In silico identification of 20S proteasome-ß5 subunit inhibitors using structure-based virtual screening.

Proteasome inhibitors have effective anti-tumor activity in cell culture and can induce apoptosis by interfering with the degradation of cell cycle proteins. 20S Proteasome is acknowledged to be a satisfactory target that has persistent properties against the human immune defense and is obligatory for the degradation of some vital proteins. This study aimed to identify potential inhibitors against 20S proteasome, specifically the ß5 subunit, using structure-based virtual screening and molecular docking to reduce the number of ligands that should be eligible for experimental assays. A total of 4961 molecules with anticancer activity were screened from the ASINEX database. The filtered compounds that showed higher docking affinity were then used in more sophisticated molecular docking simulations with AutoDock Vina for validation. Finally, six drug molecules (BDE 28974746, BDE 25657353, BDE 29746159, BDD 27844484, BDE 29746109, and BDE 29746162) exhibited highly significant interactions compared to the positive controls were retained. Among these six molecules, three molecules (BDE 28974746, BDE 25657353, and BDD 27844484) showed high binding affinity and binding energy compared with Carfilzomib and Bortezomib. Molecular simulation and dynamics studies of the top three drug molecules in each case allowed us to draw further conclusions about their stability with the ß5 subunit. Computed absorption, distribution, metabolism, excretion and toxicity studies on these derivatives showed encouraging results with very low toxicity, distribution, and absorption. These compounds may serve as potential hits for further biological evaluation in the development of new proteasome inhibitors.Communicated by Ramaswamy H. Sarma.

Functional and quantitative evaluation of the 20S proteasome in serum and intracellular in145 moroccan patients with hematologic malignancies.

BACKGROUND: Regulatory degradation of intracellular proteins plays an essential role in most biological processes, particularly in the control of cell proliferation and differentiation. In eukaryotes, intracellular proteolysis is largely provided by the Ubiquitin / Proteasome system. Alterations and dysfunction of protein degradation by the Ubiquitin / Proteasome system, such as transcription factors, cell cycle regulators or tumor suppressor proteins, have been linked to human. Pathologies, including blood cancers. Mainly localized in the nucleus and cytoplasm of cells, the proteasome can be detected in the cell culture supernatant or in the peripheral blood of patients. This study deals with the problems of the search for serum markers specific to certain pathologies and which would be useful in the prevention, diagnosis and monitoring of cancers and which could be used as a therapeutic tool. METHODS: The functional and quantitative analysis of the proteasome is carried out at the serum and subcellular level during a pathological phenomenon in a population of 145 Moroccan patients (sex ratio: 1.10 / average age: 47.9 ± 15, 3 years) using an indirect ELISA test and a follow-up of the fluorescence emitted after enzymatic digestion of specific peptides by proteolytic activity (chymotrypsin-like). RESULTS: The evolutionary trend proteasome subcellular is significantly linked to the rate of chymotrypsin-like activity. The entire population of 60 patients called back for a second blood test. After three months of treatment reported a significant drop in the rate and the activity of the proteasome in serum and intracellular level. CONCLUSIONS: Although the serum proteasome level is a potential new tool for the monitoring of. Patientswithliquid cancer. TRIAL REGISTRATION: retrospectively registered.

The role of the ubiquitin-proteasome pathway in skin cancer development: 26S proteasome-activated NF-κB signal transduction.

The Ubiquitin-Proteasome System plays a central role in signal transduction associated with stress, in the skin in particular by the control of NF-κB pathways. Under normal conditions, the inhibitory protein IκB is phosphorylated by kinases, then ubiquitinated and ends up at the proteasome to be degraded. The present short review discusses recent progress in the inhibition of NF-κB activation by proteasome inhibitors prevents the degradation of protein IκB, which accumulates in the cytosol, and there by the activation of NF-κB. Moreover, would not only limit the expression of adhesion molecules and cytokines involved in metastatic processes, but also increase the sensitivity of cancer cells to apoptosis. Considering this fact, the activity of NF-κB is regulated by the phosphorylation and proteasome-dependent degradation of its inhibitor Iκb. In this scenario, the use of a proteasome inhibitor might be an effective strategy in the treatment of skin cancer with constitutive activation of NF-κB.

Antitumor Effect of Inula viscosa Extracts on DMBA-Induced Skin Carcinoma Are Mediated by Proteasome Inhibition.

The aim of this work is to evaluate the antitumor effect mediated by the proteasome inhibitors of Inula viscosa extracts on skin carcinogenesis. Female Swiss albino mice were divided into five groups depending on the combination of skin cancer-inducing 7,12-dimethylbenz(a)anthracene (DMBA) and extract of Inula viscosa treatments. Histology of the affected skin and measurement of proteasome activity were performed to demonstrate the effect of Inula viscosa on mice. The identification of the molecules responsible for this inhibitory activity was carried out through the docking studies. The results showed that Inula viscosa extracts inhibit the development of papilloma in mice. Therefore, the best chemopreventive action of Inula viscosa was observed on mice in which extract treatment was performed before and after the induction of skin carcinogenesis. It was revealed that the ingestion of extracts Inula viscosa delays the formation of skin papillomas in animals and simultaneously decreases the size and number of papillomas, which is also reflected on the skin histology of the mice treated. Structure-activity relationship information obtained from component of Inula viscosa particularly tomentosin, inuviscolide, and isocosticacid demonstrated that distinct bonding modes in ß 1, ß 2, and ß 5 subunits determine its selectivity and potent inhibition for ß 5 subunit.

Phytochemical Analysis and Toxicity Study of Aristolochia paucinervis Rhizomes Decoction Used in Moroccan Alternative Medicine: Histopathological and Biochemical Profiles.

ETHNOPHARMACOLOGICAL RELEVANCE: Aristolochia paucinervis (A. paucinervis) (Aristolochiaceae) is a plant frequently used in Moroccan alternative medicine. The aim of the current study is to investigate the phytochemical composition of rhizomes decoction of A. paucinervis (RDA) and to evaluate its acute and subacute toxicity following the OECD guidelines. MATERIALS AND METHODS: The qualitative phytochemical analysis of A. paucinervis was performed using standard qualitative phytochemical procedures. The acute toxicity of rhizomes decoction of the studied plant was evaluated in mice at single doses of 1, 2, and 4 g/kg of body weight for 14 days. In subacute toxicity study, the decoction was orally administered to mice at three different doses (0.5, 1, and 1.5 g/kg/day) for 28 days. Histopathological and biochemical parameters were investigated. RESULTS: The preliminary phytochemical screening showed the presence of flavonoids, saponins, alkaloids, and polyphenols and the absence of anthraquinones, sterols, and terpenes. There was no mortality and no significant changes occurred in animals treated with 1 and 2 g/kg in the acute toxicity model. The signs of toxicity and morbidity were remarkable with the highest tested dose (4g/kg). LD50 (dose required to kill 50% of the test population) was determined as 4 g/kg. Repeated oral administration of 1 and 1.5 g/kg/day of RDA for 28 days induced significant disturbance of serum parameters (AST, ALT, LDH, urea, creatinine). Kidney and liver extracted from mice fed with 1 and 1.5 g/kg/day showed significant histopathological injuries as tubular necrosis, inflammatory infiltrate, tubular degeneration, necrosis, and hepatic cholestasis. Meanwhile, neither histopathological nor biochemical alterations were observed in mice treated with 0.5 g/kg/day of body weight in comparison to the control group. CONCLUSION: RDA showed toxicity in mice at a dose of 1 g/kg/day under subacute toxicity conditions. RDA is safe at a single dose inferior to 4 g/kg of body weight. The plant extract prepared by decoction showed more poisonous effect than the extract prepared by maceration at room temperature.

Influence of age, castration, and testosterone on T cell subsets in healthy and leukemia grafted mice.

The distribution of T cell subsets in pubertal (2 months) and post-pubertal (10 months) mice showed a significant decrease in the percentage of CD4+ splenocytes and peripheral blood lymphocytes (PBL) with age, unlike the percentage of CD8+ cells in PBL, which remained unchanged. The change in the distribution of T cell subsets in the spleen and blood occurred in 2 months old castrated mice, as in 10 months old animals. P388 tumor grew better in post-pubertal and in castrated mice than in young mice. The intact mice survived longer than the castrated ones. The relative number of CD4+, CD8+ and CD2+ splenocytes was lower in transplanted intact mice than that in controls. The CD8+ and CD2+ subsets in the blood of 2 months transplanted mice were higher than those in controls, whereas in PBL, in 10 months old and castrated mice, the T lymphocyte subsets remain unchanged. Depo-testosterone (DT) injection strongly reduced weight and tumor growth in all the intact and castrated animals. A significant correlation is observed between the tumor weight and testosterone level in the plasma of the 2 months old DT treated mice. Moreover, DT injection induced a significant increase in the percentage of blood CD8+ cells in all the batches. These data indicate that physiologically, androgens affect the age-related distribution of lymphocyte T subsets and suggest that they slow down tumor growth, besides causing a direct effect, through an immunological process.