Spectroscopic, biochemical and computational studies of bioactive DNA minor groove binders targeting 5'-WGWWCW-3' motif.

Spectroscopic, biochemical, and computational modelling studies have been used to assess the binding capability of a set of minor groove binding (MGB) ligands against the self-complementary DNA sequences 5'-d(CGCACTAGTGCG)-3' and 5'-d(CGCAGTACTGCG)-3'. The ligands were carefully designed to target the DNA response element, 5'-WGWWCW-3', the binding site for several nuclear receptors. Basic 1D 1H NMR spectra of the DNA samples prepared with three MGB ligands show subtle variations suggestive of how each ligand associates with the double helical structure of both DNA sequences. The variations among the investigated ligands were reflected in the line shape and intensity of 1D 1H and 31P-{1H} NMR spectra. Rapid visual inspection of these 1D NMR spectra proves to be beneficial in providing valuable insights on MGB binding molecules. The NMR results were consistent with the findings from both UV DNA denaturation and molecular modelling studies. Both the NMR spectroscopic and computational analyses indicate that the investigated ligands bind to the minor grooves as antiparallel side-by-side dimers in a head-to-tail fashion. Moreover, comparisons with results from biochemical studies offered valuable insights into the mechanism of action, and antitumor activity of MGBs in relation to their structures, essential pre-requisites for future optimization of MGBs as therapeutic agents.

Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors.

INTRODUCTION: Altered epigenetic map is frequently observed in cancer and recent investigations have demonstrated a pertinent role of epigenetic modifications in the response to many anticancer drugs including the DNA damaging agents. Topoisomerase I (Top I) is a well-known nuclear enzyme that is critical for DNA function and cell survival and its inhibition causes DNA strand breaks and cell cycle arrest. Inhibitors of human Top I have proven to be a prosperous chemotherapeutic treatment for a vast number of cancer patients. While the treatment is efficacious in many cases, resistance and altered cellular response remain major therapeutic issues. AREAS COVERED: This review highlights the evidence available till date on the influence of different epigenetic modifications on the response to Top I inhibitors as well as the implications of targeting epigenetic alterations for improving the efficacy and safety of Top I inhibitors. EXPERT OPINION: The field of epigenetic research is steadily growing. With its assistance, we could gain better understanding on how drug response and resistance work. Epigenetics can evolve as possible biomarkers and predictors of response to many medications including Top I inhibitors, and could have significant clinical implications that necessitate deeper attention.HIGHLIGHTSEpigenetic alterations, including DNA methylation and histone modifications, play a pertinent role in the response to several anticancer treatments, including DNA damaging agents like Top I inhibitors.Although camptothecin derivatives are used clinically as Top I inhibitors for management of cancer, certain types of cancer have inherent and or acquired resistance that limit the curative potential of them.Epigenetic modifications like DNA hypomethylation can either increase or decrease sensitivity to Top I inhibitors by different mechanisms.The combination of Top I inhibitors with the inhibitors of histone modifying enzymes can result in enhanced cytotoxic effects and sensitization of resistant cells to Top I inhibitors.MicroRNAs were found to directly influence the expression of Top I and other proteins in cancer cells resulting in positive or negative alteration of the response to Top I inhibitors.lncRNAs and their genetic polymorphisms have been found to be associated with Top I function and the response to its inhibitors.Clinical trials of epigenetic drugs in combination with Top I inhibitors are plentiful and some of them showed potentially promising outcomes.

Management of ST-segment elevation myocardial infarction in comparison to European society of cardiology guidelines in Alexandria University Hospitals, Egypt.

BACKGROUND: For patients with ST-elevation myocardial infarction (STEMI), early reperfusion with primary percutaneous coronary intervention (PPCI) or thrombolytic treatment is essential to prevent major adverse cardiac events. The aim of the study is to compare the current status of managing STEMI patients at **** with European Society of Cardiology guidelines recommendations. Prospective cohort of all patients presenting with ST-elevation myocardial infarction (STEMI) between March 2020 and February 2021 in Alexandria University hospitals. Reporting patterns, causes of delay, and reperfusion status for all STEMI patients were noted. MACE: (Mortality, Re-infarction, Stroke, or Heart failure) was reported and compared among different management strategies. RESULTS: The study was conducted over one year on 436 patients, 280 (64.2%) of them underwent PPCI, 32 (7.3%) received thrombolysis, and 124 (28.5%) had a conservative strategy. Patients' mean age was 55.2 years, 72.2% were smokers and 80.9% were men. Family history was positive in 14.2% of patients, 33.5% had diabetes, 7.3% had renal impairment, and 41.5% had hypertension. The median pre-hospital waiting time was 360 min; the mean pre-hospital waiting time was 629.0 ± 796.7 min. The median Emergency Room waiting time was 48.24 ± 89.30 min. The median time from CCU admission to wire crossing was 40.0 min with a mean value 53.86 ± 49.0 min. The mean ischemia duration was 408 min, while the total ischemic time was 372 min. All patients who presented within 12 h received reperfusion therapy either a PPCI or thrombolysis at a rate of 71.5%, with 35.0% of those patients achieving prompt reperfusion in accordance with ESC guidelines. The PPCI group mortality rate was 2.9%, in comparison to 12.9% in the conservative group, which was statistically significant (P < 0.001). Overall in-hospital mortality was 5.5%, and total MACE was 27.3%. A statistically significant difference was observed between the three management groups as regards MACE rate, being 15%, 28.1%, and 54.8% in PPCI, thrombolysis, and conservative groups, respectively. CONCLUSIONS: Despite financial and technical constraints, appropriate, timely reperfusion was near to achieving the ESC guidelines for the management of STEMI. The most common reperfusion strategy was PPCI, with an in-hospital death rate of less than 5% in the PPCI group. There was a concern about the increase in the total ischemia time due to some financial and technical constraints.

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011-2020): Current Status and Future Prospects.

Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011-2020).

A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors.

HER4 is a receptor tyrosine kinase that is required for the evolution of normal body systems such as cardiovascular, nervous, and endocrine systems, especially the mammary glands. It is activated through ligand binding and activates MAPKs and PI3K/AKT pathways. HER4 is commonly expressed in many human tissues, both adult and fetal. It is important to understand the role of HER4 in the treatment of many disorders. Many studies were also conducted on the role of HER4 in tumors and its tumor suppressor function. Mostly, overexpression of HER4 kinase results in cancer development. In the present article, we reviewed the structure, location, ligands, physiological functions of HER4, and its relationship to different cancer types. HER4 inhibitors reported mainly from 2016 to the present were reviewed as well.

Current status and future prospects of p38α/MAPK14 kinase and its inhibitors.

P38α (which is also named MAPK14) plays a pivotal role in initiating different disease states such as inflammatory disorders, neurodegenerative diseases, cardiovascular cases, and cancer. Inhibitors of p38α can be utilized for treatment of these diseases. In this article, we reviewed the structural and biological characteristics of p38α, its relationship to the fore-mentioned disease states, as well as the recently reported inhibitors and classified them according to their chemical structures. We focused on the articles published in the literature during the last decade (2011-2020).

Cerebral venous sinus thrombosis in Saudi Arabia.

OBJECTIVE: To analyze the clinical patterns, etiologies, treatment, and outcome of cerebral venous sinus thrombosis (CVST) in 2 major cities of Saudi Arabia, Jeddah and Al-Baha. METHODS: One hundred and eleven patients diagnosed as CVST were identified from the medical records at King Abdulaziz Medical City, Jeddah, and King Fahad Hospital, Al-Baha, Saudi Arabia, from January 1990 through November 2010. We retrospectively analyzed the data, compared it with local and international studies, and reviewed the literature. RESULTS: There were 92 adults and 19 children. Among adults, females predominated, while more boys were affected than girls. The mean age of onset was 29.5 years. The most common clinical presentations were headache, focal neurologic deficits, seizures, papilledema, and decreased level of consciousness. The main risk factors identified were pregnancy/ puerperium, antiphospholipid antibody syndrome, oral contraceptive pills, malignancy, and infections. Multiple sinuses were affected in 51 patients (45.9%). When a single sinus was involved, the superior sagittal sinus (24.3%) was the most common. Seventy-four patients recovered completely, 23 patients recovered partially, and 10 patients died. Bad prognostic factors included incurable co-morbid conditions, late presentation, and status epilepticus. CONCLUSION: Pregnancy/puerperium was the most common etiological factor in our series. Clinical features were similar to international series. Behcet`s disease was not a major etiological factor in our series. Most patients had involvement of multiple sinuses. Prompt treatment with anticoagulation resulted in complete or partial recovery in 87.4% of patients.