Bioactive constituents from natural sources are of great interest as alternatives to synthetic compounds for the treatment of various diseases, including diabetes mellitus. In the present study, phytochemicals present in Leucaena leucocephala (Lam.) De Wit leaves were identified by gas chromatography-mass spectrometry and further examined by qualitative and quantitative methods. α-Amylase enzyme activity assays were performed and revealed that L. leucocephala (Lam.) De Wit leaf extract inhibited enzyme activity in a dose-dependent manner, with efficacy similar to that of the standard α-amylase inhibitor acarbose. To determine which phytochemicals were involved in α-amylase enzyme inhibition, in silico virtual screening of the absorption, distribution, metabolism, excretion, and toxicity properties was performed and pharmacophore dynamics were assessed. We identified hexadecenoic acid and oleic acid ((Z)-octadec-9-enoic acid) as α-amylase inhibitors. The binding stability of α-amylase to those two fatty acids was confirmed in silico by molecular docking and a molecular dynamics simulation performed for 100 ns. Together, our findings indicate that L. leucocephala (Lam.) De Wit-derived hexadecanoic acid and oleic acid are natural product-based antidiabetic compounds that can potentially be used to manage diabetes mellitus.

Phytochemical Profiling in Conjunction with In Vitro and In Silico Studies to Identify Human α-Amylase Inhibitors in Leucaena leucocephala (Lam.) De Wit for the Treatment of Diabetes Mellitus.

Family with sequence similarity 72 A (FAM72A) is a pivotal mitosis-promoting factor that is highly expressed in various types of cancer. FAM72A interacts with the uracil-DNA glycosylase UNG2 to prevent mutagenesis by eliminating uracil from DNA molecules through cleaving the N-glycosylic bond and initiating the base excision repair pathway, thus maintaining genome integrity. In the present study, we determined a specific FAM72A-UNG2 heterodimer protein interaction using molecular docking and dynamics. In addition, through in silico screening, we identified withaferin B as a molecule that can specifically prevent the FAM72A-UNG2 interaction by blocking its cell signaling pathways. Our results provide an excellent basis for possible therapeutic approaches in the clinical treatment of cancer.

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing.

Glioblastoma (GBM) is the most common primary central nervous system tumor in adults, accounting for approximately 80% of all brain-related malignancies [...]

Novel Treatment Strategies for Glioblastoma-A Summary.

GTPase activating proteins (GAPs) were initially considered as the inhibitors of cell signaling pathways because of their nature to activate the intrinsic GTPase activity of the RhoGTPases. But recent studies of dysregulated GAPs in many cancers such as glioblastoma, colorectal cancer, breast cancer, and renal cancer have elucidated the important roles of GAPs in carcinogenesis and GAPs have been shown to perform multiple nonconventional functions in different contexts. We have discussed the recent developments in the roles played by different types of srGAPs (SLIT-ROBO Rho GTPase-activating proteins) in cancer.

The emerging roles of srGAPs in cancer.

Background The family with sequence similarity 72 member A (FAM72A) protein has been identified as an effector of multiple pathological processes in many cancers. The value of FAM72A in HCC remains largely unknown. Methods Data from TCGA-LIHC, ICGC-LIRI-JP, IMvigor210, cBioPortal, GeneMANIA, and TIMER were processed and visualized to explore the association between FAM72A and the prognosis, stemness phenotype, mutational burden, immune cell infiltration, and drug sensitivity in HCC patients. Potential pathways were also revealed. Furthermore, we experimentally verified the results in vivo and in vitro using immunohistochemistry, western blotting, and CCK-8 assays. Results First, FAM72A mRNA expression was significantly upregulated in HCC. High FAM72A expression was independently associated with a poor prognosis. Experimental validation confirmed that FAM72A was remarkably overexpressed in HCC patients and mice. Moreover, FAM72A knockdown suppressed HCC cell proliferation. In addition, the frequency of TP53 mutations was significantly higher in the high FAM72A expression group. Subsequently, the enrichment analysis revealed that FAM72A was closely related to immune processes and mTOR pathways. Silencing FAM72A increased the expression levels of mTOR in HCC cell lines. The FAM72A-mTOR pathway was strongly associated with a poor prognosis for patients with HCC. Patients with high FAM72A expression levels might be more resistant to sorafenib. Furthermore, the expression of FAM72A and mTOR was significantly associated with the abundance of some tumor-infiltrating immune cells, especially CD4+ T cells. Finally, patients with high levels of FAM72A and mTOR were more sensitive to immunotherapy. Conclusions FAM72A, a member of the FAM72 family, might be a prognostic and immunotherapeutic target for HCC patients.

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Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma

Neural stem cells (NSCs) offer great potential for regenerative medicine due to their excellent ability to differentiate into various specialized cell types of the brain. In the central nervous system (CNS), NSC renewal and differentiation are under strict control by the regulation of the pivotal SLIT-ROBO Rho GTPase activating protein 2 (SRGAP2)-Family with sequence similarity 72 (FAM72) master gene (i.e., |-SRGAP2-FAM72-|) via a divergent gene transcription activation mechanism. If the gene transcription control unit (i.e., the intergenic region of the two sub-gene units, SRGAP2 and FAM72) gets out of control, NSCs may transform into cancer stem cells and generate brain tumor cells responsible for brain cancer such as glioblastoma multiforme (GBM). Here, we discuss the surveillance of this |-SRGAP2-FAM72-| master gene and its role in GBM, and also in light of FAM72 for diagnosing various types of cancers outside of the CNS.

https://www.mdpi.com/2072-6694/13/5/1025/pdf

FAM72, Glioblastoma Multiforme (GBM) and Beyond.

Carbon (C), hydrogen (H), nitrogen (N), oxygen (O), and sulfur (S) atoms intrigue as they are the foundation for amino acid (AA) composition and the folding and functions of proteins and thus define and control the survival of a cell, the smallest unit of life. Here, we calculated the proteomic atom distribution in >1500 randomly selected species across the entire current phylogenetic tree and identified uracil-5-methyltransferase (U5MTase) of the protozoan parasite Plasmodium falciparum (Pf, strain Pf3D7), with a distinct atom and AA distribution pattern. We determined its apicoplast location and in silico 3D protein structure to refocus attention exclusively on U5MTase with tremendous potential for therapeutic intervention in malaria. Around 300 million clinical cases of malaria occur each year in tropical and subtropical regions of the world, resulting in over one million deaths annually, placing malaria among the most serious infectious diseases. Genomic and proteomic research of the clades of parasites containing Pf is progressing slowly and the functions of most of the ∼5300 genes are still unknown. We applied a 'bottom-up' comparative proteomic atomics analysis across the phylogenetic tree to visualize a protein molecule on its actual basis - i. e., its atomic level. We identified a protruding Pf3D7-specific U5MTase, determined its 3D protein structure, and identified potential inhibitory drug molecules through in silico drug screening that might serve as possible remedies for the treatment of malaria. Besides, this atomic-based proteome map provides a unique approach for the identification of parasite-specific proteins that could be considered as novel therapeutic targets.

Pok Son Kim

Papers

FAM72, Glioblastoma Multiforme (GBM) and Beyond.

Proteomic Atomics Reveals a Distinctive Uracil-5-Methyltransferase