Cutaneous squamous cell carcinoma (SCC) and the DNA damage response: pATM expression patterns in pre-malignant and malignant keratinocyte skin lesions

Recent evidence suggests that an initial barrier to the emergence of tumours is a DNA damage response that evokes a counter-response which arrests the growth of, or eliminates, damaged cells. Early precursor lesions express markers of an activated DNA damage response in several types of tumour, with a diminishing response in more advanced cancers. An important marker of DNA damage is ATM which becomes phosphorylated (pATM) upon activation. We have investigated pATM expression patterns in cultured keratinocytes, skin explants and a spectrum of pre-malignant to malignant keratinocyte skin lesions by immunohistochemistry. We found that pATM was mainly localised to the Golgi apparatus, which contrasts with its nuclear localisation in other tissues. Upon UV irradiation there is transient formation of pATM in nuclear foci, consistent with recruitment to the sites of DNA damage. By immunohistochemistry we show pATM expression in precancerous keratinocyte lesions is greater and predominantly nuclear when compared to the invasive lesions where pATM is weaker and predominantly cytoplasmic. Our results are consistent with the hypothesis that the DNA damage response acts as a barrier to cutaneous tumour formation, but also suggests that ATM expression in skin is different compared to other tissues. This may be a consequence of the constant exposure of skin to UVR, and has implications for skin carcinogenesis.     

Anthocyanins Protect Against Ethanol-Induced Neuronal Apoptosis via GABAB1 Receptors Intracellular Signaling in Prenatal Rat Hippocampal Neurons

Here, we investigated the possible involvement of gamma-aminobutyric acid B1 receptor (GABA_B1R) in mediating the protective effects of black soybean anthocyanins against ethanol-induced apoptosis in prenatal hippocampal neurons because GABARs are known to play an important role in the development of central nervous system. Treatments were performed on primary cultures of prenatal rat hippocampal neurons transfected with or without GABA_B1R small interfering RNA (siRNA). The results showed that, when ethanol treatment was followed by anthocyanins treatment, cellular levels of proapoptotic proteins such as Bax, activated caspase-3, and cleaved poly (ADP-ribose) polymerase 1 (PARP-1) were decreased, and the cellular level of the antiapoptotic protein Bcl-2 was increased compared to treatment with ethanol alone. Furthermore, the effects of ethanol on cellular levels of GABA_B1R and its downstream signaling molecules such as protein kinase A, calcium/calmodulin-dependent protein kinase II (CaMKII), and phosphorylated cAMP response element binding protein were diminished or reversed by anthocyanins treatment. The ability of anthocyanins to reverse the effects of ethanol on cellular levels of Bax, Bcl-2, active caspase-3, cleaved PARP-1, GABA_B1R, and CaMKII were abrogated in cells transfected with GABA_B1R siRNA. In a GABA_B1R-dependent manner, anthocyanins also inhibited the ability of ethanol to elevate intracellular free Ca²⁺ level and increase the proportion of cells with low mitochondrial membrane potential in the population. Cell apoptosis assay and morphological studies also confirmed the neuroprotective effect of anthocyanins against ethanol via GABA_B1R. Our data suggest that GABA_B1R plays an important role in the neuroprotective effects of anthocyanins against ethanol.     

Mechanisms of β-adrenergic receptors agonists in mediating pro and anti-apoptotic pathways in hyperglycemic Müller cells

Molecular Biology Reports - The current study aimed to investigate the stimulatory effect of beta-adrenergic receptors (β-ARs) on brain derived neurotropic factor (BDNF) and cAMP response...     

Monoclonal antibodies as cancer therapeutics

Three main targets were subjected for the most approved monoclonal antibodies (mAbs) in cancer therapy: EGFR in solid cancer, the clusters of differentiation in blood cancer and VEGF in angiogenesis. Meanwhile side effects, the elevated costs and resistance problems are limiting the efficiency of mAbs as targeted therapy. The combinatory therapy with chemo or radiotherapy has improved the efficiency of mAbs. The present review aims to shed more light on the immunotherapy and the related patents that were developed for cancer treatment.     

Evaluation of irrigation effects using diluted salted water based on electrophysiological properties of plants

Effect of salt stress and subsequent re-watering on growth and electrophysiological characteristics of Orychophragmus violaceus and Brassica napus was investigated, to construct a model for prediction of an appropriate regime for dilution of saline water. Different concentrations of NaCl, Na₂SO₄ and blend of both salts were applied with Hoagland solution. Growth and electrophysiology traits were highly restricted at high concentration levels. According to the results, the best dilution point was 5–2.5% for NaCl and Na₂SO₄ alternatively, whereas it was 10–0.0% for blend of salts. After re-watering, O. violaceus restore better leaf tensity under medium levels, because the effect of NaCl concentration on leaf tensity (X_NC–LT) was 1.66%, which was lower in O. violaceus than the effect of X_NC–LT (2.88%) in B. napus, followed by the same trend for all treatments. Therefore, the effect of salinity in O. violaceus and B. napus may also be reduced effectively by dilution of saline irrigation.     

A PLETHORA/PIN-FORMED/auxin network mediates prehaustorium formation in the parasitic plant Striga hermonthica

The parasitic plant Striga (Striga hermonthica) invades the host root through the formation of a haustorium and has detrimental impacts on cereal crops. The haustorium results from the prehaustorium, which is derived directly from the differentiation of the Striga radicle. The molecular mechanisms leading to radicle differentiation shortly after germination remain unclear. In this study, we determined the developmental programs that regulate terminal prehaustorium formation in S. hermonthica at cellular resolution. We showed that shortly after germination, cells in the root meristem undergo multiplanar divisions. During growth, the meristematic activity declines and associates with reduced expression of the stem cell regulator PLETHORA1 and the cell cycle genes CYCLINB1 and HISTONE H4. We also observed a basal localization of the PIN-FORMED (PIN) proteins and a decrease in auxin levels in the meristem. Using the structural layout of the root meristem and the polarity of outer-membrane PIN proteins, we constructed a mathematical model of auxin transport that explains the auxin distribution patterns observed during S. hermonthica root growth. Our results reveal a fundamental molecular and cellular framework governing the switch of S. hermonthica roots to form the invasive prehaustoria.

The parasitic plant Striga hermonthica forms its invasive organ, the prehaustorium, by inducing differentiation of the radicle by arresting cell division.     

Leishmania infantum 5’-Methylthioadenosine Phosphorylase presents relevant structural divergence to constitute a potential drug target

Background

So far, little is known about the molecular mechanisms of amyotrophic lateral sclerosis onset and progression caused by SOD1 mutations. One of the hypotheses is based on SOD1 misfolding resulting from mutations and subsequent deposition of its cytotoxic aggregates. This hypothesis is complicated by the fact that known SOD1 mutations of similar clinical effect could be distributed over the whole protein structure.

Results

In this work, a measure of hydrogen bond stability in conformational states was studied with elastic network analysis of 35 SOD1 mutants. Twenty-eight hydrogen bonds were detected in nine of 35 mutants with their stability being significantly different from that with the wild-type. These hydrogen bonds were formed by the amino acid residues known from the literature to be located in contact between SOD1 aggregates. Additionally, residues disposed between copper binding sites of both protein subunits were found from the models to form a stiff core, which can be involved in mechanical impulse transduction between these active centres.

Conclusions

The modelling highlights that both stability of the copper binding site and stability of the dimer can play an important role in ALS progression.

     

Cross regulation between mTOR signaling and <Emphasis Type="Italic">O</Emphasis>-GlcNAcylation

The hexosamine biosynthetic pathway (HBP) integrates glucose, amino acids, fatty acids and nucleotides metabolisms for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP-GlcNAc is the nucleotide sugar donor for O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) processes. O-GlcNAc transferase (OGT) is the enzyme which transfers the N-acetylglucosamine (O-GlcNAc) residue onto target proteins. Several studies previously showed that glucose metabolism dysregulations associated with obesity, diabetes or cancer correlated with an increase of OGT expression and global O-GlcNAcylation levels. Moreover, these diseases present an increased activation of the nutrient sensing mammalian target of rapamycin (mTOR) pathway. Other works demonstrate that mTOR regulates protein O-GlcNAcylation in cancer cells through stabilization of OGT. In this context, we studied the cross-talk between these two metabolic sensors in vivo in obese mice predisposed to diabetes and in vitro in normal and colon cancer cells. We report that levels of OGT and O-GlcNAcylation are increased in obese mice colon tissues and colon cancer cells and are associated with a higher activation of mTOR signaling. In parallel, treatments with mTOR regulators modulate OGT and O-GlcNAcylation levels in both normal and colon cancer cells. However, deregulation of O-GlcNAcylation affects mTOR signaling activation only in cancer cells. Thus, a crosstalk exists between O-GlcNAcylation and mTOR signaling in contexts of metabolism dysregulation associated to obesity or cancer.     

Treatment of acute myocardial infarction with anisoylated plasminogen streptokinase activator complex.

A controlled trial in 149 patients admitted to a district hospital with probable myocardial infarction tested the effect of 30 units of anisoylated plasminogen streptokinase activator complex (APSAC) on indices of infarct size. Patients were grouped prospectively according to whether they entered the trial within two and a half hours (early entry) or between two and a half and four hours (late entry) after onset of the symptoms. Sixty seven of 73 patients in the control group showed increased plasma activity of myocardial creatine kinase isoenzyme that was diagnostic of infarction compared with only 60 of 76 who received APSAC. The difference was significant overall but occurred predominantly in the early entry group. The patients who received APSAC had more early ventricular arrhythmias, compatible with reperfusion, and showed greater preservation of R waves during admission to hospital. Unwanted effects were generally minor and more common in the actively managed group than the control group (26% v 3%). After nine to 12 months of follow up 12 patients in the control group had died compared with seven in the actively managed group. The ease of administration and the apparent efficacy of APSAC suggest that it is suitable for use in a district hospital for patients with suspected acute myocardial infarction.