Effect of fluorine position on the coordinating ability of fluorosalicylic acids--an experimental study complemented with computations

The complexation of 3-, 4-, and 6-fluorosalicylic acids (HL) with copper(II) was investigated in aqueous solution by pH-potentiometry combined with UV-visible spectrophotometry, and in 50 v/v % water-methanol mixture by the two-dimensional ESR simulation method. Both methods showed the formation of [CuLH₋₁] and [CuL₂H₋₂]²⁻ of high stabilities, and, at low excess of ligand, the ESR-silent mixed hydroxido complex [Cu₂L₂H₋₃]⁻. Further species were also identified by the two-dimensional ESR simulation method: [CuL]⁺ in the acidic region, the minor dimer [Cu₂L₂H₋₂], and the cis and the trans isomers for [CuL₂H₋₂]²⁻. The position of the fluorine atom in the aromatic ring had significant effect on the coordination abilities of the ligands, in good correlation with their reported biological activities. It was 3-fluorosalicylic acid, which formed the most stable complexes [CuLH₋₁] and [CuL₂H₋₂]²⁻, while the mononuclear complexes with 6-fluorosalicylic acid were found to be the least stable. For the other ligands (including 5-fluorosalicylic acid studied recently), complexes of medium stabilities were formed. For the interpretation of these findings, ab initio and semi-empirical quantum chemical calculations were carried out for the ligand molecules, isolated and surrounded by water molecules, respectively.     

The physiological response of larval <Emphasis Type="Italic">Chironomus riparius</Emphasis> (Meigen) to abrupt brackish water exposure

The physiological response of larval Chironomus riparius was examined following direct transfer from freshwater (FW) to brackish water (BW; 20% seawater). Endpoints of hydromineral status (hemolymph Na⁺, Cl⁻, and K⁺ levels, hemolymph pH, body water content, and whole body Na⁺/K⁺-ATPase and V-type H⁺-ATPase activity) were examined 1, 3, 5, 12 and 24 h following BW transfer. Larvae transferred from FW to FW served as a control. Hemolymph Na⁺ and Cl⁻ levels increased following BW transfer. Hemolymph pH was initially regulated, but significantly decreased after 24 h in BW. Changes in hemolymph ions were not caused by osmotic loss of water from the hemolymph, since larvae tightly regulated total body moisture content. Furthermore, salinity did not affect hemolymph K⁺. When larvae were transferred to BW, Na⁺/K⁺-ATPase (NKA) activity did not significantly alter relative to FW control animals. In contrast, V-type H⁺-ATPase (VA) activity in C. riparius significantly decreased in BW. In FW-reared C. riparius, whole body NKA and VA activities were equivalent. However, in the isolated gut with intact Malpighian tubules of FW-reared C. riparius, VA activity was significantly greater than whole body while NKA activity was equivalent. This suggested that gut and/or Malpighian tubule VA activity contributes significantly to whole body VA activity and that a decline in whole body VA activity in BW may be closely linked to alterations in the physiology of gut and Malpighian tubule tissue. Taken together, data indicate that VA is important for ion uptake in FW and that the NKA does not play a major role in regulating ion homeostasis when larvae are acutely exposed to BW.     

Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci

BMI1 is required for the self-renewal of stem cells in many tissues including the lung epithelial stem cells, Bronchioalveolar Stem Cells (BASCs). Imprinted genes, which exhibit expression from only the maternally or paternally inherited allele, are known to regulate developmental processes, but what their role is in adult cells remains a fundamental question. Many imprinted genes were derepressed in Bmi1 knockout mice, and knockdown of Cdkn1c (p57) and other imprinted genes partially rescued the self-renewal defect of Bmi1 mutant lung cells. Expression of p57 and other imprinted genes was required for lung cell self-renewal in culture and correlated with repair of lung epithelial cell injury in vivo. Our data suggest that BMI1-dependent regulation of expressed alleles at imprinted loci, distinct from imprinting per se, is required for control of lung stem cells. We anticipate that the regulation and function of imprinted genes is crucial for self-renewal in diverse adult tissue-specific stem cells.     

Expression and one step intein-mediated purification of biologically active human G-CSF in Escherichia coli

Molecular Biology Reports - Recombinant form of granulocyte colony stimulating factor (G-CSF) was first approved by FDA in 1998 for chemotherapy induced neutropenia. However, despite production of...     

Determining the interaction behavior of calf thymus DNA with berberine hydrochloride in the presence of linker histone: a biophysical study

Abstract

The binding of small molecules with histone-DNA complexes can cause an interference in vital cellular processes such as cell division and the growth of cancerous cells that results in apoptosis. It is significant to study the interaction of small molecules with histone-DNA complex for the purpose of better understanding their mechanism of action, as well as designing novel and more effective drug compounds. The fluorescence quenching of ct-DNA upon interaction with Berberine has determined the binding of Berberine to ct-DNA with K_sv?=?9.46?×?10⁷ M^?1. K_sv value of ct-DNA-Berberine in the presence of H1 has been observed to be 3.10?×?10⁷ M^?1, indicating that the H1 has caused a reduction in the binding affinity of Berberine to ct-DNA. In the competitive emission spectrum, ethidium bromide (EB) and acridine orange (AO) have been examined as intercalators through the addition of Berberine to ct-DNA complexes, which includes ctDNA-EB and ctDNA-AO. Although in the presence of histone H1 , we have observed signs of competition through the induced changes within the emission spectra, yet there has been apparently no competition between the ligands and probes. The viscosity results have confirmed the different behaviors of interaction between ctDNA and Berberine throughout the binary and ternary systems. We have figured out the IC50 and viability percent values at three different time durations of interaction between Berberine and MCF7 cell line. The molecular experiments have been completed by achieving the results of MTT assay, which have been confirmed to be in good agreement with molecular modeling studies.

Communicated by Ramaswamy H. Sarma     

New Engineered Fusion Peptide with Dual Functionality: Antibacterial and Strong Binding to Hydroxyapatite

International Journal of Peptide Research and Therapeutics - One of the main challenges in oral disease is prevention of bacterial infections considering antibiotic resistance as a result of...     

Markers of T Cell Infiltration and Function Associate with Favorable Outcome in Vascularized High-Grade Serous Ovarian Carcinoma

Background

When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL) could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer.

Methodology and Principal Findings

In 196 high-grade serous ovarian tumors, we confirmed that the tumor vascularity as measured by the marker CD31 was associated with improved patient disease-specific survival. We also found that tumors positive for markers of TIL (CD8, CD4 and forkhead box P3 (FoxP3)) and T cell function (granzyme B and T-cell restricted intracellular antigen-1 (TIA-1)) correlated significantly with elevated vascularity. In vitro, hypoxic CD8 T cells showed reduced cytolytic activity, secreted less effector cytokines and upregulated autophagy. Survival analysis revealed that patients had a significant improvement in disease-specific survival when FoxP3 expressing cells were present in CD31-high tumors compared to patients with FoxP3 expressing cells in CD31-low tumors [HR: 2.314 (95% CI 1.049–5.106); p = 0.0377]. Patients with high vascular endothelial growth factor (VEGF) expressing tumors containing granzyme B positive cells had improved survival compared to patients with granzyme B positive cells in VEGF-low tumors [HR: 2.522 (95% CI 1.097–5.799); p = 0.0294].

Significance

Overall, this data provides a rationale for developing strategies aimed at improving the adaptability and function of TIL to hypoxic tumor conditions.     

RASopathic Skin Eruptions during Vemurafenib Therapy

Purpose

Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.

Patients and Methods

Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.

Results

Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).

Conclusion

Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.