Vernonia amygdalina Delile Induces Apoptotic Effects of PC3 Cells: Implication in the Prevention of Prostate Cancer.

Background: Prostate cancer (PCa) is one of the common cancers in males and its incidence keeps increasing globally. Approximately 81% of PCa is diagnosed during the early stage of the disease. The treatment options for prostate care include surgery, radiotherapy, and chemotherapy, but these treatments often have side effects that may lead to issues such as impotence or decreased bowel function. Our central goal is to test the apoptotic effects of Vernonia amygdalina Delile (an edible medicinal plant that is relatively inexpensive, nontoxic, and virtually without side effects) for the prevention of PCa using human adenocarcinoma (PC-3) cells as a test model. Methods: To address our central goal, PC-3 cells were treated with Vernonia amygdalina Delile (VAD). Cell cycle arrest and cell apoptosis were evaluated by Flow Cytometry assessment. Nucleosomal DNA fragmentation was detected by agarose gel electrophoresis. Results: Flow cytometry data showed that VAD induced cell cycle arrest at the G0/G1 checkpoint and significantly upregulated caspase-3 in treated cells compared to the control cells. Agarose gel electrophoresis resulted in the formation of DNA ladders in VAD-treated cells. Conclusions: These results suggest that inhibition of cancer cell growth, induction of cell cycle arrest, and apoptosis through caspase-3 activation and nucleosomal DNA fragmentation are involved in the therapeutic mechanisms of VAD as a candidate drug towards the prevention and/or treatment of PCa.

Horizontal and Vertical Transport of Uranium in an Arid Weapon-Tested Ecosystem.

Armor-penetrating projectiles and fragments of depleted uranium (DU) have been deposited in soils at weapon-tested sites. Soil samples from these military facilities were analyzed by inductively coupled plasma-optical emission spectroscopy and X-ray diffraction to determine U concentrations and transport across an arid ecosystem. Under arid conditions, both vertical transport driven by evaporation (upward) and leaching (downward) and horizontal transport of U driven by surface runoff in the summer were observed. Upward vertical transport was simulated and confirmed under laboratory-controlled conditions, to be leading to the surface due to capillary action via evaporation during alternating wetting and drying conditions. In the field, the 92.8% of U from DU penetrators and fragments remained in the top 5 cm of soil and decreased to background concentrations in less than 20 cm. In locations prone to high amounts of water runoff, U concentrations were reduced significantly after 20 m from the source due to high surface runoff. Uranium was also transported throughout the ecosystem via plant uptake and wild animal consumption between trophic levels, but with limited accumulation in edible portions in plants and animals.

A laboratory preparation procedure for studying bioaccumulation of U and its subcellular form in earthworms (Diplocardia spp.).

Uranium (U) is a ubiquitous trace element in soils. With increasing in application of U in nuclear energy and nuclear weapon, a large amount of U was dissipated into the environment including soil and water. Earthworm may be an eco-indicator for U bioaccumulation, transformation and transport across the ecosystem. There have been a variety of methods preformed to assess the bioaccumulation of uranium in small organisms such as earthworms, including uranium speciation, subcellular separation, and total U accumulation. All methods require an initial grinding preparation process that allows for the further fractionation of metals and metalloids in earthworms. The slime like mucus that coats the body of a worm presents a challenge in the disintegration and dissolution of the worm body. In order to analyze U subcellular forms, we developed a reliable and effective procedure to grind the worm body into a uniform fine suspension. We conducted a comparative study of disintegration of worms with 3 grinding techniques (agate mortar, liquid nitrogen freezing then agate mortar, and direct sonication) that would assist U subcellular analyses and bioaccumulation. The essences of this new development was as follows:•A scheme for preparation of earthworm samples for investigation of subcellular U forms in earthworms from U.S. army weapon test range soil with various U forms.•The direct sonication of earthworms was found to be the most proficient process in achieving the best preparation for U subcellular analyses with the high precision.

A laboratory simulation to investigate effects of moistures on U distribution among solid phase components in army range soils.

Uranium is a naturally occurring radioactive trace element found in rocks, soils, and coals. U may contaminate groundwater and soil from nuclear power plant operations, spent fuel reprocessing, high-level waste disposal, ore mining and processing, or manufacturing processes. Yuma Proving Ground in Arizona, USA has been used depleted uranium ballistics for 36 years where U has accumulated in this army testing site. The objective of this study is to develop a laboratory scheme on the effects of soil moisture regiments on the distribution and partitioning of U in army range soil among solid phase components to mimic U biogeochemical processes in the field. Three moisture regiments were saturated paste, field capacity, and wetting-drying cycle which covered major scenarios in fields from the wet summer season to the dry winter season. Uranium in soils with different forms of U (UO2, UO3, uranyl, and schoepite) was fractionated into 8 operationally defined solid components with sequential selective dissolution procedure. The essences of this new development were as following:•A scheme was developed for investigation of U distribution, partitioning and transformation among solid phase components in army weapon test range soils with various U forms under 3 soil moisture regimes.•Soil moisture was one of major environmental factors in controlling biogeochemical processes and fates of U in army weapon test site.

Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy.

Cisplatin and other platinum-based drugs, such as carboplatin, ormaplatin, and oxaliplatin, have been widely used to treat a multitude of human cancers. However, a considerable proportion of patients often relapse due to drug resistance and/or toxicity to multiple organs including the liver, kidneys, gastrointestinal tract, and the cardiovascular, hematologic, and nervous systems. In this study, we sought to provide a comprehensive review of the current state of the science highlighting the use of cisplatin in cancer therapy, with a special emphasis on its molecular mechanisms of action, and treatment modalities including the combination therapy with natural products. Hence, we searched the literature using various scientific databases., such as MEDLINE, PubMed, Google Scholar, and relevant sources, to collect and review relevant publications on cisplatin, natural products, combination therapy, uses in cancer treatment, modes of action, and therapeutic strategies. Our search results revealed that new strategic approaches for cancer treatment, including the combination therapy of cisplatin and natural products, have been evaluated with some degree of success. Scientific evidence from both in vitro and in vivo studies demonstrates that many medicinal plants contain bioactive compounds that are promising candidates for the treatment of human diseases, and therefore represent an excellent source for drug discovery. In preclinical studies, it has been demonstrated that natural products not only enhance the therapeutic activity of cisplatin but also attenuate its chemotherapy-induced toxicity. Many experimental studies have also reported that natural products exert their therapeutic action by triggering apoptosis through modulation of mitogen-activated protein kinase (MAPK) and p53 signal transduction pathways and enhancement of cisplatin chemosensitivity. Furthermore, natural products protect against cisplatin-induced organ toxicity by modulating several gene transcription factors and inducing cell death through apoptosis and/or necrosis. In addition, formulations of cisplatin with polymeric, lipid, inorganic, and carbon-based nano-drug delivery systems have been found to delay drug release, prolong half-life, and reduce systemic toxicity while other formulations, such as nanocapsules, nanogels, and hydrogels, have been reported to enhance cell penetration, target cancer cells, and inhibit tumor progression.

Distribution and Fractionation of Uranium in Weapon Tested Range Soils.

Uranium is a chemically toxic and radioactive heavy metal. Depleted uranium (DU) is the byproduct of the uranium enrichment process, with a majority of U as uranium-238, and a lower content of the fissile isotope uranium-235 than natural uranium. Uranium-235 is mainly used in nuclear reactors and in the manufacture of nuclear weapons. Exposure is likely to have an impact on humans or the ecosystem where military operations have used DU. Yuma Proving Ground in Arizona, USA has been using depleted uranium ballistics for 36 years. At a contaminated site in the Proving Grounds, soil samples were collected from the flat, open field and lower elevated trenches that typically collect summer runoff. Spatial distribution and fractionation of uranium in the fields were analyzed with total acid digestion and selective sequential dissolution with eight operationally defined solid-phase fractions. In addition to uranium, other trace elements (As, Ba, Co, Cr, Cu, Hg, Mo, Nb, Pd, Pb, V, Zn, Zr) were also assessed. Results show that the trench area in the testing site had a higher accumulation of total U (12.4%) compared to the open-field soil with 279 mg/kg U. Among the eight solid-phase components in the open-field samples, U demonstrated stronger affinities for the amorphous iron-oxide bound, followed by the carbonate bound, and the residual fractions. However, U in the trench area had a stronger binding to the easily reducible oxide bound fraction, followed by the carbonate-bound and amorphous iron-oxide-bound fractions. Among other trace elements, Nb, As, and Zr exhibited the strongest correlations with U distribution among solid-phase components. This study indicates a significant spatial variation of U distribution in the shooting range site. Fe/Mn oxides and carbonate were the major solid-phase components for binding U in the weapon test site.

Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy.

Cisplatin and other platinum-based chemotherapeutic drugs have been used extensively for the treatment of human cancers such as bladder, blood, breast, cervical, esophageal, head and neck, lung, ovarian, testicular cancers, and sarcoma. Cisplatin is commonly administered intravenously as a first-line chemotherapy for patients suffering from various malignancies. Upon absorption into the cancer cell, cisplatin interacts with cellular macromolecules and exerts its cytotoxic effects through a series of biochemical mechanisms by binding to Deoxyribonucleic acid (DNA) and forming intra-strand DNA adducts leading to the inhibition of DNA synthesis and cell growth. Its primary molecular mechanism of action has been associated with the induction of both intrinsic and extrinsic pathways of apoptosis resulting from the production of reactive oxygen species through lipid peroxidation, activation of various signal transduction pathways, induction of p53 signaling and cell cycle arrest, upregulation of pro-apoptotic genes/proteins, and down-regulation of proto-oncogenes and anti-apoptotic genes/proteins. Despite great clinical outcomes, many studies have reported substantial side effects associated with cisplatin monotherapy, while others have shown substantial drug resistance in some cancer patients. Hence, new formulations and several combinational therapies with other drugs have been tested for the purpose of improving the clinical utility of cisplatin. Therefore, this review provides a comprehensive understanding of its molecular mechanisms of action in cancer therapy and discusses the therapeutic approaches to overcome cisplatin resistance and side effects.

Therapeutic strategies and potential implications of silver nanoparticles in the management of skin cancer.

Skin cancer (SC) is the most common carcinoma affecting 3 million people annually in the United States and millions of people worldwide. It is classified as melanoma SC (MSC) and non-melanoma SC (NMSC). NMSC represents approximately 80% of SC and includes squamous cell carcinoma and basal cell carcinoma. MSC, however, has a higher mortality rate than SC because of its ability to metastasize. SC is a major health problem in the United States with significant morbidity and mortality in the Caucasian population. Treatment options for SC include cryotherapy, excisional surgery, Mohs surgery, curettage and electrodessication, radiation therapy, photodynamic therapy, immunotherapy, and chemotherapy. Treatment is chosen based on the type of SC and the potential for side effects. Novel targeted therapies are being used with increased frequency for large tumors and for metastatic disease. A scoping literature search on PubMed, Google Scholar, and Cancer Registry websites revealed that traditional chemotherapeutic drugs have little effect against SC after the cancer has metastasized. Following an overview of SC biology, epidemiology, and treatment options, this review focuses on the mechanisms of advanced technologies that use silver nanoparticles in SC treatment regimens.

Low Doses of Cisplatin Induce Gene Alterations, Cell Cycle Arrest, and Apoptosis in Human Promyelocytic Leukemia Cells.

Cisplatin is a known antitumor drug, but its mechanisms of action are not fully elucidated. In this research, we studied the anticancer potential of cisplatin at doses of 1, 2, or 3 µM using HL-60 cells as a test model. We investigated cisplatin effects at the molecular level using RNA sequencing, cell cycle analysis, and apoptotic assay after 24, 48, 72, and 96 hours of treatment. The results show that many genes responsible for molecular and cellular functions were significantly altered. Cisplatin treatment also caused the cells to be arrested at the DNA synthesis phase, and as the time increases, the cells gradually accumulated at the sub-G1 phase. Also, as the dose increases, a significant number of cells entered into the apoptotic and necrotic stages. Altogether, the data show that low doses of cisplatin significantly impact the viability of HL-60 cells, through modulation of gene expression, cell cycle, and apoptosis.

Preclinical Assessment of Low Doses of Cisplatin in the Management of Acute Promyelocytic Leukemia.

Cis-diamminedichloroplatinum (II) (cisplatin) is the most widely used chemotherapeutic drug for various cancers, but its effectiveness is limited by tumor cell resistance and the severe side effects it causes. Since high level of cisplatin is cytotoxic to both cancer and normal cells, the goal of the present study was to explore the effectiveness of prolonged low doses of cisplatin in the management of leukemia. To achieve our goal, human leukemia (HL-60) cells were treated with different doses (1, 2, or 3 µM) of cisplatin for 24, 48, 72 and 96 hours. Cell viability was assessed by MTS assay. Both oxidative stress damage and genotoxicity were estimated by antioxidants, lipid peroxidation, and comet assays, respectively. Data obtained from the MTS assay demonstrated that cisplatin treatment decreased the number of viable tumor cells by direct cell killing or by simply decreasing the rate of cellular proliferation in a dose- and time-dependent fashion. The results of the lipid peroxidation showed a significant increase (p<0.05) of malondialdehyde levels with increasing cisplatin doses. Results obtained from super oxide dismutase and catalase assays showed a gradual increase in antioxidant enzyme activity in cisplatin-treated cells compared to control cells. Data generated from the Comet assay demonstrated a significant dose-dependent increase in genotoxicity with respect to DNA damage as a result of cisplatin treatment. Taken together, our research demonstrated that cisplatin-induced cytotoxicity in HL-60 cells is mediated at least in part via induction of oxidative stress and oxidative damage.

Cisplatin in cancer therapy: molecular mechanisms of action.

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug. It has been used for treatment of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other platinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used. Furthermore, combination therapies of cisplatin with other drugs have been highly considered to overcome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochemical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or in combination with other drugs) for the treatment of various human cancers. A special attention is paid to its molecular mechanisms of action, and its undesirable side effects.