Wnt Signaling in Inner Blood–Retinal Barrier Maintenance

The retina is a light-sensing ocular tissue that sends information to the brain to enable vision. The blood–retinal barrier (BRB) contributes to maintaining homeostasis in the retinal microenvironment by selectively regulating flux of molecules between systemic circulation and the retina. Maintaining such physiological balance is fundamental to visual function by facilitating the delivery of nutrients and oxygen and for protection from blood-borne toxins. The inner BRB (iBRB), composed mostly of inner retinal vasculature, controls substance exchange mainly via transportation processes between (paracellular) and through (transcellular) the retinal microvascular endothelium. Disruption of iBRB, characterized by retinal edema, is observed in many eye diseases and disturbs the physiological quiescence in the retina’s extracellular space, resulting in vision loss. Consequently, understanding the mechanisms of iBRB formation, maintenance, and breakdown is pivotal to discovering potential targets to restore function to compromised physiological barriers. These unraveled targets can also inform potential drug delivery strategies across the BRB and the blood–brain barrier into retinas and brain tissues, respectively. This review summarizes mechanistic insights into the development and maintenance of iBRB in health and disease, with a specific focus on the Wnt signaling pathway and its regulatory role in both paracellular and transcellular transport across the retinal vascular endothelium.

Lemon maturation causes anatomical and biochemical changes at the flavedo tissue level

Plants mobilize the photosynthates by three transport pathways: apoplastic, symplastic through plasmodesmata (PD), and transcellular. In flavedo of postharvest mature lemons, a high activity of cell wall-bound invertase (WI), an enzyme associated with transcellular transport of monosaccharides, has been detected. In order to elucidate whether this high enzymatic activity is related to restricted transport in the symplastic pathway with fruit maturation, the aim of the present work was to compare anatomical and biochemical parameters in peel tissues of immature and mature lemons. Anatomical structure focusing on cell walls, callose deposition, WI activity, and sucrose content were analyzed in peel tissues of immature and mature lemons. The parenchyma of flavedo tissue of immature lemons presented an elevated number of primary pit fields (PPF). These PPF, associated to PD or cell wall interruptions, had the appearance of a string of beads. However, in mature lemons, the number of PPF was scarce due to callose deposition. WI activity and apoplastic sucrose content increased significantly in flavedo of mature lemons in comparison to immature lemons. Present findings lay structural and functional bases relevant to understand differences between immature and mature lemons, which would help to design agricultural practices in pre- and post-harvest management.

Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy

Tau-specific immunotherapy is an attractive therapeutic strategy for the treatment of Alzheimer's disease and other tauopathies. However, targeting tau effectively remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes 99.9% of peripherally administered antibodies. We have previously shown that the delivery of tau-specific monoclonal antibody (mAb) with low-intensity scanning ultrasound in combination with intravenously injected microbubbles (SUS+MB) increases the passage of IgG antibodies into the brain. SUS+MB transiently opens tight junctions to allow paracellular transport, but also facilitates transcellular transport, particularly for larger cargoes. However, therapeutic efficacy after enhanced brain delivery has not been explored. To assess whether ultrasound-mediated delivery of tau-specific mAbs leads to an enhanced therapeutic response, K369I tau transgenic K3 mice were passively immunised once weekly for 12 weeks with a novel mAb, RNF5, in combination with SUS+MB. While none of the treatment arms improved behaviour or motor functions in these mice, we found that both RNF5 and SUS+MB treatments on their own reduced tau pathology, but, surprisingly, the combination of both (RNF5+SUS+MB) did not achieve an additive reduction in tau pathology. This was despite observing increased antibody penetration in the brain. Interestingly, a significant fraction of the antibody in the combination treatment was visualized in brain endothelial cells, suggesting that paracellular transport may not be the preferred uptake mechanism for RNF5. Taken altogether, more research is warranted to develop SUS+MB as a delivery modality for anti-tau antibodies.

NANO-BIOTECHNOLOGY AND ITS INNOVATIVE PERSPECTIVE IN DIABETES MANAGEMENT

: Diabetes occurs due to the imbalance of glucose in the body known as glucose homeostasis, thus leading to metabolic changes in the body. The two stages hypoglycemia or hyperglycemia classify diabetes into various categories. Various bio-nanotechnological approaches are coupled up with nano particulates, polymers, liposome, various gold plated and solid lipid particulates, regulating transcellular transport, non specific cellular uptake, and paracellular transport, leading to oral, trans-dermal , pulmonary, buccal , nasal , specific gene oriented administration to avoid the patient’s non compliance with the parental routes of administration. Phytochemicals are emerging strategies for the future prospects of diabetes management.

Reproductive biology, embryonic development and matrotrophy in the phylactolaemate bryozoan Plumatella casmiana

Bryozoa is a phylum of aquatic, colonial suspension-feeders within the Lophotrochozoa. In the Phylactolaemata embryonic development occurs in an internal brood sac on the body wall accompanied by extraembryonic nutrition. Owing to previous contradictive descriptions, many aspects of their sexual reproduction require restudy. Consequently, this study analyses embryogenesis of the freshwater bryozoan Plumatella casmiana by serial sections, 3D reconstruction and transmission electron microscopy. Early embryos cleave and soon develop into blastulae with a small central cavity. The mesoderm forms by delamination starting from the distal side towards the proximal end. In later embryos two polypides form on the posterior side that ultimately will be covered by a ciliated mantle in the larva. Embryos increase in size during development and form temporary cell contacts to the embryo sac. Mesodermal cells of the embryo sac show signs of transcellular transport indicating that embryos are nourished by transferring nutrients from the maternal coelom towards the brood cavity. This study clarifies several details such as mesoderm formation and the onset of bud development. Embryos are connected to their respective embryo sacs by a variety of temporary cytoplasmic processes formed by both tissues during embryogenesis, including a ‘placental’ ring zone. Although ultrastructural data of these cell contacts are not entirely conclusive about their function, we suggest that embryos absorb nutrients via the entire surface. The close opposition of embryos to the embryo sac implies placentation as matrotrophic mode in phylactolaemate bryozoans, with embryo sacs acting as placental analogues.

In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP+ was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP+ uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 μM) and the inhibition of ASP+ uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 μM). Ondansetron (0.5–20 μM) inhibited the basolateral-to-apical transcellular transport of ASP+ up to 64%. Higher concentrations (10 and 20 μM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP+. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 μM caused significant intracellular accumulation of ASP+. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.

The Functions, Methods, and Mobility of Mitochondrial Transfer Between Cells

Mitochondria are vital organelles in cells, regulating energy metabolism and apoptosis. Mitochondrial transcellular transfer plays a crucial role during physiological and pathological conditions, such as rescuing recipient cells from bioenergetic deficit and tumorigenesis. Studies have shown several structures that conduct transcellular transfer of mitochondria, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), and Cx43 gap junctions (GJs). The intra- and intercellular transfer of mitochondria is driven by a transport complex. Mitochondrial Rho small GTPase (MIRO) may be the adaptor that connects the transport complex with mitochondria, and myosin XIX is the motor protein of the transport complex, which participates in the transcellular transport of mitochondria through TNTs. In this review, the roles of TNTs, EVs, GJs, and related transport complexes in mitochondrial transcellular transfer are discussed in detail, as well as the formation mechanisms of TNTs and EVs. This review provides the basis for the development of potential clinical therapies targeting the structures of mitochondrial transcellular transfer.

Divergent Regulation of OCT and MATE Drug Transporters by Cadmium Exposure

Coordinated transcellular transport by the uptake via organic cation transporters (OCTs) in concert with the efflux via multidrug and toxin extrusion proteins (MATEs) is an essential system for hepatic and renal drug disposition. Despite their clinical importance, the regulation of OCTs and MATEs remains poorly characterized. It has been reported that cadmium (Cd2+) increase the activities of OCTs while being a substrate of MATEs. Here, we found that human (h) OCT2 protein, as compared with hMATE1, was more active in trafficking between the plasma membrane and cytoplasmic storage pool. Cd2+ exposure could significantly enhance the translocation of hOCT2 and hOCT1, but not hMATE1, to the plasma membrane. We further identified that candesartan, a widely prescribed angiotensin II receptor blocker, behaved similarly toward OCT2 and MATE1 as Cd2+ did. Importantly, Cd2+ and candesartan treatments could lead to an enhanced accumulation of metformin, which is a well-characterized substrate of OCTs/MATEs, in mouse kidney and liver, respectively. Altogether, our studies have uncovered possible divergent regulation of OCTs and MATEs by certain xenobiotics, such as Cd2+ and candesartan due to the different cellular trafficking of these two families of transporter proteins, which might significantly affect drug disposition in the liver and kidney.