Innovative prophylactic and therapeutic approaches in liver cirrhosis.

Liver cirrhosis is the consequence of chronicisation and of the evolution of untreated liver diseases. The complexity of the disease and the complications it can cause have been and are still intensively researched, aiming to discover new therapies or improve existing ones for the effective management of liver cirrhosis. Currently, the treatment used is directed against the cause that caused the disease, if it is known; in advanced cases, liver transplantation is the only valid therapeutic option. Hepatoprotectors that are currently on the market are numerous, having as common properties the antioxidant, anti-inflammatory, stabilizing properties of the hepatocytic membrane; A few examples: the ethanolic extract of Curcuma longa, the extract from the plant called Sophora flavescens, the extract of Glycyrrhiza glabra, silymarin (extracted from Sylibum marianum), the extract of Ganoderma lucidum, etc. Liver cirrhosis is accompanied by generalized hypovitaminosis, so supplementing the diet with hydro- and liposoluble vitamins is mandatory. Protein-caloric malnutrition can be prevented by a hyperprotein diet, especially beneficial being the supplementation with branched-chain amino acids, which are also applicable in the prophylaxis and treatment of hepatic encephalopathy. Nanoparticles are a state-of-the-art therapeutic option, proving increased bioavailability, for example polydopamine nanoparticles loaded with l-arginine have been tested as therapy in liver cirrhosis. Among the innovative treatment directions in liver cirrhosis are hybrid products (e.g. hybrid polymer nanoparticles loaded with caffeic acid), cell cultures and artificial or bioartificial liver support.

Hybrid Material Based on Vaccinium myrtillus L. Extract and Gold Nanoparticles Reduces Oxidative Stress and Inflammation in Hepatic Stellate Cells Exposed to TGF-ß.

(1) Background: The study aimed to investigate the impact of gold nanoparticles capped with Cornus sanguinea (NPCS) and mixed with a fruit extract (Vaccinum myrtillus L.-VL) on human hepatic stellate cells (LX-2) exposed to TGF-ß. (2) Methods: NPCS were characterized by UV-Vis, transmission electron microscopy (TEM), zeta potential measurement, X-ray diffraction (XRD) and energy dispersive spectroscopy (EDX). The cytotoxic effects of VL, NPCS and of the hybrid compounds obtained by mixing the two components in variable proportions (NPCS-VL) were assessed. LDH activity, MDA levels, secretion of inflammation markers, the expression of fibrogenesis markers and collagen I synthesis were estimated after treating the cells with a mixture of 25:25 µg/mL NPCS and VL. (3) Results: TEM analysis showed that NPCS had spherical morphology and homogenous distribution, while their formation and elemental composition were confirmed by XRD and EDX analysis. TGF-ß increased cell membrane damage as well as secretion of IL-1ß, IL-1α and TLR4. It also amplified the expression of α-SMA and type III collagen and induced collagen I deposition. NPCS administration reduced the inflammation caused by TGF-ß and downregulated α-SMA expression. VL diminished LDH activity and the secretion of proinflammatory cytokines. The NPCS-VL mixture maintained IL-1ß, IL-1α, TLR4 and LDH at low levels after TGF-ß exposure, but it enhanced collagen III expression. (4) Conclusions: The mixture of NPCS and VL improved cell membrane damage and inflammation triggered by TGF-ß and mitigated collagen I deposition, but it increased the expression of collagen III, suggestive of a fibrogenetic effect of the hybrid material.

Blue Light-Ocular and Systemic Damaging Effects: A Narrative Review.

Light is a fundamental aspect of our lives, being involved in the regulation of numerous processes in our body. While blue light has always existed in nature, with the ever-growing number of electronic devices that make use of short wavelength (blue) light, the human retina has seen increased exposure to it. Because it is at the high-energy end of the visible spectrum, many authors have investigated the theoretical harmful effects that it poses to the human retina and, more recently, the human body, given the discovery and characterization of the intrinsically photosensitive retinal ganglion cells. Many approaches have been explored, with the focus shifting throughout the years from examining classic ophthalmological parameters, such as visual acuity, and contrast sensitivity to more complex ones seen on electrophysiological assays and optical coherence tomographies. The current study aims to gather the most recent relevant data, reveal encountered pitfalls, and suggest future directions for studies regarding local and/or systemic effects of blue light retinal exposures.

Low Doses of Celecoxib Might Promote Phenotype Switching in Cutaneous Melanoma Treated with Dabrafenib-Preliminary Study.

Background: Cutaneous melanoma is a heterogeneous tumor with a rapidly switching molecular and cellular phenotype. The invasive phenotype switching characterized by MITFlow/AXLhigh predicts early resistance to multiple targeted drugs in melanoma. Celecoxib proved to be a valuable adjuvant in cutaneous melanoma in preclinical studies. Our in vitro study evaluated for the first time whether celecoxib could prevent phenotype switching in two human melanoma cell lines treated with dabrafenib. Methods: All in vitro experiments were carried out on BRAF-V600E-positive A375 and SK-MEL-28 human melanoma cell lines, and subjected to a celecoxib and dabrafenib drug combination for 72 h. Melanoma cells were already in the MITFlow/AXLhigh end of the spectrum. Of main interest was the evaluation of the key proteins expressed in phenotype switching (TGF-ß, MITF, AXL, YAP, TAZ), as well as cell death mechanisms correlated with oxidative stress production. Results: Celecoxib significantly enhanced the apoptotic effect of dabrafenib in each melanoma cell line compared to the dabrafenib group (p < 0.0001). Even though celecoxib promoted low MITF expression, this was correlated with high receptor tyrosine kinase AXL levels in A375 and SK-MEL-28 cell lines (p < 0.0001), a positive marker for the phenotype switch to an invasive state. Conclusion: This preliminary study highlighted that celecoxib might promote MITFlow/AXLhigh expression in cutaneous melanoma treated with dabrafenib, facilitating phenotype switching in vitro. Our results need further confirmation, as this finding could represent an important limitation of celecoxib as an antineoplastic drug.

Effects of Gold Nanoparticles Functionalized with Bioactive Compounds from Cornus mas Fruit on Aorta Ultrastructural and Biochemical Changes in Rats on a Hyperlipid Diet-A Preliminary Study.

Cornus mas L. extract (CM) presents hypolipidemic, antioxidant and anti-inflammatory activity. Gold nanoparticles (AuNPs) are considered potent delivery systems and may be used to release pharmaceutical compounds at the level of injury. In our study, we used gold nanoparticles functionalized with bioactive compounds from Cornus mas L. (AuNPsCM) in an experimental model of a high-fat diet (HFD), and we assessed their effects on aorta wall but also in the serum, as compared to Cornus mas (CM) administration. Sprague Dawley female rats were fed for 9 months with an HFD. During the last month of the experiment, we randomly allocated the animals into three groups that received, by oral gavage: saline solution, CM solution (0.158 mg/mL polyphenols) or AuNPsCM solution (260 µg Au/kg/day), while a Control group received a standard diet and saline solution. At the end of the experiment, we performed an ultrasonography of the aorta and left ventricle and a histology and transmission electron microscopy of the aorta walls; we investigated the oxidative stress and inflammation in aorta homogenates and in serum and, in addition, the lipid profile. AuNPsCM presented better effects in comparison with the natural extract (CM) on lipid peroxidation (p < 0.01) and TNF-alpha (p < 0.001) in aorta homogenates. In serum, both CM and AuNPsCM decreased the triglycerides (p < 0.001) and C-reactive protein (CM, p < 0.01; AuNPsCM, p < 0.001) and increased the antioxidant protection (p < 0.001), in comparison with the HFD group. In intima, AuNPsCM produced ultrastructural lesions, with the disorganization of intima and subendothelial connective layer, whereas CM administration preserved the intima normal aspect, but with a thinned subendothelial connective layer. AuNPsCM oral administration presented certain antioxidant, anti-inflammatory and hypolipidemic effects in an experimental model of HFD, but with a negative impact on the ultrastructure of aorta walls, highlighted by the intima disorganization.

Physalis alkekengi L. Extract Reduces the Oxidative Stress, Inflammation and Apoptosis in Endothelial Vascular Cells Exposed to Hyperglycemia.

To find new natural remedies in diabetes, this study investigated the biological activity of two extracts obtained from the fruits (PhyF) and herba (PhyH) of Physalis alkekengi var. franchetii L. on human umbilical vein endothelial cells (HUVECs) exposed to normo- and hyperglycemic conditions. The biological effect was quantified by malondialdehyde, IL-31 and IL-33 levels in correlation with physico-chemical characterization and antioxidant activity. Additionally, from PhyP extract, the caspase-3, IL-6, IL-10, tumor necrosis factor (TNF)-α and nuclear transcription factor NFkB expressions were evaluated. HPLC analysis revealed a significant number of phenolic compounds, especially in PhyF extract, with a good antioxidant activity as highlighted by TEAC, CUPRAC or DPPH methods. On HUVECS cells, the extracts were not toxic even at high concentrations. Particularly PhyF extract, diminished lipid peroxidation and inhibited the IL-31 and IL-33 secretions induced by hyperglycemia. The inhibitory effect on proinflammatory cytokines was noticed after both doses of PhyF extract in parallel with the upregulation of anti-inflammatory cytokine IL-10. Moreover, PhyF, especially in a low dose, reduced caspase-3 active form. These experimental findings suggest that Physalis fruits extract exerted beneficial effects in hyperglycemia by inhibition of oxidative stress, inflammation and apoptosis being a good adjuvant option in diabetes.