Cyclooxygenase-2 (COX-2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo- and radiotherapy. COX-2 is released by cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX-2 induces cancer stem cell (CSC)-like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX-2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX-2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX-2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX-2 on cancer cells or its regulation. Members of mitogen-activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor-κβ are main upstream modulators for COX-2 in cancer cells. COX-2 also has interactions with a number of hormones within the body. Inhibition of COX-2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX-2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX-2 inhibition also sensitizes cancer cells to treatments like radio- and chemotherapy. Chemotherapeutic agents adversely induce COX-2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX-2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer.

Cyclooxygenase-2 in cancer: A review.

The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that is based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health. The concept that there are levels of exposure that do not cause adverse effects is inherent in setting acceptable daily intakes (ADIs) for chemicals with known toxicological profiles. The TTC principle extends this concept by proposing that a de minimis value can be identified for many chemicals, in the absence of a full toxicity database, based on their chemical structures and the known toxicity of chemicals which share similar structural characteristics. The establishment and application of widely accepted TTC values would benefit consumers, industry and regulators. By avoiding unnecessary toxicity testing and safety evaluations when human intakes are below such a threshold, application of the TTC approach would focus limited resources of time, cost, animal use and expertise on the testing and evaluation of substances with the greatest potential to pose risks to human health and thereby contribute to a reduction in the use of animals. An Expert Group of the European branch of the International Life Sciences Institute-ILSI Europe-has examined the TTC principle for its wider applicability in food safety evaluation. The Expert Group examined metabolism and accumulation, structural alerts, endocrine disrupting chemicals and specific endpoints, such as neurotoxicity, teratogenicity, developmental toxicity, allergenicity and immunotoxicity, and determined whether such properties or endpoints had to be taken into consideration specifically in a step-wise approach. The Expert Group concluded that the TTC principle can be applied for low concentrations in food of chemicals that lack toxicity data, provided that there is a sound intake estimate. The use of a decision tree to apply the TTC principle is proposed, and this paper describes the step-wise process in detail. Proteins, heavy metals and polyhalogenated-dibenzodioxins and related compounds were excluded from this approach. When assessing a chemical, a review of prior knowledge and context of use should always precede the use of the TTC decision tree. The initial step is the identification and evaluation of possible genotoxic and/or high potency carcinogens. Following this step, non-genotoxic substances are evaluated in a sequence of steps related to the concerns that would be associated with increasing intakes. For organophosphates a TTC of 18microg per person per day (0.3 microg/kg bw/day) is proposed, and when the compound is not an OP, the TTC values for the Cramer structural classes III, II and I, with their respective TTC levels (e.g. 1800, 540 and 90 microg per person per day; or 30, 9 and 1.5 microg/kg bw /day), would be applied sequentially. All other endpoints or properties were shown to have a distribution of no observed effect levels (NOELs) similar to the distribution of NOELs for general toxicity endpoints in Cramer classes I, II and III. The document was discussed with a wider audience during a workshop held in March 2003 (see list of workshop participants).

Structure-Based Thresholds of Toxicological Concern (TTC): Guidance for Application to Substances Present at Low Levels in the Diet

In vivo methods for drug absorption – Comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects

Pharmaceutical assessment of polyvinylpyrrolidone (PVP): As excipient from conventional to controlled delivery systems with a spotlight on COVID-19 inhibition.

Anti-inflammatory activity of natural stilbenoids: A review.

Metallic and metal oxide nanoparticles (NPs), including titanium dioxide NPs, among polymeric NPs, liposomes, micelles, quantum dots, dendrimers, or fullerenes, are becoming more and more important due to their potential use in novel medical therapies. Titanium dioxide (titanium(IV) oxide, titania, TiO2) is an inorganic compound that owes its recent rise in scientific interest to photoactivity. After the illumination in aqueous media with UV light, TiO2 produces an array of reactive oxygen species (ROS). The capability to produce ROS and thus induce cell death has found application in the photodynamic therapy (PDT) for the treatment of a wide range of maladies, from psoriasis to cancer. Titanium dioxide NPs were studied as photosensitizing agents in the treatment of malignant tumors as well as in photodynamic inactivation of antibiotic-resistant bacteria. Both TiO2 NPs themselves, as well as their composites and combinations with other molecules or biomolecules, can be successfully used as photosensitizers in PDT. Moreover, various organic compounds can be grafted on TiO2 nanoparticles, leading to hybrid materials. These nanostructures can reveal increased light absorption, allowing their further use in targeted therapy in medicine. In order to improve efficient anticancer and antimicrobial therapies, many approaches utilizing titanium dioxide were tested. Results of selected studies presenting the scope of potential uses are discussed in this review.

https://www.mdpi.com/2079-4991/10/2/387/pdf

Titanium Dioxide Nanoparticles: Prospects and Applications in Medicine.

Titanium dioxide (TiO2) is a material of diverse applications commonly used as a food additive or cosmetic ingredient. Its prevalence in products of everyday use, especially in nanosize, raises concerns about safety. Current findings on the safety of titanium dioxide nanoparticles (TiO2 NPs) used as a food additive or a sunscreen compound are reviewed and systematized in this publication. Although some studies state that TiO2 NPs are not harmful to humans through ingestion or via dermal exposure, there is a considerable number of data that demonstrated their toxic effects in animal models. The final agreement on the safety of this nanomaterial has not yet been reached among researchers. There is also a lack of official, standardized guidelines for thorough characterization of TiO2 NPs in food and cosmetic products, provided by international authorities. Recent advances in the application of ‘green-synthesized’ TiO2 NPs, as well as comparative studies of the properties of ‘biogenic’ and ‘traditional’ nanoparticles, are presented. To conclude, perspectives and directions for further studies on the toxicity of TiO2 NPs are proposed.

Titanium Dioxide Nanoparticles in Food and Personal Care Products-What Do We Know about Their Safety?

COX-2 inhibitors: a novel strategy in the management of breast cancer.

A rapid high performance liquid chromatographic method was developed and validated for determination of atorvastatin in pharmaceutical dosage forms, and for evaluation of its stability in the solid phase. Separation of atorvastatin was successfully achieved on a C-18 column utilizing water--acetonitrile at the volumetric ratio of 48:52, adjusted to pH 2.0 with 80% ortho-phosphoric acid. The detection wavelength was 245 nm. The method was validated and the response was found to be linear in the drug concentration range of 0.04 mg/mL - 0.4 mg/mL. The mean values +/- RSD of the slope and the correlation coefficient were 8.192 +/- 0.260 and 0.999, respectively. The RSD values for intra- and interday precision were < 1.00% and 0.90%, respectively. The degradation kinetic of atorvastatin at 363 K in a relative humidity of 76.4% was observed to be autocatalytic first order reaction. The kinetic parameters were as follows: k (where k represents the velocity constant; s(-1)) = (1.42 +/- 0.19) 10(-6); t(0.5) (where t(0.5) represents the time needed for a 50% decay of atorvastatin; days) = 32.82 +/- 0.9; t(0.1) (where t(0.1) represents the time needed for a 10% decay of atorvastatin; days) = 13.86 +/- 0.8.

/pdf/validation-of-hplc-method-for-determination-of-atorvastatin-1v63mswbvo.pdf

Validation of HPLC method for determination of atorvastatin in tablets and for monitoring stability in solid phase.

The renin-angiotensin system has been established as an attractive target for pharmacological interventionsince the discovery of first angiotensin-converting enzyme inhibitors (ACE-Is). In fact, these drugs are primarilyused in the management of cardiovascular system-related diseases and renal insufficiency. Their mechanism ofaction involves the adjustment of balance between vasoconstrictive, hypertrophic and salt/water-retentive angiotensinII and vasodilatory and natriuretic bradykinin by the inhibition of angiotensin II biosynthesis and bradykinindegradation. Currently there are thirteen family members approved for use in humans. They differ in structure,chemistry and pharmacokinetic and pharmacodynamic properties yet they display a similar pharmacologic andtoxicologic profile. All of them are effective in the treatment of hypertension as well as in cardiac insufficiency or diabetic nephropathy.Although they are generally well-tolerated several serious side-effects including life-threatening angioedema, renal failure and persistentdry cough could occur during the administration of ACE-Is, which may require the cessation of therapy. Furthermore, to provide maximumsafety and efficiency of ACE-Is-based therapy, the knowledge of the related drug interactions and chronokinetics seems to be anabsolute requirement. Here we discuss the above-mentioned issues regarding the pharmaceutical and chemical properties of the commercially-used ACE-Is.

Beata Stanisz

Papers

Titanium Dioxide Nanoparticles: Prospects and Applications in Medicine.

Titanium Dioxide Nanoparticles in Food and Personal Care Products-What Do We Know about Their Safety?

COX-2 inhibitors: a novel strategy in the management of breast cancer.

Validation of HPLC method for determination of atorvastatin in tablets and for monitoring stability in solid phase.

Chemistry and Pharmacology of Angiotensin-Converting Enzyme Inhibitors