Primary mesenchymal stromal cells in co-culture with leukaemic HL-60 cells are sensitised to cytarabine-induced genotoxicity, while leukaemic cells are protected

Tumour microenvironments are hallmarked in many cancer types. In haematological malignancies, bone marrow (BM) mesenchymal stromal cells (MSC) protect malignant cells from drug-induced cytotoxicity. However, less is known about malignant impact on supportive stroma. Notably, it is unknown whether these interactions alter long-term genotoxic damage in either direction. The nucleoside analogue cytarabine (ara-C), common in haematological therapies, remains the most effective agent for acute myeloid leukaemia, yet one-third of patients develop resistance. This study aimed to evaluate the bidirectional effect of MSC and malignant cell co-culture on ara-C genotoxicity modulation. Primary MSC, isolated from patient BM aspirates for haematological investigations, and malignant haematopoietic cells (leukaemic HL-60) were co-cultured using trans-well inserts, prior to treatment with physiological dose ara-C. Co-culture genotoxic effects were assessed by micronucleus and alkaline comet assays. Patient BM cells from chemotherapy-treated patients had reduced ex vivo survival (P = 0.0049) and increased genotoxicity (P = 0.3172) than untreated patients. It was shown for the first time that HL-60 were protected by MSC from ara-C-induced genotoxicity, with reduced MN incidence in co-culture as compared to mono-culture (P = 0.0068). Comet tail intensity also significantly increased in ara-C-treated MSC with HL-60 influence (P = 0.0308). MSC sensitisation to ara-C genotoxicity was also demonstrated following co-culture with HL60 (P = 0.0116), which showed significantly greater sensitisation when MSC-HL-60 co-cultures were exposed to ara-C (P = 0.0409). This study shows for the first time that malignant HSC and MSC bidirectionally modulate genotoxicity, providing grounding for future research identifying mechanisms of altered genotoxicity in leukaemic microenvironments. MSC retain long-term genotoxic and functional damage following chemotherapy exposure. Understanding the interactions perpetuating such damage may inform modifications to reduce therapy-related complications, such as secondary malignancies and BM failure.

Physiological Dose of EGCG Attenuates the Health Defects of High Dose by Regulating MEMO-1 in Caenorhabditis elegans

EGCG, as a dietary-derived antioxidant, has been extensively studied for its beneficial health effects. Nevertheless, it induces the transient increase in ROS and leads to the hormetic extension of lifespan. How exactly biology-benefiting effects with the minimum severe adverse are realized remains unclear. Here, we showed that physiological dose of EGCG could help moderate remission in health side effects exposed to high doses, including shortened lifespan, reduced body size, decreased pharyngeal pumping rate, and dysfunctional body movement in C. elegans. Furthermore, we found this result was caused by the physiological dose of EGCG to block the continued ROS accumulation and triggered acclimation responses after stressor removal. Also, in this process, we observed that EGCG downregulated the key redox protein MEMO-1 to activate the feedback loop of NADPH oxidase-mediated redox signaling. Our data indicates that the feedback signal induced by NADPH oxidase may contribute to the health-protective mechanism of dietary polyphenols in vivo.

Biologic Effect of Hydrogen Sulfide and Its Role in Traumatic Brain Injury

Ever since endogenous hydrogen sulfide (H2S) was found in mammals in 1989, accumulated evidence has demonstrated that H2S functions as a novel neurological gasotransmitter in brain tissues and may play a key role in traumatic brain injury. It has been proved that H2S has an antioxidant, anti-inflammatory, and antiapoptosis function in the neuron system and functions as a neuroprotective factor against secondary brain injury. In addition, H2S has other biologic effects such as regulating the intracellular concentration of Ca2+, facilitating hippocampal long-term potentiation (LTP), and activating ATP-sensitive K channels. Due to the toxic nature of H2S when exceeding the physiological dose in the human body, only a small amount of H2S-related therapies was applied to clinical treatment. Therefore, it has huge therapeutic potential and has great hope for recovering patients with traumatic brain injury.

Iodine Deficiency in the World and in Ukraine: Current State of the Problem

Today, efforts of governments and communities are aimed at coping with severe impacts of new viral disease outbreaks caused by SARS-Cov-2. However, there are gaps in care for patients with many chronic diseases, and programs to prevent the most common conditions are being prevented or stopped. This applies to diseases directly related to eating disorders. To solve the problem at the population level, it is critically necessary to adopt legislative acts regulating the universal iodization of table salt in the country. Currently, in Ukraine, potassium iodate is used for salt enrichment, which is a more stable compound than iodide that was used earlier. Potassium iodate allows you to store iodized salt for a year or more, does not change the taste and smell of food, and can be used for preserving and storing food. For the most vulnerable categories of the population (newborns, children, pregnant women and mothers who are breastfeeding), the use of iodine supplements remains relevant. The optimal tool for such preventive interventions is supplements containing the physiological dose of iodine. On the Ukrainian market, they are presented in the form of pills of potassium iodide with a content of 100 mcg and 200 mcg of iodine. The common goal should be Ukraine without iodine deficiency, where each person receives the amount of iodine corresponding to their needs, and children are provided with the opportunity for adequate intellectual development. No conflict of interest was declared by the authors. Key words: children, pregnant women, iodine deficiency, iodine supplements.

Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia in preterm infants

Historically, postnatal corticosteroids have been used to prevent and treat bronchopulmonary dysplasia (BPD), a significant cause of morbidity and mortality in preterm infants. Administering dexamethasone to prevent BPD in the first 7 days post-birth has been associated with increasing risk for cerebral palsy, while early inhaled corticosteroids appear to be associated with an increased risk of mortality. Neither medication is presently recommended to prevent BPD. New evidence suggests that prophylactic hydrocortisone, when initiated in the first 48 hours post-birth, at a physiological dose, and in the absence of indomethacin, improves survival without BPD, with no adverse neurodevelopmental effects at 2 years. This therapy may be considered by clinicians for infants at highest risk for BPD. Routine dexamethasone therapy for all ventilator-dependent infants is not recommended, but after the first week post-birth, clinicians may consider a short course of low-dose dexamethasone (0.15 mg/kg/day to 0.2 mg/kg/day) for individual infants at high risk for, or with evolving, BPD. There is no evidence that hydrocortisone is an effective or safe alternative to dexamethasone for treating evolving or established BPD. Current evidence does not support inhaled corticosteroids for the treatment of BPD.

Murburn concept: a paradigm shift in cellular metabolism and physiology

Two decades of evidence-based exploratory pursuits in heme-flavin enzymology led to the formulation of a new biological electron/moiety transfer paradigm, called murburn concept. Murburn is a novel literary abstraction from “mured burning” or “mild unrestricted burning”. This concept was invoked to explain the longstanding conundrum of maverick physiological dose responses and also applied to remodel the prevailing understanding of drug metabolism and cellular respiration. A conglomeration of simple ideas grounded in the known principles of thermodynamics and reaction chemistry, murburn concept invokes catalytic/functional roles for diffusible reactive species or radicals. Hitherto, diffusible reactive species were primarily seen as toxic agents of chaos, non-conducible to the maintenance of life-order. Since the murburn paradigm offers a distinctly different perspective for several biological phenomena, researchers holding conventional views of cellular metabolism pose a direct conflict of interests to the advancement of murburn concept. Murburn schemes are poised to integrate numerous metabolic motifs with holistic physiological outcomes; redefining pursuits in biology and medicine. To advance this agenda, I present a brief account of murburn concept and point out how redundant ideas are still advocated in some prestigious journals.

PSVII-36 Examining the effect of a physiological dose of the polyamine; spermine, on myogenic regulatory transcription factor expression

Examining the effect of a physiological dose of the polyamine; spermine, on myogenic regulatory transcription factor expression. Spermine is a micronutrient derived from amino acids. It affects cell growth, proliferation, differentiation and gene regulation in many cell types. Polyamines have long been overlooked with respect to their biological effects on muscle growth. Myogenic regulatory factors (myoD, myf5) initiate, promote and regulate myogenesis. Supporting myogenic transcription factors transcription and by such enhancing muscle production in livestock, through nutrition may be possible with dietary spermine supplementation. We examined the effect of spermine (0.5mM) in undifferentiated c2c12 muscle cells at two time points (8hr and 16hr). Using TaqMan-MGB qRT-PCR we quantified mRNA for key myogenic regulatory factors in a minimum of three experiments each containing 3 technical replicates. We report a significant increase in myoD (P = 0.02) and myf5 (P = 0.05) mRNA at 8hr following spermine treatment as compared to controls (no spermine). After 16 hr exposure to spermine (0.5mM) treatment myoD (P = 0.01) remained significantly different from controls. Our results indicate that spermine supports myogenesis through expression of increased myogenic regulatory factors at early stages of myogenesis. These findings support the need to further test the hypothesis that spermine promotes increased muscle growth and ultimately may represent a dietary means to maximize muscle growth in livestock species.

A rare case of Vitamin D dependent rickets type II: a case report

Vitamin D-dependent type II rickets (VDDRII) is a rare autosomal recessive disorder caused by mutation in the vitamin D receptor gene, leading to end-organ resistance to 1,25(OH)2 vitamin D3. It presents with refractory rickets and growth retardation presenting in the first year of life. It is frequently associated with alopecia totalis. Due to target organresistance, its response to vitamin D is poor. The recommended treatment is giving supra physiological dose of 1,25(OH)2 vitamin D3 and a high dose of oral or intravenous calcium. The response of alopecia to treatment is generally poor. We present a 3 ½ year-old male child with VDDR II whose alopecia and rickets partially responded to 1,25(OH)2 vitamin D3.