Prefoldin Function in Cellular Protein Homeostasis and Human Diseases

Cellular functions are largely performed by proteins. Defects in the production, folding, or removal of proteins from the cell lead to perturbations in cellular functions that can result in pathological conditions for the organism. In cells, molecular chaperones are part of a network of surveillance mechanisms that maintains a functional proteome. Chaperones are involved in the folding of newly synthesized polypeptides and assist in refolding misfolded proteins and guiding proteins for degradation. The present review focuses on the molecular co-chaperone prefoldin. Its canonical function in eukaryotes involves the transfer of newly synthesized polypeptides of cytoskeletal proteins to the tailless complex polypeptide 1 ring complex (TRiC/CCT) chaperonin which assists folding of the polypeptide chain in an energy-dependent manner. The canonical function of prefoldin is well established, but recent research suggests its broader function in the maintenance of protein homeostasis under physiological and pathological conditions. Interestingly, non-canonical functions were identified for the prefoldin complex and also for its individual subunits. We discuss the latest findings on the prefoldin complex and its subunits in the regulation of transcription and proteasome-dependent protein degradation and its role in neurological diseases, cancer, viral infections and rare anomalies.

Bioactive effects of citrus flavonoids and role in the prevention of atherosclerosis and cancer

Citrus fruits are the main fruits of the Mediterranean diet and have been long recognized for their beneficial effects on human health. Observational studies have shown a significant association between dietary flavo-noid intake and reduced risk of cardiovascular and malignant diseases. The beneficial effects of citrus fruits on human health appear to be due to their high content in vitamins, minerals and fibers. In particular, the an-tioxidant and anti-inflammatory activities have been indicated as some of the mechanisms through which citrus fruits may thwarts the development of chronic degenerative diseases such as atherosclerosis and can-cer. This review would critically examine the results from numerous studies carried out in order assess the contribute of citrus flavonoids to the prevention of chronic pathological conditions including athero-sclerosis and cancer.

Diagnostic Approach to Macrocephaly in Children

Macrocephaly affects up to 5% of the pediatric population and is defined as an abnormally large head with an occipitofrontal circumference (OFC) >2 standard deviations (SD) above the mean for a given age and sex. Taking into account that about 2–3% of the healthy population has an OFC between 2 and 3 SD, macrocephaly is considered as “clinically relevant” when OFC is above 3 SD. This implies the urgent need for a diagnostic workflow to use in the clinical setting to dissect the several causes of increased OFC, from the benign form of familial macrocephaly and the Benign enlargement of subarachnoid spaces (BESS) to many pathological conditions, including genetic disorders. Moreover, macrocephaly should be differentiated by megalencephaly (MEG), which refers exclusively to brain overgrowth, exceeding twice the SD (3SD—“clinically relevant” megalencephaly). While macrocephaly can be isolated and benign or may be the first indication of an underlying congenital, genetic, or acquired disorder, megalencephaly is most likely due to a genetic cause. Apart from the head size evaluation, a detailed family and personal history, neuroimaging, and a careful clinical evaluation are crucial to reach the correct diagnosis. In this review, we seek to underline the clinical aspects of macrocephaly and megalencephaly, emphasizing the main differential diagnosis with a major focus on common genetic disorders. We thus provide a clinico-radiological algorithm to guide pediatricians in the assessment of children with macrocephaly.

Galectin-3 promotes the adipogenic differentiation of PDGFRα+ cells and ectopic fat formation in regenerating muscle

Worldwide prevalence of obesity is associated with the increase of lifestyle-related diseases. The accumulation of intermuscular adipose tissue (IMAT) is considered a major problem whereby obesity leads to sarcopenia and metabolic disorders and thus is a promising target for treating these pathological conditions. However, whereas obesity-associated IMAT is suggested to originate from PDGFRα+ mesenchymal progenitors, processes underlying their adipogenesis remain largely unexplored. Here, we comprehensively investigated intra- and extracellular changes associated with these processes using single-cell RNA sequencing (scRNA-Seq) and mass spectrometry. Our scRNA-Seq analysis identified a small PDGFRα+ cell population in obese mice directed strongly toward adipogenesis. Proteomic analysis showed that the appearance of this cell population is accompanied by an increase in galectin-3 in interstitial environments, which was found to activate adipogenic PPARγ signals in PDGFRα+ cells. Moreover, IMAT formation during muscle regeneration was significantly suppressed in galectin-3 KO mice. Our findings, together with these multi-omics datasets, could unravel microenvironmental networks during muscle regeneration highlighting possible therapeutic targets against IMAT formation in obesity.

Tannins as Hemostasis Modulators

The hemostasis system is often affected by complications associated with cardiovascular diseases, which results in thromboembolic events. Compounds of plant origin and plant extracts are considered as a promising source of substances that could modulate the functioning of the hemostasis system and thus reduce the risk of thromboembolism. Among them, tannins, which are plant-origin compounds with potential effects in hemostasis, deserve a special mention. This paper describes the hemostasis-modifying ability of three groups of tannins, namely ellagitannins, gallotannins, and procyanidins. The review highlights the desirable as well as undesirable influence of tannins on specific components of hemostasis, namely platelets, coagulation system, fibrinolysis system, and endothelium, and the multidirectional effect of these compounds on the thrombotic process. Studies performed under normal and pathological conditions such as diabetes or hypercoagulation are described, and the pathophysiology-dependent action of tannins is also highlighted. Most of the studies presented in the paper were performed in vitro, and due to the low bioavailability of tannins more studies should be conducted in the future to understand their actual activity in vivo.

Precision and Advanced Nano-Phytopharmaceuticals for Therapeutic Applications

Phytopharmaceuticals have been widely used globally since ancient times and acknowledged by healthcare professionals and patients for their superior therapeutic value and fewer side-effects compared to modern medicines. However, phytopharmaceuticals need a scientific and methodical approach to deliver their components and thereby improve patient compliance and treatment adherence. Dose reduction, improved bioavailability, receptor selective binding, and targeted delivery of phytopharmaceuticals can be likely achieved by molding them into specific nano-formulations. In recent decades, nanotechnology-based phytopharmaceuticals have emerged as potential therapeutic candidates for the treatment of various communicable and non-communicable diseases. Nanotechnology combined with phytopharmaceuticals broadens the therapeutic perspective and overcomes problems associated with plant medicine. The current review highlights the therapeutic application of various nano-phytopharmaceuticals in neurological, cardiovascular, pulmonary, and gastro-intestinal disorders. We conclude that nano-phytopharmaceuticals emerge as promising therapeutics for many pathological conditions with good compliance and higher acceptance.

A Broad Overview on Pituitary Adenylate Cyclase-Activating Polypeptide Role in the Eye: Focus on Its Repairing Effect in Cornea

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a neuropeptide with widespread distribution throughout the central and peripheral nervous system as well as in many other peripheral organs. It plays cytoprotective effects mediated mainly through the activation of specific receptors. PACAP is known to play pleiotropic effects on the eye, including the cornea, protecting it against different types of insult. This review firstly provides an overview of the anatomy of the cornea and summarizes data present in literature about PACAP’s role in the eye and, in particular, in the cornea, either in physiological or pathological conditions.

Sub-chronic effects of Baccharis dracunculifolia treatment on biochemical, oxidative, and histopathological parameters in diabetic rats

Background: Oxidative stress and the mild inflammatory process present in diabetes play a critical role in the pathogenesis of the disease and its comorbidities. This understanding has opened new avenues and targets for developing improved treatments since the risk factors associated with diabetes may be reduced through non-pharmacological interventions. In this sense, plant extracts could be efficient in preventing or assisting these pathological conditions treatment. Methods: Diabetes mellitus was induced in 24 rats, which were allocated in 4 groups: Control (CT), Control+Baccharis (CT-B), Diabetes (DB), and Diabetes+Baccharis (DB-B). For 28 days, the animals of CT-B and DB-B groups were treated, via gavage, with B. dracunculifolia extract at 50 mg.kg-1. Results: The DB group presented higher values than the DB-B group on parameters such as creatinine (26.42%), urea (31.42%), and triglycerides (60.80%). Creatinine and triglycerides values of DB-B group (0.39±0.01 e 75.0±8.4, receptively) were equivalent to the values of CT group (0.32±0.01 e 71.7±5.4) and of CT-B group (0.39±0.01, and 58.8±4.5). The treatment with B. dracunculifolia improved the levels of fasting glucose and response of glucose tolerance (32%), insulin (52,17%) and lipid peroxidation (liver 33.33%, kidney 38.77%) when compared to the DB group. Conclusions: The phenolic compounds and the anti-inflammatory activity of the extract of Baccharis dracunculifolia may be responsible for the hypoglycemic effect observed in the study.

Evaluation of the Mucoadhesive Properties of Chitosan-Based Microstructured Lipid Carrier (CH-MLC)

Different mucoadhesive systems have been studied in recent years to increase the residence time of the delivery systems and to prolong the release of the drug. The aim of this work was to evaluate the mucoadhesive properties of chitosan-based Microstructured Lipid Carrier (CH-MLC) with a new approach which requires chitosan and mucin to be compacted into a tablet and mucoadhesion to be assessed on a non-mucoadhesive substrate. This type of test showed that chitosan maintains a close bond with mucin even in the presence of a fluid and even encapsulated in microparticles. After this, using a bioreactor, the release of N-acetylcysteine (NAC) from the microparticles (NA-CH-MLC) through a layer of mucus mimicking the pathological conditions of a patient with cystic fibrosis was tested. The release of the active from NAC-CH-MLC demonstrated how the chitosan inside the microparticles acts as a penetration enhancer and how the microparticles can impart a prolonged release over time.

Quantitative Assessment of 3D Printed Blood Vessels Produced with J750™ Digital Anatomy™ for Suture Simulation

Blood vessels anastomosis is one of the most challenging and delicate tasks to learn in many surgical specialties, especially for vascular and abdominal surgeons. Such a critical skill implies a learning curve that goes beyond technical execution. The surgeon needs to gain proficiency in adapting gestures and the amount of force expressed according to the type of tissue he/she is dealing with. In this context, surgical simulation is gaining a pivotal role in the training of surgeons, but currently available simulators can provide only standard or simplified anatomies, without the chance of presenting specific pathological conditions and rare cases. 3D printing technology, allowing the manufacturing of extremely complex geometries, find a perfect application in the production of realistic replica of patient-specific anatomies. According to available technologies and materials, morphological aspects can be easily handled, while the reproduction of tissues mechanical properties still poses major problems, especially when dealing with soft tissues. The present work focuses on blood vessels, with the aim of identifying – by means of both qualitative and quantitative tests – materials combinations able to best mimic the behavior of the biological tissue during anastomoses, by means of J750™ Digital Anatomy™ technology and commercial photopolymers from Stratasys. Puncture tests and stitch traction tests are used to quantify the performance of the various formulations. Surgical simulations involving anastomoses are performed on selected clinical cases by surgeons to validate the results. A total of 37 experimental materials were tested and 2 formulations were identified as the most promising solutions to be used for anastomoses simulation. Clinical applicative tests, specifically selected to challenge the new materials, raised additional issues on the performance of the materials to be considered for future developments.