Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A typical ALL treatment includes three phases: remission induction and consolidation and maintenance, preceded by a prednisone prephase. Poor prednisone response (PPR) is defined as the presence of ≥1.0 × 10⁹ blasts/L in the peripheral blood on day eight of therapy and results in significantly frequent relapses and worse outcomes. Hence, identifying risk factors of steroid resistance and finding methods of overcoming that resistance may significantly improve patients’ outcomes. A mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway seems to be a particularly attractive target, as its activation leads to steroid resistance via a phosphorylating Bcl-2-interacting mediator of cell death (BIM), which is crucial in the steroid-induced cell death. Several mutations causing activation of MAPK-ERK were discovered, notably the interleukin-7 receptor (IL-7R) pathway mutations in T-cell ALL and rat sarcoma virus (Ras) pathway mutations in precursor B-cell ALL. MAPK-ERK pathway inhibitors were demonstrated to enhance the results of dexamethasone therapy in preclinical ALL studies. This report summarizes steroids’ mechanism of action, resistance to treatment, and prospects of steroids therapy in pediatric ALL.     

Photocatalytic Degradation of 4,4′-Isopropylidenebis(2,6-dibromophenol) on Magnetite Catalysts vs. Ozonolysis Method: Process Efficiency and Toxicity Assessment of Disinfection By-Products

Flame retardants have attracted growing environmental concern. Recently, an increasing number of studies have been conducted worldwide to investigate flame-retardant sources, environmental distribution, living organisms’ exposure, and toxicity. The presented studies include the degradation of 4,4′-isopropylidenebis(2,6-dibromophenol) (TBBPA) by ozonolysis and photocatalysis. In the photocatalytic process, nano- and micro-magnetite (n-Fe₃O₄ and μ-Fe₃O₄) are used as a catalyst. Monitoring of TBBPA decay in the photocatalysis and ozonolysis showed photocatalysis to be more effective. Significant removal of TBBPA was achieved within 10 min in photocatalysis (ca. 90%), while for ozonation, a comparable effect was observed within 70 min. To determine the best method of TBBPA degradation concentration on COD and TOC, the removals were examined. The highest oxidation state was obtained for photocatalysis on μ-Fe₃O₄, whereas for n-Fe₃O₄ and ozonolysis, the COD/TOC ratio was lower. Acute toxicity results show noticeable differences in the toxicity of TBBPA and its degradation products to Artemia franciscana and Thamnocephalus platyurus. The EC₅₀ values indicate that TBBPA degradation products were toxic to harmful, whereas the TBPPA and post-reaction mixtures were toxic to the invertebrate species tested. The best efficiency in the removal and degradation of TBBPA was in the photocatalysis process on μ-Fe₃O₄ (reaction system 1). The examined crustaceans can be used as a sensitive test for acute toxicity evaluation.     

Existing Drugs Considered as Promising in COVID-19 Therapy

COVID-19 is a respiratory disease caused by newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease at first was identified in the city of Wuhan, China in December 2019. Being a human infectious disease, it causes high fever, cough, breathing problems. In some cases it can be fatal, especially in people with comorbidities like heart or kidney problems and diabetes. The current COVID-19 treatment is based on symptomatic therapy, so finding an appropriate drug against COVID-19 remains an immediate and crucial target for the global scientific community. Two main processes are thought to be responsible for the COVID-19 pathogenesis. In the early stages of infection, disease is determined mainly by virus replication. In the later stages of infection, by an excessive immune/inflammatory response, leading to tissue damage. Therefore, the main treatment options are antiviral and immunomodulatory/anti-inflammatory agents. Many clinical trials have been conducted concerning the use of various drugs in COVID-19 therapy, and many are still ongoing. The majority of trials examine drug reposition (repurposing), which seems to be a good and effective option. Many drugs have been repurposed in COVID-19 therapy including remdesivir, favipiravir, tocilizumab and baricitinib. The aim of this review is to highlight (based on existing and accessible clinical evidence on ongoing trials) the current and available promising drugs for COVID-19 and outline their characteristics.     

Effects of SARS-CoV-2 Inflammation on Selected Organ Systems of the Human Body

Introduction and purpose of the study: SARS-CoV-2 virus does not only affect the respiratory system. It may cause damage to many organ systems with long-term effects. The latest scientific reports inform that this virus leaves a long-term trace in the nervous, circulatory, respiratory, urinary and reproductive systems. It manifests itself in disturbances in the functioning of the organs of these systems, causing serious health problems. The aim of the study was to review the latest research into the long-term effects of COVID-19 and determine how common these symptoms are and who is most at risk. Based on a literature review using the electronic scientific databases of PubMed and Web of Science on the long-term effects of SARS-CoV-2 infection, 88 studies were included in the analysis. The information contained in the analyzed literature shows that the SARS-CoV-2 virus can cause multi-organ damage, causing a number of long-term negative health complications. Conclusions: There is evidence that the virus can cause long-term complications lasting more than six months. They mainly concern disturbances in the functioning of the nervous, circulatory and respiratory systems. However, these studies are small or short-lasting, and many are speculative.     

Myo-inositol hexakisphosphate degradation by Bifidobacterium infantis ATCC 15697

The ability of five strains of different bifidobacterial species (Bifidobacterium animalis, B. bifidum, B. infantis, B. longum, B. pseudolongum) isolated from human and animal gut to degrade myo-inositol hexaphosphate or phytic acid (InsP(6)) has been evaluated. The disappearance of phytate and the generation of lower myo-inositol phosphates were determined in a complex medium in which phytic acid was the only source of phosphorus. Bifidobacterium infantis ATCC 15697 showed the highest level of phytate-degrading activity. This strain displayed optimal activity at slight acid pH (6.0-6.5) and 50 degrees C, but also retained high activity levels at neutral pH and 37 degrees C. B. infantis ATCC 15697 produced maximum activity during the stationary phase of growth and when 1% lactose was used as carbon source. In contrast, the presence of inorganic phosphate in the growth medium inhibited phytase activity. The ability of B. infantis ATCC 15697 to generate lower myo-inositol phosphates and, particularly, accumulate myo-inositol tri-phosphates (InsP(3)) from partial hydrolysis of InsP(6) could contribute to the reduction of the anti-nutritional properties of InsP(6) and the generation of intermediate compounds with beneficial properties during food processing and gastrointestinal transit.     

Specific cationic photoinitiators for near UV and visible LEDs: Iodonium versus ferrocenium structures

Two iodonium salts based on a coumarin chromophore are investigated for polymerization upon light emitting diode irradiations (LEDs). They work as one‐component photoinitiators. They initiate the cationic polymerization of epoxides (under air) and vinylethers (laminate) upon exposure to violet LEDs (385 and 405 nm). Excellent polymerization profiles are recorded. Their efficiency is quite similar to that of a ferrocenium salt. Interpenetrating polymer networks can also be obtained through a concomitant cationic/radical photopolymerization of an epoxy/acrylate blend monomer. The light absorption properties of these new salts as well as the involved photochemical mechanisms are investigated for the first time through electron spin resonance, laser flash photolysis, steady state photolysis experiments. Molecular orbital calculations are also used to shed some light on the initiation mechanisms. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42759.     

Carotenoids from Marine Sources as a New Approach in Neuroplasticity Enhancement

An increasing number of people experience disorders related to the central nervous system (CNS). Thus, new forms of therapy, which may be helpful in repairing processes’ enhancement and restoring declined brain functions, are constantly being sought. One of the most relevant physiological processes occurring in the brain for its entire life is neuroplasticity. It has tremendous significance concerning CNS disorders since neurological recovery mainly depends on restoring its structural and functional organization. The main factors contributing to nerve tissue damage are oxidative stress and inflammation. Hence, marine carotenoids, abundantly occurring in the aquatic environment, being potent antioxidant compounds, may play a pivotal role in nerve cell protection. Furthermore, recent results revealed another valuable characteristic of these compounds in CNS therapy. By inhibiting oxidative stress and neuroinflammation, carotenoids promote synaptogenesis and neurogenesis, consequently presenting neuroprotective activity. Therefore, this paper focuses on the carotenoids obtained from marine sources and their impact on neuroplasticity enhancement.     

The Influence of Betulin and Its Derivatives EB5 and ECH147 on the Antioxidant Status of Human Renal Proximal Tubule Epithelial Cells

Betulin and its derivatives, 28-propyne derivative EB5 and 29-diethyl phosphonate analog ECH147, are promising compounds in anti-tumor activity studies. However, their effect on kidney cells has not yet been studied. The study aimed to determine whether betulin and its derivatives—EB5 and ECH147—influence the viability and oxidative status of human renal proximal tubule epithelial cells (RPTECs). The total antioxidant capacity of cells (TEAC), lipid peroxidation product malondialdehyde (MDA) level, and activity of antioxidant enzymes (SOD, CAT, and GPX) were evaluated. Additionally, the mRNA level of genes encoding antioxidant enzymes was assessed. Cisplatin and 5-fluorouracil were used as reference substances. Betulin and its derivatives affected the viability and antioxidant systems of RPTECs. Betulin strongly reduced TEAC in a concentration-dependent manner. All tested compounds caused an increase in MDA levels. The activity of SOD, CAT, and GPX, and the mRNA profiles of genes encoding antioxidant enzymes depended on the tested compound and its concentration. Betulin showed an cisplatin-like effect, indicating its nephrotoxic potential. Betulin derivatives EB5 and ECH147 showed different impacts on the antioxidant system, which gives hope that these compounds will not cause severe consequences for the kidneys in vivo.     

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

One of the strategies in the search for safe and effective analgesic drugs is the design of multitarget analgesics. Such compounds are intended to have high affinity and activity at more than one molecular target involved in pain modulation. In the present contribution we summarize the attempts in which fentanyl or its substructures were used as a μ-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached. The non-opioid ‘second’ targets included proteins as diverse as imidazoline I₂ binding sites, CB₁ cannabinoid receptor, NK₁ tachykinin receptor, D₂ dopamine receptor, cyclooxygenases, fatty acid amide hydrolase and monoacylglycerol lipase and σ₁ receptor. Reviewing the individual attempts, we outline the chemistry, the obtained pharmacological properties and structure-activity relationships. Finally, we discuss the possible directions for future work.