Tissue Barriers最新文献

The incidence of kidney disease from acute and chronic conditions continues to escalate worldwide. Interventions to replace renal function after organ failure remain limited to dialysis or transplantation, as human kidneys exhibit a limited capacity to repair damaged cells or regenerate new ones. In contrast, animals ranging from flies to fishes and even some mammals like the spiny mouse exhibit innate abilities to regenerate their kidney cells following injury. Now, a recent study has illuminated how the Mexican salamander, Ambystoma mexicanum, most commonly known as the axolotl, possesses a kidney with remarkable similarity to humans, which can robustly regenerate following acute chemical damage. These discoveries position the axolotl as a new model that can be used to advance our understanding about the fundamental mechanisms of kidney regeneration.

Traumatic penumbra (TP) is a secondary injury area located around the core area of traumatic brain injury after brain trauma, and is an important factor affecting the outcome of traumatic brain injury (TBI). The main pathological change caused by TP is brain edema, including (cellular brain edema and vascular brain edema). The formation and development of brain edema in the TP area are closely related to the blood-brain barrier (BBB) and vascular endothelial growth factor (VEGF). VEGF is a vascular permeability factor that can promote angiogenesis and increase BBB permeability, and there is a debate on the pros and cons of its role in early TBI. Therefore, in the early stage of TBI, when using the VEGF inhibitor bevacizumab to treat TP area brain edema, the timing of bevacizumab administration is particularly important, and there are currently no relevant literature reports. This article explores the treatment time window and optimal treatment time point of bevacizumab in the treatment of cerebral edema in the TP area by administering the same dose of bevacizumab at different time points after brain injury in rats. The results showed that there was traumatic brain edema in TP area, BBB structure and function were damaged, VEGF expression and angiogenesis were increased. Compared with TBI + NS Group, after Bevacizumab treatment, brain edema in TP area was alleviated, BBB structure and function were improved, VEGF expression and angiogenesis were decreased in each treatment group, and the effect of TBI + Bevacizumab 1 h group was the most significant. Bevacizumab can be used as a targeted therapy for traumatic brain edema. The therapeutic time window of bevacizumab for traumatic brain edema is within 12 hours after TBI, and 1 h is the optimal therapeutic time point.

Background: A number of peptide incretin receptor agonists (IRAs) show promise as therapeutics for Alzheimer's disease (AD) and Parkinson's disease (PD). Transport across the blood-brain barrier (BBB) is one way for IRAs to act directly within the brain. To determine which IRAs are high priority candidates for treating these disorders, we have studied their brain uptake pharmacokinetics.

Methods: We quantitatively measure the ability of four IRAs to cross the BBB. We injected adult male CD-1 mice intravenously with ¹²⁵I- or ¹⁴C-labeled albiglutide, dulaglutide, DA5-CH, or tirzepatide and used multiple-time regression analyses to measure brain kinetics up to 1 hour. For those IRAs failing to enter the brain 1 h after intravenous injection, we also investigated their ability to enter over a longer time frame (i.e., 6 h).

Results: Albiglutide and dulaglutide had the fastest brain uptake rates within 1 hour. DA5-CH appears to enter the brain rapidly, reaching equilibrium quickly. Tirzepatide does not appear to cross the BBB within 1 h after iv injection but like albumin, did so slowly over 6 h, presumably via the extracellular pathways.

Conclusions: We find that IRAs can cross the BBB by two separate processes; one that is fast and one that is slow. Three of the four IRAs investigated here have fast rates of transport and should be taken into consideration for testing as AD and PD therapeutics as they would have the ability to act quickly and directly on the brain as a whole.

Cilia are hair-like structures found on the surface of nearly all vertebrate cell types where they have central roles in regulating development and orchestrating physiological events. There is growing interest in understanding the mechanisms of ciliogenesis due to the profound consequences that follow from the absence of proper ciliary function, which include diseases that affect the renal, respiratory, reproductive, nervous, visual, and digestive systems, among others. Now, a recent report has discerned new roles for the transcription factor estrogen-related receptor gamma a (esrrγa) in ciliated cell ontogeny within the embryonic zebrafish kidney and other tissues. Further, the team of researchers discovered that genetic ablation of murine homolog ERRγ in adult kidney epithelial cells led to shortened cilia, which precedes cystogenesis. These intriguing findings expand our fundamental understanding of the pathological basis of cilia defects, which is relevant for identifying future therapeutic targets for ciliopathies.

Paraprobiotics and postbiotics represent a valid alternative to probiotic strains for ameliorating and preserving a healthy intestinal epithelial barrier (IEB). The present study investigated the effects of surface layer proteins (S-layer) of the dairy strain Lactobacillus helveticus ATCC® 15009™ (Lb ATCC® 15009™), as paraprobiotic, on the morpho-functional modulation of IEB in comparison to live or heat-inactivated Lb ATCC® 15009™ in an in vitro co-culture of Caco-2/HT-29 70/30 cells. Live or heat-inactivated Lb ATCC® 15009™ negatively affected transepithelial electrical resistance (TEER) and paracellular permeability, and impaired the distribution of Claudin-1, a tight junction (TJ) transmembrane protein, as detected by immunofluorescence (IF). Conversely, the addition of the S-layer improved TEER and decreased permeability in physiological conditions in co-cultures with basal TEER lower than 50 ohmcm², indicative of a more permeable physiological IEB known as leaky gut. Transmission electron microscopy (TEM) and IF analyses suggested that the S-layer induces a structural TJ rearrangement and desmosomes' formation. S-layer also restored TEER and permeability in the presence of LPS, but not of a mixture of pro-inflammatory cytokines (TNF-α plus IFN-γ). IF analyses showed an increase in Claudin-1 staining when LPS and S-layer were co-administered with respect to LPS alone; in addition, the S-layer counteracted the reduction of alkaline phosphatase detoxification activity and the enhancement of pro-inflammatory interleukin-8 release both induced by LPS. Altogether, these data corroborate a paraprobiotic role of S-layer from Lb ATCC® 15009™ as a possible candidate for therapeutic and prophylactic uses in conditions related to gastrointestinal health and correlated with extra-intestinal disorders.

The development of new therapies is hampered by the lack of predictive, and patient-relevant in vitro models. Organ-on-chip (OOC) technologies can potentially recreate physiological features and hold great promise for tissue and disease modeling. However, the non-standardized design of these chips and perfusion control systems has been a barrier to quantitative high-throughput screening (HTS). Here we present a scalable OOC microfluidic platform for applied kinetic in vitro assays (AKITA) that is applicable for high, medium, and low throughput. Its standard 96-well plate and 384-well plate layouts ensure compatibility with existing laboratory workflows and high-throughput data collection and analysis tools. The AKITA plate is optimized for the modeling of vascularized biological barriers, primarily the blood-brain barrier, skin, and lung, with precise flow control on a custom rocker. The integration of trans-epithelial electrical resistance (TEER) sensors allows rapid and repeated monitoring of barrier integrity over long time periods. Together with automated liquid handling and compound permeability testing analyses, we demonstrate the flexibility of the AKITA platform for establishing human-relevant models for preclinical drug and precision medicine's efficacy, toxicity, and permeability under near-physiological conditions.

Small intestine perforation is a serious medical condition that requires immediate medical attention. The traditional course of treatment entails resection followed by anastomosis; however, it has complications such as small bowel syndrome (SBS), anastomotic leakage, and fistula formation. Here, a novel strategy is demonstrated, that utilizes the xenogeneic, decellularized goat small intestine as a patch for small intestine regeneration in cases of intestinal perforation. The goat small intestine scaffold underwent sodium dodecyl sulfate decellularization, which revealed consistent, quick, and effective decellularization. Decellularization contributed the least amount of extracellular matrix degradation while maintaining the intestinal architecture. By implanting the decellularized goat small intestine scaffolds (DGSIS) on the chorioallantoic membrane (CAM), no discernible loss of angiogenesis was seen in the CAM region, and this enabled the DGSIS to be evaluated for biocompatibility in ovo. The DGSIS was then xeno-transplanted as a patch on a small intestine perforation rat model. After 30 days post transplant, barium salt used as contrast gastrointestinal X-ray imaging revealed no leakage or obstruction in the small intestine. Histology, scanning electron microscopy, and immunohistochemistry assisted in analyzing the engraftment of host cells into the xeno patch. The xeno-patch expressed high levels of E-cadherin, α-smooth muscle actin (α-SMA), Occludin, Zonnula occluden (ZO-1), Ki 67, and Na⁺/K⁺-ATPase. The xeno-patch was consequently recellularized and incorporated into the host without causing an inflammatory reaction. As an outcome, decellularized goat small intestine was employed as a xenograft and could be suitable for regeneration of the perforated small intestine.

It is known that there are abnormalities of tight junction functions, cell migration and mitochondrial metabolism in human endometriosis and endometrial carcinoma. In this study, we investigated the effects of growth factors and their inhibitors on the epithelial permeability barrier, cell migration and mitochondrial metabolism in 2D and 2.5D cultures of human endometrioid endometrial carcinoma Sawano cells. We also investigated the changes of bicellular and tricellular tight junction molecules and ciliogenesis induced by these inhibitors. The growth factors TGF-β and EGF affected the epithelial permeability barrier, cell migration and expression of bicellular and tricellular tight junction molecules in 2D and 2.5D cultures of Sawano cells. EW-7197 (a TGF-β receptor inhibitor), AG1478 (an EGFR inhibitor) and SP600125 (a JNK inhibitor) affected the epithelial permeability barrier, cell migration and mitochondrial metabolism and prevented the changes induced by TGF-β and EGF in 2D and 2.5D cultures. EW-7197 and AG1478 induced ciliogenesis in 2.5D cultures. In conclusion, TGF-β and EGF promoted the malignancy of endometrial cancer via interplay among the epithelial permeability barrier, cell migration and mitochondrial metabolism. EW-7197 and AG1478 may be useful as novel therapeutic treatments options for endometrial cancer.

Titanium dioxide fine particles (TiO₂-FPs) and nanoparticles (TiO₂-NPs) are the most widely used whitening pigments worldwide. Inhalation of TiO₂-FPs and TiO₂-NPs can be harmful as it triggers toxicity in the airway epithelial cells. The airway epithelium serves as the respiratory system's first line of defense in which airway epithelial cells are significant targets of inhaled pathogens and environmental particles. Our group previously found that TiO₂-NPs lead to a disrupted barrier in the polarized airway epithelial cells. However, the effect of TiO₂-FPs on the respiratory epithelial barrier has not been examined closely. In this study, we aimed to compare the effects of TiO₂-FPs and TiO₂-NPs on the structure and function of the airway epithelial barrier. Additionally, we hypothesized that 8-Bromo-cAMP, a cyclic adenosine monophosphate (cAMP) derivative, would alleviate the disruptive effects of both TiO₂-FPs and TiO₂-NPs. We observed increased epithelial membrane permeability in both TiO₂-FPs and TiO₂-NPs after exposure to 16HBE cells. Immunofluorescent labeling showed that both particle sizes disrupted the structural integrity of airway epithelial tight junctions and adherens junctions. TiO₂-FPs had a slightly more, but insignificant impact on the epithelial barrier disruption than TiO₂-NPs. Treatment with 8-Bromo-cAMP significantly attenuated the barrier-disrupting impact of both TiO₂-FPs and TiO₂-NPs on cell monolayers. Our study demonstrates that both TiO₂-FPs and TiO₂-NPs cause comparable barrier disruption and suggests a protective role for cAMP signaling. The observed effects of TiO₂-FPs and TiO₂-NPs provide a necessary understanding for characterizing the pathways involved in the defensive role of the cAMP pathway on TiO₂-induced airway barrier disruption.