Cyclin-dependent Protein Kinase Research Articles

The anticancer potential of chemical constituents of Moringa oleifera targeting CDK-2 inhibition in estrogen receptor positive breast cancer using in-silico and in vitro approches

Most of the breast cancers are estrogen receptor-positive recurring with a steady rate of up to 20 years dysregulating the normal cell cycle. Dinaciclib is still in clinical trials and considered as a research drug against such cancers targeting CDK2.The major goal of this study was to identify the potential inhibitors of CDK-2 present in Moringa oleifera for treating hormonal receptor positive breast cancers. For this purpose, in silico techniques; molecular docking, MM-GBSA and molecular dynamics simulations were employed to screen Moringa oleifera compounds and their anticancer potential was determined against CDK-2 protein targets. Among 36 compounds of Moringa oleifera reported in literature, chlorogenic acid (1), quercetin (2), ellagic acid (3), niazirin (4), and kaempferol (5) showed good affinity with the target. The interaction of the compounds was visualized using PYMOL software. The profiles of absorption, distribution, metabolism, excretion (ADME) and toxicity were determined using SWISS and ProTox II webservers. The MTT assay was performed in-vitro using MCF-7 cancer cell lines to validate the anticancer potential of Moringa oleifera leaf extract.MTT assay results revealed no significant change in proliferation of Mcf-7 cells following 24 h treatment with fraction A (petroleum ether). However, significant antiproliferative effect was observed at 200 µg/mL dose of fraction B (ethyl acetate) and cell viability was reduced to 40%.In conclusion, the data suggested that all the compounds with highest negative docking score than the reference could be the potential candidates for cyclin dependent kinase-2 (CDK-2) inhibition while ellagic acid, chlorogenic acid and quercetin being the most stable and potent inhibitors to treat estrogen receptor positive breast cancer targeting CDK-2. Moreover, the data suggested that further investigation is required to determine the optimum dose for significant antiproliferative effects using in-vivo models to validate our findings of in-silico analysis.

The Correlation of P16 Expression with Degree of Differentiation and Tumor Stage in Cervical Squamous Cell Carcinoma (CSCC)

Background
 Cervical squamous cell carcinoma (CSCC) represents 70-80% of all cervical cancer cases. This cancer ranks 4th most common death cause due to malignancy in women. Cervical SCC patients were found at an older age and were detected at an advanced stage. High risk human papillomavirus (HPV) infection is main cause of SCC. Protein cyclin-dependent kinase inhibitor 2A also called p16 is a well-known tumor suppressor protein involved in cell cycle regulation, senescence, apoptosis, cell invasion and angiogenesis. This p16 protein can be used as surrogate marker for HPV infection. From several previous studies, there were differences between p16 expression relationship with differentiation degree and cervical SCC tumor stage results. Relationship research between p16 expression and differentiation degree and tumor stage of cervical SCC patients has never been conducted in West Sumatra.
 
 Methods
 This research was retrospective observational cross-sectional study with 35 cervical SCC cases that have been diagnosed at Anatomical Pathology Laboratory, RSUP Dr. M. Djamil Padang period January 2018-December 2019. Samples were obtained by simple random sampling from paraffin blocks derived from tumor tissue. The histopathological slide was reassessed to assess differentiation degree and tumor stage data were obtained from the patient's medical record. p16 expression in tumor cells was seen by immunohistochemical examination. To determine the correlation, bivariate statistical analysis was performed using the chi-square test with significance p<0.05 level.
 
 Results
 p16 high expression was found in 22 cases, tended to be higher in degree of well differentiation (40.9%) and moderate differentiation (50.0%) and was higher at an advanced stage (90.9%). Statistically, there is no correlation between p16 expression and differentiation degree with p value=0.138. There was no correlation between p16 expression and tumor stage with p value=0.337.
 
 Conclusions
 This study concluded that p16 expression was not associated with differentiation degree and tumor stage in cervical SCC.

Discovery of small molecule degraders for modulating cell cycle.

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

Cyclin-dependent kinases: Masters of the eukaryotic universe.

A family of structurally related cyclin-dependent protein kinases (CDKs) drives many aspects of eukaryotic cell function. Much of the literature in this area has considered individual members of this family to act primarily either as regulators of the cell cycle, the context in which CDKs were first discovered, or as regulators of transcription. Until recently, CDK7 was the only clear example of a CDK that functions in both processes. However, new data points to several "cell-cycle" CDKs having important roles in transcription and some "transcriptional" CDKs having cell cycle-related targets. For example, novel functions in transcription have been demonstrated for the archetypal cell cycle regulator CDK1. The increasing evidence of the overlap between these two CDK types suggests that they might play a critical role in coordinating the two processes. Here we review the canonical functions of cell-cycle and transcriptional CDKs, and provide an update on how these kinases collaborate to perform important cellular functions. We also provide a brief overview of how dysregulation of CDKs contributes to carcinogenesis, and possible treatment avenues. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Processing > 3' End Processing RNA Processing > Splicing Regulation/Alternative Splicing.

Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases.

The rational design of cyclin-dependent protein kinase (CDK) inhibitors presumes the development of approaches for accurate prediction of selectivity and the activity of small molecular weight anticancer drug candidates. Aiming at attenuation of general toxicity of low selectivity compounds, we herein explored the new chemotype of imidazole-4-N-acetamide substituted derivatives of the pan-CDK inhibitor PHA-793887. Newly synthesized compounds 1-4 containing an aliphatic methyl group or aromatic radicals at the periphery of the scaffold were analyzed for the prediction of relative free energies of binding to CDK1, -2, -5, and -9 using a protocol based on non-equilibrium (NEQ) thermodynamics. This methodology allows for the demonstration of a good correlation between the calculated parameters of interaction of 1-4 with individual targets and the values of inhibitory potencies in in vitro kinase assays. We provide evidence in support of NEQ thermodynamics as a time sparing, precise, and productive approach for generating chemical inhibitors of clinically relevant anticancer targets.

Strain variation in gene expression impact of hyphal cyclin Hgc1 in Candida albicans.

Formation of hyphae is a key virulence trait of the fungal pathogen Candida albicans. Hypha morphogenesis depends upon the cyclin Hgc1, which acts together with cyclin-dependent protein kinase Cdc28 to phosphorylate effectors that drive polarized growth. Hgc1 has also been implicated in gene regulation through its effects on 2 transcription factors, Efg1 and Ume6. Here, we report RNA-sequencing (RNA-seq) analysis of 2 pairs of hgc1Δ/Δ mutants and their respective wild-type strains, which lie in 2 different genetic backgrounds. We find that hgc1Δ/Δ mutations alter expression of 271 genes in both genetic backgrounds and 266 of those genes respond consistently with regard to up- or down-regulation. Consistency is similar to what has been observed with efg1Δ/Δ mutations and greater than observed with nrg1Δ/Δ mutations in these 2 backgrounds. The gene expression response includes genes under Efg1 control, as expected from prior studies. Hgc1-responsive genes also include ergosterol biosynthetic genes and bud neck-related genes, which may reflect interactions between Hgc1 and additional transcription factors as well as effects of Hgc1 on cellular length-to-width ratios.

A study on synthesis, antioxidant, anticancer activities and docking study of novel benzimidazoloyl thiazole derivatives

2-(Substituted-amino)-5-(1-methylbenzimidazol-2-oyl)thiazoles have been synthesized by the reaction of 2-(2-bromoacetyl)-1-methylbenzimidazole and 1-(substituted-amino)-3-(N,N-dimethylimidoyl)thioureas in the presence of triethyl amine. The structure of the newly synthesized benzmidazoloyl thiazole analogues have been confirmed by spectroscopic techniques. The in vitro antioxidant activity has been studied using DPPH assay and anticancer activity has been studied using MTT assay against human colon adenocarcinoma cells. In silico studies have been performed to predict the binding modes of the compounds with the cyclin-dependent kinase protein 5FGK. It is evident from the current results that all the synthesized compounds exhibit remarkable antioxidant and anticancer potential.

Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery.

Cyclin-dependent kinase 5 (CDK5) protein plays an important role not only in the central nervous system but also in the periphery, including immune response, regulation of insulin secretion, and cancer development and progression. Consequently, targeting the CDK5 protein is a potential strategy for the treatment of many diseases, especially cancer and neurodegenerative diseases. To date, numerous pan-CDK inhibitors have entered clinical trials. Nevertheless, limited clinical efficacy and severe adverse effects have prompted the application of new techniques to optimize clinical efficacy and minimize adverse events. In this Perspective, we highlight the protein properties, biofunctions, relevant signaling pathways, and associations with cancer development and proliferation of CDK5, and analyze the clinical status of pan-CDK inhibitors and the preclinical status of CDK5-specific inhibitors. In addition, CDK5-selective inhibitors, protein-protein interaction inhibitors, proteolytic-targeting chimera (PROTAC) degraders, and dual-target CDK5 inhibitors are discussed.

An Interpretable Multitask Framework BiLAT Enables Accurate Prediction of Cyclin-Dependent Protein Kinase Inhibitors.

The cyclin-dependent protein kinases (CDKs) are protein-serine/threonine kinases with crucial effects on the regulation of cell cycle and transcription. CDKs can be a hallmark of cancer since their excessive expression could lead to impaired cell proliferation. However, the selectivity profile of most developed CDK inhibitors is not enough, which have hindered the therapeutic use of CDK inhibitors. In this study, we propose a multitask deep learning framework called BiLAT based on SMILES representation for the prediction of the inhibitory activity of molecules on eight CDK subtypes (CDK1, 2, 4-9). The framework is mainly composed of an improved bidirectional long short-term memory module BiLSTM and the encode layer of the Transformer framework. Additionally, the data enhancement method of SMILES enumeration is applied to improve the performance of the model. Compared with baseline predictive models based on three conventional machine learning methods and two multitask deep learning algorithms, BiLAT achieves the best performance with the highest average AUC, ACC, F1-score, and MCC values of 0.938, 0.894, 0.911, and 0.715 for the test set. Moreover, we constructed a targeted external data set CDK-Dec for the CDK family, which mainly contains bait values screened by 3D similarity with active compounds. This dataset was utilized in the subsequent evaluation of our model. It is worth mentioning that the BiLAT model is interpretable and can be used by chemists to design and synthesize compounds with improved activity. To further verify the generalization ability of the multitask BiLAT model, we also conducted another evaluation on three public datasets (Tox21, ClinTox, and SIDER). Compared with several currently popular models, BiLAT shows the best performance on two datasets. These results indicate that BiLAT is an effective tool for accelerating drug discovery.

Mitochondrial creatine kinase 1 regulates the cell cycle in non-small cell lung cancer via activation of cyclin-dependent kinase 4

BackgroundNon-small cell lung cancer (NSCLC) is the main type of the most common malignant tumor in the world. Previous studies have shown that the expression level of mitochondrial creatine kinase 1 (CKMT1) is abnormal in NSCLC, but the mechanism of its effect remains unclear. Therefore, in this study, we intend to clarify the potential mechanism of CKMT1 in NSCLC and provide the theoretical basis for the clinical application of CKMT1.MethodsThe function of CKMT1 in NSCLC was identified by analyzing the GEO dataset and evaluating using in vitro and in vivo models. Protein mass spectrometry was used to find proteins interacting with CKMT1, and Co-immunoprecipitation (Co-IP) and GST-pull down experiments were used to verify the interaction between proteins. The immunofluorescence (IF) assay was used to explore the functional position of CKMT1 in cells. The effect of CKMT1 expression level on the efficacy of paclitaxel (TAX) in the treatment of NSCLC was analyzed by a combined TAX experiment in vivo and in vitro.ResultsCKMT1 expression was increased in NSCLC and CKMT1 promoted the proliferation of NSCLC cells in vitro and in vivo. CKMT1 knockdown resulted in a significantly increased G0/G1 fraction and decreased S phase cell fraction, indicating G1 phase arrest. Mechanically, the cyclin-dependent kinase 4 (CDK4) was identified to interact with CKMT1, and the crucial binding areas were focused on the DH domain of CKMT1 and the N- and C-terminal of CDK4. A fraction of the CDK4 proteins colocalize and interact with the CKMT1 at mitochondria, the level of phosphorylated CDK4 was regulated by CKMT1. Hence, the decrease in CKMT1 expression level could increase the antitumor effect of G2/M cell cycle antagonist-TAX in NSCLC in vitro and in vivo.ConclusionsCKMT1 could interact with CDK4 in mitochondria and regulate the phosphorylated level of CDK4, thus contributing to the proliferation and cell cycle transition of NSCLC cells. And CKMT1 could be a potential target to improve the sensitivity of chemotherapy based on TAX.

Facile synthesis of copolymerized cellulose grafted hydrogel doped calcium oxide nanocomposites with improved antioxidant activity for anti-arthritic and controlled release of doxorubicin for anti-cancer evaluation

The combination treatment is considered an approach to attaining synergistic impact while minimizing applied dosage. Hydrogels are analogous to the tissue environment attributed to hydrophilic and porous structure. Despite extensive study in biological and biotechnological domains, their restricted mechanical strength and limited functionalities impede their potential uses. Emerging strategies are centred on research and developing nanocomposite hydrogels to combat these issues. Herein, we prepared copolymerized hydrogel by grafting poly-acrylic acid P(AA) onto cellulose nanocrystals (CNC) and adding CNC-g-PAA as dopant (2 and 4 wt%) in calcium oxide (CaO) nanoparticles to generate an effective hydrogel doped nanocomposite (NCH) (CNC-g-PAA/CaO) for biomedical applications such as anti-arthritic, anti-cancer, and antibacterial investigations alongside their comprehensive characterization. CNC-g-PAA/CaO (4 %), compared to other samples, had a substantially higher antioxidant potential (72.21 %). Doxorubicin, a potential chemotherapeutic drug, was then effectively loaded into NCH (99 %) via electrostatic interaction, and pH-triggered based release was found to be >57.9 % in 24 h. Furthermore, molecular docking investigation against targeted protein Cyclin-dependent kinase 2 and in vitro cytotoxicity study verified the improved antitumor effectiveness of CNC-g-PAA and CNC-g-PAA/CaO. These outcomes indicated that hydrogels might serve as potential delivery vehicles for innovative multifunctional biomedical applications.

Network Pharmacology and Experimental Validation to Explore the Effect and Mechanism of Kanglaite Injection Against Triple-Negative Breast Cancer.

Kanglaite injection (KLTi), made of Coix seed oil, has been shown to be effective in the treatment of numerous cancers. However, the anticancer mechanism requires further exploration. This study aimed to investigate the underlying anticancer mechanisms of KLTi in triple-negative breast cancer (TNBC) cells. Public databases were searched for active compounds in KLTi, their potential targets and TNBC-related targets. KLTi's core targets and signaling pathways were determined through compound-target network, protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was carried out to predict the binding activity between active ingredients and key targets. In vitro experiments were conducted to further validate the predictions of network pharmacology. Fourteen active components of KLTi were screened from the database. Fifty-three candidate therapeutic targets were selected, and bioinformatics analysis was performed to identify the top two active compounds and three core targets. GO and KEGG enrichment analyses indicated that KLTi exerts therapeutic effects on TNBC through the cell cycle pathway. Molecular docking results showed that the main compounds of KLTi exhibited good binding activity to key target proteins. Results from in vitro experiments showed that KLTi inhibited proliferation and migration of TNBC cell lines 231 and 468, induced apoptosis, blocked cells in the G2/M phase, downregulated the mRNA expression of seven G2/M phase-related genes cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), and checkpoint kinase 1 (CHEK1), cell division cycle 25A (CDC25A), cell division cycle 25B (CDC25B), maternal embryonic leucine zipper kinase (MELK), and aurora kinase A (AURKA), as well as downregulated CDK1 protein expression and up-regulated protein expression of Phospho-CDK1. By utilizing network pharmacology, molecular docking, and in vitro experiments, KLTi was confirmed to have anti-TNBC effects by arresting cell cycle and inhibiting CDK1 dephosphorylation.

Transcriptional Reprogramming Regulates Tumor Cell Survival in Response to Ionizing Radiation: a Role of p53.

Senexin B, a non-toxic selective inhibitor of cyclin-dependent protein kinases 8 and 19 (CDK8 and CDK19), in combination with γ-photon irradiation in doses of 2-10 Gy increased the death of colon adenocarcinoma cell line HCT116 (intact p53) in a logarithmically growing culture, which was accompanied by the prevention of cell cycle arrest and a decrease of "senescence" phenotype. The effect of senexin B in cells with intact p53 is similar to that of Tp53 gene knockout: irradiated HCT116p53KO cells passed through the interphase and died independently of senexin B. The inhibitor reduced the ability of cells to colony formation in response to irradiation; p53 status did not affect the effectiveness of the combination of radiation and senexin B. Thus, the CDK8/19 inhibitor senexin B increased cell sensitivity to radiotherapy by mechanisms dependent and independent of p53 status.

Dynamic changes of 3'UTR length during oocyte-to-zygote transition of in vitro pig embryos.

Alternative polyadenylation (APA) generates different 3'-untranslated regions (3'UTRs) to regulate gene expression and localization, and affects a variety of biological processes. Here, we characterized the 3'UTR dynamics during the oocyte-to-zygote transition by analysing our previously reported porcine single-cell RNA-seq (scRNA-seq) datasets (in vitro matured metaphase II (MII) oocytes, in vitro fertilized zygotes (IVF1) and parthenogenetically activated 1-cell embryos (PA1)). After IVF1 versus MII comparison, dynamic analyses of APA from RNA-seq (DaPars) method identified 139 mRNAs with significantly different 3'UTRs (padj .≤ .05), mainly enriched in cell cycle, regulation of cyclin-dependent protein kinase activity, histone modification, mRNA surveillance, and regulation of actin cytoskeleton. For PA1 versus MII comparison, 105 mRNAs with significantly different 3'UTRs (padj .≤ .05) were identified to be mainly enriched in intracellular transport, mitotic spindle organization, cell cycle, pyruvate metabolism and glycolysis/gluconeogenesis. Furthermore, there were 7 mRNAs with more significant 3'UTR differences (|△PDUI| ≥ 0.45 and |log2 [PDUI ratio]| ≥ 0.59) respectively in IVF1 versus MII (Lrp2bp, Mtfr2, Nhlrc2, Psip1, Smu1, Ssr1 and Wtap) and PA1 versus MII (Asf1b, Dimt1, Nap1l1, Ncoa4, Nudt21, Pnn and Rpl15) comparisons. Integrative genomics viewer analysis further identified that 3'UTRs of Psip1, Smu1, Ssr1 and Wtap had more than 140 nt average length changes, whereas those of Dimt1, Nap1l1 and Rpl15 were shortened with more than 460 nt. Regulatory elements (PAS, CPE, microRNA binding sites and m6 A sites) in 3'UTRs of different lengths were predicted. Our findings provide useful information to further investigate the molecular mechanism of 3'UTR in regulating the oocyte-to-zygote transition of pig embryos.

Identification of potential biomarkers for colorectal cancer by clinical database analysis and Kaplan-Meier curves analysis.

This study aimed to explore critical genes as potential biomarkers for the diagnosis and prognosis of colorectal cancer (CRC) for clinical utility. To identify and screen candidate genes involved in CRC carcinogenesis and disease progression, we downloaded microarray datasets GSE89076, GSE73360, and GSE32323 from the GEO database identified differentially expressed genes (DEGs), and performed a functional enrichment analysis. A protein-protein interaction network was constructed, and correlated module analysis was performed using STRING and Cytoscape. The Kaplan-Meier survival curve shows the survival of the hub genes. The expression of cyclin-dependent kinase (CDK1), cyclin B1 (CCNB1), and PCNA in tissues and changes in tumor grade were analyzed. A total of 329 DEGs were identified, including 264 upregulated and 65 downregulated genes. The functions and pathways of DEGs include the mitotic cell cycle, poly(A) RNA binding replication, ATP binding, DNA replication, ribosome biogenesis in eukaryotes, and RNA transport. Forty-seven Hub genes were identified, and biological process analysis showed that these genes were mainly enriched in cell cycle and DNA replication. Patients with mutations in CDK1, PCNA, and CCNB1 had poorer survival rates. CDK1, PCNA, and CCNB1 were significantly overexpressed in the tumor tissues. The expression of CDK1 and CCNB1 gradually decreased with increasing tumor grade. CDK1, CCNB1, and PCNA can be used as potential markers for the diagnosis and prognosis of CRC. These genes are overexpressed in colon cancer tissues and are associated with low survival rates in CRC patients.

Design, synthesis, and biological evaluation of indolin-2-one derivatives as novel cyclin-dependent protein kinase 8 (CDK8) inhibitors

Cyclin-dependent protein kinase 8 (CDK8) plays important roles in regulating fibrotic growth factors and inflammatory signaling pathways. Long-term chronic inflammation of the lungs can lead to idiopathic pulmonary fibrosis (IPF). Abnormal alveolar epithelial regeneration leads to the release of various fibrotic growth factors and the activation of inflammatory cells. CDK8 regulates profibrotic cytokines broadly implicated in the pathogenesis of fibrosis. Therefore, inhibition of CDK8 is considered a promising strategy for treating IPF. Here, CDK8 inhibitors were designed and optimized using a fragment-based drug design strategy. Testing results revealed that 71% of the synthesized compounds inhibited CDK8 activity better than the original compound E966–0530. Of these compounds, compound 4k exhibited the strongest CDK8 enzyme-inhibiting activity (IC50 =129 nM). Notably, it displayed a 13-fold increase in potency when compared to E966–0530. Experiments on toxicity and inhibition of epithelial-mesenchymal transition (EMT) protein expressions showed that compound 4k can inhibit EMT protein expressions, but with no significant cytotoxicity for alveolar epithelial cells. Compound 4k showed a potent inhibitory effect in cell migration assays. Furthermore, compound 4k significantly inhibited the phosphorylation of p-Smad3 and RNA Pol II, which are critical mediators in the fibrotic response signaling pathway. Compound 4k remarkably reduced TGF-β1-induced oxidative stress. The above results reveal optimized CDK8 inhibitors with potential use for IPF therapeutic treatment.

Two new alkaloids from Dendrobium nobile Lindl. exhibited neuroprotective activity, and dendrobine alleviated Aβ1-42 -induced apoptosis by inhibiting CDK5 activation in PC12 cells.

Dendrobium nobile Lindl. is registered in the Chinese Pharmacopoeia as a traditional medicine. Phytochemical investigation of the ethanol extract of D. nobile Lindl. stems yielded three alkaloid compounds, including two new compounds dendroxine B (2) and denrine B (3) as well as one known compound dendrobine (1). Here, we identified the structure of these compounds using spectroscopic analyses and compared them with those described in previous studies. Compounds 1-3 were found to show protective effect against amyloid-β 1-42 (Aβ1-42 )-induced neurotoxicity in rat pheochromocytoma (PC12) cells, among which dendrobine exhibited the most significant neuroprotective effect. Hoechst 33342/propidium iodidestaining indicated that dendrobine ameliorated Aβ1-42 -induced apoptosis. Moreover, quantitative real-time polymerase chain reaction and western blot analysis analysis demonstrated that dendrobine suppressed the activation of cyclin-dependent kinase 5 (CDK5), upregulated Bcl-2 expression, and downregulated Bax, cyto-c, and caspase-3 expression. Molecular docking analysis and surface plasmon resonance assay suggested that dendrobine directly bound to CDK5 protein with a KD value of 2.05 × 10-4 M. In summary, alkaloids are the neuroprotective constituents of D. nobile Lindl., and dendrobine protected PC12 cells against Aβ1-42 -induced apoptosis by inhibiting CDK5 activation.

Downregulation of CDC25C in NPCs Disturbed Cortical Neurogenesis.

Cell division regulators play a vital role in neural progenitor cell (NPC) proliferation and differentiation. Cell division cycle 25C (CDC25C) is a member of the CDC25 family of phosphatases which positively regulate cell division by activating cyclin-dependent protein kinases (CDKs). However, mice with the Cdc25c gene knocked out were shown to be viable and lacked the apparent phenotype due to genetic compensation by Cdc25a and/or Cdc25b. Here, we investigate the function of Cdc25c in developing rat brains by knocking down Cdc25c in NPCs using in utero electroporation. Our results indicate that Cdc25c plays an essential role in maintaining the proliferative state of NPCs during cortical development. The knockdown of Cdc25c causes early cell cycle exit and the premature differentiation of NPCs. Our study uncovers a novel role of CDC25C in NPC division and cell fate determination. In addition, our study presents a functional approach to studying the role of genes, which elicit genetic compensation with knockout, in cortical neurogenesis by knocking down in vivo.

IN SILICO EVALUATION OF BINDING INTERACTION AND ADME PROPERTIES OF NOVEL 5-(THIOPHEN-2-YL)-1,3,4-OXADIAZOLE-2-AMINE DERIVATIVES AS ANTI-PROLIFERATIVE AGENTS

Objective: The objective of this research was the virtual design of nine novel 1,3,4-oxadiazole derivatives and evaluating their antiproliferative activity as potential cyclin-dependent kinase 2 (CDK-2) inhibitors, which is a major component in cell cycle and proliferation. Methods: CDK-2 structure, PDB ID, 2R3J, co-crystallized with ligand SCJ from protein data bank was chosen to be docked with a series of nine 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine derivatives to evaluate their abilities as potential anti-proliferative agents using Glide software (Maestro 11.4) one of Schrodinger software (Schrodinger, 2018). In addition, the pharmacokinetic properties of these derivatives were evaluated using the Swiss-ADME web tool. Results: Molecular modeling proposed that these 1,3,4-oxadiazole derivatives have powerful binding interaction with the active binding site of CDK-2 protein. In this article, two molecules have been observed as the most effective as they have docking scores of (-10.654 and-10.169 kcal/mol) respectively, whereas the binding score of the reference ligand was (-9.919 Kcal/mol) and most of the derivatives have fulfilled the Swiss-ADME parameters as potential orally active compounds. Conclusion: Novel 1,3,4-oxadiazole derivatives had shown promising results to be considered as lead compounds for developing new anti-proliferative agents as two compounds (P-1 and P-5) exhibit better docking score at 2R3J active site than the reference ligand with further biological and pharmacological evaluation required.

Kaempferol regulates the thermogenic function of adipocytes in high-fat-diet-induced obesity via the CDK6/RUNX1/UCP1 signaling pathway.

Activation of adipose tissue thermogenesis is a promising strategy in the treatment of obesity and obesity-related metabolic disorders. Kaempferol (KPF) is a predominant dietary flavonoid with multiple pharmacological properties, such as anti-inflammatory and antioxidant activities. In this study, we sought to characterize the role of KPF in adipocyte thermogenesis. We demonstrated that KPF-treated mice were protected from diet-induced obesity, glucose tolerance, and insulin resistance, accompanied by markedly increased energy expenditure, ex vivo oxygen consumption of white fat, and increased expression of proteins related to adaptive thermogenesis. KPF-promoted beige cell formation is a cell-autonomous effect, since the overexpression of cyclin-dependent kinase 6 (CDK6) in preadipocytes partially reversed browning phenotypes observed in KPF-treated cells. Overall, these data implicate that KPF is involved in promoting beige cell formation by suppressing CDK6 protein expression. This study provides evidence that KPF is a promising natural product for obesity treatment by boosting energy expenditure.