Interplay between Mast Cells and Regulatory T Cells in Immune-Mediated Cholangiopathies

Immune-mediated cholangiopathies are characterised by the destruction of small and large bile ducts causing bile acid stasis, which leads to subsequent inflammation, fibrosis, and eventual cirrhosis of the liver tissue. A breakdown of peripheral hepatic immune tolerance is a key feature of these diseases. Regulatory T cells (Tregs) are a major anti-inflammatory immune cell subset, and their quantities and functional capacity are impaired in autoimmune liver diseases. Tregs can undergo phenotypic reprogramming towards pro-inflammatory Th1 and Th17 profiles. The inflamed hepatic microenvironment influences and can impede normal Treg suppressive functions. Mast cell (MC) infiltration increases during liver inflammation, and active MCs have been shown to be an important source of pro-inflammatory mediators, thus driving pathogenesis. By influencing the microenvironment, MCs can indirectly manipulate Treg functions and inhibit their suppressive and proliferative activity. In addition, direct cell-to-cell interactions have been identified between MCs and Tregs. It is critical to consider the effects of MCs on the inflammatory milieu of the liver and their influence on Treg functions. This review will focus on the roles and crosstalk of Tregs and MCs during autoimmune cholangiopathy pathogenesis progression.     

The Beneficial Effects of Triterpenic Acid and Acteoside in an In Vitro Model of Nonalcoholic Steatohepatitis (NASH)

Triterpenic acid (TA) and acteoside (ACT), the major components of APPLIVER and ACTEOS, respectively, have been reported to exert hepatoprotective effects, but the molecular mechanisms remain elusive, particularly in the NAFLD/NASH context. We assessed their effects in our well-established in vitro model resembling the pathophysiological mechanisms involved in NASH. Human hepatocytes and hepatic stellate cells were exposed to free fatty acids (FFA) alone or in combination with APPLIVER and ACTEOS as a mono- or co-culture. Steatosis, inflammation, generation of reactive oxygen species (ROS), and collagen deposition were determined. ACTEOS reduced both the TNF-α and ROS production, and, most importantly, attenuated collagen deposition elicited by the excess of FFA in the co-culture model. APPLIVER also showed inhibition of both TNF-α production and collagen deposition caused by FFA accumulation. The compounds alone did not induce any cellular effects. The present study showed the efficacy of APPLIVER and ACTEOS on pathophysiological mechanisms related to NASH. These in vitro data suggest that these compounds deserve further investigation for possible use in NASH treatment.     

The Therapeutic Role of Exercise and Probiotics in Stressful Brain Conditions

Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurological disorders such as Parkinson’s disease, Alzheimer’s dementia, ischemic stroke, and head and spinal cord injury. The increased production of reactive oxygen species (ROS) has been associated with mitochondrial dysfunction, altered metal homeostasis, and compromised brain antioxidant defence. All these changes have been reported to directly affect synaptic activity and neurotransmission in neurons, leading to cognitive dysfunction. In this context two non-invasive strategies could be employed in an attempt to improve the aforementioned stressful brain status. In this regard, it has been shown that exercise could increase the resistance against oxidative stress, thus providing enhanced neuroprotection. Indeed, there is evidence suggesting that regular physical exercise diminishes BBB permeability as it reinforces antioxidative capacity, reduces oxidative stress, and has anti-inflammatory effects. However, the differential effects of different types of exercise (aerobic exhausted exercise, anaerobic exercise, or the combination of both types) and the duration of physical activity will be also addressed in this review as likely determinants of therapeutic efficacy. The second proposed strategy is related to the use of probiotics, which can also reduce some biomarkers of oxidative stress and inflammatory cytokines, although their underlying mechanisms of action remain unclear. Moreover, various probiotics produce neuroactive molecules that directly or indirectly impact signalling in the brain. In this review, we will discuss how physical activity can be incorporated as a component of therapeutic strategies in oxidative stress-based neurological disorders along with the augmentation of probiotics intake.     

Amorphous Inclusion Complexes: Molecular Interactions of Hesperidin and Hesperetin with HP-Β-CD and Their Biological Effects

This study aimed at obtaining hesperidin (Hed) and hesperetin (Het) systems with HP-β-CD by means of the solvent evaporation method. The produced systems were identified using infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). Moreover, in silico docking and molecular dynamics studies were performed to assess the most preferable site of interactions between tested compounds and HP-β-CD. The changes of physicochemical properties (solubility, dissolution rate, and permeability) were determined chromatographically. The impact of modification on biological activity was tested in an antioxidant study as well as with regards to inhibition of enzymes important in pathogenesis of neurodegenerative diseases. The results indicated improvement in solubility over 1000 and 2000 times for Hed and Het, respectively. Permeability studies revealed that Hed has difficulties in crossing biological membranes, in contrast with Het, which can be considered to be well absorbed. The improved physicochemical properties influenced the biological activity in a positive manner by the increase in inhibitory activity on the DPPH radical and cholinoesterases. To conclude the use of HP-β-CD as a carrier in the formation of an amorphous inclusion complex seems to be a promising approach to improve the biological activity and bioavailability of Hed and Het.     

Difference in miRNA Expression in Functioning and Silent Corticotroph Pituitary Adenomas Indicates the Role of miRNA in the Regulation of Corticosteroid Receptors

Corticotroph pituitary adenomas commonly cause Cushing’s disease (CD), but some of them are clinically silent. The reason why they do not cause endocrinological symptoms remains unclear. We used data from small RNA sequencing in adenomas causing CD (n = 28) and silent ones (n = 20) to explore the role of miRNA in hormone secretion and clinical status of the tumors. By comparing miRNA profiles, we identified 19 miRNAs differentially expressed in clinically functioning and silent corticotroph adenomas. The analysis of their putative target genes indicates a role of miRNAs in regulation of the corticosteroid receptors expression. Adenomas causing CD have higher expression of hsa-miR-124-3p and hsa-miR-135-5p and lower expression of their target genes NR3C1 and NR3C2. The role of hsa-miR-124-3p in the regulation of NR3C1 was further validated in vitro using AtT-20/D16v-F2 cells. The cells transfected with miR-124-3p mimics showed lower levels of glucocorticoid receptor expression than control cells while the interaction between miR-124-3p and NR3C1 3′ UTR was confirmed using luciferase reporter assay. The results indicate a relatively small difference in miRNA expression between clinically functioning and silent corticotroph pituitary adenomas. High expression of hsa-miR-124-3p in adenomas causing CD plays a role in the regulation of glucocorticoid receptor level and probably in reducing the effect of negative feedback mediated by corticosteroids.     

Quality Attributes and Shelf Life of High-Pressure Preserved Beef as Affected by Pre-treatment Conditions

This study analyzed the effects of high hydrostatic pressure (HHP) and composition of the pre-treatment immersion step, on quality attributes (color and lipid oxidation) and shelf life based on microbial counts of a beef product, during cold storage at 0 °C. Meat slices were immersed in a preservative solution containing sodium nitrite, ascorbic acid, and two different concentrations of NaCl (30 and 60 g/L); HHP of 400 and 600 MPa were applied. Results were compared with those of an untreated beef control. Color parameters of the HHP-treated beef were visually acceptable (a* > 14) in all tested cases, although they were affected by NaCl concentration and the applied pressure. HHP increased TBARS index, observing higher values at 600 than at 400 MPa; samples immersed in the solution containing 30 g/L NaCl presented higher TBARS values. However, in all cases, they remained below the detection limit of rancid meat products (<1 mg MDA/kg). Beef samples immersed in the solution with the highest concentration of NaCl (60 g/L) and subjected to 400 or 600 MPa maintained their microbial stability over 5 and 6 weeks, respectively, at 0 °C; these shelf life values were higher than those observed in the samples treated with 30 g/L NaCl.     

Surface Modification of Luminescent LnIII Fluoride Core–Shell Nanoparticles with Acetylsalicylic acid (Aspirin): Synthesis,Spectroscopic and in Vitro Hemocompatibility Studies

Luminescent lanthanide fluoride core–shell (LaF₃:Tb³⁺,Ce³⁺@SiO₂-NH₂) nanoparticles, with acetylsalicylic acid (aspirin) coated on the surface have been obtained. The synthesized products, which combine the potential located in the silica shell with the luminescent activity of the core, were characterized in detail with the use of luminescence spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and transmission electron microscopy (TEM) methods. The in vitro effects of the modified luminescent nanoparticles on human red blood cell (RBC) membrane permeability, RBC shape, and sedimentation rate were investigated to assess the hemocompatibility of the obtained compounds. This study demonstrates that LaF₃: Tb³⁺ 5 %, Ce³⁺ 10 %@SiO₂-NH₂ nanoparticles with acetylsalicylic acid (aspirin) coated on the surface are very good precursors for multifunctional drug-delivery systems or bio-imaging probes that can be used safely in potential biomedical applications.     

Let the light be a guide: Chromophore communication in metal-organic frameworks

The photonic characteristics of chromophore-containing metal-organic frameworks(MOFs)have led to extensive photophysical studies in an effort to capitalize on the potency of precisely controlled chromophore ensembles.Several examples have laid the foundation that demonstrates how photophysical properties of chromophores can be manipulated by tuning their communications(interactions)through integration within a MOF matrix.The main focus of this review is on harnessing the versatile MOF platform to accentuate the photophysical properties of integrated chromophores.In particular,this review will highlight chromophore dynamics that enhance,alter,or tune the photoluminescence response of single-and multi-chromophore-containing scaffolds,as well as alignment-guided anisotropic fluorescence.Building upon this groundwork,utilization of a hybrid crystalline motif can induce preferential orientation of chromophores resulting in enhanced communication and tailored behavior compared to randomly oriented emissive molecules.Moreover,frameworks that produce upconverted emission via sensitized triplet-triplet annihilation(sTTA),excited-state absorption(ESA),energy transfer upconversion(ETU),multi-photon absorption(MPA),or second-harmonic generation(SHG)can invoke dynamic control of material properties using photochromic linkers and will be discussed herein with a focus on the effects of chromophore alignment.Integration within a framework is a vehicle tofuse chromophores into solid-state platforms,opening an avenue for chromophore utilization in applications such as portable electronics that require solids or thin films.For those reasons,the design of chromophore-containing MOFs with desirable properties that rely on the alignment and communication of hundreds of chromophores within a single platform is a pressing demand for the development of futuristic technologies.     

The First Homologous Expression System for the β-Lytic Protease of Lysobacter capsici VKM B-2533T,a Promising Antimicrobial Agent

A successful homologous expression system based on Lysobacter capsici VKM B-2533^T and the plasmid pBBR1-MCS5 was first developed for a promising bacteriolytic enzyme of this bacterium, β-lytic protease (Blp). In the expression strains, blp gene expression under the regulation of the GroEL(A) and T5 promoters increased by 247- and 667-fold, respectively, as compared with the wild-type strain. After the cultivation of the expression strains L. capsici P_GroEL(A)-blp and L. capsici P_T5-blp, the Blp yield increased by 6.7- and 8.5-fold, respectively, with respect to the wild-type strain. The cultivation of the expression strain L. capsici P_T5-blp was successfully scaled up. Under fermentation conditions the yield of the enzyme increased by 1.6-fold. The developed homologous system was used to express the gene of the bacteriolytic serine protease (Serp) of L. capsici VKM B-2533^T. The expression of the serp gene in L. capsici P_T5-serp increased by 585-fold. The developed homologous system for the gene expression of bacteriolytic Lysobacter enzymes is potentially biotechnologically valuable, and is promising for creating highly efficient expression strains.