In vitro study on anti-proliferative and anti-cancer activity of picrosides in triple-negative breast cancer.

Picrorhiza kurroa, an "Indian gentian," a known Himalayan medicinal herb with rich source of phytochemicals like picrosides I, II, and other glycosides, has been traditionally used for the treatment of liver and respiratory ailments. Picrosides anti-proliferative, anti-oxidant, anti-inflammatory and other pharmacological properties were evaluated in treating triple-negative breast cancer (TNBC). Picroside I and II were procured from Sigma-Aldrich and were analyzed for anti-cancer activity in triple-negative breast cancer (MDA-MB-231) cells. Cell viability was analyzed using MTT and trypan blue assays. Apoptosis was analyzed through DNA fragmentation and Annexin V/PI flow cytometric analysis. Wound healing and cell survival assays were employed to determine the inhibition of invasion capacity and anti-proliferative activity of picrosides in MDA-MB-231 cells. Measurement of intracellular ROS was studied through mitochondrial membrane potential assessment using DiOC6 staining for anti-oxidant activity of picrosides in MDA-MB-231 cells. Both Picroside I and II have shown decreased cell viability of MDA-MB-231 cells with increasing concentrations. IC50 values of 95.3 µM and 130.8 µM have been obtained for Picroside I and II in MDA-MB-231 cells. Early apoptotic phase have shown an increase of 20% (p < 0.05) with increasing concentrations (0, 50, 75, and 100 µM) of Picroside I and 15% (p < 0.05) increase with Picroside II. Decrease in mitochondrial membrane potential of 2-2.5-fold (p < 0.05) was observed which indicated decreased reactive oxygen species (ROS) generation with increasing concentrations of Picroside I and II. An increasing percentage of 70-80% (p < 0.05) cell population was arrested in G0/G1 phase of cell cycle after Picroside I and II treatment in cancer cells. Our results suggest that Picroside I and II possess significant anti-proliferative and anti-cancer activity which is mediated by inhibition of cell growth, decreased mitochondrial membrane potential, DNA damage, apoptosis, and cell cycle arrest. Therefore, Picroside I and II can be developed as a potential anti-cancer drug of future and further mechanistic studies are underway to identify the mechanism of anti-cancer potential.

A Review on Picrosides Targeting NFκB and its Proteins for Treatment of Breast Cancer.

Breast cancer is the most frequently diagnosed disease causing most deaths in women worldwide. Chemotherapy and neo-adjuvant therapy are the standard method of treatment in early stages of breast cancer. However drug resistance in breast cancer limit the use of these methods for treatment. Research focus is now shifted towards identifying natural phytochemicals with lower toxicity. This review illustrates the NF κB interaction with different signaling pathways in normal condition, breast cancer and other cancer and thus represent a potential target for treatment. No reports are available on the action of picrosides on NFκB and its associated proteins for anticancer activity. In the present review, potential interaction of picrosides with NF-κB and its associated proteins is reviewed for anticancer action. Further, an important facet of this review entails the ADMET analysis of Picroside, elucidating key ADMET properties which serves to underscore the crucial characteristics of Picroside as a potential drug for treating breast cancer. Furthermore, in silico analysis of Picrosides was executed in order to get potential binding modes between ligand (Picrosides II) and NFκB.

Toxicity evaluation of silver nanoparticles synthesized from naringin flavonoid on human promyelocytic leukemic cells and human blood cells.

Increasing applications of silver nanoparticles (AgNPs) in multiple products like cosmetics, medicines, drugs, paints, and other new materials have raised concern for their toxic effects on living beings and the surrounding environment. In the present study, cytotoxicity and genotoxicity of AgNPs synthesized using plant flavonoid (Naringin) as a reducing agent were investigated on human promyelocytic leukemic (HL-60) cells and human blood as an in vitro model. The LC50 of AgNPs was found to be 4.85 µM. Dose-dependent increase in cell death and caspase activity was observed in the presence of AgNPs. The comet assay showed a 60%-70% (p < .05) increase in tail DNA at 0.48 and 0.96 µM AgNPs. CBMN in PBMCs also confirmed the genotoxic potential of AgNPs-induced DNA damage. AgNPs resulted in 1.5-1.54 fold (p < .05) increase in the level of ROS in HL-60 cells after 12 h of exposure. AgNP showed toxicity in human cells through ROS generation and cellular damage through membrane dysfunction, caspase activation, apoptosis, and DNA damage.

A Double-Edged Sword: The Anti-Cancer Effects of Emodin by Inhibiting the Redox-Protective Protein MTH1 and Augmenting ROS in NSCLC.

Background: Reactive oxygen species (ROS), playing a two-fold role in tumorigenesis, are responsible for tumor formation and progression through the induction of genome instability and pro-oncogenic signaling. The same ROS is toxic to cancer cells at higher levels, oxidizing free nucleotide precursors (dNTPs) as well as damaging DNA leading to cell senescence. Research has highlighted the tumor cell-specific expression of a redox-protective phosphatase, MutT homolog 1 (MTH1), that performs the enzymatic conversion of oxidized nucleotides (like 8-oxo-dGTP) to their corresponding monophosphates, up-regulated in numerous cancers, circumventing their misincorporation into the genomic DNA and preventing damage and cell death. Methods: To identify novel natural small molecular inhibitors of MTH1 to be used as cancer therapeutic agents, molecular screening for MTH1 active site binders was performed from natural small molecular libraries. Emodin was identified as a lead compound for MTH1 active site functional inhibition and its action on MTH1 inhibition was validated on non-small cell lung cancer cellular models (NSCLC). Results: Our study provides strong evidence that emodin mediated MTH1 inhibition impaired NSCLC cell growth, inducing senescence. Emodin treatment enhanced the cellular ROS burdens, on one hand, damaged dNTP pools and inhibited MTH1 function on the other. Our work on emodin indicates that ROS is the key driver of cancer cell-specific increased DNA damage and apoptosis upon MTH1 inhibition. Consequently, we observed a time-dependent increase in NSCL cancer cell susceptibility to oxidative stress with emodin treatment. Conclusions: Based on our data, the anti-cancer effects of emodin as an MTH1 inhibitor have clinical potential as a single agent capable of functioning as a ROS inducer and simultaneous blocker of dNTP pool sanitation in the treatment of NSCL cancers. Collectively, our results have identified for the first time that the potential molecular mechanism of emodin function, increasing DNA damage and apoptosis in cancer cells, is via MTH1 inhibition.

"Picrosides" from Picrorhiza kurroa as potential anti-carcinogenic agents.

The steady rise in life expectancy, modern life style and changing environmental conditions are responsible for increasing incidence of cancer. A number of chemical drugs have been used for cancer treatment; however the induction of genotoxic, carcinogenic and teratogenic effects limits their use. Alternatively, plant phytochemicals have been proven effective chemopreventive agents. This review illustrates the use of "picrosides" derived from Picrorhiza kurroa for the treatment of cancer. We have detailed the anti-oxidant and anti-inflammatory action of picrosides as the key mechanism in reducing oncogenesis. Action of picrosides on detoxifying enzymes, cell cyle regulation and induction of signal transducers inhibiting apoptosis has also been reviewed. The present review highlights the use of picrosides as an important therapeutic agent against different types of cancer.

Oxidative Stress and Genotoxicity of Zinc Oxide Nanoparticles to Pseudomonas Species, Human Promyelocytic Leukemic (HL-60), and Blood Cells.

In the present study, toxicity of commercial zinc oxide nanoparticles (ZnO NPs) was studied on the bacterium Pseudomonas sp., human promyelocytic leukemia (HL-60) cells, and peripheral blood mononuclear cells (PBMC). The toxicity was assessed by measuring growth, cell viability, and protein expression in bacterial cell. The bacterial growth and viability decreased with increasing concentrations of ZnO NP. Three major proteins, ribosomal protein L1 and L9 along with alkyl hydroperoxides reductase, were upregulated by 1.5-, 1.7-, and 2.0-fold, respectively, after ZnO NP exposure. The results indicated oxidative stress as the leading cause of toxic effect in bacteria. In HL-60 cells, cytotoxic and genotoxic effects along with antioxidant enzyme activity and reactive oxygen species (ROS) generation were studied upon ZnO NP treatment. ZnO NP exhibited dose-dependent increase in cell death after 24-h exposure. The DNA-damaging potential of ZnO NP in HL-60 cells was maximum at 0.05 mg/L concentration. Comet assay showed 70-80% increase in tail DNA at 0.025 to 0.05 mg/L ZnO NP concentration. A significant increase of 1.6-, 1.4-, and 2.0-fold in ROS level was observed after 12 h. Genotoxic potential of ZnO NPs was also demonstrated in PBMC through DNA fragmentation. Thus, ZnO NP, besides being an essential element having antibacterial activity, also showed toxicity towards human cells (HL-60 and PBMC).

Release, transport and toxicity of engineered nanoparticles.

Recent developments in nanotechnology have facilitated the synthesis of novel engineered nanoparticles (ENPs) that possess new and different physicochemical properties. These ENPs have been ex tensive ly used in various commercial sectors to achieve both social and economic benefits. However. the increasing production and consumption of ENPs by many different industries has raised concerns about their possible release and accumulation in the environment. Released EN Ps may either remain suspended in the atmosphere for several years or may accumulate and eventually be modified int o other substances. Settled nanoparticles can he easily washed away during ra in s. and therefore may easily enter the food chain via water and so il. Thus. EN Ps can contaminate air. water and soil and can subsequently pose adverse risks to the health of different organisms. Studies to date indicate that ENP transport to and within the ecosystem depend on their chemical and physical properties (viz .. size. shape and solubility) . Therefore. the EN Ps display variable behavior in the environment because of their individual properties th at affect their tendency for adsorption, absorption, diffusional and colloidal interaction. The transport of EN Ps also influences their fate and chemical transformation in ecosystems. The adsorption, absorption and colloidal interaction of ENPs affect their capacity to be degraded or transformed, whereas the tendency of ENPs to agglomerate fosters their sedimentation. How widely ENPs are transported and their environmental fate influence how tox ic they may become to environmental organisms. One barrier to fully understanding how EN Ps are transformed in the environment and how best to characterize their toxicity, is related to the nature of their ultrafine structure. Experiments with different animals, pl ants, and cell lines have revealed that ENPs induce toxicity via several cellular pathways that is linked to the size. shape. surface area, agglomeration state. and sur face charge of the ENP involved. Future research is needed to elucidate the mechanisms by which nanoparticles act to induce their tox ic effects aft er they reach various ecosystems. Moreover. work is needed to develop a holistic approach for better understanding the effects that ENPs produce at the cellular and genetic level.

Stress response of Pseudomonas species to silver nanoparticles at the molecular level.

In recent years, silver nanoparticles (AgNPs) have been shown to possess broad antibacterial activity. The present study investigated the cytotoxicity of AgNPs to a common soil bacterium, Pseudomonas sp. The molecular mechanism involved in its stress response to AgNPs was also studied. The minimum inhibitory concentration (MIC) of AgNPs was found to be 0.2 mg/L. At a sublethal concentration of 0.1 mg/L AgNPs, the protein expression profile of Pseudomonas showed overexpression of stress proteins such as ribosomal proteins S2 and L9, alkyl hydroperoxide reductase/thiol-specific antioxidant (AhpC/TSA) family protein, and keto-hydroxyglutarate aldolase (KHGA). The upregulation of these proteins was further confirmed by quantitative polymerase chain reaction. The results showed increased expression of ribosomal protein S2, KHGA, AhpC/TSA, and ribosomal protein L9 by 1.09-, 3.41-, 1.52-, and 1.56-fold, respectively (p < 0.05), after AgNP exposure compared with control. The present study clearly demonstrates that AgNPs are toxic to soil bacteria and induce oxidative and metabolic stress.

Synthesis and characterization of silver nanoparticles using Cynodon dactylon leaves and assessment of their antibacterial activity.

Many methods of synthesizing silver nanoparticles (Ag-NPs) by reducing Ag⁺ ions using aqueous/organic extracts of various plants have been reported in the past, but the methods are rather slow. In this investigation, silver nanoparticles were quickly synthesized from aqueous silver nitrate through a simple method using leaf extract of a plant--Cynodon dactylon which served as reducing agent, while sunlight acted as a catalyst. The formation of Ag-NPs was indicated by gradual change in colour and pH and confirmed by ultraviolet--visible spectroscopy. The Ag-NPs showed a surface plasmon resonance at 451 nm. Based on the decrease in pH, a possible mechanism of the synthesis of Ag-NPs involving hydroxyl (OH⁻) ions of polyphenols of the leaf extract is postulated. Ag-NPs having (111) and (200) crystal lattices were confirmed by X-ray diffraction. Scanning electron microscopy revealed the spherical nature of the Ag-NPs, while transmission electron microscopy showed that the nanoparticles were polydispersed with a size range of 8-10 nm. The synthesized Ag-NPs also demonstrated their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Salmonella typhimurium.

Heat stroke presented with disseminated intravascular coagulation and bilateral intracerebral bleed.

Heat stroke is a life-threatening condition which is characterised by nausea, vomiting, confusion, disorientation and coma. Aggressive treatment in the form of intravenous fluids along with other symptomatic management can be life saving. Here we present an unusual case of heat stroke followed by disseminated intravascular coagulation, multiple organ dysfunction with bilateral intracerebral bleed who survived with judicious management and recovered without any neurological sequeale.