Antileishmanial metallodrugs and the elucidation of new drug targets linked to post-translational modifications machinery: pitfalls and progress

Despite the increasing number of manuscripts describing potential alternative antileishmanial compounds, little is advancing on translating these knowledges to new products to treat leishmaniasis. This is in part due to the lack of standardisations during pre-clinical drug discovery stage and also depends on the alignment of goals among universities/research centers, government and pharmaceutical industry. Inspired or not by drug repurposing, metal-based antileishmanial drugs represent a class that deserves more attention on its use for leishmaniasis chemotherapy. Together with new chemical entities, progresses have been made on the knowledge of parasite-specific drug targets specially after using CRISPR/Cas system for functional studies. In this regard, Leishmania parasites undergoe post-translational modification as key regulators in several cellular processes, which represents an entire new field for drug target elucidation, once this is poorly explored. This perspective review describes the advances on antileishmanial metallodrugs and the elucidation of drug targets based on post-translational modifications, highlighting the limitations on the drug discovery/development process and suggesting standardisations focused on products addressed to who need it most.

Evaluation of post-translational modifications in histone proteins: A review on histone modification defects in developmental and neurological disorders

Post-translational modification (PTM) in histone proteins is a covalent modification which mainly consists ofmethylation, phosphorylation, acetylation, ubiquitylation, SUMOylation, glycosylation, and ADP-ribosylation.PTMs have fundamental roles in chromatin structure and function. Histone modifications have also beenknown as epigenetic markers. The PTMs that have taken place in histone proteins can affect gene expressionby altering chromatin structure. Histone modifications act in varied biological processes such as transcriptionalactivation/inactivation, chromosome packaging, mitosis, meiosis, apoptosis, and DNA damage/repair. Defectsin the PTMs pathway have been associated with the occurrence and progression of various human diseases,such as cancer, heart failure, autoimmune diseases, and neurodegenerative disorders such as Parkinson’sdisease, Alzheimer’s disease, and Huntington’s disease. Histone modifications are reversible and used aspotential targets for cancer therapy and prevention. Recent different histone PTMs have key roles in cancercells since it has been shown that histone PTMs markers in cancers are acetylation, methylation, phosphorylation, and ubiquitylation. In this review, we have summarized the six most studied histone modifications andhave examined the role of these modifications in the development of cancer.

Elucidation and genetic intervention of CO2 concentration mechanism in Chlamydomonas reinhardtii for increased plant primary productivity

Post-translational modification (PTM) in histone proteins is a covalent modification which mainly consists ofmethylation, phosphorylation, acetylation, ubiquitylation, SUMOylation, glycosylation, and ADP-ribosylation.PTMs have fundamental roles in chromatin structure and function. Histone modifications have also beenknown as epigenetic markers. The PTMs that have taken place in histone proteins can affect gene expressionby altering chromatin structure. Histone modifications act in varied biological processes such as transcriptionalactivation/inactivation, chromosome packaging, mitosis, meiosis, apoptosis, and DNA damage/repair. Defectsin the PTMs pathway have been associated with the occurrence and progression of various human diseases,such as cancer, heart failure, autoimmune diseases, and neurodegenerative disorders such as Parkinson’sdisease, Alzheimer’s disease, and Huntington’s disease. Histone modifications are reversible and used aspotential targets for cancer therapy and prevention. Recent different histone PTMs have key roles in cancercells since it has been shown that histone PTMs markers in cancers are acetylation, methylation, phosphorylation, and ubiquitylation. In this review, we have summarized the six most studied histone modifications andhave examined the role of these modifications in the development of cancer.

Oxidative Stress Modulates the Expression Pattern of Peroxiredoxin-6 in Peripheral Blood Mononuclear Cells of Asthmatic Patients and Bronchial Epithelial Cells

PURPOSE: Reduction-oxidation reaction homeostasis is vital for regulating inflammatory conditions and its dysregulation may affect the pathogenesis of chronic airway inflammatory diseases such as asthma. Peroxiredoxin-6, an important intracellular anti-oxidant molecule, is reported to be highly expressed in the airways and lungs. The aim of this study was to analyze the expression pattern of peroxiredoxin-6 in the peripheral blood mononuclear cells (PBMCs) of asthmatic patients and in bronchial epithelial cells (BECs).METHODS: The expression levels and modifications of peroxiredoxin-6 were evaluated in PBMCs from 22 asthmatic patients. Phosphorylated and acetylated peroxiredoxin-6 in hydrogen peroxide-treated human BECs was detected using immunoprecipitation analysis. The expression level of peroxiredoxin-6 was also investigated in BECs treated with hydrogen peroxide. Cycloheximide and proteasome inhibitors were used to determine whether peroxiredoxin-6 is degraded by proteasomes.RESULTS: Peroxiredoxin-6 expression was significantly reduced in the PBMCs of asthmatic patients compared to control subjects. Distinct modification patterns for peroxiredoxin-6 were observed in the PBMCs of asthmatic patients using 2-dimensional-electrophoresis. The levels of phosphorylated serine and acetylated lysine in peroxiredoxin-6 were significantly increased in the BECs following hydrogen peroxide treatment. The level of peroxiredoxin-6 expression was reduced in hydrogen peroxide-stimulated BECs, presumably due to proteasomes.CONCLUSIONS: The expression of peroxiredoxin-6, which is down-regulated in the immune cells of asthmatic patients and BECs, can be modified by oxidative stress. This phenomenon may have an effect on asthmatic airway inflammation.

Advances in Post-translational Modifications and Endometriosis / 中国医学科学院学报

Proteins exert their roles in life activities via post-translational modifications(PTMs),which include phosphorylation,acetylation,ubiquitination,glycosylation,and methylation.These modifications can change the functions of proteins and play key roles in a variety of diseases.Endometriosis is a common disease in women of childbearing age,although its molecular mechanisms remain unclear.Recent studies have shown that PTMs may be involved in the pathogenesis of endometriosis.Here we review the roles of PTMs in the occurrence and development of endometriosis and the potential medical treatments.

Post-translational modifications of proteins and cancer immunotherapy / 药学学报

Post-translational modifications (PTMs) of proteins is an important mode of protein function regulation, which is essential for the structure and function of proteins under physiological and pathological conditions, and the types of modifications is wide. Cancer immunotherapy refers to an effective method for cancer treatment by activating or normalizing disabled immune cells. In recent years, researchers have found that many types of PTM are involved in the process of proliferation, activation and metabolic reprogramming of immune cells in cancer microenvironment, and may affect the efficacy of cancer immunotherapy. Therefore, this article reviews the effects of several different PTMs on immune cells in cancer microenvironment, and aims to provide new ideas for cancer immunotherapy.

Genomic comparisons of Rhizobium species using in silico AFLP-PCR, endonuclease restriction, and AMPylating enzymes

Background: The whole-genome sequences of nine Rhizobium species were evaluated using different in silico molecular techniques such as AFLP-PCR, restriction digest, and AMPylating enzymes. The entire genome sequences were aligned with progressiveMauve and visualized by reconstructing phylogenetic tree using NTSYS pc 2.11X. The "insilico.ehu.es" was used to carry out in silico AFLP-PCR and in silico restriction digest of the selected genomes. Post-translational modification (PTM) and AMPylating enzyme diversity between the proteome of Rhizobium species were determined by novPTMenzy. Results: Slight variations were observed in the phylogeny based on AFLP-PCR and PFGE and the tree based on whole genome. Results clearly demonstrated the presence of PTMs, i.e., AMPylation with the GS-ATasE (GlnE), Hydroxylation, Sulfation with their domain, and Deamidation with their specific domains (AMPylating enzymes) GS-ATasE (GlnE), Fic, and Doc (Phosphorylation); Asparagine_hydroxylase and Collagen_prolyl_lysyl_hydroxylase; Sulfotransferase; and CNF (Cytotoxic Necrotizing Factors), respectively. The results pertaining to PTMs are discussed with regard to functional diversities reported in these species. Conclusions: The phylogenetic tree based on AFLP-PCR was slightly different from restriction endonuclease- and PFGE-based trees. Different PTMs were observed in the Rhizobium species, and the most prevailing type of PTM was AMPylation with the domain GS-ATasE (GlnE). Another type of PTM was also observed, i.e., Hydroxylation and Sulfation, with the domains Asparagine_hydroxylase and Collagen_prolyl_lysyl_hydroxylase and Sulfotransferase, respectively. The deamidation type of PTM was present only in Rhizobium sp. NGR234. How to cite: Qureshi MA, Pervez MT, Babar ME, et al. Genomic comparisons of Rhizobium species using in silico AFLP-PCR, endonuclease restrictions and ampylating enzymes.

Application and development of spectral network cluster method in post-translational modifications of identification peptides / 生物工程学报

Mass spectrometry and database searching are necessary to identify proteins and peptides. With the rapid development of mass spectrometry technology, mass spectrometry data in proteomics are acquired very quickly, providing a powerful method to identify large-scale proteins and peptides, making mass spectrometry data-based proteomics research more and more into the mainstream. The traditional database searching method has many limitations to identify post-translational modifications of peptides. This paper systematically reviews the development, theoretical concept and applications of spectral network method, and the advantages of spectral network library to identify peptides.

Mechanism of migration and release of high mobility group box-1 / 中南大学学报(医学版)

High mobility group box-1 (HMGB1) is an evolutionarily conserved protein,which widely exists in mammals.HMGB 1 contains the nucleus localization sequences.Intracellular and extracellular HMGB1 shows different biological functions.Extracellular HMGB1 is closely related to sepsis,cancer,rheumatoid immune,atherosclerosis,ischemia-reperfusion injury and so on.The mobilization of HMGB 1 from the nucleus to the cytoplasm and subsequent release involves the processes of post-translation modification,active secretion and nuclear localization.

Post-Translational Modifications of Cardiac Mitochondrial Proteins in Cardiovascular Disease: Not Lost in Translation

Protein post-translational modifications (PTMs) are crucial in regulating cellular biology by playing key roles in processes such as the rapid on and off switching of signaling network and the regulation of enzymatic activities without affecting gene expressions. PTMs lead to conformational changes in the tertiary structure of protein and resultant regulation of protein function such as activation, inhibition, or signaling roles. PTMs such as phosphorylation, acetylation, and S-nitrosylation of specific sites in proteins have key roles in regulation of mitochondrial functions, thereby contributing to the progression to heart failure. Despite the extensive study of PTMs in mitochondrial proteins much remains unclear. Further research is yet to be undertaken to elucidate how changes in the proteins may lead to cardiovascular and metabolic disease progression in particular. We aimed to summarize the various types of PTMs that occur in mitochondrial proteins, which might be associated with heart failure. This study will increase the understanding of cardiovascular diseases through PTM.

Modulation of the Transcriptional Activity of Peroxisome Proliferator-Activated Receptor Gamma by Protein-Protein Interactions and Post-Translational Modifications

Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a nuclear receptor superfamily; members of which play key roles in the control of body metabolism principally by acting on adipose tissue. Ligands of PPARgamma, such as thiazolidinediones, are widely used in the treatment of metabolic syndromes and type 2 diabetes mellitus (T2DM). Although these drugs have potential benefits in the treatment of T2DM, they also cause unwanted side effects. Thus, understanding the molecular mechanisms governing the transcriptional activity of PPARgamma is of prime importance in the development of new selective drugs or drugs with fewer side effects. Recent advancements in molecular biology have made it possible to obtain a deeper understanding of the role of PPARgamma in body homeostasis. The transcriptional activity of PPARgamma is subject to regulation either by interacting proteins or by modification of the protein itself. New interacting partners of PPARgamma with new functions are being unveiled. In addition, post-translational modification by various cellular signals contributes to fine-tuning of the transcriptional activities of PPARgamma. In this review, we will summarize recent advancements in our understanding of the post-translational modifications of, and proteins interacting with, PPARgamma, both of which affect its transcriptional activities in relation to adipogenesis.

Advances in Research on Sumoylation of Breast Cancer-Related Proteins / 中国实验动物学报

Small ubiquitin-like modifiers (SUMO) are a family of proteins that modulate important functional properties,including protein interaction,subcellular localization,protein dimerization,DNA binding and/or transactivation of transcription factors.It has been suggested that SUMO proteins may play an important role in breast carcinogenesis by sumoylation of estrogen signaling proteins such as co-regulators,and breast cancer-related proteins.

Molecular structure and regulate mechanisms of the peptidyl prolyl cis/trans isomerase Pin1 / 医学研究生学报

The peptidyl prolyl cis/trans isomerase Pin1 specifically binds phosphorylated Ser/Thr-Pro protein motifs and catalyzes the cis/trans isomerization of the peptide bond,changes the conformation and influences the stability and activity of the substrates.To date,a subset of proteins has been identified as substrates for Pin1.Pin1 interacts with its substrates and plays crucial roles in cell cycle,neural pathology and immune response.Accumulating studies have revealed that Pin1 isomerase activity is regulated by its post-translational modifications,including phosphorylation and oxidation.Over-expression or regulative imbalance of Pin1 plays an important role in the pathogenesis and therapeutics of human diseases such as cancer and AD.