Single-cell Transcriptome Analysis Identifies Senescent Osteocytes as Contributors to Bone Destruction in Breast Cancer Metastasis.

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression that disrupts the balance between osteoclasts and osteoblasts, leading to bone lesions. Whether such reprogramming affects matrix-embedded osteocytes remains poorly understood. Here, we demonstrate that osteocytes in breast cancer bone metastasis develop premature senescence and a distinctive senescence-associated secretory phenotype (SASP) that favors bone destruction. Single-cell RNA sequencing identified osteocytes from mice with breast cancer bone metastasis enriched in senescence and SASP markers and pro-osteoclastogenic genes. Using multiplex in situ hybridization and AI-assisted analysis, we detected osteocytes with senescence-associated distension of satellites, telomere dysfunction, and p16Ink4a expression in mice and patients with breast cancer bone metastasis. In vitro and ex vivo organ cultures showed that breast cancer cells promote osteocyte senescence and enhance their osteoclastogenic potential. Clearance of senescent cells with senolytics suppressed bone resorption and preserved bone mass in mice with breast cancer bone metastasis. These results demonstrate that osteocytes undergo pathological reprogramming by breast cancer cells and identify osteocyte senescence as an initiating event triggering bone destruction in breast cancer metastases.

Colony Stimulating Factor-1 Receptor: An emerging target for neuroinflammation PET imaging and AD therapy.

Although neuroinflammation is a significant pathogenic feature of many neurologic disorders, its precise function in-vivo is still not completely known. PET imaging enables the longitudinal examination, quantification, and tracking of different neuroinflammation biomarkers in living subjects. Particularly, PET imaging of Microglia, specialised dynamic immune cells crucial for maintaining brain homeostasis in central nervous system (CNS), is crucial for staging the neuroinflammation. Colony Stimulating Factor- 1 Receptor (CSF-1R) PET imaging is a novel method for the quantification of neuroinflammation. CSF-1R is mainly expressed on microglia, and neurodegenerative disorders greatly up-regulate its expression. The present review primarily focuses on the development, pros and cons of all the CSF-1R PET tracers reported for neuroinflammation imaging. Apart from neuroinflammation imaging, CSF-1R inhibitors are also reported for the therapy of neurodegenerative diseases such as Alzheimer's disease (AD). AD is a prevalent, advancing, and fatal neurodegenerative condition that have the characteristic feature of persistent neuroinflammation and primarily affects the elderly. The aetiology of AD is profoundly influenced by amyloid-beta (Aß) plaques, intracellular neurofibrillary tangles, and microglial dysfunction. Increasing evidence suggests that CSF-1R inhibitors (CSF-1Ri) can be helpful in preclinical models of neurodegenerative diseases. This review article also summarises the most recent developments of CSF-1Ri-based therapy for AD.

A NOTCH3-CXCL12-driven myeloma-tumor niche signaling axis promotes chemoresistance in multiple myeloma.

Multiple myeloma (MM) remains incurable due to disease relapse and drug resistance. Notch signals from the tumor microenvironment (TME) confer chemoresistance, but the cellular and molecular mechanisms are not entirely understood. Using clinical and transcriptomic datasets, we found that NOTCH3 is upregulated in CD138+ cells from newly diagnosed MM (NDMM) patients compared to healthy individuals and increased in progression/relapsed MM (PRMM) patients. Further, NDMM patients with high NOTCH3 expression exhibited worse responses to bortezomib (BOR)-based therapies. Cells of the TME, including osteocytes, upregulated NOTCH3 in MM cells and protected them from apoptosis induced by BOR. NOTCH3 activation (NOTCH3OE) in MM cells decreased BOR anti-MM efficacy and its ability to improve survival in in vivo myeloma models. Molecular analyses revealed that NDMM and PRMM patients with high NOTCH3 exhibit CXCL12 upregulation. TME cells upregulated CXCL12 and activated the CXCR4 pathway in MM cells in a NOTCH3-dependent manner. Moreover, genetic or pharmacologic inhibition of CXCL12 in NOTCH3OE MM cells restored sensitivity to BOR regimes in vitro and in human bones bearing NOTCH3OE MM tumors cultured ex vivo. Our clinical and preclinical data unravel a novel NOTCH3-CXCL12 pro-survival signaling axis in the TME and suggest that osteocytes transmit chemoresistance signals to MM cells.

Theranostic Potential of Adaptive Cold Atmospheric Plasma with Temozolomide to Checkmate Glioblastoma: An In Vitro Study.

Cold atmospheric plasma (CAP) has been used for the treatment of various cancers. The anti-cancer properties of CAP are mainly due to the reactive species generated from it. Here, we analyze the efficacy of CAP in combination with temozolomide (TMZ) in two different human glioblastoma cell lines, T98G and A172, in vitro using various conditions. We also establish an optimized dose of the co-treatment to study potential sensitization in TMZ-resistant cells. The removal of cell culture media after CAP treatment did not affect the sensitivity of CAP to cancer cells. However, keeping the CAP-treated media for a shorter time helped in the slight proliferation of T98G cells, while keeping the same media for longer durations resulted in a decrease in its survivability. This could be a potential reason for the sensitization of the cells in combination treatment. Co-treatment effectively increased the lactate dehydrogenase (LDH) activity, indicating cytotoxicity. Furthermore, apoptosis and caspase-3 activity also significantly increased in both cell lines, implying the anticancer nature of the combination. The microscopic analysis of the cells post-treatment indicated nuclear fragmentation, and caspase activity demonstrated apoptosis. Therefore, a combination treatment of CAP and TMZ may be a potent therapeutic modality to treat glioblastoma. This could also indicate that a pre-treatment with CAP causes the cells to be more sensitive to chemotherapy treatment.

In Vitro and In Vivo Enhancement of Temozolomide Effect in Human Glioblastoma by Non-Invasive Application of Cold Atmospheric Plasma.

Glioblastoma (GBM) is one of the most aggressive forms of adult brain cancers and is highly resistant to treatment, with a median survival of 12-18 months after diagnosis. The poor survival is due to its infiltrative pattern of invasion into the normal brain parenchyma, the diffuse nature of its growth, and its ability to quickly grow, spread, and relapse. Temozolomide is a well-known FDA-approved alkylating chemotherapy agent used for the treatment of high-grade malignant gliomas, and it has been shown to improve overall survival. However, in most cases, the tumor relapses. In recent years, CAP has been used as an emerging technology for cancer therapy. The purpose of this study was to implement a combination therapy of CAP and TMZ to enhance the effect of TMZ and apparently sensitize GBMs. In vitro evaluations in TMZ-sensitive and resistant GBM cell lines established a CAP chemotherapy enhancement and potential sensitization effect across various ranges of CAP jet application. This was further supported with in vivo findings demonstrating that a single CAP jet applied non-invasively through the skull potentially sensitizes GBM to subsequent treatment with TMZ. Gene functional enrichment analysis further demonstrated that co-treatment with CAP and TMZ resulted in a downregulation of cell cycle pathway genes. These observations indicate that CAP can be potentially useful in sensitizing GBM to chemotherapy and for the treatment of glioblastoma as a non-invasive translational therapy.

Targeting Notch Inhibitors to the Myeloma Bone Marrow Niche Decreases Tumor Growth and Bone Destruction without Gut Toxicity.

Systemic inhibition of Notch with γ-secretase inhibitors (GSI) decreases multiple myeloma tumor growth, but the clinical use of GSI is limited due to its severe gastrointestinal toxicity. In this study, we generated a GSI Notch inhibitor specifically directed to the bone (BT-GSI). BT-GSI administration decreased Notch target gene expression in the bone marrow, but it did not alter Notch signaling in intestinal tissue or induce gut toxicity. In mice with established human or murine multiple myeloma, treatment with BT-GSI decreased tumor burden and prevented the progression of multiple myeloma-induced osteolytic disease by inhibiting bone resorption more effectively than unconjugated GSI at equimolar doses. These findings show that BT-GSI has dual anti-myeloma and anti-resorptive properties, supporting the therapeutic approach of bone-targeted Notch inhibition for the treatment of multiple myeloma and associated bone disease. SIGNIFICANCE: Development of a bone-targeted Notch inhibitor reduces multiple myeloma growth and mitigates cancer-induced bone destruction without inducing the gastrointestinal toxicity typically associated with inhibition of Notch.

Role of Osteocytes in Cancer Progression in the Bone and the Associated Skeletal Disease.

PURPOSE OF REVIEW: The goal of this manuscript is to review the current knowledge on the role of osteocytes in cancer in the bone, discuss the potential of osteocytes as a therapeutic target, and propose future research needed to understand the crosstalk between cancer cells and osteocytes in the tumor niche. RECENT FINDINGS: Numerous studies have established that cancer cells manipulate osteocytes to facilitate invasion and tumor progression in bone. Moreover, cancer cells dysregulate osteocyte function to disrupt physiological bone remodeling, leading to the development of bone disease. Targeting osteocytes and their derived factors has proven to effectively interfere with the progression of cancer in the bone and the associated bone disease. Osteocytes communicate with cancer cells and are also part of the vicious cycle of cancer in the bone. Additional studies investigating the role of osteocytes on metastases to the bone and the development of drug resistance are needed.

Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging.

Positron emission tomography (PET) imaging of the translocator 18 kDa protein (TSPO) with radioligands has become an effective means of research in peripheral inflammatory conditions that occur in many diseases and cancers. The peripheral sterile inflammatory diseases (PSIDs) are associated with a diverse group of disorders that comprises numerous enduring insults including the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system. TSPO has recently been introduced as a potential biomarker for peripheral sterile inflammatory diseases (PSIDs). The major critical issue related to PSIDs is its timely characterization and localization of inflammatory foci for proper therapy of patients. As an alternative to metabolic imaging, protein imaging expressed on immune cells after activation is of great importance. The five transmembrane domain translocator protein-18 kDa (TSPO) is upregulated on the mitochondrial cell surface of macrophages during inflammation, serving as a potential ligand for PET tracers. Additionally, the overexpressed TSPO protein has been positively correlated with various tumor malignancies. In view of the association of escalated TSPO expression in both disease conditions, it is an immensely important biomarker for PET imaging in oncology and PSIDs. In this review, we summarize the most outstanding advances on TSPO-targeted PSIDs and cancer in the development of TSPO ligands as a potential diagnostic tool, specifically discussing the last five years.

A Physically Triggered Cell Death via Transbarrier Cold Atmospheric Plasma Cancer Treatment.

Cold atmospheric plasma (CAP) is a near room-temperature ionized gas composed of highly reactive species. CAP also generates thermal radiation, ultraviolet radiation, and electromagnetic (EM) waves. So far, nearly all biological effects of CAP have relied on the chemical factors in CAP. Here, we first show that the EM emission from CAP can lead to the death of melanoma cells via a transbarrier contactless method. Compared with reactive species, the effect of the physical factors causes much stronger growth inhibition on a reactive species-resistant melanoma cell line B16F10. Such a physically triggered growth inhibition is due to a new cell death type, characterized by the rapid leakage of bulk solutions from the cells, resulting in cytoplasm shrinkage and bubbling on the cell membrane. The physically based CAP-triggered cell death can occur even there is a macroscale gap between the bulk CAP and cells, which includes an air gap (∼8 mm) and a dielectric material of the dish or plate (∼1 mm). Either a too large or a too small gap will inhibit such cell death. The physically triggered cellular pressure may cause the bubbling on cells, which can be inhibited in a hypotonic environment via the extracellular osmotic pressure. This study builds a foundation to use CAP as a physically based noninvasive cancer treatment.

The anti-glioblastoma effect of cold atmospheric plasma treatment: physical pathway v.s. chemical pathway.

Cold atmospheric plasma (CAP), a near room temperature ionized gas, has shown potential application in many branches of medicine, particularly in cancer treatment. In previous studies, the biological effect of CAP on cancer cells and other mammalian cells has been based solely on the chemical factors in CAP, particularly the reactive species. Therefore, plasma medicine has been regarded as a reactive species-based medicine, and the physical factors in CAP such as the thermal effect, ultraviolet irradiation, and electromagnetic effect have been regarded as ignorable factors. In this study, we investigated the effect of a physical CAP treatment on glioblastoma cells. For the first time, we demonstrated that the physical factors in CAP could reinstate the positive selectivity on CAP-treated astrocytes. The positive selectivity was a result of necrosis, a new cell death in glioblastoma cells characterized by the leak of bulk water from the cell membrane. The physically-based CAP treatment overcomed a large limitation of the traditional chemically based CAP treatment, which had complete dependence on the sensitivity of cells to reactive species. The physically-based CAP treatment is a potential non-invasive anti-tumor tool, which may have wide application for tumors located in deeper tissues.

Cold plasma seed priming modulates growth, redox homeostasis and stress response by inducing reactive species in tomato (Solanum lycopersicum).

Seed germination and vegetative growth are two important plant growing stages that are vulnerable to physical and biological stress. Improvement in crop germination potential and seedling growth rate generally leads to high crop productivity. Cold plasma is a promising technology used to improve seed germination and growth. Structural changes on tomato seed surface exposed with cold air plasma jet for a different time period (1 min, 5 min, 10 min) was examined by SEM. For in-depth study, different physiological parameter such as seed germination and seedling growth, biochemical parameter such as reactive species status, antioxidants and phytohormone, and molecular analysis of various gene expression was also evaluated. Drought stress tolerance potential of cold plasma primed tomato seedling was also examined under 30% PEG stress. Cold plasma seed priming modulates tomato seed coat and improves the germination efficiency. It also induces growth, antioxidants, phytohormone, defense gene expression, and drought stress tolerance potential of tomato seedling. Cold plasma seeds priming augment the reactive species at a molecular level within seedlings, which changes the biochemistry and physiological parameters of plants by inducing different cellular signaling cascades.

Cold Atmospheric Plasma as a Novel Therapeutic Tool for the Treatment of Brain Cancer.

BACKGROUND: Studies from the past few years revealed the importance of Cold Atmospheric Plasma (CAP) on various kinds of diseases, including brain cancers or glioblastoma (GBM), and hence coined a new term 'Plasma Medicine' in the modern world for promising therapeutic approaches. Here, we focus on the efficacy of CAP and its liquid derivatives on direct interactions or with specific nanoparticles to show pivotal roles in brain cancer treatment. METHOD: In the present review study, the authors studied several articles over the past decades published on the types of CAP and its effects on different brain cancers and therapy. RESULTS: A growing body of evidence indicates that CAP and its derivatives like Plasma Activated Media/ Water (PAM/PAW) are introduced in different kinds of GBM. Recent studies proposed that CAP plays a remarkable role in GBM treatment. To increase the efficacy of CAP, various nanoparticles of different origins got specific attention in recent times. In this review, different strategies to treat brain cancers, including nanoparticles, are discussed as enhancers of CAP induced targeted nanotherapeutic approach. CONCLUSION: CAP treatment and its synergistic effects with different nanoparticles hold great promise for clinical applications in early diagnosis and treatment of GBM treatment. However, results obtained from previous studies were still in the preliminary phase, and there must be a concern over the use of optimal methods for a dosage of CAP and nanoparticles for complete cure of GBM.

Cold Atmospheric Plasma and Silymarin Nanoemulsion Activate Autophagy in Human Melanoma Cells.

BACKGROUND: Autophagy is reported as a survival or death-promoting pathway that is highly debatable in different kinds of cancer. Here, we examined the co-effect of cold atmospheric plasma (CAP) and silymarin nanoemulsion (SN) treatment on G-361 human melanoma cells via autophagy induction. METHODS: The temperature and pH of the media, along with the cell number, were evaluated. The intracellular glucose level and PI3K/mTOR and EGFR downstream pathways were assessed. Autophagy-related genes, related transcriptional factors, and autophagy induction were estimated using confocal microscopy, flow cytometry, and ELISA. RESULTS: CAP treatment increased the temperature and pH of the media, while its combination with SN resulted in a decrease in intracellular ATP with the downregulation of PI3K/AKT/mTOR survival and RAS/MEK transcriptional pathways. Co-treatment blocked downstream paths of survival pathways and reduced PI3K (2 times), mTOR (10 times), EGFR (5 times), HRAS (5 times), and MEK (10 times). CAP and SN co-treated treatment modulates transcriptional factor expressions (ZKSCAN3, TFEB, FOXO1, CRTC2, and CREBBP) and specific genes (BECN-1, AMBRA-1, MAP1LC3A, and SQSTM) related to autophagy induction. CONCLUSION: CAP and SN together activate autophagy in G-361 cells by activating PI3K/mTOR and EGFR pathways, expressing autophagy-related transcription factors and genes.

Cold atmospheric plasma generated reactive species aided inhibitory effects on human melanoma cells: an in vitro and in silico study.

Malignant melanoma is considered to be a heterogeneous disease that arises from altered genes and transformed melanocytes. In this study, special softjet cold atmospheric plasma was used to treat three different human melanoma cells using air and N2 gases to check the anti-melanoma activity. The physical effects by plasma revealed an increase in the temperature with the gradual reduction in pH at 60 sec, 180 sec and 300 sec air and N2 plasma treatment. Cellular toxicity revealed a decreased in cell survival (~50% cell survival using air gas and <~60% cell survival using N2 gas at 60 sec plasma treatment in G-361 cells). Gene analysis by q-PCR revealed that 3 min and 5 min air and N2 plasma treatment activated apoptotic pathways by triggering apoptotic genes in all three melanoma cell lines. The apoptosis was confirmed by DAPI staining and its related pathways were further explored according to protein-protein docking, and their probable activation mechanism was revealed. The pathways highlighted that activation of apoptosis which leads to cellular cascades and hence stimulation ASK1 (docking method) revealed that softjet plasma can be an effective modality for human melanoma treatment.

Pulsed high-power microwaves do not impair the functions of skin normal and cancer cells in vitro: A short-term biological evaluation.

Over the past few decades, microwave (MW) radiation has been widely used, and its biological effects have been extensively investigated. However, the effect of MW radiation on human skin biology is not well understood. We study the effects of pulsed high-power microwaves (HPMs) on melanoma (G361 and SK-Mel-31) and normal human dermal fibroblast (NHDF) cells. A pulsed power generator (Chundoong) was used to generate pulsed HPMs (dominant frequency: 3.5 GHz). For treatment 1, 5, 15, and 45 shots are given to cells in which the electromagnetic energy of 0.6 J was delivered to the cells at each trigger shot. Cell viability, proliferation rate, apoptosis, cell death, metabolic activity, and oxygen-free radical regulation were evaluated after the MW exposure at low and high doses. MW exposure increased the viabilities and proliferation rates of both melanoma cell lines in a dose-dependent manner, while no significant effects on the fibroblast cells were observed. We found an elevated level of ATP and mitochondrial activity in melanoma cells. Also, it was observed that MW exposure did not affect cell death in melanoma and fibroblast cells. A polymerase chain reaction analysis indicated that the MWs induced dose-dependent proliferation markers without affecting the cell cycle and apoptotic genes in the melanoma cells. Our findings show the differential effects of the MW radiation on the melanoma cells, compared to those on the fibroblast cells.

Cold Atmospheric Plasma-Activated Water Irrigation Induces Defense Hormone and Gene expression in Tomato seedlings.

Plants are very vulnerable to pathogen attacks and environmental stress as they are exposed to harsh environments in natural conditions. However, they have evolved a self-defense system whereby reactive oxygen and nitrogen species (RONS) act as double-edged swords by imposing (at higher concentration) and mitigating (at lower concentration) environmental stress. Cold plasma is emerging as a feasible option to produce a variety of RONS in a controlled manner when amalgamate with water. Cold plasma activated/treated water (PAW) contains a variety of RONS at concentrations, which may help to activate the plant's defense system components. In the present study, we examine the effect of cold atmospheric-air jet plasma exposure (15 min, 30 min, and 60 min) on the water's RONS level, as well as the impact of PAW irrigation, (assigned as 15PAW, 30PAW, and 60PAW) on tomato seedlings growth and defense response. We found that PAW irrigation (priming) upregulate seedlings growth, endogenous RONS, defense hormone (salicylic acid and jasmonic acid), and expression of key pathogenesis related (PR) gene. 30 min PAW contains RONS at concentrations which can induce non-toxic signaling. The present study suggests that PAW irrigation can be beneficial for agriculture as it modulates plant growth as well as immune response components.

Preventing the Solid Cancer Progression via Release of Anticancer-Cytokines in Co-Culture with Cold Plasma-Stimulated Macrophages.

Non-thermal atmospheric pressure plasma sources operated in ambient environments are known to generate a variety of reactive oxygen and nitrogen species which could be applied for various biomedical applications. Herein, we fabricate a micro-dielectric barrier discharge plasma device by using screen-printing technology and apply it for studying immuno-stimulatory effects. We demonstrate a tumor-suppressive role for plasma-stimulated macrophages in metastatic solid cancers that directly elicit proliferation and are responsible for tumor relapse mediated by mesenchymal shift. Using microarray analysis, we observed that cold plasma stimulates and differentiates monocyte cells into macrophages as demonstrated by expression of several cytokine/chemokine markers. Moreover, plasma treatment stimulates the differentiation of pro-inflammatory (M1) macrophages to a greater extent. These stimulated macrophages favor anti-tumorigenic immune responses against metastasis acquisition and cancer stem cell maintenance in solid cancers in vitro. Differentiation of monocytes into anticancer macrophages could improve the efficacy of plasma treatment, especially in modifying pro-tumor inflammatory microenvironment through effecting highly resistant immunosuppressive tumor cells associated with tumor relapse.

Cold atmospheric plasma and silymarin nanoemulsion synergistically inhibits human melanoma tumorigenesis via targeting HGF/c-MET downstream pathway.

BACKGROUND: Recent studies claimed the important role of cold atmospheric plasma (CAP) with nanotechnology in cancer treatments. In this study, silymarin nanoemulsion (SN) was used along with air CAP as therapeutic agent to counter human melanoma. METHODS: In this study, we examined the combined treatment of CAP and SN on G-361 human melanoma cells by evaluating cellular toxicity levels, reactive oxygen and nitrogen species (RONS) levels, DNA damage, melanoma-specific markers, apoptosis, caspases and poly ADP-ribose polymerase-1 (PARP-1) levels using flow cytometer. Dual-treatment effects on the epithelial-mesenchymal transition (EMT), Hepatocyte growth factor (HGF/c-MET) pathway, sphere formation and the reversal of EMT were also assessed using western blotting and microscopy respectively. SN and plasma-activated medium (PAM) were applied on tumor growth and body weight and melanoma-specific markers and the mesenchymal markers in the tumor xenograft nude mice model were checked. RESULTS: Co-treatment of SN and air CAP increased the cellular toxicity in a time-dependent manner and shows maximum toxicity at 200 nM in 24 h. Intracellular RONS showed significant generation of ROS (< 3 times) and RNS (< 2.5 times) in dual-treated samples compared to control. DNA damage studies were assessed by estimating the level of γ-H2AX (1.8 times), PD-1 (> 2 times) and DNMT and showed damage in G-361 cells. Increase in Caspase 8,9,3/7 (> 1.5 times), PARP level (2.5 times) and apoptotic genes level were also observed in dual treated group and hence blocking HGF/c-MET pathway. Decrease in EMT markers (E-cadherin, YKL-40, N-cadherin, SNAI1) were seen with simultaneously decline in melanoma cells (BRAF, NAMPT) and stem cells (CD133, ABCB5) markers. In vivo results showed significant reduction in SN with PAM with reduction in tumor weight and size. CONCLUSIONS: The use of air CAP using µ-DBD and the SN can minimize the malignancy effects of melanoma cells by describing HGF/c-MET molecular mechanism of acting on G-361 human melanoma cells and in mice xenografts, possibly leading to suitable targets for innovative anti-melanoma approaches in the future.

Biological and medical applications of plasma-activated media, water and solutions.

Non-thermal atmospheric pressure plasma has been proposed as a new tool for various biological and medical applications. Plasma in close proximity to cell culture media or water creates reactive oxygen and nitrogen species containing solutions known as plasma-activated media (PAM) or plasma-activated water (PAW) - the latter even displays acidification. These plasma-treated solutions remain stable for several days with respect to the storage temperature. Recently, PAM and PAW have been widely studied for many biomedical applications. Here, we reviewed promising reports demonstrating plasma-liquid interaction chemistry and the application of PAM or PAW as an anti-cancer, anti-metastatic, antimicrobial, regenerative medicine for blood coagulation and even as a dental treatment agent. We also discuss the role of PAM on cancer initiation cells (spheroids or cancer stem cells), on the epithelial mesenchymal transition (EMT), and when used for metastasis inhibition considering its anticancer effects. The roles of PAW in controlling plant disease, seed decontamination, seed germination and plant growth are also considered in this review. Finally, we emphasize the future prospects of PAM, PAW or plasma-activated solutions in biomedical applications with a discussion of the mechanisms and the stability and safety issues in relation to humans.

Zinc complex of tryptophan appended 1,4,7,10-tetraazacyclododecane as potential anticancer agent: Synthesis and evaluation.

With the rising incidences of cancer cases, the quest for new metal based anticancer drugs has led to extensive research in cancer biology. Zinc complexes of amino acid residue side chains are well recognized for hydrolysis of phosphodiester bond in DNA at faster rate. In the presented work, a Zn(II) complex of cyclen substituted with two l-tryptophan units, Zn(II)-Cyclen-(Trp)2 has been synthesized and evaluated for antiproliferative activity. Zn(II)-Cyclen-(Trp)2 was synthesized in ∼70% yield and its DNA binding potential was evaluated through QM/MM study which suggested good binding (G=-9.426) with B-DNA. The decrease in intensity of the positive and negative bands of CT-DNA at 278nm and 240nm, respectively demonstrated an effective unwinding of the DNA helix with loss of helicity. The complex was identified as an antiproliferative agent against U-87MG cells with 5 fold increase in apoptosis with respect to control (2h post incubation, IC50 25µM). Electrophoresis and comet assay studies exhibited an increase in DNA breakage after treatment with complex while caspase-3/ß-actin cleavage established a caspase-3 dependent apoptosis pathway in U-87 MG cells after triggering DNA damage. In vivo tumor specificity of the developed ligand was validated after radiocomplexation with 99mTc (>98% radiochemical yield and specific activity of 2.56GBq/µmol). Avid tumor/muscle ratio of >6 was depicted in biodistribution and SPECT imaging studies in U-87 MG xenograft model nude mice.