Hexokinase 2 Inhibition and Biological Effects of BNBZ and Its Derivatives: The Influence of the Number and Arrangement of Hydroxyl Groups

Hexokinase 2 (HK2), an enzyme of the sugar kinase family, plays a dual role in glucose metabolism and mediating cancer cell apoptosis, making it an attractive target for cancer therapy. While positive HK2 expression usually promotes cancer cells survival, silencing or inhibiting this enzyme has been found to improve the effectiveness of anti-cancer drugs and even result in cancer cell death. Previously, benitrobenrazide (BNBZ) was characterized as a potent HK2 inhibitor with good anti-cancer activity in mice, but the effect of its trihydroxy moiety (pyrogallol-like) on inhibitory activity and some cellular functions has not been fully understood. Therefore, the main goal of this study was to obtain the parent BNBZ (2a) and its three dihydroxy derivatives 2b–2d and to conduct additional physicochemical and biological investigations. The research hypothesis assumed that the HK2 inhibitory activity of the tested compounds depends on the number and location of hydroxyl groups in their chemical structure. Among many studies, the binding affinity to HK2 was determined and two human liver cancer cell lines, HepG2 and HUH7, were used and exposed to chemicals at various times: 24 h, 48 h and 72 h. The study showed that the modifications to the structures of the new BNBZ derivatives led to significant changes in their activities. It was also found that these compounds tend to aggregate and exhibit toxic effects. They were found to contribute to: (a) DNA damage, (b) increased ROS production, and (c) disruption of cell cycle progression. It was observed that, HepG2, occurred much more sensitive to the tested chemicals than the HUH7 cells; However, regardless of the used cell line it seems that the increase in the expression of HK2 in cancer cells compared to normal cells which have HK2 at a very low level, is a serious obstacle in anti-cancer therapy and efforts to find the effective inhibitors of this enzyme should be intensified.     

Pathogenetic Mechanisms of Hypertension–Brain-Induced Complications: Focus on Molecular Mediators

There is growing evidence that hypertension is the most important vascular risk factor for the development and progression of cardiovascular and cerebrovascular diseases. The brain is an early target of hypertension-induced organ damage and may manifest as stroke, subclinical cerebrovascular abnormalities and cognitive decline. The pathophysiological mechanisms of these harmful effects remain to be completely clarified. Hypertension is well known to alter the structure and function of cerebral blood vessels not only through its haemodynamics effects but also for its relationships with endothelial dysfunction, oxidative stress and inflammation. In the last several years, new possible mechanisms have been suggested to recognize the molecular basis of these pathological events. Accordingly, this review summarizes the factors involved in hypertension-induced brain complications, such as haemodynamic factors, endothelial dysfunction and oxidative stress, inflammation and intervention of innate immune system, with particular regard to the role of Toll-like receptors that have to be considered dominant components of the innate immune system. The complete definition of their prognostic role in the development and progression of hypertensive brain damage will be of great help in the identification of new markers of vascular damage and the implementation of innovative targeted therapeutic strategies.     

Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer

Gastric cancer represents a significant disease burden worldwide. The factors that initiate cancer are not well understood. Chronic inflammation such as that triggered by H. pylori infection is the most significant cause of gastric cancer. In recent years, organoid cultures developed from human and animal adult stem cells have facilitated great advances in our understanding of gastric homeostasis. Organoid models are now being exploited to investigate the role of host genetics and bacterial factors on proliferation and DNA damage in gastric stem cells. The impact of a chronic inflammatory state on gastric stem cells and the stroma has been less well addressed. This review discusses what we have learned from the use of organoid models to investigate cancer initiation, and highlights questions on the contribution of the microbiota, chronic inflammatory milieu, and stromal cells that can now be addressed by more complex coculture models.     

Blood Thiol Redox State in Chronic Kidney Disease

Thiols (sulfhydryl groups) are effective antioxidants that can preserve the correct structure of proteins, and can protect cells and tissues from damage induced by oxidative stress. Abnormal levels of thiols have been measured in the blood of patients with moderate-to-severe chronic kidney disease (CKD) compared to healthy subjects, as well as in end-stage renal disease (ESRD) patients on haemodialysis or peritoneal dialysis. The levels of protein thiols (a measure of the endogenous antioxidant capacity inversely related to protein oxidation) and S-thiolated proteins (mixed disulphides of protein thiols and low molecular mass thiols), and the protein thiolation index (the molar ratio of the S-thiolated proteins to free protein thiols in plasma) have been investigated in the plasma or red blood cells of CKD and ESRD patients as possible biomarkers of oxidative stress. This type of minimally invasive analysis provides valuable information on the redox status of the less-easily accessible tissues and organs, and of the whole organism. This review provides an overview of reversible modifications in protein thiols in the setting of CKD and renal replacement therapy. The evidence suggests that protein thiols, S-thiolated proteins, and the protein thiolation index are promising biomarkers of reversible oxidative stress that could be included in the routine monitoring of CKD and ESRD patients.     

Molecular Mechanisms and Physiological Changes behind Benign Tracheal and Subglottic Stenosis in Adults

Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS.     

The BDNF/TrkB Neurotrophin System in the Sensory Organs of Zebrafish

The brain-derived neurotrophic factor (BDNF) was discovered in the last century, and identified as a member of the neurotrophin family. BDNF shares approximately 50% of its amino acid with other neurotrophins such as NGF, NT-3 and NT-4/5, and its linear amino acid sequences in zebrafish (Danio rerio) and human are 91% identical. BDNF functions can be mediated by two categories of receptors: p75NTR and Trk. Intriguingly, BDNF receptors were highly conserved in the process of evolution, as were the other NTs’ receptors. In this review, we update current knowledge about the distribution and functions of the BDNF-TrkB system in the sensory organs of zebrafish. In fish, particularly in zebrafish, the distribution and functions of BDNF and TrkB in the brain have been widely studied. Both components of the system, associated or segregated, are also present outside the central nervous system, especially in sensory organs including the inner ear, lateral line system, retina, taste buds and olfactory epithelium.     

Treatment of Critical Size Femoral Bone Defects with Biomimetic Hybrid Scaffolds of 3D Plotted Calcium Phosphate Cement and Mineralized Collagen Matrix

To treat critical-size bone defects, composite materials and tissue-engineered bone grafts play important roles in bone repair materials. The purpose of this study was to investigate the bone regenerative potential of hybrid scaffolds consisting of macroporous calcium phosphate cement (CPC) and microporous mineralized collagen matrix (MCM). Hybrid scaffolds were synthetized by 3D plotting CPC and then filling with MCM (MCM-CPC group) and implanted into a 5 mm critical size femoral defect in rats. Defects left empty (control group) as well as defects treated with scaffolds made of CPC only (CPC group) and MCM only (MCM group) served as controls. Eight weeks after surgery, micro-computed tomography scans and histological analysis were performed to analyze the newly formed bone, the degree of defect healing and the activity of osteoclasts. Mechanical stability was tested by 3-point-bending of the explanted femora. Compared with the other groups, more newly formed bone was found within MCM-CPC scaffolds. The new bone tissue had a clamp-like structure which was fully connected to the hybrid scaffolds and thereby enhanced the biomechanical strength. Together, the biomimetic hybrid MCM-CPC scaffolds enhanced bone defect healing by improved osseointegration and their differentiated degradation provides spatial effects in the process of critical-bone defect healing.     

A Modular Composite Device of Poly(Ethylene Oxide)/Poly(Butylene Terephthalate) (PEOT/PBT) Nanofibers and Gelatin as a Dual Drug Delivery System for Local Therapy of Soft Tissue Tumors

In the clinical management of solid tumors, the possibility to successfully couple the regeneration of injured tissues with the elimination of residual tumor cells left after surgery could open doors to new therapeutic strategies. In this work, we present a composite hydrogel–electrospun nanofiber scaffold, showing a modular architecture for the delivery of two pharmaceutics with distinct release profiles, that is potentially suitable for local therapy and post-surgical treatment of solid soft tumors. The composite was obtained by coupling gelatin hydrogels to poly(ethylene oxide)/poly(butylene terephthalate) block copolymer nanofibers. Results of the scaffolds’ characterization, together with the analysis of gelatin and drug release kinetics, displayed the possibility to modulate the device architecture to control the release kinetics of the drugs, also providing evidence of their activity. In vitro analyses were also performed using a human epithelioid sarcoma cell line. Furthermore, publicly available expression datasets were interrogated. Confocal imaging showcased the nontoxicity of these devices in vitro. ELISA assays confirmed a modulation of IL-10 inflammation-related cytokine supporting the role of this device in tissue repair. In silico analysis confirmed the role of IL-10 in solid tumors including 262 patients affected by sarcoma as a negative prognostic marker for overall survival. In conclusion, the developed modular composite device may provide a key-enabling technology for the treatment of soft tissue sarcoma.     

On the Efficacy of ZnO Nanostructures against SARS-CoV-2

In 2019, the new coronavirus disease (COVID-19), related to the severe acute respiratory syndrome coronavirus (SARS-CoV-2), started spreading around the word, giving rise to the world pandemic we are still facing. Since then, many strategies for the prevention and control of COVID-19 have been studied and implemented. In addition to pharmacological treatments and vaccines, it is mandatory to ensure the cleaning and disinfection of the skin and inanimate surfaces, especially in those contexts where the contagion could spread quickly, such as hospitals and clinical laboratories, schools, transport, and public places in general. Here, we report the efficacy of ZnO nanoparticles (ZnONPs) against SARS-CoV-2. NPs were produced using an ecofriendly method and fully characterized; their antiviral activity was tested in vitro against SARS-CoV-2, showing a decrease in viral load between 70% and 90%, as a function of the material’s composition. Application of these nano-antimicrobials as coatings for commonly touched surfaces is envisaged.