Interplay between Systemic Glycemia and Neuroprotective Activity of Resveratrol in Modulating Astrocyte SIRT1 Response to Neuroinflammation.

The flow of substances between the blood and the central nervous system is precisely regulated by the blood-brain barrier (BBB). Its disruption due to unbalanced blood glucose levels (hyper- and hypoglycemia) occurring in metabolic disorders, such as type 2 diabetes, can lead to neuroinflammation, and increase the risk of developing neurodegenerative diseases. One of the most studied natural anti-diabetic, anti-inflammatory, and neuroprotective compounds is resveratrol (RSV). It activates sirtuin 1 (SIRT1), a key metabolism regulator dependent on cell energy status. The aim of this study was to assess the astrocyte SIRT1 response to neuroinflammation and subsequent RSV treatment, depending on systemic glycemia. For this purpose, we used an optimized in vitro model of the BBB consisting of endothelial cells and astrocytes, representing microvascular and brain compartments (MC and BC), in different glycemic backgrounds. Astrocyte-secreted SIRT1 reached the highest concentration in hypo-, the lowest in normo-, and the lowest in hyperglycemic backgrounds. Lipopolysaccharide (LPS)-induced neuroinflammation caused a substantial decrease in SIRT1 in all glycemic backgrounds, as observed earliest in hyperglycemia. RSV partially counterbalanced the effect of LPS on SIRT1 secretion, most remarkably in normoglycemia. Our results suggest that abnormal glycemic states have a worse prognosis for RSV-therapy effectiveness compared to normoglycemia.

Salidroside: A Promising Agent in Bone Metabolism Modulation.

Rhodiola rosea, a long-lived herbaceous plant from the Crassulaceae group, contains the active compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and adenosine monophosphate-activated protein kinase, essential for bone formation and growth. It enhances osteogenic activity by increasing alkaline phosphatase activity and mineralization markers, while upregulating key regulatory proteins including runt-related transcription factor 2 and osterix. Additionally, salidroside facilitates angiogenesis via the hypoxia-inducible factor 1-alpha and vascular endothelial growth factor pathway, crucial for coupling bone development with vascular support. Its antioxidant properties offer protection against bone loss by reducing oxidative stress and promoting osteogenic differentiation through the nuclear factor erythroid 2-related factor 2 pathway. Salidroside has the capability to counteract the negative effects of glucocorticoids on bone cells and prevents steroid-induced osteonecrosis. Additionally, it exhibits multifaceted anti-inflammatory actions, notably through the inhibition of tumor necrosis factor-alpha and interleukin-6 expression, while enhancing the expression of interleukin-10. This publication presents a comprehensive review of the literature on the impact of salidroside on various aspects of bone tissue metabolism, emphasizing its potential role in the prevention and treatment of osteoporosis and other diseases affecting bone physiology.

Effect of substrate stiffness on the osteogenic differentiation of bone marrow stem cells and bone-derived cells.

There is a profound dependence of cell behaviour on the stiffness of its microenvironment. To gain a better understanding of the regulation of cellular differentiation by mechanical cues, we investigated the influence of matrix stiffness (E = 1.46 kPa and E = 26.12 kPa) on differentiated osteogenic cell lineage of bone marrow stem cells (BM-MSCs) and bone-derived cells (BDCs) using flexible collagen-coated polyacrylamide substrates. Differentiation potential was determined by measuring alkaline phosphatase activity, expression of osteoblast-specific markers including alkaline phosphatase, osteocalcin, Runx2 and collagen type I, as well as assessment of mineralisation (Alizarin Red S staining). We found that osteogenic differentiation can be regulated by the rigidity of the substrate, which may depend on the commitment in multi- or uni-potent targeting cells. Osteogenic differentiation of BM-MSCs was enhanced on a stiff substrate compared to a soft one, whereas BDCs osteogenic differentiation did not vary depending on the substrate stiffness. The data help in understanding the role of the external mechanical determinants in stem cell differentiation, and can also be useful in translational approach in functional tissue engineering.

[Kidney transplants from donors burdened metabolic acidosis in the course of poisoning with methanol and carbon monoxide]. / Transplantacje nerek od dawców obciazonych kwasica metaboliczna w przebiegu zatruc metanolem i tlenkiem wegla.

The question of obtaining organs from donors who died of methanol poisoning has been discussed in the medical literature for many years. The results of such transplants published so far are very optimistic. However, the possibility of permanent and significant injury to transplanted organs caused by poisons or its metabolites raises serious concerns regarding the procedure. The long-term effects of intensive treatment of poisoning need to be considered as well. Metabolic acidosis and high blood osmolality are agents with recognized damaging potential impairing organ function at cellular level. The study traced the fate of kidney transplants from 13 donors who died of methanol poisoning and one isoned with carbon monoxide. The donors group consisted of 12 men and 2 women, of mean age 49 years (SD +/- 7.93). The kidneys were transplanted 20 men and 8 women. The mean age of recipients was 50.29 years (SD +/- 12.9). At the time of admission to the Department of Toxicology all donors presented with profound metabolic acidosis and high plasma osmolality (mean 434.71 mOsm/kg H2O (SD +/- 73.29). Metabolic acidosis was treated high doses of sodium bicarbonate (mean infusion volume of was 409 ml) before the HD procedure. Blood methanol levels were between 125 and 470 mg% (mean 317.23 SD +/- 136.83). The carboxyhaemoglobin concentration of in the donor poisoned with carbon monoxide was 47.2%. Transplantation was performed after confirmation of the brain death, the period of cold ischemia (CIT) ranged from 6 to 22 hours (mean 16.06 hours; SD +/- 3.99). Kidneys have taken function immediately after transplantation in 21 recipients. In seven cases, patients required two or three HD procedures. A total of 16 dialysis were performed post-transplants. In the group of patients, the mean glomerular filtration rate (GFR) at 3 months after transplantation was 46.71 ml/min/1.73m2 (SD +/- 10.89). During the 18 months follow-up a constant upward trend to the mean GFR 50.55 was noticed. In the group of donors, the mean blood urea concentration (BUN) 3 months after transplantation was 61.43 mg/dL, including 7 patients with BUN within the range of 80-100 mg/dL. At 18 months post transplant, the average concentration was 42.36 mg/dL, with no cases exceeding 55 mg/dL. Similarly, serum creatinine level normalized with the mean value of 3.01 mg/dL at 3 months and 1.68 mg/dL at 18 months post the procedure. There was no case exceeding 2 mg/dL. One recipient died of a heart attack after a period of more than 18 months after transplantation. However, the transplant was efficiently active at all times (GFR 56-60 ml).

Influence of phosvitin and calcium gluconate concentration on permeation and intestinal absorption of calcium ions.

The effect of egg yolk phosvitin on the permeation and absorption of calcium was investigated in vitro in relation to calcium gluconate concentration. Obtained results indicate that phosvitin significantly reduces the intestinal calcium absorption from 1 and 10 mM of calcium gluconate solution. It is associated with the formation of the complex of Ca (II) ions with phosvitin. The process of calcium permeation increases under phosvitin influence when calcium gluconate concentrations rise up to 10 mM. At a higher concentration of calcium gluconate (20 mM), no effect of phosvitin was seen on permeation of calcium ions.

The influence of condition on permeation of Ca(II) ions from solutions of selected calcium's salts through model membrane.

The permeation of calcium's ions from calcium solutions of fumarate, gluconate, and citrate through model membrane from the donor chamber to the acceptor chamber has been examined. Process was traced depending on the concentration of the appropriate calcium's salts (1, 2.5, and 5 mmol/l) and pH value of acceptor environment (1.3, 6.2, and 7.4) which imitated natural conditions appearing in the digestive tract. The amount of permeating Ca(II) ions (percent) and their Ca(II) availability AUC (0-6 h) has been determined. In dependence on the conditions, penetration was as follows: 30.3-95.2% of calcium ions from fumarate solution; 73.0-90.1% of Ca(II) from citrate solution; and 19.0-95.0% of Ca from gluconate solution. The investigation indicates that the amount of permeated Ca(II) ions and their availability are connected with the concentration of the calcium salt and pH of acceptor environment. Fumarate and citrate are available at pH value of acceptor environment 1.3 and 6.2 and gluconate at the pH value of 6.2 and 7.4. These substances are practically unavailable from the acceptor environment at pH value 1.3 for gluconate and 7.4 for fumarate. Results suggest that calcium citrate can be available for organism independently from pH value of acceptor environment.

A model for calcium permeation into small intestine.

An in vitro model was used to simulate the intestinal permeation of calcium ions depending on the type of salt (carbonate, fumarate, citrate, or gluconate), its concentration (1.0, 2.5, 5.0, or 10 mM/l), and pH (1.3, 4.2, 6.2, or 7.5). To simulate the conditions for calcium permeation in a patient in a fasting state, the solutions were placed in contact with segments of small intestine of pig: stomach, duodenum, jejunum, and ileum. The percent permeation, its rate, and half-time were measured in each case. In all cases, the maximum permeation was seen at 1 mM concentration, depending on pH: 100% for carbonate at pH 1.3; 82% for fumarate, pH 6.2; 79.5% for citrate at pH 4.2, and 81% for gluconate at pH 7.4. The maximum rate of permeation (% h(-1)) was also observed at 1 mM: 2.16 for carbonate at pH 1.3, 0.29 for fumarate at pH 6.2, 0.26 for citrate at pH 4.2, and 0.28 for gluconate at pH 7.4. The shortest half-time permeation (t (1/2), h) for 1 mM solutions depended also on pH (in parentheses): carbonate 0.3 (1.3), fumarate 2.4 (6.2), citrate 2.6 (4.2), and gluconate 2.5 (7.4). The results suggest that calcium carbonate and citrate can be recommended to patients with normal gastric acidity and hyperacidity while fumarate and gluconate to patients with hypoacidity.