effects of MPs on lettuce, that is, AMF exacerbated small-size MPs toxicity in lettuce (e.g., reduced plant biomass, photosynthesis, etc), and it weakened large-sized MPs toxicity (e.g., increased plant height, antioxidant enzyme activity, etc). The above phenomenon mainly because of the change in AMF on the plant root structure, which can be visually observed through the intraradical and extraradical hyphae. The symbiotic structure (hyphae) formed by AMF and host plants root could enhance the absorption pathway for small-sized MPs in lettuce, although not for large-sized MPs. Additionally, the effects of AMF varied with the soil environment of differently sized MPs, which promoted the migration of small-particle MPs to plants but aggravated large-particle MPs fixation at the soil interface. These findings could deepen the understanding of MPs pollution in terrestrial systems and provide theoretical basis and technical support to accurately assess soil MPs pollution.