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Fulltext In silico identification of novel tuberculosis drug targets in mycobacterium tuberculosis P450 enzymes by interaction study with azole drugs

Suresh Kumar

Malaysian Journal of Medicine and Health Sciences, 2020;16(101):24-30.
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Introduction: Tuberculosis (TB) is one of the utmost serious infectious diseases worldwide. The emergence of multi- drug resistance demands the development of better or new putative drug targets for tuberculosis. Recent studies sug- gest Mycobacterium tuberculosis cytochrome P450 enzymes as promising drug targets and azole drugs as potential inhibitors. Methods: Various computational tools, like Expasy Protparam, Swiss model, RaptorX and Phyre2 were used to analyze 12 Mycobacterium tuberculosis P450 enzymes and determine their three-dimensional structure. The structural validation was done through a Ramachandran plot using RAMPAGE server. The docking of P450 enzymes with azole drugs was done with autodock ver 4.2.6. Results: Based on sub-cellular localization prediction using CEL- LO tool, P450 enzymes CYP123A1, CYP132A1, CYP135A1, CYP136A1, CYP140A1, and CYP143A1 were predicted to be in the cytoplasm. Through structure assessment by Ramachandran plot, the best homology modelled proteins were docked with azole drugs like clotrimazole, croconazole, econazole, fluconazole, itraconazole, itraconazole, ketaconazole and micronazole by using autodock. By docking method it is identified that ketaconazole drug has a high affinity towards most of the mycobacterium P450 enzymes followed by the itrconazole drug. CYP123A1 enzyme is preferable as a drug target due to high binding affinity towards ketoconazole followed by CYP135A1, CYP140A1 enzymes. Conclusion: This study would help in identifying putative novel drug targets in Mycobacterium tuberculosis, which can lead to promising candidates for the optimization and development of novel anti-mycobac- terial agents.

Matched MeSH terms: Cytoplasm
LC-MS analysis reveals biological and metabolic processes essential for Candida albicans biofilm growth

Munusamy K, Loke MF, Vadivelu J, Tay ST

Microb Pathog, 2021 Mar;152:104614.
PMID: 33202254 DOI: 10.1016/j.micpath.2020.104614

Candidiasis is the most common fungal infection associated with high morbidity and mortality among immunocompromised patients. The ability to form biofilm is essential for Candida albicans pathogenesis and drug resistance. In this study, the planktonic cell and biofilm proteomes of C. albicans SC5314 strain analyzed using Liquid Chromatography-Mass Spectrometry (LC-MS) were compared. In total, 280 and 449 proteins are annotated from the planktonic cell and biofilm proteomes, respectively. The biofilm proteome demonstrated significantly higher proportion of proteins associated with the endomembrane system, mitochondrion and cytoplasm than planktonic proteome. Among proteins detected, 143 and 207 biological processes are annotated, of which, 38 and 102 are specific to the planktonic cell and biofilm proteomes, respectively, while 105 are common biological processes. The specific biological processes of C. albicans planktonic cell proteome are associated with cell polarity, energy metabolism and nucleotide (purine) metabolism, oxido-reduction coenzyme metabolic process, monosaccharide and amino acid (methionine) biosynthesis, regulation of anatomical structure morphogenesis and cell cycling, and single organism reproduction. Meanwhile, regulation of cellular macromolecule biosynthesis and metabolism, transcription and gene expression are major biological processes specifically associated with C. albicans biofilm proteome. Biosynthesis of leucine, isoleucine, and thiocysteine are highlighted as planktonic-related pathways, whereas folate metabolism, fatty acid metabolism and biosynthesis of amino acids (lysine, serine and glycine) are highlighted as biofilm-related pathways. In summary, LC-MS-based proteomic analysis reveals different adaptative strategies of C. albicans via specific biological and metabolic processes for planktonic cell and biofilm lifestyles. The mass spectrometry data are available via ProteomeXchange with identifiers PXD007830 (for biofilm proteome) and PXD007831 (for planktonic cell proteome).

Matched MeSH terms: Cytoplasm
Hedgehog signalling molecule, SMO is a poor prognostic marker in bladder cancer

Mohd Ariffin K, Abd Ghani F, Hussin H, Md Said S, Yunus R, Veerakumarasivam A, et al.

Malays J Pathol, 2021 Apr;43(1):49-54.
PMID: 33903305

INTRODUCTION: Hedgehog (HH) pathway is an important signalling cascade for growth and patterning during embryonic development. Constitutive activation of Hedgehog pathway can be found in various types of malignancies including medulloblastoma, basal cell carcinoma, gastrointestinal, breast, pancreatic, prostate cancer and leukaemia. Little is known about the expression and role of Hedgehog signalling in bladder cancer.
MATERIALS AND METHODS: The purpose of this study was to investigate the immunohistochemical expression of SMO in 112 bladder cancer cases and determine their association with demographic and clinicopathological parameters. Bladder cancer tissues were obtained from the Hospital Kuala Lumpur.
RESULTS: SMO was expressed in the cytoplasm of all cases of bladder cancer. 6 cases (5.4%) showed low expression, while 106 cases (94.6%) showed high expression. Positive expression of SMO protein was correlated with a few variables which include grade and stage of tumour, lymph node metastasis and distant metastasis. SMO expression showed statistically significant association with higher grade (p=0.001) and higher stage (p=0.042) of bladder cancer. SMO expression also showed borderline association with lymph node metastasis (p=0.056).
CONCLUSION: These findings indicate that SMO expression may be a poor prognostic marker in bladder cancer.

Matched MeSH terms: Cytoplasm
Fulltext The Cytoplasmic Actins in the Regulation of Endothelial Cell Function

Dugina VB, Shagieva GS, Shakhov AS, Alieva IB

Int J Mol Sci, 2021 Jul 22;22(15).
PMID: 34360602 DOI: 10.3390/ijms22157836

The primary function of the endothelial cells (EC) lining the inner surface of all vessels is to regulate permeability of vascular walls and to control exchange between circulating blood and tissue fluids of organs. The EC actin cytoskeleton plays a crucial role in maintaining endothelial barrier function. Actin cytoskeleton reorganization result in EC contraction and provides a structural basis for the increase in vascular permeability, which is typical for many diseases. Actin cytoskeleton in non-muscle cells presented two actin isoforms: non-muscle β-cytoplasmic and γ-cytoplasmic actins (β-actins and γ-actins), which are encoded by ACTB and ACTG1 genes, respectively. They are ubiquitously expressed in the different cells in vivo and in vitro and the β/γ-actin ratio depends on the cell type. Both cytoplasmic actins are essential for cell survival, but they perform various functions in the interphase and cell division and play different roles in neoplastic transformation. In this review, we briefly summarize the research results of recent years and consider the features of the cytoplasmic actins: The spatial organization in close connection with their functional activity in different cell types by focusing on endothelial cells.

Matched MeSH terms: Cytoplasm/metabolism*
Fulltext Development of a 3D Tumor Spheroid Model from the Patient's Glioblastoma Cells and Its Study by Metabolic Fluorescence Lifetime Imaging

Yuzhakova DV, Lukina MM, Sachkova DA, Yusubalieva GM, Baklaushev VP, Mozherov AM, et al.

Sovrem Tekhnologii Med, 2023;15(2):28-38.
PMID: 37389023 DOI: 10.17691/stm2023.15.2.03

Patient-specific in vitro tumor models are a promising platform for studying the mechanisms of oncogenesis and personalized selection of drugs. In case of glial brain tumors, development and use of such models is particularly relevant as the effectiveness of such tumor treatment remains extremely unsatisfactory. The aim of the study was to develop a model of a 3D tumor glioblastoma spheroid based on a patient's surgical material and to study its metabolic characteristics by means of fluorescence lifetime imaging microscopy of metabolic coenzymes.
MATERIALS AND METHODS: The study was conducted with tumor samples from patients diagnosed with glioblastoma (Grade IV). To create spheroids, primary cultures were isolated from tumor tissue samples; the said cultures were characterized morphologically and immunocytochemically, and then planted into round-bottom ultra low-adhesion plates. The number of cells for planting was chosen empirically. The characteristics of the growth of cell cultures were compared with spheroids from glioblastomas of patients with U373 MG stable line of human glioblastoma. Visualization of autofluorescence of metabolic coenzymes of nicotinamide adenine dinucleotide (phosphate) NAD(P)H and flavin adenine dinucleotide (FAD) in spheroids was performed by means of an LSM 880 laser scanning microscope (Carl Zeiss, Germany) with a FLIM module (Becker & Hickl GmbH, Germany). The autofluorescence decay parameters were studied under normoxic and hypoxic conditions (3.5% О2).
RESULTS: An original protocol for 3D glioblastoma spheroids cultivation was developed. Primary glial cultures from surgical material of patients were obtained and characterized. The isolated glioblastoma cells had a spindle-shaped morphology with numerous processes and a pronounced granularity of cytoplasm. All cultures expressed glial fibrillary acidic protein (GFAP). The optimal seeding dose of 2000 cells per well was specified; its application results in formation of spheroids with a dense structure and stable growth during 7 days. The FLIM method helped to establish that spheroid cells from the patient material had a generally similar metabolism to spheroids from the stable line, however, they demonstrated more pronounced metabolic heterogeneity. Cultivation of spheroids under hypoxic conditions revealed a transition to a more glycolytic type of metabolism, which is expressed in an increase in the contribution of the free form of NAD(P)H to fluorescence decay.
CONCLUSION: The developed model of tumor spheroids from patients' glioblastomas in combination with the FLIM can serve as a tool to study characteristics of tumor metabolism and develop predictive tests to evaluate the effectiveness of antitumor therapy.

Matched MeSH terms: Cytoplasm
Fulltext Unearthing the role of septins in viral infections

Khairat JE, Hatta MNA, Abdullah N, Azman AS, Calvin SYM, Syed Hassan S

Biosci Rep, 2024 Mar 29;44(3).
PMID: 38372298 DOI: 10.1042/BSR20231827

Septin proteins are a subfamily of closely related GTP-binding proteins conserved in all species except for higher plants and perform essential biological processes. Septins self-assemble into heptameric or octameric complexes and form higher-order structures such as filaments, rings, or gauzes by end-to-end binding. Their close association with cell membrane components makes them central in regulating critical cellular processes. Due to their organisation and properties, septins function as diffusion barriers and are integral in providing scaffolding to support the membrane's curvature and stability of its components. Septins are also involved in vesicle transport and exocytosis through the plasma membrane by co-localising with exocyst protein complexes. Recently, there have been emerging reports of several human and animal diseases linked to septins and abnormalities in their functions. Most of our understanding of the significance of septins during microbial diseases mainly pertains to their roles in bacterial infections but not viruses. This present review focuses on the known roles of septins in host-viral interactions as detailed by various studies.

Matched MeSH terms: Cytoplasm/metabolism