Non-toxic Action Research Articles

Review of the anticancer properties of 6-shogaol: Mechanisms of action in cancer cells and future research opportunities.

Cancer is a major global health challenge that affects every nation and accounts for a large portion of the worldwide disease burden. Furthermore, cancer cases will rise significantly in the next few decades. The Food and Drug Administration has approved more than 600 drugs for treating diverse types of cancer. However, many conventional anticancer medications cause side effects, and drug resistance develops as the treatment proceeds with a concomitant impact on patients' quality of life. Thus, exploring natural products with antitumor properties and nontoxic action mechanisms is essential. Ginger (Zingiber officinale Roscoe) rhizome has a long history of use in traditional medicine, and it contains biologically active compounds, gingerols and shogaols. The main ginger shogaol is 6-shogaol, whose concentration dramatically increases during the processing of ginger, primarily due to the heat-induced conversion of 6-gingerol. Some studies have demonstrated that 6-shogaol possesses biological and pharmacological properties, such as antioxidant, anti-inflammatory, and anticancer activities. The mechanism of action of 6-shogaol as an anticancer drug includes induction of paraptosis, induction of apoptosis, increase in the production of reactive oxygen species, induction of autophagy, and the inhibition of AKT/mTOR signaling. Despite this knowledge, the mechanism of action of 6-shogaol is not fully understood, and the scientific data on its therapeutic dose, safety, and toxicity are not entirely described. This review article examines the potential of 6-shogaol as an anticancer drug, addressing the limitations of current medications; it covers 6-shogaol's attributes, mechanism of action in cancer cells, and opportunities for future research.

Phytochemical Composition, Antioxidant Capacity and Toxicological Properties of Eucalyptus cinerea F. Muell. ex Benth Essential Oils in Rats

Eucalyptus cinerea F. Muell. ex Benth (Myrtaceae) is used in traditional Tunisian medicine to treat gastrointestinal disorders and other diseases. The aim of this study was to determine the chemical composition of essential oils of Eucalyptus cinerea (ECEO) and their antioxidant and toxicological capacities. The EO was extracted by steam distillation, its chemical composition of EO was determined by gas chromatography and mass spectrometry (GC-MS) and the antioxidant activity was evaluated by the DPPH• test. The accute toxicity of ECEO was carried out on healthy female Wistar rats with increasing doses (0, 50..., and 1000 mg Kg-1 b.w). The results showed that essential oils contain a complex mixture of monoterpenes and sesquiterpenes and the 1,8-cineole (41.87%) represents the main compound. The different chemical compounds of ECEO are endowed with good antioxidant ability. More importantly, we have demonstrated, in vivo, that the LD50 is greater than 1000 mg/kg body weight (b.w.) for ECEO. In conclusion, we suggest that the proportion of terpenoids present in the E. cinerea essential oils could be among the active principles responsible for the antioxidant activity demonstrated in vitro by ECEO as well as non-toxic action against tested animals.

Synthesis, structure–activity relationship studies using density functional theory and in silico molecular docking on substituted benzohydrazide derivatives

The present study demonstrates the utility of benzohydrazide derivatives based on an approach to identify potential targets for a series of synthesized compounds that show potent anticancer activities against four cancer cell lines compared to other structurally related molecules. Benzohydrazide compounds have been synthesized effectively by the condensation of aldehyde and hydrazide at a 1:1 molar ratio. The complete series of compounds 1a-j were characterized by FT-IR, NMR, and one of them by single-crystal X-ray diffraction. The crystal structure of compound 1a shows a trans configuration around the CN bond and crystallized in a monoclinic system with C 2/c space group. All compounds exhibited good anticancer activity against four cancer cell lines such as A375 (human malignant melanoma), A549 (human lung adenocarcinoma), HT-29 (human epithelial intestinal) and MDA-MB-232(human metastatic breast). Among them, compound 1e shows the highest cytotoxic effect against the HT29 (IC50 = 0.47 µM) and A375 (IC50 = 0.80 µM) cell lines. Other compounds also exhibited promising anticancer activity. In addition, the nontoxic action was verified using the cytocompatibility assay on the L929 normal cell line and the hemolysis assay on human red blood cells. Parameters such as HOMO-LUMO energies, Hirshfeld surface analysis, and Molecular Electrostatic Potential (MEP) surface have been calculated using DFT and compared to experimental values of compounds 1a-c. In silico molecular docking studies revealed that the compound 1 h interacted very strongly with the 1T46 protein, with a docking score of −9.7 kcal/mol and very good binding via π–π, π-alkyl and π–σ interactions as compared to the standard drug. As a result of their potent cytotoxicity activities and computational analysis, these can be considered promising anticancer agents.

Assessment of cytotoxicity, acute, subacute toxicities and antioxidant activities (in vitro) of Sanghuangporus vaninii crude polysaccharide

Ethnopharmacology relevanceSanghuangporus vaninii (S. vaninii), as a traditional large medicinal fungus, has a history of more than 2000 years in Chinese history and has been widely used to treat female diseases such as vaginal discharge, amenorrhea, and uterine bleeding, and recent pharmacological studies have also found that it has antioxidant, anti-inflammatory, and anti-tumor physiological activity, which has received more and more attention. Aim of the studyThe objective was to evaluate cytotoxicity and the acute, subacute toxicity, and in vitro antioxidant activity of S. vaninii crude polysaccharide (SVP). Materials and methodsThe monosaccharide composition of SVP was determined by HPLC (high-performance liquid chromatography). The cytotoxicity of different concentrations of SVP on three types of cells (HT-22, Kupffer macrophages, HEK293) was assessed using CCk-8. The acute toxicity in vivo was evaluated for 14 days after the administration of SVP (2500,5000, or 10,000 mg/mL). For the evaluation of subacute toxicity, mice were daily treated for 28 days with SVP (2500,5000, or 10,000 mg/mL). In addition, DPPH, hydroxyl radical, and superoxide anion radical were used to evaluate the in vitro antioxidant activity of SVP. ResultsSVP was not toxic in all three cell lines tested. In vitro antioxidant tests on the extracts showed that SVP possessed a strong antioxidant capacity in vitro. In the acute study, the no-observed-adverse-effect level (NOAEL) in male and female rats was 10，000 mg/kg body weight. There were also no deaths or severe toxicity associated with SVP in subacute studies. However, SVP treatment had a decreasing effect on body weight in mice of both sexes (2500, 5000, and 10000 mg/kg). At doses (5000 and 10,000 mg/kg), SVP had a reduced effect on food intake in both male and female mice. In addition, there were significant effects on organ coefficients of the liver, lung, and kidney. Hematological analysis showed significantly lower LYM (%) values in mice of both sexes, with significantly lower MCH (pg) values obtained in males (5000 mg/kg and 10000 mg/kg) and higher GRAN (%) values in females. In addition, the RDW-SD (fL) values were significantly lower in the male mice given the highest dose. Biochemical tests showed that there were no significant changes in ALT, AST, TP, and Cr levels after SVP treatment. In histopathological analysis, mild liver toxicity was observed in both female mice treated with 10,000 mg/kg SVP. ConclusionThe extract of SVP showed a predominance of polysaccharide compounds, with non-toxic action in vivo. Our approach revealed SVP on the chemical composition and suggests a high margin of safety in the popular use of medicinal fungi. In conclusion, our results suggest that SVP is safe, and can be used as health care products and food.

New2-((2-(2,4-dinitrophenyl)hydrazineeylidene) derivatives: design, synthesis, in silico, and in vitro anticancer studies

A series of novel hydrazone compounds have been synthesized by the condensation of hydrazines and different substituted salicylaldehydes at a molar ratio of 1:1 in one step reaction and characterized by FT-IR, ESI-MS, 1H NMR, and single crystal x-ray diffraction. The crystal structure of the compound shows a trans configuration around the C = N bond and triclinic system with P −1/-p 1. Synthesized compounds were screened for cytotoxicity activities against A375 (melanoma), HT-29 (Colon), and A549 (lung) cancer cell lines. Among them, compound 2 exhibited the highest cytotoxic effect against the A375 cell line (IC50 = 0.30 µM) and HT-29 cell line (1.68 µM), compared to those of apatinib as a reference standard drug (0.28, 1.49 µM, respectively). The cytocompatibility assay on the L929 normal cell line and the hemolysis assay on human RBC were used to validate the non-toxic action. From DFT calculation, the various parameters such as HOMO-LUMO energies, Hirshfeld, and MEP have been studied. Furthermore, in silico molecular docking with three receptors was studied. Among four compounds, compound 2 has the lowest binding energy against cyclin dependent kinase (ΔGb = −9.3 kcal/mol). In addition to this, molecular dynamics (MD) simulation was also performed. Based on this study, these novel hydrazones can be considered a promising anticancer agent due to their potent cytotoxicity activities and computational analysis. Communicated by Ramaswamy H. Sarma

Use of Polyhexanidine in Treating Chronic Wounds

Chronic wounds have a long period of healing, being impeded by numerous factors, as infections. Polyhexanidine is a new broad spectrum antiseptic with non-toxic action which is used lately in wound cleaning solutions. A case control study was realized with two groups of patients treated with silver sulfodiazine and with polyhexanidine, the last group having an accelerated healing evolution. Besides the bactericide action, polyhexanidine has also no cytotoxicity, good tolerability and anti-inflammatory proprieties.

Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency

Recombinant proteins are important therapeutics due to potent, highly specific, and nontoxic actions in vivo. However, they are expensive medicines to manufacture, chemically unstable, and difficult to administer with low patient uptake and compliance. Small molecule drugs are cheaper and more bioavailable, but less target-specific in vivo and often have associated side effects. Here we combine some advantages of proteins and small molecules by taking short amino acid sequences that confer potency and selectivity to proteins, and fixing them as small constrained molecules that are chemically and structurally stable and easy to make. Proteins often use short alpha-helices of just 1-4 helical turns (4-15 amino acids) to interact with biological targets, but peptides this short usually have negligible alpha-helicity in water. Here we show that short peptides, corresponding to helical epitopes from viral, bacterial, or human proteins, can be strategically fixed in highly alpha-helical structures in water. These helix-constrained compounds have similar biological potencies as proteins that bear the same helical sequences. Examples are (i) a picomolar inhibitor of Respiratory Syncytial Virus F protein mediated fusion with host cells, (ii) a nanomolar inhibitor of RNA binding to the transporter protein HIV-Rev, (iii) a submicromolar inhibitor of Streptococcus pneumoniae growth induced by quorum sensing pheromone Competence Stimulating Peptide, and (iv) a picomolar agonist of the GPCR pain receptor opioid receptor like receptor ORL-1. This approach can be generally applicable to downsizing helical regions of proteins with broad applications to biology and medicine.

Review: 50 years later: is metformin a vascular drug with antidiabetic properties?

Since the clinical demonstration of a protective effect of metformin against chronic diabetic angiopathy in the United Kingdom Prospective Diabetes Study, many data have accumulated which confirm such effects in acute or chronic situations as diverse as ischaemia, non-diabetic insulin resistant states and diabetes. Recent years have provided several mechanisms of action and further documented some unique properties of this compound such as improvements in microcirculatory flow, glycation and oxidative stress. In particular, the latter effect could be shown in mitochondria, i.e. the most important sources of reactive oxygen species in diabetes. Specific, non-toxic actions of metformin at the level of the mitochondrial respiratory chain also prevent apoptosis, another mechanism to explain the long-term protection afforded by metformin. Noteworthy, most of these effects of metformin are unrelated to drug dosage and largely independent of its antihyperglycaemic effect (intrinsic properties). These new data open potential avenues for larger therapeutic utilisations of this drug, 50 years after its launch for the treatment of type 2 diabetes.

Production of azadirachtin from plant tissue culture: State of the art and future prospects

With increasing awareness towards environment-friendly and non-toxic pesticide azadirachtin obtained from neem tree (Azadirachta indica) is gaining more and more importance. Its broad-spectrum activity, peculiar mode of action. eco-friendly and non-toxic action towards beneficial organisms has offered many advantages over chemical pesticides. All currently use commercial formulations based on azadirachtin contains azadirachtin extracted from seeds of naturally grown whole plants which is labour intensive process depending upon many uncontrollable geographical and climatic factors. Plant tissue culture can be a potential process for the production, offering consistent, stable and controlled supply of this bioactive compound, However the research on tissue culture aspects of production are in preliminary stage and requires culture and process optimization for the development of a commercially viable process. This review states the present status and future challenges of plant tissue culture for azadirachtin production.

Parallel increases in lipid and protein oxidative markers in several mouse brain regions after methamphetamine treatment

The neurotoxic actions of methamphetamine (METH) may be mediated in part by reactive oxygen species (ROS). Methamphetamine administration leads to increases in ROS formation and lipid peroxidation in rodent brain; however, the extent to which proteins may be modified or whether affected brain regions exhibit similar elevations of lipid and protein oxidative markers have not been investigated. In this study we measured concentrations of TBARs, protein carbonyls and monoamines in various mouse brain regions at 4 h and 24 h after the last of four injections of METH (10 mg/kg/injection q 2 h). Substantial increases in TBARs and protein carbonyls were observed in the striatum and hippocampus but not the frontal cortex nor the cerebellum of METH-treated mice. Furthermore, lipid and protein oxidative markers were highly correlated within each brain region. In the hippocampus and striatum elevations in oxidative markers were significantly greater at 24 h than at 4 h. Monoamine levels were maximally reduced within 4 h (striatal dopamine [DA] by 95% and serotonin [5-HT] in striatum, cortex and hippocampus by 60-90%). These decrements persisted for 7 days after METH, indicating effects reflective of nerve terminal damage. Interestingly, NE was only transiently depleted in the brain regions investigated (hippocampus and cortex), suggesting a pharmacological and non-toxic action of METH on the noradrenergic nerve terminals. This study provides the first evidence for concurrent formation of lipid and protein markers of oxidative stress in several brain regions of mice that are severely affected by large neurotoxic doses of METH. Moreover, the differential time course for monoamine depletion and the elevations in oxidative markers indicate that the source of oxidative stress is not derived directly from DA or 5HT oxidation.

SupraMolecular BioVectors (SMBV) improve antisense inhibition of erbB-2 expression.

New therapeutic strategies are now being developed against adenocarcinoma associated with erbB-2 amplification, particularly by inhibiting p185erbB-2 expression. Antisense oligodeoxynucleotides seem promising for this purpose as long as they are efficiently protected against degradation and targeted into the cells. We present antisense oligonucleotide carriers, the supramolecular biovectors (SMBVs), for which we have already demonstrated the ability to improve both cellular uptake and protection of oligodeoxynucleotide. The present work demonstrates that SMBVs elicit a specific and non-toxic action of antisense compounds in a cell model, irrespective of their sensitivity to nucleases. This is a major point, considering the specificity problems associated with the use of nuclease-resistant phosphorothioate oligodeoxynucleotide. SMBVs improve antisense efficiency of oligodeoxynucleotide designed against p185erbB-2, with a complete growth arrest of SK-Br-3, human adenocarcinoma mammary cells that overexpress p185erbB-2 and no effect on MCF-7 cells that normally express p185erbB-2. The comparison of SMBVs with DOTAP reveals the statistically higher efficiency of SMBVs, which allows the antisense inhibition of p185erbB-2 expression in 65-75% of SK-Br-3 cells (P < 0.05). The efficiency and controlled synthesis of SMBVs underline their potentialities as oligodeoxynucleotide carriers for in vivo experiments.

Chemical Modification by Maleimide of Toxic and Nontoxic Ouabain Actions on Neuromuscular Transmission in the Frog.

A dual action of ouabain on the Mg(2+)-blocked frog neuromuscular transmission was studied in two different experimental procedures by measuring the mean quantal content (m) of endplate potentials evoked during repetitive nerve stimulation. The nontoxic action of low-dose (1 microM) ouabain was observed as a counterclockwise pivoting of the linear stimulation frequency versus the log m relation, termed frequency augmentation-potentiation (FAP), whereas the toxic effect of higher doses (> or = 10 microM) of ouabain was recorded as a slow exponential increase in m. Since neural Na+,K(+)-ATPase consists of two or three isoforms, the nontoxic action of low-dose ouabain was anticipated to be a consequence of the selective inhibition of ouabain-sensitive alpha(+) (alpha 2 and alpha 3 or neural type) Na+,K(+)-ATPase activity. Such a possibility was assessed by applying epsilon-maleimidocaproic acid (MCA), a membrane-impermeant sulfhydryl reagent. MCA 15 microM was found in the present study to suppress the nontoxic effect of ouabain without altering the toxic effect. The results strongly suggest that the toxic and nontoxic actions of ouabain are the result of actions on different entities. The ouabain-sensitive neural type Na+,K(+)-ATPase, which is abundant in neural tissues, seems to play an important role in modulation of transmitter release observable as FAP.

Abnormal granulocyte feedback regulation of colony forming and colony stimulating activity-producing cells from patients with chronic myelogenous leukemia

Colony inhibiting activity (CIA), which can be obtained from human polymorphonuclear neutrophil leukocytes (PMN), reduces the numbers of bone marrow and blood (density < 1.070 g/cm 3) cells which can spontaneously proliferate in vitro to form colonies and clusters. However, PMN from patients with chronic myelogenous leukemia (CML) were quantitatively deficient in CIA regardless of the patient's clinical status or in vitro growth patterns. Even greater differences in (CIA) between normal and CML-PMN were unmasked by high speed centrifugation of PMN-extracts. Potency of CIA from normal PMN could be enhanced by removal of material pelleted after centrifugation at 160,000 g. Removal of the pellet also decreased the 37°C temperature sensitivity of CIA. CIA from CML-PMN was not enhanced by this procedure. CIA obtained from CML-PMN had the same site of action as that from normal PMN. Although not species specific, CML-CIA was specific in its non-toxic action on the Colony Stimulating Activity (CSA)-producing cell; both CFU-c and cell-free CSA molecules were not affected. A further defect was noted in that target cells (density < 1.070 g/cm 3) from patients with CML were less sensitive than normal targets to inhibition with low concentrations of CIA from normal PMN. However, high concentrations of CIA were as active against CML as against normal targets. The reasons for the decreased sensitivity of CML targets are discussed. These negative feedback abnormalities in vitro may partially explain granulocytic hyperplasia associated with CML.