Investigation the effects of vitreous humor on proliferation and dedifferentiation of differentiated NTERA2 cells

Mammals have a limited capacity to regenerate their tissues and organs. One of the mechanisms associated with natural regeneration is dedifferentiation. Several small molecules such as vitamin C and growth factors could improve reprogramming efficiency. In this study, the NTERA2-D1 (NT2) cells were induced towards differentiation (NT2-RA) with 10-5 M retinoic acid (RA) for three days and then subjected to various amounts of vitreous humor (VH). Results show that the growth rate of these cells was reduced, while this rate was partly restored upon treatment with VH (NT2-RA-VH). Cell cycle analysis with PI method also showed that the numbers of cells at the S phase of the cell cycle in these cells were increased. The levels of SSEA3 and TRA-1-81 antigens in NT2-RA were dropped but they increased in NT2- RA-VH to a level similar to the NT2 cells. The level of SSEA1 had an opposite pattern. Expression of OCT4 gene dropped after RA treatment, but it was recovered in NT2-RA-VH cells. In conclusion, we suggest VH as a potent mixture for improving the cellular reprogramming leading to dedifferentiation.

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.

Culture and genomic analysis of Symbiopectobacterium purcellii, gen.nov. sp. nov., isolated from the leafhopper Empoasca decipiens

Bacterial endosymbionts are found in multiple arthropod species, where they play crucial roles as nutritional symbionts, defensive symbionts or reproductive parasites. Recent work has highlighted a new clade of heritable microbes within the gammaproteobacteria that enter into both obligate and facultative symbioses, with an obligately required unculturable symbiont recently given the name Cand. Symbiopectobacterium. In this study, we describe a culturable rod shaped non-flagellated bacterial symbiont from this clade isolated from the leafhopper Empoasca decipiens. The symbiont is related to the transovarially-transmitted 'BEV' bacterium that was first isolated from the leafhopper Euscelidius variegatus by Alexander Purcell, and we therefore name the symbiont Symbiopectobacterium purcellii sp. nov. gen. nov. We further report the closed genome sequence for S. purcellii. The genome is atypical for a heritable microbe, being large in size, without profound AT bias and with little evidence of pseudogenization. The genome is predicted to encode Type II, III and VI secretion systems and associated effectors and a non-ribosomal peptide synthase array likely to produce bioactive small molecules. Predicted metabolism is more complete than for other symbionts in the Symbiopectobacterium clade, and the microbe is predicted to synthesize a range of B vitamins. However, Biolog plate analysis indicate metabolism is depauperate compared to the sister clade, represented by Pectobacterium carotovorum. A quorum-sensing pathway related to that of Pectobacterium spp. (containing an overlapping expI-expR1 pair in opposite directions and a "solo" expR2) is evidenced, and LC-MS/MS analysis reveals the presence of 3-hydroxy-C10-HSL as the sole N-acylhomoserine lactone (AHL) in our strain. This AHL profile is profoundly divergent from that of other Erwinia and Pectobacterium spp., which produce mostly 3-oxo-C6- and 3-oxo-C8-HSL and could aid group identification. Thus, this microbe denotes one that has lost certain pathways associated with a saprophytic lifestyle but represents an important baseline against which to compare other members of the genus Symbiopectobacterium that show more profound integration into host biology.

Dereplikace látek a de novo charakterizace malých molekul z hmotnostních spekter

We describe the molecular dereplication principles and de novo characterization of small molecules obtained from liquid-chromatography mass spectrometry and imaging mass spectrometry data sets. Our methodology aims at supporting chemists and computer programmers to understand the hidden computing algorithms used for metabolomics mass spectrometry data processing. The approaches have been made available in the open-source tool CycloBranch. The presented tutorial extends the interpretation of mass spectra portfolia described in a series of papers published in Chemicke Listy, issues 2/2020 and 3/2020.

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer

Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/β-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/β-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/β-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.

From an Al4-Cluster to Al+ Complexes: Lessons on Metalloidal Clustering

Low-valent aluminium compounds are among the most reactive and widely researched main-group compounds. Since the isolation of [(AlCp*)4] in 1991 as the first stable, molecular AlI compound, a variety of highly reactive neutral or anionic low-valent aluminium complexes were developed. In particular, the strongly basic aluminyl anions allowed for nucleophilic activation of a large variety of small molecules and formation of elusive transition-metal complexes. By contrast, an accessible cationic, low-valent aluminium compound combining the nucleophilicity of low-valent compounds with the electrophilicity of aluminium is hitherto unknown. Here, we report the synthesis of [Al(AlCp*)3]+[Al(ORF)4]– (RF = C(CF3)3) via a simple metathesis route. Unexpectedly, the complex ion forms a dimer in the solid state and in concentrated solutions. Addition of Lewis bases results in monomerization and coordination to the unique formal Al+ atom giving [(L)xAl(AlCp*)3]+ salts with L = hexaphenylcarbodiphosporane (cdp; x = 1), tetramethylethylenediamine (tmeda; x = 1) and 4-dimethylamino-pyridine (dmap; x = 3). Depending on the donor strength of the ligand added, the Al+–AlCp* bonds in the [(L)xAl(AlCp*)3]+ cluster cations can be finely tuned between very strong (L = nothing) to very weak and approaching isolated [Al(L)3]+ ions (L = dmap). We anticipate our easily accessible low-valent aluminium cation salts to be the starting point for investigation and potential application of this unusual compound class. In particular, the ambiphilic reactivity of the cationic, low-valent compounds will be studied. Moreover, knowledge gained from the stabilization of the reported complex salts is expected to facilitate the isolation and application of novel cationic, low-valent Al complexes.