Quinoxalinone substituted pyrrolizine (4h)-induced dual inhibition of AKT and ERK instigates apoptosis in breast and colorectal cancer by modulating mitochondrial membrane potential.

AKT and ERK 1/2 play a pivotal role in cancer cell survival, proliferation, migration, and angiogenesis. Therefore, AKT and ERK 1/2 are considered crucial targets for cancer intervention. In this study, we envisaged the role of AKT and ERK signaling in apoptosis regulation in presence of compound 4h, a novel synthetic derivative of quinoxalinone substituted spiropyrrolizines exhibiting substantial antiproliferative activity in various cancer cell lines. Structurally 4h is a spiropyrrolizine derivative. Molecular docking analysis revealed that compound 4h shows strong binding affinity with AKT-1 (-9.5 kcal/mol) and ERK2 (-9.0 kcal/mol) via binding at allosteric sites of AKT and active site of ERK2. The implications of 4h binding with these two survival kinases resulted in the obstruction for ATP binding, hence, hampering their phosphorylation dependent activation. We demonstrate that 4h mediated apoptotic induction via disruption in the mitochondrial membrane potential of MCF-7 and HCT-116 cells and 4h-mediated inhibition of survival pathways occurred in a wild type PTEN background and is diminished in PTEN-/- cells. In 4T1 mammary carcinoma model, 4h exhibited pronounced reduction in the tumor size and tumor volume at significantly low doses. Besides, 4h reached the highest plasma concentration of 5.8 µM within a period of 1 h in mice model intraperitoneally. Furthermore, 4h showed acceptable clearance with an adequate elimination half-life and satisfactory pharmacokinetic behaviour, thus proclaiming as a potential lead molecule against breast and colorectal cancer by specifically inhibiting simultaneously AKT and ERK1/2 kinases.

ß-(4-fluorobenzyl) Arteannuin B induced interaction of ATF-4 and C/EBPß mediates the transition of breast cancer cells from autophagy to senescence.

ATF-4 is a master regulator of transcription of genes essential for cellular-adaptive function. In response to the quantum and duration of stress, ATF-4 diligently responds to both pro-apoptotic and pro-survival signals converging into either autophagy or apoptosis/senescence. Despite emerging cues implying a relationship between autophagy and senescence, how these two processes are controlled remains unknown. Herein, we demonstrate ß-(4-fluorobenzyl) Arteannuin B (here after Arteannuin 09), a novel semisynthetic derivative of Arteannuin B, as a potent ER stress inducer leading to the consistent activation of ATF-4. Persistent ATF-4 expression at early time-points facilitates the autophagy program and consequently by upregulating p21 at later time-points, the signaling is shifted towards G2/M cell cycle arrest. As bZIP transcription factors including ATF-4 are obligate dimers, and because ATF-4 homodimers are not highly stable, we hypothesized that ATF-4 may induce p21 expression by physically interacting with another bZIP family member i.e., C/EBPß. Our co-immunoprecipitation and co-localization studies demonstrated that ATF-4 is principally responsible for the autophagic potential of Arteannuin 09, while as, induction of both ATF-4 and C/EBPß is indispensable for the p21 regulated-cell cycle arrest. Interestingly, inhibition of autophagy signaling switches the fate of Arteannuin 09 treated cells from senescence to apoptosis. Lastly, our data accomplished that Arteannuin 09 is a potent inhibitor of tumor growth and inducer of premature senescence in vivo.

Heterochiral dipeptide d-phenylalanyl- l-phenylalanine (H-D Phe-L Phe-OH) as a potential inducer of metastatic suppressor NM23H1 in p53 wild-type and mutant cells.

In recent years, significant progress has been made to the use-case of small peptides because of their diversified edifice and hence their versatile application scope in cancer therapy. Here we identify the heterochiral dipeptide H-D Phe-L Phe-OH (F1) as a potent inducer of the metastatic suppressor NM23H1. We divulge the effect of F1 on the major EMT/metastasis-associated genes and the implications on the invasion and migration ability of cancer cells. The anti-invasive potential of F1 was directly correlated with NM23H1 expression. Mechanistically, F1 treatment elevated p53 levels as validated by localization and transcriptional studies. In the NM23H1 knockdown condition, F1 failed to induce any p53 expression/nuclear localization, indicating that the upregulation in p53 expression by F1 is NM23H1 dependent. We also demonstrate how the antimetastatic potential of F1 is primarily mediated through NM23H1 irrespective of the p53 status of the cell. However, both NM23H1 and a functional p53 protein in conjunction govern the apoptotic and cytostatic potential of F1. Coimmunoprecipitation studies unraveled the augmentation of the p53 and NM23H1 interaction in p53 wild-type cells. However, in p53 mutated cells, no such enrichment was evidenced. We employed mouse isogenic cell lines (4T-1 and 4T-1 p53) to determine the in vivo efficacy of F1 (spontaneous and experimental models). Decreased tumor volume in the cohort injected with 4T-1 p53 cells demonstrated that while the antimetastatic potential of F1 was reliant on NM23H1, p53 activation was required for ablation of primary tumor burden. Our findings unravel that F1 treatment induces significant abrogation of the migration, invasion and metastatic potential of both p53 wild-type and p53 deficient cancers mediated through NM23H1.

Induction of p53 mediated mitochondrial apoptosis and cell cycle arrest in human breast cancer cells by plant mediated synthesis of silver nanoparticles from Bergenia ligulata (Whole plant).

The biological synthesis of nanoparticles is a growing research trend because it has numerous pharmaceutical and biomedical applications. The present study describes the preparation, characterization and anti-cancer evaluation of silver nanoparticles synthesized using an aqueous extract of Bergenia ligulata whole plant as a reducing agent. The physiochemical properties of the Bergenia ligulata silver nanoparticles (BgAgNPs) were measured by ultraviolet-visible spectrophotometry, Fourier transform infrared spectrophotmetry (FTIR), X-ray powder diffraction (XRD) and Scanning electron microscopy (SEM) analysis for identifying functional groups, crystallinity, structural and morphological features, respectively. Further, BgAgNps, along with the Bergenia ligulata aqueous extract (BgAE), were investigated for their effects on cell proliferation and apoptosis through MTT, colony-forming assay, wound-healing assay and flow cytometry-based approaches. The cytotoxic effects were more pronounced in cells treated with BgAgNps in comparison to BgAE. These effects were evidenced by the decreasing cell viability, migration capacity and loss of characteristic morphological features. In addition, BgAgNps unveiled significant induction of apoptosis in human breast cancer (MCF-7) cells, possibly through oxidative stress-mediated reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP). Moreover, molecular mechanism-based studies revealed that BgAgNps robustly augmented p53 levels and pro-apoptotic downstream targets of p53 like Bax and cleaved caspase 3 in MCF-7 cells. Of note, BgAgNps had little or no cytotoxic effect on p53-deficient cancer cells (Mda-mb-231 and SW-620). These findings confirm that the BgAgNPs exhibited superior anti-cancer potential and could be exploited as a promising, cost-effective, and environmentally benign strategy in treating this disease in the future.

Green synthesis of zinc oxide nanoparticles using Eucalyptus lanceolata leaf litter: characterization, antimicrobial and agricultural efficacy in maize.

In the present study, green synthesis of zinc oxide nanoparticles (ZnO NP) using Eucalyptus lanceolatus (leaf litter) extract was explored after characterization with UV spectrophotometery, Fourier Transform Infrared analysis, X-ray diffraction and TEM studies. ZnO NPs stability was ensured with - 32.1 mV zeta potential, while TEM showed ZnO NP as hexagonal structure (100 nm). In vitro antimicrobial activity showed potential of ZnO NP against pathogens causing diseases in maize plants. Both in vitro and in vivo studies of ZnO NP and ZnSO4 (200 ppm and 400 ppm) over a two year period (2019, 2020) were conducted on Zea mays L. var. PG2458. ZnO NP seed priming improved seed vigor index, germination percentage, shoot and root length and fresh biomass. Foliar application improved stem diameter and leaf surface area. Physiological status was relatively better, while reproductive attributes got altered to guide resource allocation for better cob growth and biomass with ZnO NP. Leaf, cob, grain and total Zn was maximum for 200 ppm ZnO NP. Translocation of Zn from leaf to cob and cob to grain was faster for ZnO NP compared to ZnSO4. Higher concentration (400 ppm) of ZnO NPs and ZnSO4 proved phytotoxic for plant growth attributes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01136-0.

Recent advances in microbial toxin-related strategies to combat cancer.

It is a major concern to treat cancer successfully, due to the distinctive pathophysiology of cancer cells and the gradual manifestation of resistance. Specific action, adverse effects and development of resistance has prompted the urgent requirement of exploring alternative anti-tumour treatment therapies. The naturally derived microbial toxins as a therapy against cancer cells are a promisingly new dimension. Various important microbial toxins such as Diphtheria toxin, Vibrio cholera toxin, Aflatoxin, Patulin, Cryptophycin-55, Chlorella are derived from several bacterial, fungal and algal species. These agents act on different biotargets such as inhibition of protein synthesis, reduction in cell growth, regulation of cell cycle and many cellular processes. Bacterial toxins produce actions primarily by targeting protein moieties and some immunomodulation and few acts through DNA. Fungal toxins appear to have more DNA damaging activity and affect the cell cycle. Algal toxins produce alteration in mitochondrial phosphorylation. In conclusion, microbial toxins and their metabolites appear to have a great potential to provide a promising option for the treatment and management to combat cancer.

Nanohydroxyapatite-, Gelatin-, and Acrylic Acid-Based Novel Dental Restorative Material.

The aim of this study was to prepare a novel dental restorative material (NDRM) and to understand its cell viability behavior. The hydroxyapatite (HA) nanopowder was synthesized using a wet chemical precipitation method using calcium hydroxide and orthophosphoric acid as precursors. The as-prepared HA nanopowder was annealed at different temperatures to get a pure compound with a Ca/P ratio close to 1.67. The optimal temperature was found to be 600 °C, whereas at a higher temperature, HA starts decomposing into CaO. The preparation of NDRM was conducted in two steps. The first step comprises the preparation of HA nanopowder- and gelatin (G)-based film using microwave heating. In the second step, the homogenized mixture of the HA-G film was mixed with different amounts of acrylic acid to form a self-flowable NDRM paste. Further, both these materials (HA nanopowder and NDRM) were characterized using FTIR, XRD, and SEM-EDX analyses. The FTIR and XRD results show the peaks corresponding to natural bone apatite and therefore confirm the formation of HA. EDX results showed the presence of Ca and P in HA nanopowder and NDRM with Ca/P ratios of 1.79 and 1.63, respectively. Synthesized NDRM was also analyzed for its in vitro cytotoxic and reproductive viability potential against normal cells using MTT and clonogenic assay. The analysis showed significantly higher cellular viability on the treatment with NDRM when compared to HA nanopowder as well as no colony suppression by both materials was observed on the normal cell line (fR2) even after exposure for 24 h, indicating its nontoxicity. The synthesized NDRM therefore can be considered as a promising candidate for dental caries restoration applications.

Oncogenic BRAF, endoplasmic reticulum stress, and autophagy: Crosstalk and therapeutic targets in cutaneous melanoma.

BRAF is a member of the RAF family of serine/threonine-specific protein kinases. Oncogenic BRAF, in particular, BRAF V600E, can disturb the normal protein folding machinery in the endoplasmic reticulum (ER) leading to accumulation of unfolded/misfolded proteins in the ER lumen, a condition known as endoplasmic reticulum (ER) stress. To alleviate such conditions, ER-stressed cells have developed a highly robust and adaptable signaling network known as unfolded protein response (UPR). UPR is ordinarily a cytoprotective response and usually operates through the induction of autophagy, an intracellular lysosomal degradation pathway that directs damaged proteins, protein aggregates, and damaged organelles for bulk degradation and recycling. Both ER stress and autophagy are involved in the progression and chemoresistance of melanoma. Melanoma, which arises as a result of malignant transformation of melanocytes, exhibits exceptionally high therapeutic resistance. Many mechanisms of therapeutic resistance have been identified in individual melanoma patients and in preclinical BRAF-driven melanoma models. Recently, it has been recognized that oncogenic BRAF interacts with GRP78 and removes its inhibitory influence on the three fundamental ER stress sensors of UPR, PERK, IRE1α, and ATF6. Dissociation of GRP78 from these ER stress sensors prompts UPR that subsequently activates cytoprotective autophagy. Thus, pharmacological inhibition of BRAF-induced ER stress-mediated autophagy can potentially resensitize BRAF mutant melanoma tumors to apoptosis. However, the underlying molecular mechanism of how oncogenic BRAF elevates the basal level of ER stress-mediated autophagy in melanoma tumors is not well characterized. A better understanding of the crosstalk between oncogenic BRAF, ER stress and autophagy may provide a rationale for improving existing cancer therapies and identify novel targets for therapeutic intervention of melanoma.

Chemical, biological and in silico assessment of Ocimum viride essential oil.

AIMS: Ocimum viride Willd. (family: Lamiaceae) is a member of the genus Ocimum, an aromatic annual and perennial herb with numerous culinary, horticultural and ethno-medicinal benefits. This study aims to explore the chemical properties of leaf essential oil (EO) from Ocimum viride and to evaluate its antimicrobial and anticancer potential. MAIN METHODS: Characterization of essential oil was done by GCMS, antimicrobial by agar well diffusion methods, in vitro cytotoxicity evaluation by MTT assay, cell death analysis was done by DNA fragmentation, cell cycle analysis, nuclear morphology analysis and molecular docking studies were also conducted. KEY FINDINGS: Essential oil from aerial parts (leaf) of Ocimum viride revealed high content of oxygenated monoterpenes, notably thymol (~50%) and γ-terpinene (~18%). Further, antibacterial analysis showed that among all the evaluated bacterial species EO showed highest sensitivity against the Bacillus subtilis and was also found most effective against HT-29 colon cancer cell line with IC50 value of ~0.034 ± 0.001µL/mL. Mechanistic studies revealed that EO inhibits the growth of HT-29 colon cancer cells probably through induction of irreparable DNA damage leading to subsequent cell death in apoptotic manner. Molecular docking analysis also supports the in vitro studies conducted by indicating the interaction of thymol with Sec A protein of Bacillus subtilis cell wall as well as with Beclin protein responsible for apoptotic corpse clearance. SIGNIFICANCE: Taken together, our results indicate that EO possesses potent antimicrobial and anticancer properties, and may find applications as effective antibacterial and in cancer therapeutics.

Cedrus deodara (Bark) Essential Oil Induces Apoptosis in Human Colon Cancer Cells by Inhibiting Nuclear Factor kappa B.

AIMS: The aim of this study is to explore essential oil from the bark of Cedrus deodara (CDEO) as an potential anticancer agent. BACKGROUND: The frontline drugs against cancer in clinical settings are posing challenges of resistance and other detrimental side-effects. This has led to the exploration of new anticancer chemical entities from natural sources, particularly plant-based products such as essential oils that serve as vast repositories of pharmacologically active substances for combating cancer. OBJECTIVE: The objective is to isolate and characterize the essential oil from the bark of Cedrus deodara (CDEO) and evaluate its potential as an anticancer agent and delineate the possible underlying mechanism of action. METHODS: Cedrus deodara essential oil from bark (CDEO) was obtained by hydro-distillation and analyzed by GC/MS for vital constituents. Further, in vitro cytotoxic potential was measured by MTT assay against a panel of cancer cell lines. The apoptosis-inducing potential of CDEO was analyzed by mitochondrial membrane potential loss (ΔΨm) and nuclear fragmentation assay. Besides, wound healing assay and colonogenic assay were employed to check the anti-metastatic potential of CDEO. Molecular docking approaches were employed for target identification, while immuno-blotting was carried out for target validation. RESULTS AND DISCUSSION: The major components identified were 2-(tert-Buyl)-6-methyl-3-(2- (trifluoromethyl) benzyl)imidazo [1,2-a]pyridine (26.32 %);9- Octadecenoic acid (8.015 %); Copaene (5.181 %);2-(4-Methoxy-2,6-dimethylphenyl) -3-methyl-2H- benzo[g]indazole(4.36 %) and 9(E),11(E)- Conjugated linoleic acid (4.299 %). Further, potent in vitro cytotoxic activity with IC50 values of 11.88 µg/ ml and 14.63 µg/ ml in colon cancer cell lines of HCT-116 and SW-620, respectively. Further, a significant and dose-dependent decrease in colony formation, cell migration, induction of ROS formation and loss in ΔΨm was observed. Additionally, major compounds identified were chosen for ligandprotein binding interaction studies to predict the molecular targets in colon cancer. It was observed that compounds such as 9-Octadecenoic acid;4H-1- Benzopyran-4-one, 3-(3,4-dimethoxyphenyl)-6,7- dimethoxy; 2-(4-Methoxy-2,6-dimethylphenyl) -3-methyl-2H-benzo [g]indazole and 2-Bornanol,5-(2,4- dinitro phenyl) hydrazono have a prominent binding affinity with NF-κB. This was also further validated by immuno-blotting results wherein CDEO treatment in colon cancer cells led to the abrogation of NFκB, and the Bcl-2-associated X protein (Bax): B-cell lymphoma (Bcl)-2 ratio was up-regulated leading to enhanced cleaved caspase 3 formation and subsequent apoptosis. CONCLUSION: These results unveil CDEO inhibits cell proliferation and induces apoptosis in colon cancer cells, which can be attributed to the abrogation of the NFκB signaling pathway.

Convergence of therapy-induced senescence (TIS) and EMT in multistep carcinogenesis: current opinions and emerging perspectives.

Drug induced resistance is a widespread problem in the clinical management of cancer. Cancer cells, when exposed to cytotoxic drugs, can reprogram their cellular machinery and resist cell death. Evasion of cell death mechanisms, such as apoptosis and necroptosis, are part of a transcriptional reprogramming that cancer cells utilize to mediate cytotoxic threats. An additional strategy adopted by cancer cells to resist cell death is to initiate the epithelial to mesenchymal transition (EMT) program. EMT is a trans-differentiation process which facilitates a motile phenotype in cancer cells which can be induced when cells are challenged by specific classes of cytotoxic drugs. Induction of EMT in malignant cells also results in drug resistance. In this setting, therapy-induced senescence (TIS), an enduring "proliferative arrest", serves as an alternate approach against cancer because cancer cells remain susceptible to induced senescence. The molecular processes of senescence have proved challenging to understand. Senescence has previously been described solely as a tumor-suppressive mechanism; however, recent evidences suggest that senescence-associated secretory phenotype (SASP) can contribute to tumor progression. SASP has also been identified to contribute to EMT induction. Even though the causes of senescence and EMT induction can be wholly different from each other, a functional link between EMT and senescence is still obscure. In this review, we summarize the evidence of potential cross-talk between EMT and senescence while highlighting some of the most commonly identified molecular players. This review will shed light on these two intertwined and highly conserved cellular process, while providing background of the therapeutic implications of these processes.

Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-ß/ Smad4 axis driving the cells towards lethal EMT.

Deregulation of TGF-ß signaling is intricately engrossed in the pathophysiology of pancreatic adenocarcinomas (PDACs). The role of TGF-ß all through pancreatic cancer initiation and progression is multifarious and somewhat paradoxical. TGF-ß plays a tumor suppressive role in early-stage pancreatic cancer by promoting apoptosis and inhibiting epithelial cell cycle progression, but incites tumor promotion in late-stage by modulating genomic instability, neo-angiogenesis, immune evasion, cell motility, and metastasis. Here, we provide evidences that Par-4 acts as one of the vital mediators to regulate TGF-ß/Smad4 pathway, wherein, Par-4 induction/over-expression induced EMT which was later culminated in to apoptosis in presence of TGF-ß via positive regulation of Smad4. Intriguingly, Par-4-/- cells were devoid of significant Smad4 induction compared to Par-4+/+ cells in presence of TGF-ß and ectopic Par-4 steadily augmented Smad4 expression by restoring TGF-ß/Smad4 axis in Panc-1 cells. Further, our FACS and western blotting results unveiled that Par-4 dragged the PDAC cells to G1 arrest in presence of TGF-ß byelevating p21 and p27 levels while attenuating Cyclin E and A levels and augmenting caspase 3 cleavage triggering lethal EMT. Through restoration of Smad4, we further establish that in BxPC3 cell line (Smad4-/-), Smad4 is essential for Par-4 to indulge TGF-ß dependent lethal EMT program. The mechanistic relevance of Par-4 mediated Smad4 activation was additionally validated by co-immunoprecipitation wherein disruption of NM23H1-STRAP interaction by Par-4 rescues TGF-ß/Smad4 pathway in PDAC and mediates the tumor suppressive role of TGF-ß, therefore serving as a vital cog to restore the apoptotic functions of TGF-ß pathway.

Quercetin as an innovative therapeutic tool for cancer chemoprevention: Molecular mechanisms and implications in human health.

Cancer is a life-threatening disease afflicting human health worldwide. Recent advances in drug discovery infrastructure and molecular approaches have helped a lot in identifying the novel drug targets for therapeutic intervention. Nevertheless, the morbidity and mortality rates because of this disease keep on rising at an alarming rate. Recently, the use of natural and synthetic molecules as innovative therapeutic tools for cancer prevention has lead to the development of cancer chemoprevention. Cancer chemoprevention is a prophylactic strategy that involves the chronic administration of one or more natural or synthetic agents to block, to inhibit, or to suppress the process of cancer development before it becomes an invasive disease. Quercetin, a dietary bioflavonoid, can specifically retard the growth of cancer cells and behaves as a potent cancer chemopreventive agent. Quercetin has multiple intracellular targets in a cancer cell. Therefore, many mechanisms have been postulated to explain its chemopreventive action. The chemopreventive effects elicited by this natural molecule in different model systems are believed to include antioxidant/pro-oxidant action, regulation of redox homeostasis, apoptosis, cell cycle arrest, anti-inflammatory action, modulation of drug metabolizing enzymes, alterations in gene expression patterns, inhibition of Ras gene expression, and modulation of signal transduction pathways. However, cell signaling networks have recently garnered attention as common molecular target for various chemopreventive effects of quercetin. In this review, we made an attempt to critically summarize the emerging knowledge on the role of quercetin in cancer chemoprevention and the underlying molecular mechanisms implicated in its chemopreventive and therapeutic effects.

Metal Incorporated g-C3N4 Nanosheets as Potential Cytotoxic Agents for Promoting Free Radical Scavenging in Cancer Cell Lines.

Besides numerous advantages, poor penetration, larger size and less efficient nanomaterials are the current challenges in nanomedicine-based therapies. Graphitic carbon nitride (g-C3N4) possesses all the constructive features to overcome the hurdles in cancer therapy. This is a detailed study on the prospects of utilizing g-C3N4 as a therapeutic agent and through this study it has been established that metal incorporations have improved their performance at in vitro levels. g-C3N4 nanomaterial was prepared by simple thermal decomposition process. The synthesized nanosheets were characterized by using UV-visible spectrometer, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction analysis (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM) and thermo-gravimetric analysis (TG/DTA). The incorporation of metal particles also has been confirmed by the above mentioned methods. Dose dependent cytotoxicity studies were performed on three different cell lines such as A549, PC-3 and MCF-7. The free radical scavenging activity of g-C3N4 nanosheets was promising using 1,1'-diphenyl-2-picrylhydrazyl (DPPH) assay. Cell scavenging activity of ˜45% with DPPH was observed at 100 µl concentrations of Ag/g-C3N4, Zn/g-C3N4 and g-C3N4. The cytotoxicity and free radical scavenging of cancer cell lines was better with metal incorporated g-C3N4 than their bare counterparts. Hence the study of these thin sheets of nanomaterial is encouraging to be explored as one of the future tools for biomedical therapeutics.

Cancer Chemoprevention and Piperine: Molecular Mechanisms and Therapeutic Opportunities.

Cancer is a genetic disease characterized by unregulated growth and dissemination of malignantly transformed neoplastic cells. The process of cancer development goes through several stages of biochemical and genetic alterations in a target cell. Several dietary alkaloids have been found to inhibit the molecular events and signaling pathways associated with various stages of cancer development and therefore are useful in cancer chemoprevention. Cancer chemoprevention has long been recognized as an important prophylactic strategy to reduce the burden of cancer on health care system. Cancer chemoprevention assumes the use of one or more pharmacologically active agents to block, suppress, prevent, or reverse the development of invasive cancer. Piperine is an active alkaloid with an excellent spectrum of therapeutic activities such as anti-oxidant, anti-inflammatory, immunomodulatory, anti-asthmatic, anti-convulsant, anti-mutagenic, antimycobacterial, anti-amoebic, and anti-cancer activities. In this article, we made an attempt to sum up the current knowledge on piperine that supports the chemopreventive potential of this dietary phytochemical. Many mechanisms have been purported to understand the chemopreventive action of piperine. Piperine has been reported to inhibit the proliferation and survival of many types of cancer cells through its influence on activation of apoptotic signaling and inhibition of cell cycle progression. Piperine is known to affect cancer cells in variety of other ways such as influencing the redox homeostasis, inhibiting cancer stem cell (CSC) self-renewal and modulation of ER stress and autophagy. Piperine can modify activity of many enzymes and transcription factors to inhibit invasion, metastasis, and angiogenesis. Piperine is a potent inhibitor of p-glycoprotein (P-gp) and has a significant effect on the drug metabolizing enzyme (DME) system. Because of its inhibitory influence on P-gp activity, piperine can reverse multidrug resistance (MDR) in cancer cells and acts as bioavailability enhancer for many chemotherapeutic agents. In this article, we emphasize the potential of piperine as a promising cancer chemopreventive agent and the knowledge we collected in this review can be applied in the strategic design of future researches particularly human intervention trials with piperine.

Iron (FeII) chelation, ferric reducing antioxidant power, and immune modulating potential of Arisaema jacquemontii (Himalayan Cobra Lily).

This study explored the antioxidant and immunomodulatory potential of ethnomedicinally valuable species, namely, Arisaema jacquemontii of north-western Himalayan region. The tubers, leaves, and fruits of this plant were subjected to extraction using different solvents. In vitro antioxidant studies were performed in terms of chelation power on ferrous ions and FRAP assay. The crude methanol extract of leaves was found to harbour better chelating capacity (58% at 100 µ g/mL) and reducing power (FRAP value 1085.4 ± 0.11 µ MFe(3+)/g dry wt.) than all the other extracts. The crude methanol extract was thus further partitioned with solvents to yield five fractions. Antioxidant study of fractions suggested that the methanol fraction possessed significant chelation capacity (49.7% at 100 µ g/mL) and reducing power with FRAP value of 1435.4 µ M/g dry wt. The fractions were also studied for immune modulating potential where it was observed that hexane fraction had significant suppressive effect on mitogen induced T-cell and B-cell proliferation and remarkable stimulating effect on humoral response by 141% and on DTH response by 168% in immune suppressed mice as compared to the controls. Therefore, it can be concluded that A. jacquemontii leaves hold considerable antioxidant and immunomodulating potential and they can be explored further for the identification of their chemical composition for a better understanding of their biological activities.

Antioxidant activity of essential oil and extracts of Valeriana jatamansi roots.

Valeriana jatamansi is an indigenous medicinal plant used in the treatment of a number of diseases. In the present study, chemical composition of the essential oil was determined by GC-MS. Seven major components were identified in Valeriana jatamansi essential oil, namely, ß-vatirenene, ß-patchoulene, dehydroaromadendrene, ß-gurjunene, patchoulic alcohol, ß-guaiene, and α-muurolene. Methanolic, aqueous, and chloroform extracts of Valeriana jatamansi roots were also prepared and analyzed for their polyphenols and flavonoid content. Antioxidant activity of essential oil and different extracts of Valeriana jatamansi roots was determined by DPPH radical scavenging and chelation power assay. A linear correlation has been obtained by comparing the antioxidant activity and polyphenols and flavonoid content of the extracts. Results indicated that antioxidant activity of methanolic extract could be attributed to the presence of rich amount of polyphenols and flavonoid. Essential oil of Valeriana jatamansi roots showed moderate antioxidant activity.

Synthesis and Spectroscopic and Biological Activities of Zn(II) Porphyrin with Oxygen Donors.

Results of investigation of the physicochemical properties of zinc complexes containing substituted phenols as axial ligand having general formula [X-Zn-t(p-CH3) PP] [where X = different phenolates as axial ligand] in impurity-free organic solvent are presented. The four-coordinated zinc porphyrin accepts one axial ligand in 1 : 1 molar ratio to form five-coordinated complex, which is purified by column chromatography and characterized by physicochemical, biological evaluation and TGA/DTA studies. Absorption spectra show two principal effects: a red shift for phenols bearing substituted electron releasing groups (-CH3, -NH2) and blue shift for phenols bearing electron withdrawing groups (-NO2, -Cl) relative to Zn-t(p-CH3) PP, respectively. (1)H NMR spectra show that the protons of the phenol ring axially attached to the central metal ion are merged with the protons of the porphyrin ring. Fluorescence spectra show two fluorescence peaks in the red region with emission ranging from 550 nm to 700 nm. IR spectra confirm the appearance of Zn-NPor and Zn-O vibrational frequencies, respectively. According to the thermal studies, the complexes have a higher thermal stability and the decomposition temperature of these complexes depends on the axial ligation. The respective complexes of X-Zn(II)-t(p-CH3) PP were found to possess higher antifungal activity (up to 90%) and higher in vitro cytotoxicity against human cancer cells lines.

Synthesis, Spectroscopic, and Biological Studies on New Zirconium(IV) Porphyrins with Axial Ligand.

A series of parasubstituted tetraphenylporphyrin zirconium(IV) salicylate complexes (SA/5-SSAZr(IV)RTPP, R = p-H, p-CH3, p-NO2, p-Cl, SA = salicylate, and 5-SSA = 5-sulfosalicylate) have been synthesized, and the spectral properties of free base porphyrins, their corresponding metallated, and axially ligated zirconium(IV) porphyrin compounds were compared with each other. A detailed analysis of ultraviolet-visible (UV-vis), proton nulcear magnetic resonance ((1)H NMR) spectroscopy, infrared (IR) spectroscopy, and elemental analysis suggested the transformation from free base porphyrins to zirconium(IV) porphyrins. The ability of the metal in this complex for extra coordination of solvent molecules was confirmed by ESI-MS spectra. Besides the fluorescence, cyclic voltammetry, and thermogravimetric studies, the complexes were also screened for antimicrobial and anticancer activities. Among all the complexes, 5-SSAZr(p-NO2TPP) shows high antibacterial activity.

Drug embedded PVP coated magnetic nanoparticles for targeted killing of breast cancer cells.

Magnetic drug targeting is a drug delivery system that can be used in loco-regional cancer treatment. Coated magnetic particles, called carriers, are very useful for delivering chemotherapeutic drugs. Magnetic carriers were synthesized by co-precipitation of iron oxide followed by coating with polyvinyl pyrrolidone (PVP). Characterization was performed using X-ray diffraction, TEM, TGA, FTIR and UV-Vis Spectroscopy. Magnetite (Fe3O4) remained as the core of the carrier. The amount of PVP bound to the iron oxide nanoparticles was estimated by thermogravimetric analysis (TGA) and the attachment of PVP to the iron oxide nanoparticles confirmed by FTIR analysis. The loading efficiency of Epirubicin hydrochloride onto the PVP coated and uncoated iron oxide nanoparticles was measured at intervals such as 1 hr and 24 hrs by UV-Vis Spectroscopy. The binding of Epirubicin hydrochloride to the PVP coated and uncoated iron oxide nanoparticles were confirmed by FTIR analysis. The present findings showed that Epirubicin hydrochloride loaded PVP coated iron oxide nanoparticles are promising for magnetically targeted drug delivery. The drug displayed increased cell cytotoxicity at lower concentrations when conjugated with the nanoparticles than being administered conventionally as individual drugs.