Exploring apoptotic induction of malabaricone A in triple-negative breast cancer cells: an acylphenol phyto-entity isolated from the fruit rind of Myristica malabarica Lam.

Myristica malabarica Lam., commonly known as Malabar nutmeg or false nutmeg, is used in traditional medicine and as a spice. Our exploration focuses on malabaricones, a distinct group of secondary metabolites isolated from the fruit rind of M. malabarica. We investigated the selective cytotoxicity of malabaricones against the triple-negative breast cancer (TNBC) cell line. In particular, malabaricone A (Mal-A) displays heightened toxicity towards TNBC cells (MDA-MB-231), with an IC50 of 8.81 ± 0.03 µM. In vitro fluorimetric assays confirmed the apoptotic capability of Mal-A and its capacity to induce nuclear fragmentation. Additionally, ultrasensitive surface-enhanced Raman spectroscopy confirms DNA fragmentation during cellular apoptosis. Cell cycle analysis indicates arrest during the sub-G0 phase by downregulating key regulatory proteins involved in cell cycle progression. Increased expression levels of caspase 3, 9, and 8 suggest involvement of both extrinsic and intrinsic apoptotic pathways. Finally, assessment of protein expression patterns within apoptotic pathways reveals upregulation of key apoptotic proteins like Fas/FasL, TNF/TNFR1, and p53, coupled with downregulation of several inhibitors of apoptosis proteins such as XIAP, cIAP-2, and Livin. These findings are further verified with in silico molecular docking. Mal-A reveals a strong affinity towards apoptotic proteins, including TNF, Fas, HTRA, Smac, and XIAP, with docking scores ranging from -5.1 to -7.2 kcal mol-1. Subsequently, molecular dynamics simulation confirms the binding stability. This conclusive in vitro evaluation validates Mal-A as a potent phyto-entity against TNBC. To the best of our knowledge, this study represents the first comprehensive anticancer evaluation of Mal-A in TNBC cells.

A comprehensive apoptotic assessment of niloticin in cervical cancer cells: a tirucallane-type triterpenoid from Aphanamixis polystachya (Wall.) Parker.

Pharmacologically active small organic molecules derived from natural resources are prominent drug candidates due to their inherent structural diversity. Herein, we explored one such bioactive molecule, niloticin, which is a tirucallane-type triterpenoid isolated from the stem barks of Aphanamixis polystachya (Wall.) Parker. After initial screening with other isolated compounds from the same plant, niloticin demonstrated selective cytotoxicity against cervical cancer cells (HeLa) with an IC50 value of 11.64 µM. Whereas the compound exhibited minimal cytotoxicity in normal epithelial cell line MCF-10A, with an IC50 value of 83.31 µM. Subsequently, in silico molecular docking studies of niloticin based on key apoptotic proteins such as p53, Fas, FasL, and TNF ß revealed striking binding affinity, reflecting docking scores of -7.2, -7.1, -6.8, and -7.2. Thus, the binding stability was evaluated through molecular dynamic simulation. In a downstream process, the apoptotic capability of niloticin was effectively validated through in vitro fluorimetric assays, encompassing nuclear fragmentation. Additionally, an insightful approach involving surface-enhanced Raman spectroscopy (SERS) re-establishes the occurrence of DNA cleavage during cellular apoptosis. Furthermore, niloticin was observed to induce apoptosis through both intrinsic and extrinsic pathways. This was evidenced by the upregulation of upstream regulatory molecules such as CD40 and TNF, which facilitate the activation of caspase 8. Concurrently, niloticin-induced p53 activation augmented the expression of proapoptotic proteins Bax and Bcl-2 and downregulation of IAPs, leading to the release of cytochrome C and subsequent activation of caspase 9. Therefore, the reflection of mitochondrial-mediated apoptosis is in good agreement with molecular docking studies. Furthermore, the anti-metastatic potential was evidenced by wound area closure and Ki67 expression patterns. This pivotal in vitro assessment confirms the possibility of niloticin being a potent anti-cancer drug candidate, and to the best of our knowledge, this is the first comprehensive anticancer assessment of niloticin in HeLa cells.

Pharmacological attenuation of melanoma by tryptanthrin pertains to the suppression of MITF-M through MEK/ERK signaling axis.

Melanoma is the most aggressive among all types of skin cancers. The current strategies against melanoma utilize BRAFV600E, as a focal point for targeted therapy. However, therapy resistance developed in melanoma patients against the conventional anti-melanoma drugs hinders the ultimate benefits of targeted therapies. A major mechanism by which melanoma cells attain therapy resistance is via the activation of microphthalmia-associated transcription factor-M (MITF-M), the key transcription factor and oncogene aiding the survival of melanoma cells. We demonstrate that tryptanthrin (Tpn), an indole quinazoline alkaloid, which we isolated and characterized from Wrightia tinctoria, exhibits remarkable anti-tumor activity towards human melanoma through the down-regulation of MITF-M. Microarray analysis of Tpn-treated melanoma cells followed by a STRING protein association network analysis revealed that differential expression of genes in melanoma converges at MITF-M. Furthermore, in vitro and in vivo studies conducted using melanoma cells with differential MITF-M expression status, endogenously or ectopically, demonstrated that the anti-melanoma activity of Tpn is decisively contingent on its efficacy in down-regulating MITF-M expression. Tpn potentiates the degradation of MITF-M via the modulation of MEK1/2-ERK1/2-MITF-M signaling cascades. Murine models demonstrate the efficacy of Tpn in attenuating the migration and metastasis of melanoma cells, while remaining pharmacologically safe. In addition, Tpn suppresses the expression of mutated BRAFV600E and inhibits Casein Kinase 2α, a pro-survival enzyme that regulates ERK1/2 homeostasis in many tumor types, including melanoma. Together, we point to a promising anti-melanoma drug in Tpn, by virtue of its attributes to impede melanoma invasion and metastasis by attenuating MITF-M.

Exploring the Cytotoxic Effects of the Extracts and Bioactive Triterpenoids from Dillenia indica against Oral Squamous Cell Carcinoma: A Scientific Interpretation and Validation of Indigenous Knowledge.

Triterpenoids are ubiquitously distributed secondary metabolites, primarily scrutinized as a source of medication and preventive measures for various chronic diseases. The ease of isolation and excellent pharmacological properties of triterpenoids are notable reasons behind the exponential rise of extensive research on the bioactive triterpenoids over the past few decades. Herein, we attempted to explore the anticancer potential of the fruit extract of the ethnomedicinal plant Dillenia indica against oral squamous cell carcinoma (OSCC) and have exclusively attributed the efficacy of the extracts to the presence of two triterpenoids, namely, betulinic acid (BA) and koetjapic acid (KA). Preliminary in vitro screening of both BA and KA unveiled that the entities could impart cytotoxicity and induce apoptosis in OSCC cell lines, which were further well-supported by virtual screening based on ligand binding affinity and molecular dynamic simulations. Additionally, the aforementioned metabolites could significantly modulate the critical players such as Akt/mTOR, NF-κB, and JAK/STAT3 signaling pathways involved in the regulation of important hallmarks of cancer like cell survival, proliferation, invasion, angiogenesis, and metastasis. The present findings provide insight and immense scientific support and integrity to a piece of indigenous knowledge. However, in vivo validation is a requisite for moving to clinical trials and developing it as a commercial drug.

Exploring Mitochondria-Mediated Intrinsic Apoptosis by New Phytochemical Entities: An Explicit Observation of Cytochrome c Dynamics on Lung and Melanoma Cancer Cells.

Hydnocarpin (Hy) is a flavonoid isolated and purified from the seeds of Hydnocarpus wightiana Blume. Herein, we have developed a built-in semi-synthetic modification on Hy by one-pot multi-component reaction and a [3 + 2] cycloaddition strategy to append five membered isoxazole and isoxazolone as new phytochemical entities (NPCEs). Two selected NPCEs viz Hy-ISO-VIII and Hy-ISO-G from the library of 20 newly synthesized derivatives after in vitro screening unveiled promising cytotoxicity and induced caspase-mediated apoptosis against the human lung and melanoma cancer cells which were well supported by virtual screening based on ligand binding affinity and molecular dynamic simulations. As a new insight, we introduced surface-enhanced Raman spectroscopy to identify the chemo-marker molecular fingerprint to confirm the cellular uptake, cytochrome c release, and DNA fragmentation in a label-free manner. The present findings throw up a surfeit of seminal reasons behind the semi-synthetic modification of Hy, stepping forward to cancer chemotherapy.

Screening of Musa balbisiana Colla. seeds for antidiabetic properties and isolation of apiforol, a potential lead, with antidiabetic activity.

BACKGROUND: 'Phytonutrients' have been reported to exert an incredible impact on the healthcare system and offer medical benefits including the prevention or treatment of lifestyle-associated diseases. We chose one of the most common and important plant families, Musaceae, for our present study and explored its antidiabetic potential. RESULTS: Seeds of the edible fruits of Musa balbisiana Colla. were investigated for their antidiabetic potential. After estimating the proximate composition, the seeds were extracted with various solvents and evaluated for antidiabetic potential in terms of the inhibition of digestive enzymes, antiglycation activity and in vitro glucose uptake. The acetone extract demonstrated the highest inhibition of α-amylase and α-glucosidase enzymes with IC50 values of 36.67 ± 0.367 and 100.61 ± 0.707 µg mL-1 , respectively. The extract also exhibited significant glycation inhibition with an IC50 value of 86.48 ± 0.751 µg mL-1 . Furthermore, a major phytochemical, apiforol, was isolated from the acetone extract for the first time, which demonstrated promising α-glucosidase inhibition (IC50  = 48.25 ± 0.255 µmol L-1 ), antiglycation property (IC50  = 114.23 ± 0.567 µmol L-1 ) and enhanced glucose uptake in L6 myoblasts. In molecular docking studies, apiforol efficiently bonded to the active sites of α-glucosidase enzyme 3A4A. CONCLUSIONS: As dietary intervention is one of the effective strategies for addressing diabetes, special attention is always given to natural food bio-actives or agro-products for better human health. The results of our study suggest that Musa balbisiana has significant potential as an ingredient in health food formulations by reducing postprandial hyperglycaemia. © 2018 Society of Chemical Industry.

Mechanochemical Synthesis and Antioxidant Activity of Curcumin-Templated Azoles.

A solvent-free, mechanochemical method for the synthesis of curcumin (1) derived 3,5-bis(styryl)pyrazoles and 3,5-bis(styryl)isoxazole (2a-g) at room temperature, with very short reaction time, is reported. Such earlier structural modifications of curcumin, at its ß-diketone unit by transforming it into an isosteric pyrazole or isoxazole unit, required prolonged heating. The evaluation of the antioxidant activity of these compounds, based on DPPH, FRAP, and ß-carotene bleaching assays, showed that several of these azoles are better antioxidants than curcumin, with the isoxazole derivative 2g being overall the best. Typically, the inhibition of 2,2-diphenyl-1-picrylhydrazyl (10(-2) mmol), expressed as EC50 values, by curcumin (1), 3,5-bis(4-hydroxy-3-methoxystyryl)pyrazole (2a), and 3,5-bis(4-hydroxy-3-methoxystyryl)isoxazole (2g) are 40 ± 0.06, 14 ± 0.18, and 8 ± 0.11 µmol, respectively. Moreover, the reported method is useful in accessing 3,5-bis(4-hydroxy-3-methoxystyryl)-1-phenylpyrazole (2b), which is important in studies related to neuroprotection and Alzheimer's disease, and 2a and 2g, which are inhibitors of protein kinases involved in neuronal excitotoxicity.