Diosmetin: A dietary flavone as modulator of signaling pathways in cancer progression.

Flavonoids, constituting the most extensive category of polyphenols, founds in a variety of plants and comprise over 9000 compounds. Diosmetin, O-methylated flavone (3',5,7-trihydroxy-4'-methoxyflavone) of flavonoid aglycone diosmin have witnessed a significant surge in recent years. Many studies showed that flavonoids induced cytotoxicity in different organ specific cancer types. Thus, current review evaluates the anticancer potential of diosmetin and shed light on its mechanism of action such as cell cycle regulation, apoptosis via both intrinsic and extrinsic pathway, autophagy and tumour progression and metastasis. It also provides comprehensive analysis of different cancer targets and their role in breast, colon, hepatic, gliomas, leukemia, lung, prostate and skin cancer. Combination studies of diosmetin to improve drug sensitivity and reduce toxicity towards normal cells has been also discussed. Besides, in vitro studies, present review also discuss the anticancer potential of diosmetin on xenograft mice model. Different natural sources of diosmetin, limitations, pharmacokinetic analysis and toxicity study also summarized in current review. The emphasis on enhancing solubility and permeability for clinical utility has been thoroughly highlighted with particular attention given to the utilization of nano formulations to overcome existing barriers. At last, in-depth analysis of current challenges and a forward-looking perspective deliberated to address the existing gaps and position it as a promising lead compound for clinical applications in cancer treatment. This discussion is boosted by diosmetin's potential anticancer properties on different cancers, makes valuable candidates in the ongoing quest for effective therapeutic interventions against cancer.

Unveiling the mechanism of essential oil action against skin pathogens: from ancient wisdom to modern science.

Essential oils are among the most well-known phyto-compounds, and since ancient times, they have been utilized in medicine. Over 100 essential oils have been identified and utilized as therapies for various skin infections and related ailments. While numerous commercial medicines are available in different dosage forms to treat skin diseases, the persisting issues include their side effects, toxicity, and low efficacy. As a result, researchers are seeking novel classes of compounds as substitutes for synthetic drugs, aiming for minimal side effects, no toxicity, and high efficacy. Essential oils have shown promising antimicrobial activity against skin-associated pathogens. This review presents essential knowledge and scientific information regarding essential oil's antimicrobial capabilities against microorganisms that cause skin infections. Essential oils mechanisms against different pathogens have also been explored. Many essential oils exhibit promising activity against various microbes, which has been qualitatively assessed using the agar disc diffusion experiment, followed by determining the minimum inhibitory concentration for quantitative evaluation. It has been observed that Staphylococcus aureus and Candida albicans have been extensively researched in the context of skin-related infections and their antimicrobial activity, including established modes of action. In contrast, other skin pathogens such as Staphylococcus epidermidis, Streptococcus pyogens, Propionibacterium acnes, and Malassezia furfur have received less attention or neglected. This review report provides an updated understanding of the mechanisms of action of various essential oils with antimicrobial properties. This review explores the anti-infectious activity and mode of action of essential against distinct skin pathogens. Such knowledge can be valuable in treating skin infections and related ailments.

THF induces apoptosis by downregulating initiation, promotion, and progression phase biomarkers in skin and lung carcinoma.

3,5,7-Trihydroxy-2-phenylchromen-4-one (THF) possesses a diverse range of pharmacological activities. Evidence suggests that THF exerts anticancer activity by distinct mechanisms of action. This study explores the anticancer potential of THF in human lung (A549) and skin (A431) cancer cells by employing different antiproliferative assays. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, neutral red uptake, sulphorhodamine B, and cell motility assays were used to confirm the anticancer potential of THF. Cell target-based and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were used to explore the effect of THF on the initiation, promotion and progression phase biomarkers of carcinogenesis. THF suppresses the activity of lipoxygenase-5 up to ~40% in both A549 and A431 cells and up to ~50% hyaluronidase activity in A549 cells. qRT-PCR assay reveals that THF inhibits the activity of phosphatidyl inositol-3 kinase/protein kinase B/mammalian target of rapamycin in both cell lines, which is responsible for the initiation of cancer. It also arrests the G2/M phase of the cell cycle in A431 cells and increases the sub-diploid population in both A549 and A431 cell lines which leads to cell death. Annexin V-FITC assay confirmed that THF induces apoptosis and necrosis in A431 and A549 cell lines. Further investigation revealed that THF not only enhances reactive oxygen species production but also modulates mitochondrial membrane potential in both cell lines. It significantly inhibits S-180 tumour formation at 5 and 10 mg/kg bw, i.p. dose. An acute skin toxicity study on mice showed that erythema and edema scores are within the acceptable range, besides acceptable drug-likeness properties and non-toxic effects on human erythrocytes. Conclusively, THF showed potent anticancer activity on skin and lung carcinoma cell lines, suppressed the level of the biomarkers and inhibited tumour growth in mice.

Monoterpenoids: An upcoming class of therapeutic agents for modulating cancer metastasis.

Monoterpenoids, a sub-class of terpenoids, are secondary metabolites frequently extracted from the essential oils of aromatic plants. Their antitumor properties including antiproliferative, apoptotic, antiangiogenic, and antimetastatic effects along with other biological activities have been the subject of extensive study due to their diverse characteristics. In recent years, numerous investigations have been conducted to understand its potential anticancer impacts, specifically focusing on antiproliferative and apoptotic mechanisms. Metastasis, a malignancy hallmark, can exert either protective or destructive influences on tumor cells. Despite this, the potential antimetastatic and antiangiogenic attributes of monoterpenoids need further exploration. This review focuses on specific monoterpenoids, examining their effects on metastasis and relevant signaling pathways. The monoterpenoids exhibit a high level of complexity as natural products that regulate metastatic proteins through various signaling pathways, including phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, mitogen-activated protein kinase/extracellular signal-regulated kinase/jun N-terminal kinase, nuclear factor kappa B, vascular endothelial growth factor, and epithelial mesenchymal transition process. Additionally, this review delves into the biosynthesis and classification of monoterpenoids, their potential antitumor impacts on cell lines, the plant sources of monoterpenoids, and the current status of limited clinical trials investigating their efficacy against cancer. Moreover, monoterpenoids depict promising potential in preventing cancer metastasis, however, inadequate clinical trials limit their drug usage. State-of-the-art techniques and technologies are being employed to overcome the challenges of utilizing monoterpenoids as an anticancer agent.

Escin-sorafenib synergy up-regulates LC3-II and p62 to induce apoptosis in hepatocellular carcinoma cells.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common solid cancer and the leading cause of cancer deaths worldwide. Sorafenib is the first drug used to treat HCC but its effectiveness needs to be improved, and it is important to find ways to treat cancer that combine sorafenib with other drugs. Synergistic therapies lower effective drug doses and side effects while enhancing the anticancer effect. PURPOSE: In the present study, the therapeutic potential of sorafenib in combination with escin and its underlying mechanism in targeting liver cancer has been established. STUDY DESIGN/METHODS: The IC50 of sorafenib and escin against HepG2, PLC/PRF5 and Huh7 cell lines were determined using MTT assay. The combination index, dose reduction index, isobologram and concentrations producing synergy were evaluated using the Chou-Talaly algorithm. The sub-effective concentration of sorafenib and escin was selected to analyze cytotoxic synergistic potential. Cellular ROS, mitochondrial membrane potential, annexin V and cell cycle were evaluated using a flow-cytometer, and autophagy biomarkers were determined using western blotting. Moreover, autophagy was knocked down using ATG5 siRNA to confirm its role. A DEN-induced liver cancer rat model was developed to check the synergy of sorafenib and escin. RESULTS: Different concentrations of escin reduced the IC50 of sorafenib in HepG2, PLC/PRF5 and Huh7 cell lines. Chou-Talaly algorithm determined cytotoxic synergistic concentrations of sorafenib and escin in these cell lines. Mechanistically, this combination over-expressed p62 and LC-II, reflecting autophagy block and induced late apoptosis, further reconfirmed by ATG5 knockdown. Sorafenib and escin combination  reduced HCC serum biomarker α-feto protein (α-FP) by 1.5 folds. This combination restricted liver weight, tumor number and size, also, conserved morphological features of liver cells. The combination selectively targeted the G0 /G1 phase of cancer cells. CONCLUSION: Escin and sorafenib combination potentially up-regulates p62 to block autophagy to induce late apoptosis in liver cancer cells.

3,5,7-trihydroxyflavone restricts proliferation of androgen-independent human prostate adenocarcinoma cells by inducing ROS-mediated apoptosis and reduces tumour growth.

Flavonoids are among the largest groups of secondary metabolites. Studies suggest that dietary intake of flavonoids reduces the risk of cancer. 3,5,7-trihydroxyflavone (THF) belongs to the flavone class of flavonoids and potentially inhibits the growth of many cancers; however, it is unexplored in prostate cancer. This study reports the antiproliferative potential of THF in prostate cancer cell line via reactive oxygen species (ROS)-mediated cascades and examines the tumour reduction potential in swiss albino mice. The potency of THF was evaluated by employing cytotoxicity assays and wound healing assays. Cell cycle, ROS, mitochondrial membrane potential (MMP), and Annexin-V-FITC assay were performed using a flow cytometer. In vivo, anticancer potential was achieved using the mice Ehrlich Ascites Carcinoma (EAC) model. THF inhibits cell growth with IC50 of 64.30 µM (MTT), 81.22 µM (NRU) and 25.81 µM (SRB), substantiated by cell migration assay. Cell-cycle analysis revealed that THF increases the subdiploid population. Furthermore, the Annexin-V-FITC assay evoked a significant induction of late apoptosis at a higher concentration of THF. THF also disrupts MMP, caused by an increased generation of ROS. In the EAC model, THF significantly inhibits tumour growth and increases the percent survival of mice and ROS levels in EAC cells. Hence, it may be concluded that THF might execute its antiproliferative effect via inducing ROS generation and could be a promising lead for preclinical and clinical validations.

Escin enhanced the efficacy of sorafenib by autophagy-mediated apoptosis in lung cancer cells.

Combining anti-cancer drugs has been exploited as promising treatment strategy to target lung cancer. Synergistic chemotherapies increase anti-cancer effect and reduce effective drug doses and side effects. In this study, therapeutic potential of escin in combination with sorafenib has been explored. 3-(4,5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide assay was used to calculate IC50 values. The synergy was evaluated using Chou-Talaly algorithm. Cellular reactive oxygen species, mitochondrial membrane potential, annexin V, and cell-cycle studies were done by flow-cytometer, and autophagy biomarkers expression were determined using western blotting. Moreover, autophagy was knocked down using ATG5 siRNA to confirm its role, diethylnitrosamine-induced lung cancer model was used to check the synergy of sorafenib/escin. Escin significantly reduced the IC50 of sorafenib in A549 and NCIH460 cells. The combination of sorafenib/escin produced a 2.95 and 5.45 dose reduction index for sorafenib in A549 and NCI-H460 cells. The combination of over-expressed p62 and LC3-II reflects autophagy block-mediated late apoptosis. This phenomenon was reconfirmed by ATG5 knockdown. This combination also selectively targeted G0/G1 phase of cancer cells. In in vivo study, the combination reduced tumour load and lower elevated serum biochemical parameters. The combination of sorafenib/escin synergistically inhibits autophagy to induce late apoptosis in lung cancer cells' G0/G1 phase.

Dietary flavonoid narirutin as a prospective antagonist of oncogenic pri/pre-microRNAs.

MicroRNAs (miRNAs) are involved in cancer progression via translational degradation in a sequence-specific manner of the 3'-untranslated region (3'UTR) of messenger RNA (mRNA). The involvement of miRNA in the biological progression of various cancer types is considered to be a potential target. Primary miRNA (pri-miRNA) and precursor-miRNA (pre-miRNA) synthesize the miRNA by dicer-catalyzed processes thus targeting pri/pre-miRNA by phytochemicals is amongst the appropriate approaches for anticancer therapies. Flavonoids category of phytochemicals is well-known for its chemotherapeutic and chemopreventive potential against multiple cancer types. However, the molecular interactions of flavonoids with miRNAs are not reported so far. Thus, this study aims to identify the promising flavonoids as the antagonist of miRNAs (pre-miR21, pri-miR-208a, pri-miR-378a, pri-miR320b, pri-miR-300, pri-miR-19b, and pre-miR-20b) using molecular docking simulations studies. Among the tested flavonoids, narirutin showed highest binding energy (-11.7 kcal/mol) against pri-miR19b followed by pri-miR-378a (-11.4 kcal/mol) > pri-miR320b (-11.2 kcal/mol) = pri-miR-300 (-11.2 kcal/mol) > pri-miR-208a (-9.0 kcal/mol) > pre-miR-20b (- 8.3 kcal/mol). The molecular dynamic simulation experiment confirmed that narirutin destabilizes the tertiary structure of pri-miRNA in comparison to apo-RNA. The finding indicates that narirutin binding with pre-miRNA causes disruption of pri-RNA structure that creates a loss of DICER-pre-miRNA interactions by hindering the pre-miRNA synthesis, thereby affecting miRNA processing. Further pharmacokinetics and toxicity prediction revealed that it is non-carcinogenic, non-mutagenic, and does not inhibit the CYPs activity. Thus, narirutin could be a possible antagonist of oncogenic miRNAs, therefore could be useful for miRNA-targeted cancer prevention and treatment.

Baicalin mediated regulation of key signaling pathways in cancer.

Baicalin has been widely investigated against different types of malignancies both at the cellular and molecular levels over the past few years. Due to its remarkable anti-proliferative potential in numerous cancer cell lines, it has created immense interest as a potential chemotherapeutic modality compared to other flavonoids. Thus, this review focuses on the recent accomplishments of baicalin and its limitations in cancer prevention and treatment. Further, combination studies and nanoformulations using baicalin to treat cancer along with the metabolism, bioavailability, toxicity, and pharmacokinetics have been discussed. The present review explains biological source, and anti-proliferative potential of baicalin against cancers including breast, colon, hepatic, leukemia, lung, and skin, as well as the relevant mechanism of action to modulate diverse signaling pathways including apoptosis, cell cycle, invasion, and migration, angiogenesis, and autophagy. The anticancer mechanism of baicalin in orthotropic and xenograft mice models have been deliberated. The combination studies of baicalin in novel therapies as chemotherapeutic adjuvants have also been summarized. The low bioavailability, fast metabolism, and poor solubility, and other significant factors that limit the clinical use of baicalin have been examined as a challenge. The improvement in the pharmacokinetics and pharmacodynamics of baicalin with newer approaches and the gaps are highlighted, which could establish baicalin as an effective and safe compound for cancer treatment as well as help to translate its potential from bench to bedside.

Synthesis and biological evaluation of substituted amide derivatives of C4-ageratochromene dimer analog.

Substituted amide derivatives of C4-ageratochromene dimer analog (19) were synthesized through structural modification of precocene-I (4a), isolated from the essential oil of Ageratum conyzoides L. The target compounds (18-20, 23I-VI, 24I-VI, and 25I-VI) were evaluated for their bone-forming effect using osteoblast differentiation assay. Seven compounds (23I, 23II, 23IV, 23VI, 24III, 24VI, and 25VI) presented good activity within 1 pM-1 nM concentration. At 1 pM concentration, the most active compound i.e. 23II showed effective mineralization of osteoblast cells along with expression of osteogenic marker genes viz RUNX 2, BMP-2, and type 1 collagen (Type-1 col) without any toxicity towards osteoblast cells. Single crystal X-ray analysis of 18 and 20 revealed that the core nucleus of these molecules bear phenyl rings in a Trans-stilbenoid system and had a good structural correlation with 17ß-estradiol (1) and diethylstilbestrol (DES, 3). In-silico study about 23II showed its structural complementarities with the LBD of estrogen receptor (ER) which indicated possible ER-mediated activity of compounds.

Purpurin: A natural anthraquinone with multifaceted pharmacological activities.

Purpurin is a naturally occurring anthraquinone isolated from the roots of Rubia cordifolia. Historically, it has been used as a red dye. However, its photosensitizing property and biological effects have deciphered its novel application. Purpurin shows antigenotoxic, anticancer, neuromodulatory, and antimicrobial potential associated with antioxidant action in in vivo and in vitro experiments. A robust antioxidant nature of purpurin is responsible for the majority of its pharmacological effects. It produces anti-inflammatory activity by reducing oxidative stress, which is a fundamental property to target diseases involving endoplasmic reticulum and mitochondrial stress. It can cross the blood-brain barrier and produce neuroprotective effects, including antidepressant and anti-Alzheimer action. It shows antimutagenic property via inhibiting essential CYP-450 enzymes. Interestingly, it gets photosensitized by UV-light and produces target-specific ROS-dependent apoptosis in cancer cells. Therefore, it owns cell killing and cell survival potential subject to the influence of external conditions. Hitherto, limited research studies are performed with purpurin to understand its therapeutic potential. Hence, this review describes and discusses different in vivo, in vitro, and in silico studies performed using purpurin. It also covers physicochemical, pharmacokinetics, and toxicology aspects of purpurin. Moreover, in the end, the prospect of purpurin in the management of cancer has also been proposed.

Geraniol exerts its antiproliferative action by modulating molecular targets in lung and skin carcinoma cells.

Geraniol, an acyclic monoterpene present in several plant species' essential oils, is utilized as a food additive. It possesses potent antiproliferative and antitumor effects ascribed to its antiinflammatory, and antioxidant properties. The study aimed to understand geraniol's mechanism in human lung and skin cancer cells by employing molecular and cell target-based assays. SRB, NRU, MTT assays, qRT-PCR, molecular docking, and EAC model were used. Geraniol inhibits the proliferation of PC-3, A431, and A549 cells (~50%) and suppresses the activity of ornithine decarboxylase (15.42 ± 0.61 µM) and hyaluronidase (57.61 ± 8.53 µM) in A549 cells; LOX-5 (25.44 ± 3.50 µM) and hyaluronidase (90.71 ± 2.38 µM) in A431 cells. The qRT-expression analysis of the targeted gene depicts non-significant change at the transcriptional level of LOX-5 in A431 cells. A robust binding interaction of geraniol with molecular targets was observed in the molecular docking studies. In Ehrlich Ascites Carcinoma model, geraniol inhibit tumor growth by 50.08% at 75 mg/kg bw and was found to be safe up to 1,000 mg/kg bw in a toxicity study. Geraniol has two prenyl units allied head-to-tail and functionalized with one hydroxyl group at its tail end could be responsible for the antiproliferative activity. These observations provide evidence for geraniol to be used as a new prototype to develop a novel anticancer agent.

Diversity of Essential Oil-Secretory Cells and Oil Composition in Flowers and Buds of Magnolia sirindhorniae and Its Biological Activities.

Magnolia sirindhorniae Noot. & Chalermglin produces fragrant flowers. The volatile oil secretary cells, quantity and quality as well as antioxidant and antimicrobial activities of the oils extracted from buds and flowers, have been investigated. The distribution of essential oil secretory cell in bud and flower revealed that the density and size of the oil cells were significantly higher in flowers compared to buds. In different floral parts, carpel has a higher oil cell density followed by gynophore and tepal. The histochemical analysis revealed the essential oil is synthesized in oil secretory cells. The volatile oil yield was 0.25 % in the buds and 0.50 % in flowers. GC/FID and GC/MS analysis identified 33 compounds contributing 83.2-83.5 % of the total essential oil composition. Linalool is the main constituent contributing 58.9 % and 51.0 % in the buds and flowers oils, respectively. The essential oil extracted from the flowers showed higher antimicrobial efficacy against Klebsiella pneumoniae and Staphylococcus aureus. Similarly, the essential oil isolated from the flowers depicts higher free radical scavenging, and antioxidant activity compared to buds' oil.

Prospects of tangeretin as a modulator of cancer targets/pathways.

To date, cancer is the second leading cause of death worldwide after cardiac arrest. A large number of synthetic drugs are available for the treatment of different types of cancer; however, a major problem associated with these drugs is its toxicity towards the normal cells. To overcome these problems, researchers explore plants derived phytochemicals because of their pleiotropic action and least toxicity towards the normal cells. Tangeretin is a polymethoxylated flavone found extensively in citrus fruits and has shown potent anti-cancer activity in different types of cancer cells. Hence, this review examines the anti-cancer activity of tangeretin via different molecular targets/pathways. Tangeretin induces apoptosis via intrinsic as well as extrinsic pathways and arrest the cell cycle. It also suppresses cell proliferation by modulating PI3K/AKT/mTOR, Notch, and MAPK signalling pathways. Besides, it induces autophagic cell death, suppresses migration, invasion, and angiogenesis. Further, the role of tangeretin in multi-drug resistance and combination therapy, different biological sources of tangeretin, its derivatives, and pharmacokinetics profile and toxicity studies are also discussed. Towards the end, the challenges associated with tangeretin usage as potential anti-cancer phytochemicals have also been discussed. Tangeretin, like a pandora's box, needs to be explored further, and more research is warranted to improve its usefulness for better human health.

Induced osteoblast differentiation by amide derivatives of stilbene: The possible osteogenic agents.

A series of amide derivatives of stilbene was synthesized and investigated for osteogenic activity. Out of sixteen, seven compounds viz19c, 19g, 19i, 24b, 25a, 25c and 26a showed significant osteoblast differentiation within 1 pM-1 µM concentrations. Amongst all, 26a was identified as most active molecule which presented effective mineralization of osteoblasts and expression of mRNA of osteogenic marker gene such as BMP-2, ALP, and Runx-2 at 1 pM. In estrogen-deficient balb/c mice, 26a showed significant osteogenic activity at 5 mg-kg-1 body weight dose. The protein expression study for estrogen receptors α and ß (ER-α & ER-ß) using mouse calvarial osteoblasts (MCOs) and molecular docking analyses showed preferential expression of ER-ß by 26a indicating the possibility of ER-ß mediated osteogenic activity of 26a.

Hesperidin-CAMKIV interaction and its impact on cell proliferation and apoptosis in the human hepatic carcinoma and neuroblastoma cells.

Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is a key regulatory molecule of cell signaling, and thereby controls its growth and proliferation, including expression of certain genes. The overexpression of CAMKIV is directly associated with the development of different types of cancers. Hesperidin is abundantly found in citrus fruits and exhibits wide range of pharmacological activities including anti-inflammatory, antibacterial and anticancerous effects. We have investigated binding mechanism of hesperidin with the CAMKIV using molecular docking methods followed by fluorescence quenching and isothermal titration calorimetric assays. An appreciable binding affinity of hesperidin was observed with CAMKIV during fluorescence quenching and isothermal titration calorimetric studies. Efficacy of hesperidin to inhibit the growth of human hepatic carcinoma (HepG2) and neuroblastoma (SH-SY5Y) cancer cell lines were investigated. Hesperidin has significantly reduced the proliferation of HepG2 and SH-SY5Y cells and induces apoptosis by activating the caspase-3-dependent intrinsic pathway through the upregulation of proapoptotic Bax protein. Hesperidin treatment reduces the mitochondrial membrane potential of HepG2 and SH-SY5Y cells. All these observations clearly anticipated hesperidin a potent inhibitor of CAMKIV which may be further exploited a newer therapeutic approach for the management of different cancer types.

Targeting Ca2+ signalling through phytomolecules to combat cancer.

Cancer is amongst the life-threatening public health issue worldwide, hence responsible for millions of death every year. It is affecting human health regardless of their gender, age, eating habits, and ecological location. Many drugs and therapies are available for its cure still the need for effective targeted drugs and therapies are of paramount importance. In the recent past, Ca2+ signalling (including channels/transporters/pumps) are being studied as a plausible target for combating the cancer menace. Many evidence has shown that the intracellular Ca2+ homeostasis is altered in cancer cells and the remodelling is linked with tumor instigation, angiogenesis, progression, and metastasis. Focusing on these altered Ca2+ signalling tool kit for cancer treatment is a cross-cutting and emerging area of research. In addition, there are numerous phytomolecules which can be exploited as a potential Ca2+ (channels/transporters/ pumps) modulators in the context of targeting Ca2+ signalling in the cancer cell. In the present review, a list of plant-based potential Ca2+ (channel/transporters/pumps) modulators has been reported which could have application in the framework of repurposing the potential drugs to target Ca2+ signalling pathways in cancer cells. This review also aims to gain attention in and support for prospective research in this field.

Evidence of vanillin binding to CAMKIV explains the anti-cancer mechanism in human hepatic carcinoma and neuroblastoma cells.

Human calcium/calmodulin-dependent protein kinase IV (CAMKIV) is a member of Ser/Thr kinase family, and is associated with different types of cancer and neurodegenerative diseases. Vanillin is a natural compound, a primary component of the extract of the vanilla bean which possesses varieties of pharmacological features including anti-oxidant, anti-inflammatory, anti-bacterial and anti-tumor. Here, we have investigated the binding mechanism and affinity of vanillin to the CAMKIV which is being considered as a potential drug target for cancer and neurodegenerative diseases. We found that vanillin binds strongly to the active site cavity of CAMKIV and stabilized by a large number of non-covalent interactions. We explored the utility of vanillin as anti-cancer agent and found that it inhibits the proliferation of human hepatocyte carcinoma (HepG2) and neuroblastoma (SH-SY5Y) cells in a dose-dependent manner. Furthermore, vanillin treatment resulted into the significant reduction in the mitochondrial membrane depolarization and ROS production that eventually leads to apoptosis in HepG2 and SH-SY5Y cancer cells. These findings may offer a novel therapeutic approach by targeting the CAMKIV using natural product and its derivative with a minimal side effect.

Antioxidant efficacy of chitosan/graphene functionalized superparamagnetic iron oxide nanoparticles.

The antioxidant potential of superparamagnetic iron oxide nanoparticles functionalized with chitosan and graphene were examined in the present work. Coprecipitation technique was followed for the synthesis of iron oxide nanoparticles. Graphene-iron oxide nanocomposites were synthesized by mechanical mixing followed by the heat treatment at moderate temperature. The chitosan coated iron oxide nanoparticles were prepared by dispersing nanoparticles in chitosan solution. The nanoparticles/nanocomposites were characterized using XRD, SEM, TEM and HAADF-STEM for phase structure, morphology and elemental analysis. The superparamagnetic behavior of nanoparticles/nanocomposites were confirmed by magnetic measurements using vibrating sample magnetometry. Antioxidant efficacy of these nanoparticles/nanocomposites were investigated in terms of free radical scavenging and reducing potential using an array of in vitro assay system. Ferric reducing antioxidant power (FRAP) and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) were used for the antioxidant capacity. The investigation suggests that the graphene improves the antiradical response of iron oxide nanoparticles at higher concentration which is almost comparable to the ascorbic acid used as standard.

Synthesis of pharmacologically important naphthoquinones and anticancer activity of 2-benzyllawsone through DNA topoisomerase-II inhibition.

Naphthoquinones are naturally occurring biologically active entities. Practical de novo syntheses of three naphthoquinones i.e. lawsone (1), lapachol (2), and ß-lapachone (3b) have been achieved from commercially available starting materials. The conversion of lapachol (2) to ß-lapachone (3b) was achieved through p-TSA/Iodine/BF3-etherate mediated regioselective cyclisation. Further, 2-alkyl and 2-benzyllawsone derivatives have been prepared as possible anticancer agents. Four derivatives exhibited significant anticancer activity and the best analogue i.e. compound 21a exhibited potential anticancer activity (IC50=5.2µM) against FaDu cell line. Compound 21a induced apoptosis through activation of caspase pathway and exerted cell cycle arrest at S phase in FaDU cells. It also exhibited significant topoisomerase-II inhibition activity. Compound 21a was found to be safe in Swiss albino mice up to 1000mg/kg oral dose.