Novel Strategies Enhancing Bioavailability and Therapeutical Potential of Silibinin for Treatment of Liver Disorders

Michal Selc,1,2 Radka Macova,2,3 Andrea Babelova1,2 1Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia; 2Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia; 3Department of Genetics, Faculty of Natural Sciences, Comenius University Bratislava, Bratislava, SlovakiaCorrespondence: Michal Selc, Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, 84511, Slovakia, Tel +421-2-32295-175, Email [email protected]: Silibinin, a bioactive component found in milk thistle extract (Silybum marianum), is known to have significant therapeutic potential in the treatment of various liver diseases. It is considered a key element of silymarin, which is traditionally used to support liver function. The main mechanisms of action of silibinin are attributed to its antioxidant properties protecting liver cells from damage caused by free radicals. Experimental studies conducted in vitro and in vivo have confirmed its ability to inhibit inflammatory and fibrotic processes, as well as promote the regeneration of damaged liver tissue. Therefore, silibinin represents a promising tool for the treatment of liver diseases. Since the silibinin molecule is insoluble in water and has poor bioavailability in vivo, new perspectives on solving this problem are being sought. The two most promising approaches are the water-soluble derivative silibinin-C-2’,3-dihydrogen succinate, disodium salt, and the silibinin-phosphatidylcholine complex. Both drugs are currently under evaluation in liver disease clinical trials. Nevertheless, the mechanism underlying silibinin biological activity is still elusive and its more detailed understanding would undoubtedly increase its potential in the development of effective therapeutic strategies against liver diseases. This review is focused on the therapeutic potential of silibinin and its derivates, approaches to increase the bioavailability and the benefits in the treatment of liver diseases that have been achieved so far. The review discusses the relevant in vitro and in vivo studies that investigated the protective effects of silibinin in various forms of liver damage. Keywords: silybin, bioavailability, liver disease, silibinin-phosphatidylcholine complex, silibinin-C-2‘ 3-dihydrogen succinat

Monitoring Durability of Limestone Cement Paste Stored at Conditions Promoting Thaumasite Formation

The durability of Portland-limestone cement with high limestone content was monitored at conditions promoting thaumasite formation. Pore structure and deterioration characteristics were assessed with X-ray micro-computed tomography and correlated with material's strength. Changes in crystalline and amorphous phases of the cement paste were investigated with X-ray powder diffraction and solid state nuclear magnetic resonance spectroscopy. Rapid deterioration was observed, evolving as a front causing concentric crack patterns followed by detachment of the part of specimen in contact with the corrosive solution. This ultimately led to loss of structural integrity after 4 months of exposure. During sulfate attack, thaumasite, ettringite and gypsum formed at the expense of portlandite, calcite and monocarboaluminate hydrate. Furthermore, polymerization of silicate chains in C-S-H and deterioration of C-S-H also occurred

Impact of gonadectomy on blood pressure regulation in ageing male and female rats

Sexual dimorphism in blood pressure has been associated with differential expression of the angiotensin II (AII) receptors and with activity of the nervous system. It is generally accepted that aging affects kidney function as well as autonomic nervous system and hormonal balance. Given that hypertension is more prevalent in men than women until women reach their seventh decade we hypothesised that females would be relatively protected from adverse effects of ageing compared to males, and that this would be mediated by the protective effect of ovarian steroids. Intact and gonadectomised male and female normotensive Wistar rats aged 6, 12 and 18 months were used to study renal function, blood pressure, heart rate and blood pressure variability. We observed that intact females had lower levels of proteinuria and higher (12.5%) creatinine clearance compared to intact males, and that this difference was abolished by castration but not by ovariectomy. Ovariectomy resulted in a change by 9% in heart rate, resulting in similar cardiovascular parameters to those observed in males or gonadectomised males. Spectral analysis of systolic blood pressure revealed that high frequency power spectra were significantly elevated in the females vs. males and were reduced by ovariectomy. Taken altogether the results show that females are protected from age-related declining renal function and to a lesser extent from rising blood pressure in comparison to males. Whilst ovariectomy had some deleterious effects in females, the strongest effects were associated with gonadectomy in males, suggesting a damaging effect of male hormones

Evaluating Biparametric Versus Multiparametric Magnetic Resonance Imaging for Diagnosing Clinically Significant Prostate Cancer: An International, Paired, Noninferiority, Confirmatory Observer Study

Background and objective: Biparametric magnetic resonance imaging (bpMRI), excluding dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), is a potential replacement for multiparametric MRI (mpMRI) in diagnosing clinically significant prostate cancer (csPCa). An extensive international multireader multicase observer study was conducted to assess the noninferiority of bpMRI to mpMRI in csPCa diagnosis. // Methods: An observer study was conducted with 400 mpMRI examinations from four European centers, excluding examinations with prior prostate treatment or csPCa (Gleason grade [GG] ≥2) findings. Readers assessed bpMRI and mpMRI sequentially, assigning lesion-specific Prostate Imaging Reporting and Data System (PI-RADS) scores (3–5) and a patient-level suspicion score (0–100). The noninferiority of patient-level bpMRI versus mpMRI csPCa diagnosis was evaluated using the area under the receiver operating curve (AUROC) alongside the sensitivity and specificity at PI-RADS ≥3 with a 5% margin. The secondary outcomes included insignificant prostate cancer (GG1) diagnosis, diagnostic evaluations at alternative risk thresholds, decision curve analyses (DCAs), and subgroup analyses considering reader expertise. Histopathology and ≥3 yr of follow-up were used for the reference standard. // Key findings and limitations: Sixty-two readers (45 centers and 20 countries) participated. The prevalence of csPCa was 33% (133/400); bpMRI and mpMRI showed similar AUROC values of 0.853 (95% confidence interval [CI], 0.819–0.887) and 0.859 (95% CI, 0.826–0.893), respectively, with a noninferior difference of –0.6% (95% CI, –1.2% to 0.1%, p < 0.001). At PI-RADS ≥3, bpMRI and mpMRI had sensitivities of 88.6% (95% CI, 84.8–92.3%) and 89.4% (95% CI, 85.8–93.1%), respectively, with a noninferior difference of –0.9% (95% CI, –1.7% to 0.0%, p < 0.001), and specificities of 58.6% (95% CI, 52.3–63.1%) and 57.7% (95% CI, 52.3–63.1%), respectively, with a noninferior difference of 0.9% (95% CI, 0.0–1.8%, p < 0.001). At alternative risk thresholds, mpMRI increased sensitivity at the expense of reduced specificity. DCA demonstrated the highest net benefit for an mpMRI pathway in cancer-averse scenarios, whereas a bpMRI pathway showed greater benefit for biopsy-averse scenarios. A subgroup analysis indicated limited additional benefit of DCE MRI for nonexperts. Limitations included that biopsies were conducted based on mpMRI imaging, and reading was performed in a sequential order. // Conclusions and clinical implications: It has been found that bpMRI is noninferior to mpMRI in csPCa diagnosis at AUROC, along with the sensitivity and specificity at PI-RADS ≥3, showing its value in individuals without prior csPCa findings and prostate treatment. Additional randomized prospective studies are required to investigate the generalizability of outcomes

Nucleation of amorphous precursor in magnesium phosphate cements: Clues to the reaction pathway

In-situ X-ray techniques indicated that in its early stages, the reaction pathway of magnesium phosphate cements involves the formation of an amorphous precursor, first detected as nanoparticles which organize themselves into larger domains. Crystallization occurs from this precursor (already containing the structural motives of the crystalline counterpart) by increasing the long-range order through relatively minor structural rearrangements. The process is compatible with multi-steps nucleation involving non-classical mechanisms, as observed in Ca-carbonates and phosphates, therefore, indicating ways to control the transformation to improve cement design

Physical-chemical-mechanical quantitative assessment of the microstructural evolution in Portland-limestone cement pastes exposed to magnesium sulfate attack at low temperature

The changes in structural integrity and microstructure of Portland-limestone cement pastes were investigated in the course of magnesium sulfate attack at low temperature. A deterioration front, consisting of three distinct layers (brucite, gypsum, leached cement matrix), swelled in time due to the expansive nature of the deterioration products, generating cracks and subsequently detaching from the sound cement matrix, continuously promoting the process. Gypsum and thaumasite characterized the leached matrix, which experienced extensive cross-linking of the aluminosilicate structures, as a result of decalcification and dealumination of the calcium silicate hydrates (C[sbnd](A[sbnd])S[sbnd]H), impairing the overall mechanical performance. C[sbnd]S[sbnd]H of low packing density was most severely affected by the process, as confirmed by the significant drop in nano-mechanical properties. The increased rate of deterioration with limestone content was tentatively attributed to the prevalent morphology of the C[sbnd]S[sbnd]H phase. Results were validated by thermodynamic simulations, indicating that the real systems did not reach equilibrium

Influence of additions of synthetic anhydrous calcium carbonate polymorphs on nanolime carbonation

The influence of synthetic anhydrous calcium carbonate polymorphs, calcite, vaterite and aragonite, on carbonation of nanolime suspension, has been investigated. The higher rates of carbonation observed after 7 days in mixtures containing vaterite and aragonite particles, found explanation in the control exerted by heterogeneous nucleation on the water-mediated reaction mechanism and in the enhanced carbon dioxide diffusivity in the sample volume, both facilitated by the higher specific surface of the powders and the microporous sample fabric. Introduction of synthetic calcium carbonate allowed for exerting control on formed polymorphs, subverting the order of their (meta-)stability. The peculiar microstructure obtained by adding aragonite rod-like particles, mitigates the propagation of desiccation cracks (which impair continuity of the carbonated nanolime film). The mechanism, although still not completely understood, likely involves the regulation of evaporation of liquid fraction and redistribution of the tensional stresses during drying and nanolime crystallization. The obtained results provide new insights into the crystallization of carbonates from nanolime particles and may help in the design of innovative compatible products for consolidation of lime-based materials and carbon dioxide sequestration

Assessing Toxic Potency of Ambient Air using Bioanalytical Methods: A Case Study using Passive Air Sampling

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Biofiltration of wastewater treatment plant effluent: Effective removal of pharmaceuticals and personal care products and reduction of toxicity

This study investigates biofiltration for the removal of dissolved organic carbon (DOC), pharmaceuticals and personal care products (PPCPs), and for the reduction of non-specific toxicity expressed as baseline toxicity equivalent concentration (baseline-TEQ). Two filtering media, sand and granular activated carbon, were tested. The influence of pre-ozonation and empty-bed contact time (EBCT, from 30 to 120 min) was determined. The experiments were performed at a pilot-scale with real WWTP effluent. A previous study showed that biological activity had developed on the filtering media and dissolved organic removal had reached a steady state before sampling commenced. The results show that biological activated carbon (BAC) has a good potential for the removal of DOC (35–60%), PPCPs (>90%) and baseline-TEQ (28–68%) even without pre-ozonation. On the contrary, the sand shows limited improvement of effluent quality. Varying the EBCT does not influence the performance of the BAC filters; however, dissolved oxygen concentration could be a limiting factor. The performances of the BAC filters were stable for over two years suggesting that the main mechanism of organic matter and PPCPs removal is biodegradation. It is concluded that BAC filtration without pre-ozonation could be implemented as a low cost advanced treatment option to improve WWTP effluent chemical quality