HLDF-6 peptides exhibit neuroprotective effects in the experimental model of preclinical Parkinson's disease.

The mechanisms of the neuroprotective action of the hexapeptides HLDF-6 encoded by the amino acid sequence 41-46 of Human Leukemia Differentiation Factor and its homoserine derivative HLDF-6H were studied in an experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of Parkinson's disease (PD). C57Bl/6 mice received two intraperitoneal injections of 18 mg/kg MPTP-HCl, with an interval of 2 hours. MPTP-induced motor dysfunction was assessed using horizontal grid test.

Upregulation of PARG in prostate cancer cells suppresses their malignant behavior and downregulates tumor-promoting genes.

Post-translational modification of nuclear proteins through the addition of poly(ADP-ribose) (pADPr) moieties is upregulated in many metastatic cancers, where the high levels of pADPr have often been associated with poor cancer prognosis. Although the inhibitors of poly(ADP-ribose) polymerases (PARPs) have been utilized as potent anti-cancer agents, their efficacy in clinical trials varied among patient groups and has often been unpredictable. Such outcome cannot be interpreted solely by the inability to keep PARP-driven DNA repair in check.

PARG suppresses tumorigenesis and downregulates genes controlling angiogenesis, inflammatory response, and immune cell recruitment.

Chemokines are highly expressed in tumor microenvironment and play a critical role in all aspects of tumorigenesis, including the recruitment of tumor-promoting immune cells, activation of cancer-associated fibroblasts, angiogenesis, metastasis, and growth. Poly (ADP-ribose) polymerase (PARP) is a multi-target transcription regulator with high levels of poly(ADP-ribose) (pADPr) being reported in a variety of cancers. Furthermore, poly (ADP-ribose) glycohydrolase (PARG), an enzyme that degrades pADPr, has been reported to be downregulated in tumor tissues with abnormally high levels of pADPr.

Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy.

Poly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have shown that the development of clear cell renal cell carcinoma (ccRCC) is associated with extreme accumulation of pADPr caused by the enhanced expression of PARP-1 and decreased PARG levels.

The pentatricopeptide repeat protein Rmd9 recognizes the dodecameric element in the 3'-UTRs of yeast mitochondrial mRNAs.

Stabilization of messenger RNA is an important step in posttranscriptional gene regulation. In the nucleus and cytoplasm of eukaryotic cells it is generally achieved by 5' capping and 3' polyadenylation, whereas additional mechanisms exist in bacteria and organelles. The mitochondrial mRNAs in the yeast comprise a dodecamer sequence element that confers RNA stability and 3'-end processing via an unknown mechanism.

Human Melanocyte-Derived Spheroids: A Precise Test System for Drug Screening and a Multicellular Unit for Tissue Engineering.

Pigmentation is the result of melanin synthesis, which takes place in melanocytes, and its further distribution. A dysregulation in melanocytes' functionality can result in the loss of pigmentation, the appearance of pigment spots and melanoma development. Tissue engineering and the screening of new skin-lightening drugs require the development of simple and reproducible models with maintained functional activity.

Yeast DEAD box protein Mss116p is a transcription elongation factor that modulates the activity of mitochondrial RNA polymerase.

DEAD box proteins have been widely implicated in regulation of gene expression. Here, we show that the yeast Saccharomyces cerevisiae DEAD box protein Mss116p, previously known as a mitochondrial splicing factor, also acts as a transcription factor that modulates the activity of the single-subunit mitochondrial RNA polymerase encoded by RPO41. Binding of Mss116p stabilizes paused mitochondrial RNA polymerase elongation complexes in vitro and favors the posttranslocated state of the enzyme, resulting in a lower concentration of nucleotide substrate required to escape the pause; this mechanism of action is similar to that of elongation factors that enhance the processivity of multisubunit RNA polymerases.

Identification of proteins associated with the yeast mitochondrial RNA polymerase by tandem affinity purification.

The abundance of mitochondrial (mt) transcripts varies under different conditions, and is thought to depend upon rates of transcription initiation, transcription termination/attenuation and RNA processing/degradation. The requirement to maintain the balance between RNA synthesis and processing may involve coordination between these processes; however, little is known about factors that regulate the activity of mtRNA polymerase (mtRNAP). Recent attempts to identify mtRNAP-protein interactions in yeast by means of a generalized tandem affinity purification (TAP) protocol were not successful, most likely because they involved a C-terminal mtRNAP-TAP fusion (which is incompatible with mtRNAP function) and because of the use of whole-cell solubilization protocols that did not preserve the integrity of mt protein complexes.

Secretory vesicle rebound hyperacidification and increased quantal size resulting from prolonged methamphetamine exposure.

Acute exposure to amphetamines (AMPHs) collapses secretory vesicle pH gradients, which increases cytosolic catecholamine levels while decreasing the quantal size of catecholamine release during fusion events. AMPH and methamphetamine (METH), however, are retained in tissues over long durations. We used optical and electron microscopic probes to measure the effects of long-term METH exposure on secretory vesicle pH, and amperometry and intracellular patch electrochemistry to observe the effects on neurosecretion and cytosolic catecholamines in cultured rat chromaffin cells.

Alpha-synuclein overexpression increases cytosolic catecholamine concentration.

Dysregulation of dopamine homeostasis and elevation of the cytosolic level of the transmitter have been suggested to underlie the vulnerability of catecholaminergic neurons in Parkinson's disease. Because several known mutations in alpha-synuclein or overexpression of the wild-type (WT) protein causes familial forms of Parkinson's disease, we investigated possible links between alpha-synuclein pathogenesis and dopamine homeostasis. Chromaffin cells isolated from transgenic mice that overexpress A30P alpha-synuclein displayed significantly increased cytosolic catecholamine levels as measured by intracellular patch electrochemistry, whereas cells overexpressing the WT protein and those from knock-out animals were not different from controls.