Inhibition of the Growth of Plasmodium falciparum in Culture by Stearylamine-Phosphatidylcholine Liposomes

We have examined the effect of stearylamine (SA) in liposomes on the viability of Plasmodium falciparum in culture by studying the inhibition of incorporation of [3H]-hypoxanthine in the nucleic acid of parasites. Stearylamine in liposomes significantly inhibits the growth of the parasites depending on the phospholipids composition. The maximum inhibition was observed when SA was delivered through Soya phosphatidylcholine (SPC) liposomes. The chain length of alkyl group and density of SA in liposomes play a significant role in inhibiting the growth of the parasites. Incorporation of either cholesterol or Distearylphosphatidylethanolamine−Methoxy-Polyethylene glycol-2000 (DSPE-mPEG-2000) in Soya phosphatidylcholine-stearylamine (SPC-SA) liposomes improves the efficacy. Intraerythrocytic entry of intact SPC-SA liposomes into infected erythrocytes was visualized using fluorescent microscopy. No hemolysis was observed in uninfected erythrocytes, and slight hemolysis was noted in infected erythrocytes at high concentrations of SPC-SA liposomes. Overall, our data suggested SA in SPC-liposomes might have potential application in malaria chemotherapy

Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations

Casein kinase-1 alpha (CK1α) is a multifunctional protein kinase that belongs to the serine/threonine kinases of the CK1α family. It is involved in various signaling pathways associated with chromosome segregation, cell metabolism, cell cycle progression, apoptosis, autophagy, etc. It has been known to involve in the progression of many diseases, including cancer, neurodegeneration, obesity, and behavioral disorders. The elevated expression of CK1α in diseased conditions facilitates its selective targeting for therapeutic management. Here, we have performed virtual screening of phytoconstituents from the IMPPAT database seeking potential inhibitors of CK1α. First, a cluster of compounds was retrieved based on physicochemical parameters following Lipinski’s rules and PAINS filter. Further, high-affinity hits against CK1α were obtained based on their binding affinity score. Furthermore, the ADMET, PAINS, and PASS evaluation was carried out to select more potent hits. Finally, following the interaction analysis, we elucidated three phytoconstituents, Semiglabrinol, Curcusone_A, and Liriodenine, posturing considerable affinity and specificity towards the CK1α binding pocket. The result was further evaluated by molecular dynamics (MD) simulations, dynamical cross-correlation matrix (DCCM), and principal components analysis (PCA), which revealed that binding of the selected compounds, especially Semiglabrinol, stabilizes CK1α and leads to fewer conformational fluctuations. The MM-PBSA analysis suggested an appreciable binding affinity of all three compounds toward CK1α

B Cell Lymphoma 2: A Potential Therapeutic Target for Cancer Therapy

Defects in the apoptosis mechanism stimulate cancer cell growth and survival. B cell lymphoma 2 (Bcl-2) is an anti-apoptotic molecule that plays a central role in apoptosis. Bcl-2 is the founding constituent of the Bcl-2 protein family of apoptosis controllers, the primary apoptosis regulators linked with cancer. Bcl-2 has been identified as being over-expressed in several cancers. Bcl-2 is induced by protein kinases and several signaling molecules which stimulate cancer development. Identifying the important function played by Bcl-2 in cancer progression and development, and treatment made it a target related to therapy for multiple cancers. Among the various strategies that have been proposed to block Bcl-2, BH3-mimetics have appeared as a novel group of compounds thanks to their favorable effects on many cancers within several clinical settings. Because of the fundamental function of Bcl-2 in the regulation of apoptosis, the Bcl-2 protein is a potent target for the development of novel anti-tumor treatments. Bcl-2 inhibitors have been used against several cancers and provide a pre-clinical platform for testing novel therapeutic drugs. Clinical trials of multiple investigational agents targeting Bcl-2 are ongoing. This review discusses the role of Bcl-2 in cancer development; it could be exploited as a potential target for developing novel therapeutic strategies to combat various types of cancers. We further highlight the therapeutic activity of Bcl-2 inhibitors and their implications for the therapeutic management of cancer

Recent Advances and Implication of Bioengineered Nanomaterials in Cancer Theranostics

Cancer is one of the most common causes of death and affects millions of lives every year. In addition to non-infectious carcinogens, infectious agents contribute significantly to increased incidence of several cancers. Several therapeutic techniques have been used for the treatment of such cancers. Recently, nanotechnology has emerged to advance the diagnosis, imaging, and therapeutics of various cancer types. Nanomaterials have multiple advantages over other materials due to their small size and high surface area, which allow retention and controlled drug release to improve the anti-cancer property. Most cancer therapies have been known to damage healthy cells due to poor specificity, which can be avoided by using nanosized particles. Nanomaterials can be combined with various types of biomaterials to make it less toxic and improve its biocompatibility. Based on these properties, several nanomaterials have been developed which possess excellent anti-cancer efficacy potential and improved diagnosis. This review presents the latest update on novel nanomaterials used to improve the diagnostic and therapeutic of pathogen-associated and non-pathogenic cancers. We further highlighted mechanistic insights into their mode of action, improved features, and limitations

Insights into the Conserved Regulatory Mechanisms of Human and Yeast Aging

Aging represents a significant biological process having strong associations with cancer, diabetes, and neurodegenerative and cardiovascular disorders, which leads to progressive loss of cellular functions and viability. Astonishingly, age-related disorders share several genetic and molecular mechanisms with the normal aging process. Over the last three decades, budding yeast Saccharomyces cerevisiae has emerged as a powerful yet simple model organism for aging research. Genetic approaches using yeast RLS have led to the identification of hundreds of genes impacting lifespan in higher eukaryotes. Numerous interventions to extend yeast lifespan showed an analogous outcome in multi-cellular eukaryotes like fruit flies, nematodes, rodents, and humans. We collected and analyzed a multitude of observations from published literature and provide the contribution of yeast in the understanding of aging hallmarks most applicable to humans. Here, we discuss key pathways and molecular mechanisms that underpin the evolutionarily conserved aging process and summarize the current understanding and clinical applicability of its trajectories. Gathering critical information on aging biology would pave the way for future investigation targeted at the discovery of aging interventions

Investigating regulated signaling pathways in therapeutic targeting of non-small cell lung carcinoma

Non-small cell lung carcinoma (NSCLC) is the most common malignancy worldwide. The signaling cascades are stimulated via genetic modifications in upstream signaling molecules, which affect apoptotic, proliferative, and differentiation pathways. Dysregulation of these signaling cascades causes cancer-initiating cell proliferation, cancer development, and drug resistance. Numerous efforts in the treatment of NSCLC have been undertaken in the past few decades, enhancing our understanding of the mechanisms of cancer development and moving forward to develop effective therapeutic approaches. Modifications of transcription factors and connected pathways are utilized to develop new treatment options for NSCLC. Developing designed inhibitors targeting specific cellular signaling pathways in tumor progression has been recommended for the therapeutic management of NSCLC. This comprehensive review provided deeper mechanistic insights into the molecular mechanism of action of various signaling molecules and their targeting in the clinical management of NSCLC

Thienopyrimidine–Chalcone Hybrid Molecules Inhibit Fas-Activated Serine/Threonine Kinase: An Approach To Ameliorate Antiproliferation in Human Breast Cancer Cells

Apoptotic evasion by cancerous cells being one of the striking hallmarks of cancer has turned into a new arena of drug discovery. A large number of pathways reported that govern the apoptotic evasion have been reported. Fas-activated serine/threonine kinase (FASTK) is a member of Ser/Thr kinase family, and it has been implicated in the apoptotic evasion and, hence, the development of cancer. Keeping this in view, a series of novel thienopyrimidine-based chalcones have been synthesized and evaluated to modulate the FASTK mediated apoptotic evasion. Initial screening was done by enzyme inhibition assay and binding studies, which showed that out of 15 synthesized compounds, 3 thienopyrimidine-based chalcone derivatives possess considerably high binding affinity and enzyme inhibitory potential (nM range) for FASTK. Cell proliferation assessment of selected compounds was performed on HEK-293 and MCF-7 cells. For MCF-7 cells, compounds <b>2</b>, <b>10</b>, and <b>12</b> show IC₅₀ values of 20.22 ± 1.50, 6.52 ± 0.82, and 8.20 ± 0.61 μM, respectively. Annexin-V and PI staining suggested that these molecules induce apoptosis in MCF-7 cells, arrest the cell cycle in the G0/G1 phase, and subsequently inhibit cell migration presumably by inhibiting FASTK and reactive oxygen species production. In conclusion, we have successfully designed, synthesized, and characterized thienopyrimidine-based chalcones that inhibit FASTK and induce apoptosis. These compounds may be exploited as potential anticancer agents