Nonlinear computational models of dynamical coding patterns in depression and normal rats: from electrophysiology to energy consumption

Major depressive disorder (MDD) is one of the most serious neuropsychiatric disorders. Exploring the pathogenesis and dynamical coding patterns of MDD can provide new targets for clinical drug treatment and new ideas for the research of other neuropsychiatric and neurodegenerative diseases. We selected the medium spiny neuron (MSN) of nucleus accumbens (NAc) as the research objective. NAc is located in the dopaminergic pathway, regulating rewards, emotions and other behaviors. Abnormalities in these behaviors are considered as the main clinical symptoms of MDD. We simulated the different spike patterns of MSNs in MDD group and control group by dynamical Hodgkin–Huxley model. The simulated results can match the electrophysiological experiments, which occurred due to following reasons: (1) The external stimulus current of MDD group was amplified by the local neural microcircuit; (2) the selective permeability to sodium was abnormally decreased; and (3) the dopamine D2 receptor signaling pathway was abnormal in the MDD group. Furthermore, we proposed a dynamical energy model, and the energy results demonstrated that the energy cost in MDD group was lower, which led to persistent depression in patients with MDD. Simultaneously, the negative-to-total energy ratio of MSN in MDD group was higher than that in control group, and the delay time of the power peak and the potential peak in MDD group was shorter than that in the control group. The results showed that the abnormal firing patterns were the direct cause of abnormal behaviors of MDD and indicated that subthreshold activities of MDD group were more intense.

theLiTE™: A Screening Platform to Identify Compounds that Reinforce Tight Junctions

Tight junctions (TJ) are formed by transmembrane and intracellular proteins that seal the intercellular space and control selective permeability of epithelia. Integrity of the epithelial barrier is central to tissue homeostasis and barrier dysfunction has been linked to many pathological conditions. TJ support the maintenance of cell polarity through interactions with the Par complex (Cdc42-Par-6-Par-3-aPKC) in which Par-6 is an adaptor and links the proteins of the complex together. Studies have shown that Par-6 overexpression delays the assembly of TJ proteins suggesting that Par-6 negatively regulates TJ assembly. Because restoring barrier integrity is of key therapeutic and prophylactic value, we focus on finding compounds that have epithelial barrier reinforcement properties; we developed a screening platform (theLiTE™) to identify compounds that modulate Par-6 expression in follicular epithelial cells from Par-6-GFP Drosophila melanogaster egg chambers. Hits identified were then tested whether they improve epithelial barrier function, using measurements of transepithelial electrical resistance (TEER) or dye efflux to evaluate paracellular permeability. We tested 2,400 compounds, found in total 10 hits. Here we present data on six of them: the first four hits allowed us to sequentially build confidence in theLiTE™ and two compounds that were shortlisted for further development (myricetin and quercetin). We selected quercetin due to its clinical and scientific validation as a compound that regulates TJ; food supplement formulated on the basis of this discovery is currently undergoing clinical evaluation in gastroesophageal reflux disease (GERD) sufferers.

The Intestinal Barrier and Permeability

The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.

Synthesis and characterization of chitosan/montmorillonite nanocomposites for application as edible coating

Edible coating can improve fruits shelf life and, consequently, reduce their waste. Chitosan, which presents a potential for chemical modifications and capacity to form films, can be an alternative for coating due to its biocompatibility, biodegradability, and antimicrobial properties. Chitosan film can be obtained through casting method presenting suitable mechanical properties, such as resistance to traction and elongation, ability to adhere to surfaces and selective permeability to gases, such as O2 and CO2. However, it is highly permeable to water vapor, which can limit its potential coating use. The properties of chitosan films can be improved through the formation of composites by inserting nanoclays as montmorillonite in the polymeric matrix. The objective of this study was to develop and characterize chitosan/montmorillonite nanocomposites for fruit coating aiming for future applications in the field of smart packaging. Nanocomposites were characterized by its microstructure, thermal, mechanical, and physicochemical properties. X-ray diffraction analysis indicated changes in crystallinity with the insertion of montmorillonite. Nanocomposites became more transparent and significantly reduced its water permeability rate with 0.5% w/w montmorillonite addition. Elastic rigidity and tensile strength of the films were improved. Chitosan/montmorillonite nanocomposites demonstrated the potential to improve the storage time of Williams pears.

Surface Characterization of Lipid Biomimetic Systems

Zeta potential and dipole potential measures are direct operational methodologies to determine the adsorption, insertion and penetration of ions, amphipathic and neutral compounds into the membranes of cells and model systems. From these results, the contribution of charged and dipole groups can be deduced. However, although each method may give apparent affinity or binding constants, care should be taken to interpret them in terms of physical meaning because they are not independent properties. On the base of a recent model in which the lipid bilayer is considered as composed by two interphase regions at each side of the hydrocarbon core, this review describes how dipole potential and zeta potential are correlated due to water reorganization. From this analysis, considering that in a cell the interphase region the membrane extends to the cell interior or overlaps with the interphase region of another supramolecular structure, the correlation of dipole and electrostatic forces can be taken as responsible of the propagation of perturbations between membrane and cytoplasm and vice versa. Thus, this picture gives the membrane a responsive character in addition to that of a selective permeability barrier when integrated to a complex system.

The Effect of Bacterial Infections, Probiotics and Zonulin on Intestinal Barrier Integrity

The intestinal barrier plays an extremely important role in maintaining the immune homeostasis of the gut and the entire body. It is made up of an intricate system of cells, mucus and intestinal microbiota. A complex system of proteins allows the selective permeability of elements that are safe and necessary for the proper nutrition of the body. Disturbances in the tightness of this barrier result in the penetration of toxins and other harmful antigens into the system. Such events lead to various digestive tract dysfunctions, systemic infections, food intolerances and autoimmune diseases. Pathogenic and probiotic bacteria, and the compounds they secrete, undoubtedly affect the properties of the intestinal barrier. The discovery of zonulin, a protein with tight junction regulatory activity in the epithelia, sheds new light on the understanding of the role of the gut barrier in promoting health, as well as the formation of diseases. Coincidentally, there is an increasing number of reports on treatment methods that target gut microbiota, which suggests that the prevention of gut-barrier defects may be a viable approach for improving the condition of COVID-19 patients. Various bacteria–intestinal barrier interactions are the subject of this review, aiming to show the current state of knowledge on this topic and its potential therapeutic applications.

The Repurposing of the Antimalaria Drug, Primaquine, as a Photosensitizer to Inactivate Cryptococcal Cells

Cryptococcal cells can manifest skin infections in immunocompromised persons. While it may be easy to diagnose cryptococcal infection, treatment often fails due to the ineffectiveness of current antifungal agents. To this end, the present study explored the repurposing of primaquine (PQ), as a photosensitizer. PDT was carried out using a germicidal ultraviolet (UV) lamp, which has a radiation output of approximately 625 µW/cm2 at a distance of 20 cm. When compared to the non-treated cells, the metabolic activity of cryptococcal cells was significantly (p < 0.05) limited. The photolytic products of PQ were observed to alter the ultrastructure of treated cells. The latter was not incidental, as the same cells were also documented to lose their selective permeability. Importantly, PDT also improved the efficiency of macrophages to kill internalized cryptococcal cells (p ≤ 0.05) when compared to non-treated macrophages. Equally importantly, PDT was not detrimental to macrophages, as their metabolic activity was not significantly (p > 0.05) limited, even when exposed to 20× the MIC (determined for cryptococcal cells) and an exposure time that was 4× longer. Taken together, the results suggest PQ has the potential to control the growth of cryptococcal cells and limit their survival inside the macrophage.

Edge-strand of BepA interacts with immature LptD on the β-barrel assembly machine to direct it to on- and off-pathways

The outer membrane (OM) of gram-negative bacteria functions as a selective permeability barrier. Escherichia coli periplasmic Zn-metallopeptidase BepA contributes to the maintenance of OM integrity through its involvement in the biogenesis and degradation of LptD, a β-barrel protein component of the lipopolysaccharide translocon. BepA either promotes the maturation of LptD when it is on the normal assembly pathway (on-pathway) or degrades it when its assembly is compromised (off-pathway). BepA performs these functions probably on the β‐barrel assembly machinery (BAM) complex. However, how BepA recognizes and directs an immature LptD to different pathways remains unclear. Here, we explored the interactions among BepA, LptD, and the BAM complex. We found that the interaction of the BepA edge-strand located adjacent to the active site with LptD was crucial not only for proteolysis but also, unexpectedly, for assembly promotion of LptD. Site-directed crosslinking analyses indicated that the unstructured N-terminal half of the β-barrel-forming domain of an immature LptD contacts with the BepA edge-strand. Furthermore, the C-terminal region of the β-barrel-forming domain of the BepA-bound LptD intermediate interacted with a 'seam' strand of BamA, suggesting that BepA recognized LptD assembling on the BAM complex. Our findings provide important insights into the functional mechanism of BepA.

Antibacterial Activity and Membrane-Targeting Mechanism of Aloe-Emodin Against Staphylococcus epidermidis

The emergence of multidrug-resistant Staphylococcus epidermidis (S. epidermidis) dwarfs the current antibiotic development and calls for the discovery of new antibacterial agents. Aloe-emodin is a plant-derived compound that holds promise to battle against these strains. This work reports the antimicrobial activity of aloe-emodin against S. epidermidis and other Gram-positive pathogenic species, manifesting minimum inhibitory concentrations (MICs) and minimum bactericidal concentration (MBCs) around 4–32 and 32–128 μg/mL, respectively. For Gram-negative bacteria tested, the MICs and MBCs of aloe-emodin were 128–256 and above 1024 μg/mL, respectively. Aloe-emodin at the MBC for 4 h eradicated 96.9% of S. epidermidis cells. Aloe-emodin treatment led to deformities in the morphology of S. epidermidis cells and the destroy of the selective permeability of the cell membranes. Analysis of the transcriptional profiles of aloe-emodin-treated cells revealed changes of genes involved in sulfur metabolism, L-lysine and peptidoglycan biosynthesis, and biofilm formation. Aloe-emodin therefore can safely control Gram-positive bacterial infections and proves to target the bacterial outer membrane.

Donnan Potential across the Outer Membrane of Gram-Negative Bacteria and Its Effect on the Permeability of Antibiotics

The cell envelope structure of Gram-negative bacteria is unique, composed of two lipid bilayer membranes and an aqueous periplasmic space sandwiched in between. The outer membrane constitutes an extra barrier to limit the exchange of molecules between the cells and the exterior environment. Donnan potential is a membrane potential across the outer membrane, resulted from the selective permeability of the membrane, which plays a pivotal role in the permeability of many antibiotics. In this review, we discussed factors that affect the intensity of the Donnan potential, including the osmotic strength and pH of the external media, the osmoregulated periplasmic glucans trapped in the periplasmic space, and the displacement of cell surface charges. The focus of our discussion is the impact of Donnan potential on the cellular permeability of selected antibiotics including fluoroquinolones, tetracyclines, β-lactams, and trimethoprim.