Delivery of miR-29a improves the permeability of cisplatin by downregulating collagen I expression.

In the clinical setting, chemotherapy is the most widely used antitumor treatment, however, chemotherapy resistance significantly limits its efficacy. Reduced drug influx is a key mechanism of chemoresistance, and inhibition of the complexity of the tumor microenvironment (TME) may improve chemotherapy drug influx and therapeutic efficiency. In the current study, we identified that the major extracellular matrix protein collagen I is more highly expressed in lung cancer tissues than adjacent tissues in patients with lung cancer. Furthermore, Kaplan-Meier analysis suggested that COL1A1 expression was negatively correlated with the survival time of patients with lung cancer. Our previous study demonstrated that miR-29a inhibited collagen I expression in lung fibroblasts. Here, we investigated the effect of miR-29a on collagen I expression and the cellular behavior of lung cancer cells. Our results suggest that transfection with miR-29a could prevent Lewis lung carcinoma (LLC) migration by downregulating collagen I expression, but did not affect the proliferation, apoptosis, and cell cycle of LLC cells. In a 3D tumoroid model, we demonstrated that miR-29a transfection significantly increased cisplatin (CDDP) permeation and CDDP-induced cell death. Furthermore, neutral lipid emulsion-based miR-29a delivery improved the therapeutic effect of cisplatin in an LLC spontaneous tumor model in vivo. In summary, this study shows that targeting collagen I expression in the TME contributes to chemotherapy drug influx and improves therapeutic efficacy in lung cancer.

22q11.2 Deletion-Associated Blood-Brain Barrier Permeability Potentiates Systemic Capillary Leak Syndrome Neurologic Features.

We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed in vitro cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient's serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by genes such as claudin-5 deleted in the 22q11.2 region promoted neurologic involvement during SCLS in this patient.

Comparison of intestinal toxicity in enhancing intestinal permeability and in causing ROS production of six PPD quinones in Caenorhabditis elegans.

As the derivatives of p-phenylenediamines (PPDs), PPD quinones (PPDQs) have received increasing attention due to their possible exposure risk. We compared the intestinal toxicity of six PPDQs (6-PPDQ, 77PDQ, CPPDQ, DPPDQ, DTPDQ and IPPDQ) in Caenorhabditis elegans. In the range of 0.01-10 µg/L, only 77PDQ (10 µg/L) moderately induced the lethality. All the examined PPDQs at 0.01-10 µg/L did not affect intestinal morphology. Different from this, exposure to 6-PPDQ (1-10 µg/L), 77PDQ (0.1-10 µg/L), CPPDQ (1-10 µg/L), DPPDQ (1-10 µg/L), DTPDQ (1-10 µg/L), and IPPDQ (10 µg/L) enhanced intestinal permeability to different degrees. Meanwhile, exposure to 6-PPDQ (0.1-10 µg/L), 77PDQ (0.01-10 µg/L), CPPDQ (0.1-10 µg/L), DPPDQ (0.1-10 µg/L), DTPDQ (1-10 µg/L), and IPPDQ (1-10 µg/L) resulted in intestinal reactive oxygen species (ROS) production and activation of both SOD-3::GFP and GST-4::GFP. In 6-PPDQ, 77PDQ, CPPDQ, DPPDQ, DTPDQ, and/or IPPDQ exposed nematodes, the ROS production was strengthened by RNAi of genes (acs-22, erm-1, hmp-2, and pkc-3) governing functional state of intestinal barrier. Additionally, expressions of acs-22, erm-1, hmp-2, and pkc-3 were negatively correlated with intestinal ROS production in nematodes exposed to 6-PPDQ, 77PDQ, CPPDQ, DPPDQ, DTPDQ, and/or IPPDQ. Therefore, exposure to different PPDQs differentially induced the intestinal toxicity on nematodes. Our data highlighted potential exposure risk of PPDQs at low concentrations to organisms by inducing intestinal toxicity.

Stable and permeable polyion complex vesicles designed as enzymatic nanoreactors.

Polymeric vesicles are perspective vehicles for fabricating enzymatic nanoreactors towards diverse biomedical and catalytic applications, yet the design of stable and permeable vesicles remains challenging. Herein, we developed polyion complex (PIC) vesicles featuring high stability and a permeable membrane for adequate enzyme loading and activation. Our design relies on co-assembly of an anionic diblock copolymer (PSS96-b-PEO113) with cationic branched poly(ethylenimine) (PEI). The polymer combination endows strong electrostatic interaction between the PSS and PEI building blocks, so their assembly can be implemented at a high salt concentration (500 mM NaCl), under which the charge interaction of the enzyme-polymer is inhibited. This control realizes the successful and safe loading of enzymes associated with the formation of stable PIC vesicles with an intrinsic permeable membrane that is favourable for enhancing enzymatic activity. The control factors for vesicle formation and enzyme loading were investigated, and the general application of loading different enzymes for cascade reaction was validated as well. Our study reveals that proper design and combination of polyelectrolytes is a facile strategy for fabricating stable and permeable polymeric PIC vesicles, which exhibit clear advantages for loading and activating enzymes, consequently boosting their diverse applications as enzymatic nanoreactors.

Neurotensin modulates ovarian vascular permeability via adherens junctions.

Neurotensin (NTS) is a 13-amino acid peptide which is highly expressed in the mammalian ovary in response to the luteinizing hormone surge. Antibody neutralization of NTS in the ovulatory follicle of the cynomolgus macaque impairs ovulation and induces follicular vascular dysregulation, with excessive pooling of red blood cells in the follicle antrum. We hypothesize that NTS is an essential intrafollicular regulator of vascular permeability. In the present study, follicle injection of the NTS receptor antagonist SR142948 also resulted in vascular dysregulation. To measure vascular permeability changes in vitro, primary macaque ovarian microvascular endothelial cells (mOMECs) were enriched from follicle aspirates and studied in vitro. When treated with NTS, permeability of mOMECs decreased. RNA sequencing (RNA-Seq) of mOMECs revealed high mRNA expression of the permeability-regulating adherens junction proteins N-cadherin (CDH2) and K-cadherin (CDH6). Immunofluorescent detection of CDH2 and CDH6 confirmed expression and localized these cadherins to the cell-cell boundaries, consistent with function as components of adherens junctions. mOMECs did not express detectable levels of the typical vascular endothelial cadherin, VE-cadherin (CDH5) as determined by RNA-Seq, qPCR, western blot, and immunofluorescence. Knockdown of CDH2 or CDH6 via siRNA abrogated the NTS effect on mOMEC permeability. Collectively, these data suggest that NTS plays an ovulation-critical role in vascular permeability maintenance, and that CDH2 and CDH6 are involved in the permeability modulating effect of NTS on the ovarian microvasculature. NTS can be added to a growing number of angiogenic regulators which are critical for successful ovulation.

Octreotide attenuates intestinal barrier damage by maintaining basal autophagy in Caco2 cells.

The intestinal mucosal barrier is of great importance for maintaining the stability of the internal environment, which is closely related to the occurrence and development of intestinal inflammation. Octreotide (OCT) has potential applicable clinical value for treating intestinal injury according to previous studies, but the underlying molecular mechanisms have remained elusive. This article is based on a cell model of inflammation induced by lipopolysaccharide (LPS), aiming to explore the effects of OCT in protecting intestinal mucosal barrier function. A Cell Counting Kit­8 assay was used to determine cell viability and evaluate the effectiveness of OCT. Gene silencing technology was used to reveal the mediated effect of somatostatin receptor 2 (SSTR2). The changes in intestinal permeability were detected through trans­epithelial electrical resistance and fluorescein isothiocyanate­dextran 4 experiments, and the alterations in tight junction proteins were detected using immunoblotting and reverse transcription fluorescence­quantitative PCR technology. Autophagosomes were observed by electron microscopy and the dynamic changes of the autophagy process were characterized by light chain (LC)3­II/LC3­I conversion and autophagic flow. The results indicated that SSTR2­dependent OCT can prevent the decrease in cell activity. After LPS treatment, the permeability of monolayer cells decreased and intercellular tight junctions were disrupted, resulting in a decrease in tight junction protein zona occludens 1 in cells. The level of autophagy­related protein LC3 was altered to varying degrees at different times. These abnormal changes gradually returned to normal levels after the combined application of LPS and SSTR2­dependent OCT, confirming the role of OCT in protecting intestinal barrier function. These experimental results suggest that OCT maintains basal autophagy and cell activity mediated by SSTR2 in intestinal epithelial cells, thereby preventing the intestinal barrier dysfunction in inflammation injury.

Non-animal models for blood-brain barrier permeability evaluation of drug-like compounds.

Diseases related to the central nervous system (CNS) are major health concerns and have serious social and economic impacts. Developing new drugs for CNS-related disorders presents a major challenge as it actively involves delivering drugs into the CNS. Therefore, it is imperative to develop in silico methodologies to reliably identify potential lead compounds that can penetrate the blood-brain barrier (BBB) and help to thoroughly understand the role of different physicochemical properties fundamental to the BBB permeation of molecules. In this study, we have analysed the chemical space of the CNS drugs and compared it to the non-CNS-approved drugs. Additionally, we have collected a feature selection dataset from Muehlbacher et al. (J Comput Aided Mol Des 25(12):1095-1106, 2011. 10.1007/s10822-011-9478-1) and an in-house dataset. This information was utilised to design a molecular fingerprint that was used to train machine learning (ML) models. The best-performing models reported in this study achieved accuracies of 0.997 and 0.98, sensitivities of 1.0 and 0.992, specificities of 0.971 and 0.962, MCCs of 0.984 and 0.958, and ROC-AUCs of 0.997 and 0.999 on an imbalanced and a balanced dataset, respectively. They demonstrated overall good accuracies and sensitivities in the blind validation dataset. The reported models can be applied for fast and early screening drug-like molecules with BBB potential. Furthermore, the bbbPythoN package can be used by the research community to both produce the BBB-specific molecular fingerprints and employ the models mentioned earlier for BBB-permeability prediction.

Gaussian accelerated molecular dynamics simulations facilitate prediction of the permeability of cyclic peptides.

Despite their widespread use as therapeutics, clinical development of small molecule drugs remains challenging. Among the many parameters that undergo optimization during the drug development process, increasing passive cell permeability (i.e., log(P)) can have some of the largest impact on potency. Cyclic peptides (CPs) have emerged as a viable alternative to small molecules, as they retain many of the advantages of small molecules (oral availability, target specificity) while being highly effective at traversing the plasma membrane. However, the relationship between the dominant conformations that typify CPs in an aqueous versus a membrane environment and cell permeability remain poorly characterized. In this study, we have used Gaussian accelerated molecular dynamics (GaMD) simulations to characterize the effect of solvent on the free energy landscape of lariat peptides, a subset of CPs that have recently shown potential for drug development (Kelly et al., JACS 2021). Differences in the free energy of lariat peptides as a function of solvent can be used to predict permeability of these molecules, and our results show that permeability is most greatly influenced by N-methylation and exposure to solvent. Our approach lays the groundwork for using GaMD as a way to virtually screen large libraries of CPs and drive forward development of CP-based therapeutics.

Skin Barrier in Atopic Dermatitis.

A compromised permeability barrier is a hallmark of atopic dermatitis (AD). Localized to the outermost skin layer, the stratum corneum (SC) is critically dependent on terminal differentiation of epidermal keratinocytes, which transform into protein-rich corneocytes surrounded by extracellular lamellae of unique epidermal lipids, conferring permeability barrier function. These structures are disrupted in AD. A leaky barrier is prone to environmental insult, which in AD elicits type 2-dominant inflammation, in turn resulting in a vicious cycle further impairing the SC structure. Therapies directed at enforcing SC structure and anti-inflammatory strategies administered by topical and systemic route as well as UV therapy have differential effects on the permeability barrier. The expanding armamentarium of therapeutic modalities for AD treatment warrants optimization of their effects on permeability barrier function.

Penetration pathways, influencing factors and predictive models for dermal absorption of exobiotic molecules: A critical review.

This review provides a comprehensive summary of the skin penetration pathways of xenobiotics, including metals, organic pollutants, and nanoparticles (NPs), with a particular focus on the methodologies employed to elucidate these penetration routes. The impacts of the physicochemical properties of exogenous substances and the properties of solvent carriers on the penetration efficiencies were discussed. Furthermore, the review outlines the steady-state and transient models for predicting the skin permeability of xenobiotics, emphasizing the models which enable realistic visualization of pharmaco-kinetic phenomena via detailed geometric representations of the skin microstructure, such as stratum corneum (SC) (bricks and mortar) and skin appendages (hair follicles and sebaceous gland units). Limitations of published research, gaps in current knowledge, and recommendations for future research are highlighted, providing insight for a better understanding of the skin penetration behavior of xenobiotics and associated health risks in practical application contexts.

In vitro mucin degradation and paracellular permeability by fecal water from Crohn's disease patients.

Aim: This study aimed to examine the impact of fecal water (FW) of active and remissive Crohn's disease (CD) patients on mucin degradation and epithelial barrier function. Methods: FW and bacterial membrane vesicles (MVs) were isolated from fresh fecal samples of six healthy controls (HCs) and 12 CD patients. Bacterial composition was determined by 16S rRNA gene amplicon sequencing. Results: In vitro FW-induced mucin degradation was higher in CD samples versus HC (p < 0.01), but not associated with specific bacterial genera. FW of three remissive samples decreased transepithelial electrical resistance in Caco-2 cells by 78-87% (p < 0.001). MVs did not induce barrier alterations. Conclusion: The higher mucin-degradation capacity of CD-derived FW might suggest contributions of microbial products to CD pathophysiology.

SARS-CoV-2 presence in recreational seawater and evaluation of intestine permeability: experimental evidence of low impact on public health.

Introduction: Coastal seawater pollution poses a public health risk due to the potential ingestion of contaminated water during recreational activities. Wastewater-based epidemiology has revealed the abundant presence of SARS-CoV-2 in seawater emitted from wastewater outlets. The objective of this research was to investigate the impact of seawater on SARS-CoV-2 infectivity to assess the safety of recreational activities in seawater. Methods: Wild SARS-CoV-2 was collected from oral swabs of COVID-19 affected patients and incubated for up to 90 min using the following solutions: (a) standard physiological solution (control), (b) reconstructed seawater (3.5% NaCl), and (c) authentic seawater (3.8%). Samples were then exposed to two different host systems: (a) Vero E6 cells expressing the ACE2 SARS-CoV-2 receptor and (b) 3D multi-tissue organoids reconstructing the human intestine. The presence of intracellular virus inside the host systems was determined using plaque assay, quantitative real-time PCR (qPCR), and transmission electron microscopy. Results: Ultrastructural examination of Vero E6 cells revealed the presence of virus particles at the cell surface and in replicative compartments inside cells treated with seawater and/or reconstituted water only for samples incubated up to 2 min. After a 90-min incubation, the presence of the virus and its infectivity in Vero E6 cells was reduced by 90%. Ultrastructural analysis performed in 3D epi-intestinal tissue did not reveal intact viral particles or infection signs, despite the presence of viral nucleic acid detected by qPCR. Indeed, viral genes (Orf1ab and N) were found in the intestinal luminal epithelium but not in the enteric capillaries. These findings suggest that the intestinal tissue is not a preferential entry site for SARS-CoV-2 in the human body. Additionally, the presence of hypertonic saline solution did not increase the susceptibility of the intestinal epithelium to virus penetration; rather, it neutralized its infectivity. Conclusion: Our results indicate that engaging in recreational activities in a seawater environment does not pose a significant risk for COVID-19 infection, despite the possible presence of viral nucleic acid deriving from degraded and fragmented viruses.

Border Control: The Role of the Microbiome in Regulating Epithelial Barrier Function.

The gut mucosal epithelium is one of the largest organs in the body and plays a critical role in regulating the crosstalk between the resident microbiome and the host. To this effect, the tight control of what is permitted through this barrier is of high importance. There should be restricted passage of harmful microorganisms and antigens while at the same time allowing the absorption of nutrients and water. An increased gut permeability, or "leaky gut", has been associated with a variety of diseases ranging from infections, metabolic diseases, and inflammatory and autoimmune diseases to neurological conditions. Several factors can affect gut permeability, including cytokines, dietary components, and the gut microbiome. Here, we discuss how the gut microbiome impacts the permeability of the gut epithelial barrier and how this can be harnessed for therapeutic purposes.

Electroacupuncture stimulation enhances the permeability of the blood-brain barrier: A systematic review and meta-analysis of preclinical evidence and possible mechanisms.

An important cellular barrier to maintain the stability of the brain's internal and external environment is the blood-brain barrier (BBB). It also prevents harmful substances from entering brain tissue through blood circulation while providing protection for the central nervous system. It should be noted, however, that the intact BBB can be a barrier to the transport of most drugs into the brain via the conventional route of administration, which can prevent them from reaching effective concentrations for the treatment of disorders affecting the central nervous system. Electroacupuncture stimulation has been shown to be effective at opening the BBB in a series of experimental studies. This study systematically analyzes the possibility and mechanism by which electroacupuncture opens the BBB. In PubMed, Web of Science, VIP Database, Wanfang Database, and the Chinese National Knowledge Infrastructure, papers have been published for nearly 22 years aimed at opening the BBB and its associated structures. A comparison of EB content between electroacupuncture and control was selected as the primary outcome. There were also results on vascular endothelial growth factor (VEGF), nerve growth factor (NGF), P-Glycoprotein (P-gp), Matrix Metalloproteinase 9 (MMP-9), and glial fibrillary acidic protein (GFAP). We utilized Review Manager software analysis to analyze correlations between studies with a view to exploring the mechanisms of similarity. Evans Blue infiltration forest plot: pooled effect size of 2.04, 95% CI: 1.21 to 2.87, P < 0.01. These results indicate that electroacupuncture significantly increases EB penetration across the BBB. Most studies have reported that GFAP, MMP-9, and VEGF were upregulated after treatment. P-gp expression decreased as well. Electroacupuncture can open the BBB, and the sparse-dense wave is currently the most effective electroacupuncture frequency for opening the BBB. VEGF plays an important role in opening the BBB. It is also important to regulate the expression of MMP-9 and GFAP and inhibit the expression of P-gp.

Mitigation effect of hesperidin on X-ray radiation-induced intestinal barrier dysfunction in Caco-2 cell monolayers.

The tight junctions (TJs) and barrier function of the intestinal epithelium are highly sensitive to radiation. However, polyphenols can be used to reverse the effects of radiation. Here, we investigated the effects of hesperidin (hesperetin-7-rhamnoglucoside) on X-ray-induced intestinal barrier dysfunction in human epithelial Caco-2 monolayers. To examine whether hesperidin mitigated the effects of X-ray exposure (2 Gy), cell survival was evaluated and intestinal barrier function was assessed by measuring the transepithelial flux, apparent permeability coefficient (Papp), and barrier integrity. Hesperidin improved the survival of Caco-2 cell monolayers and attenuated X-ray exposure-induced intestinal barrier dysfunction. For fluorescein transport experiments, transepithelial flux and Papp of fluorescein in control group were significantly elevated by X-ray, but were restored to near control by 10 µM hesperidin pretreatment. Further, X-ray exposure decreased the barrier integrity and TJ interruption by reducing TJ-related proteins occludin and claudin-4, whereas cell monolayers pretreated with hesperidin before X-ray exposure were reinstated to control level. It was concluded that hesperidin treatment before X-ray exposure alleviated X-ray-induced intestinal barrier dysfunction through regulation of TJ-related proteins. These results indicate that hesperidin prevents and mitigates X-ray-induced intestinal barrier dysfunction.

Disruption of intestinal epithelial permeability in the Co-culture system of Caco-2/HT29-MTX cells exposed individually or simultaneously to acrylamide and ochratoxin A.

Mycotoxins and thermal processing hazards are common contaminants in various foods and cause severe problems in terms of food safety and health. Combined use of acrylamide (AA) and ochratoxin A (OTA) would result in more significant intestinal toxicity than either toxin alone, but the underlying mechanisms behind this poor outcome remain unclear. Herein, we established the co-culture system of Caco-2/HT29-MTX cells for simulating a real intestinal environment that is more sensitive to AA and OTA, and showed that the combination of AA and OTA could up-regulate permeability of the intestine via increasing LY permeabilization, and decreasing TEER, then induce oxidative stress imbalance (GSH, SOD, MDA, and ROS) and inflammatory system disorder (TNF-α, IL-1ß, IL-10, and IL-6), thereby leading a rapid decline in cell viability. Western blot, PAS- and AB-staining revealed that AA and OTA showed a synergistic effect on the intestine mainly through the disruption of tight junctions (TJs) and a mucus layer. Furthermore, based on correlation analysis, oxidative stress was more relevant to the mucus layer and TJs. Therefore, our findings provide a better evaluation model and a potential mechanism for further determining or preventing the combined toxicity caused by AA and OTA.

Rectifying artificial nanochannels with multiple interconvertible permeability states.

Transmembrane channels play a vital role in regulating the permeation process, and have inspired recent development of biomimetic channels. Herein, we report a class of artificial biomimetic nanochannels based on DNAzyme-functionalized glass nanopipettes to realize delicate control of channel permeability, whereby the surface wettability and charge can be tuned by metal ions and DNAzyme-substrates, allowing reversible conversion between different permeability states. We demonstrate that the nanochannels can be reversibly switched between four different permeability states showing distinct permeability to various functional molecules. By embedding the artificial nanochannels into the plasma membrane of single living cells, we achieve selective transport of dye molecules across the cell membrane. Finally, we report on the advanced functions including gene silencing of miR-21 in single cancer cells and selective transport of Ca2+ into single PC-12 cells. In this work, we provide a versatile tool for the design of rectifying artificial nanochannels with on-demand functions.

Saponaria officinalis saponins as a factor increasing permeability of Candida yeasts' biomembrane.

Saponins are a large group of compounds, produced mostly by plants as a side product of their metabolic activity. These compounds have attracted much attention over the years mostly because of their surface activity and antibacterial, anti-inflammatory and antifungal properties. On the other hand, most of the hitherto research has concerned the action of saponins against microbial cells as a whole. Therefore, knowing the possible interaction of saponins with biomembrane, we decided to check in-vitro the influence of saponin-rich extract of Saponaria officinalis on spheroplasts of two Candida sp. The obtained results show that 10 mg L- 1 of extract increased the permeability of spheroplasts up to 21.76% relative to that of the control sample. Moreover, the evaluation of surface potential has revealed a decrease by almost 10 mV relative to that of the untreated samples. Such results suggest its direct correlation to integration of saponins into the biomembrane structure. The obtained results have proved the antifungal potential of saponins and their ability of permeabilization of cells. This proves the high potential of saponins use as additives to antifungal pharmaceutics, which is expected to lead to improvement of their action or reduction of required dosage.

Absorption and transport properties of a codfish-derived peptide and its protective effect on bone loss in ovariectomized mice.

A potential osteogenic tetradecapeptide with the amino acid sequence GETNPADSKPGSIR (P-GM-2) was identified from Gadus morhua. The present study aimed to elucidate its absorption and transport properties using Caco-2/HT29-MTX co-culture monolayers and to evaluate its osteogenic activity using an ovariectomized mouse model. The results showed that P-GM-2 could cross Caco-2/HT29-MTX co-culture barriers intactly with an apparent permeability coefficient of 4.02 × 10-6 cm s-1via the TJ-mediated passive paracellular pathway. Pharmacokinetic results revealed that P-GM-2 was detectable in the blood of mice within 5 min of oral administration and reached its maximum concentration at 30 min. Furthermore, the oral administration of P-GM-2 for a duration of three months has been found to effectively regulate the secretion of key markers of bone turnover, thereby protecting against bone microstructure degeneration and bone loss in ovariectomized mice. Importantly, no toxicity related to the treatment was observed. Taken together, these findings offer valuable insights into the absorption and transport mechanisms of P-GM-2, highlighting its potential as a safe and effective active ingredient for preventing osteoporosis.

Quantifying blood-brain barrier permeability in patients with ischemic stroke using non-contrast MRI.

Increased blood-brain barrier permeability (BBBP) after ischemic stroke predisposes patients to hemorrhagic conversion. While altered BBBP can impact patient recovery, it is not routinely assessed during the workup of acute ischemic stroke (AIS). We study the effectiveness of the non-contrast MRI sequences diffusion-prepared pseudocontinuous arterial spin labeling (DP-pCASL) and Neurite Orientation Dispersion and Density Imaging (NODDI) in assessing BBBP and correlating to tissue microstructure after ischemic insult. Twelve patients with AIS were prospectively enrolled to undergo our multimodal MR imaging, which generated the DP-pCASL-derived cerebral blood flow (CBF), arterial transit time (ATT), and water exchange rate (kw) and the NODDI-derived b0, mean diffusivity (MD), orientation dispersion index (ODI), intracellular volume fraction (ICVF), and isotropic volume fraction (ISO) parametric maps. The mean age of the patients was 70.2 ± 14.8 with an average NIHSS of 13.0 (7.3-19.8). MR imaging was performed on average at 53.7 (27.8-93.3) hours from stroke symptom onset. The water exchange rate (kw) of the infarcted area and its contralateral territory were 89.7 min-1 (66.7-121.9) and 89.9 min-1 (65.9-106.0) respectively (p = 0.887). Multivariable linear regression analysis showed that b0, ODI, ISO and mechanical thrombectomy were significant predictors of kw. DP-pCASL and NODDI are promising non-contrast sequences for the routine assessment of BBBP.