Synthesis and in-vitro anti-proliferative evaluation of some pyrazolo[1,5-a]pyrimidines as novel larotrectinib analogs.

A series of 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3-carbonitriles 11a-j and 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3,6-dicarbonitriles 16a-c was synthesized by the reaction of 5-amino-3-phenyl-1H-pyrazole-4-carbonitrile (5) with 3-(dimethylamino)-1-arylprop-2-en-1-ones 6a-j or 2-aryl-3-(dimethylamino)acrylonitriles 12a-c, respectively. In addition, 7-amino-5-oxo-2-phenyl-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (22) was prepared from the reaction of compound 5 with ethyl cyanoacetate. The anticancer activity of the newly synthesized compounds against Huh-7, HeLa, MCF-7 and MDA-MB231 cell lines showed moderate activity of compound 11f as anti-proliferative agent against Huh-7 cell line with IC50 = 6.3 µM when compared with doxorubicin (IC50 = 3.2 µM). On the other hand, compound 16b revealed potent anti-proliferative activity against HeLa cell line with IC50 = 7.8 µM when compared with doxorubicin (IC50 = 8.1 µM). Also compound 11i exhibited a promising anti-proliferative activity against MCF-7 cell line (IC50 = 3.0 µM) whereas IC50 of doxorubicin = 5.9 µM, finally compounds 11i and 16b have potent activity as anti-proliferative agents against MDA-MB231 cell line with IC50 = 4.32 and 5.74 µM, respectively when compared with doxorubicin (IC50 = 6.0 µM).

Enhancing the Stability of Strawberry Anthocyanins Complexed to ß-Cyclodextrin and Starch toward Heat, Oxidation, and Irradiation.

The instability of anthocyanins limits their application in food supplementation and in the food industry. Stabilities of strawberry anthocyanins (AN) were improved by complexation with both ß-CD and starch against heat, H2O2, light, and UV irradiation. The stability of AN against H2O2 (2.21 mM) dropped (<20%) in 6 h but was enhanced in ß-CD (49.32%) and starch (96.84%) complexes. Under light conditions, AN in the solid and solution (3.88 g/100 mL) forms degraded to 36.49 and 11.11%, while ß-CD and starch complexes displayed stabilities of 98.20 and 91.76%, respectively, after 60 days. Under UV irradiation, AN showed similar instability where both AN forms expressed stabilities of 36.75 and 66.18%, respectively, after 168 h, while ß-CD and starch complexes exhibited 51.13 and 40.10%, respectively. LC-MS-ESI showed that photoirradiation of both destroyed the full conjugation of the flavylium ring of the major components, pelargonidin and cyanidin hexoses; the mechanism was proposed. Docking binding models of major AN components in ß-CD were obtained.

Pioglitazone improves skeletal muscle functions in reserpine-induced fibromyalgia rat model.

BACKGROUND: Fibromyalgia (FM) is characterized by musculoskeletal pain, fatigue, sleep and memory disturbance. There is no definitive cure yet for FM-related health problems. Peroxisome proliferator-activated receptor's (PPAR's) activation is associated with insulin sensitisation and improved glucose metabolism. PPAR-γ was reported to alleviate FM allodynia. Limited data are discussing its effect on motor disorders. OBJECTIVE: To investigate the potential effect of PPAR-γ agonists (pioglitazone, as one member of thiazolidinediones (TZD)) on motor dysfunction in reserpine-induced FM in a rat model. MATERIALS AND METHODS: Thirty-six male Wistar rats were divided into negative control (n = 9) and reserpine-induced FM (n = 27) groups. The latter was subdivided into three equal subgroups (n = 9), positive control (untreated FM model), pioglitazone-treated and GW9662-treated. We evaluated muscle functions and activity of chloramphenicol acetyltransferase, superoxide dismutase, malondialdehyde, and serum levels of interleukin-8 and monocyte chemoattractant protein-1. RESULTS: Pioglitazone significantly relieved fatigue, improved muscle performance, reduced inflammatory cytokines and enhanced antioxidant's activity, while GW9662, a known PPAR-γ antagonist, aggravated the FM manifestations in the rat model. CONCLUSION: PPAR-γ agonists show a promising role against FM-associated motor dysfunctions.

Burden and Outcome of Vitamin D Deficiency Among Critically Ill Patients: A Prospective Study.

BACKGROUND: Vitamin D deficiency is a prevalent condition among critically ill patients. Information about the relationship between vitamin D levels and outcomes in the intensive care unit (ICU) is sparse. PURPOSE: To evaluate vitamin D status among critically ill patients and its relevance to severity of illness, ICU stay period, and mortality. METHODS: This prospective multicenter study was conducted in the ICUs of Fayoum, Cairo, Alazhar, and Ain Shams university hospitals. All patients were subjected to interview questionnaire, laboratory investigation, vitamin D level assessment, and severity of illness evaluation using the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) score. RESULTS: In total, 250 patients were included in the study. The median age was 62 (40-73) years, and most patients were male (52%). The median serum level of vitamin D was 19 (7-40.6). Vitamin D was deficient in 197 patients (78.8%) on admission. While we grouped the ICU patients as vitamin D deficient, insufficient, and sufficient, vitamin D-deficient patients had more severe diseases (mean APACHE II score, 44 ± 15; P = .014). Prolonged ICU stay was observed among the deficient group but with no significant association. The overall mortality rate was 6.8%; of these, 70.5% were vitamin D-deficient patients. However, logistic regression analysis demonstrated that vitamin D deficiency was not an independent risk factor for mortality. CONCLUSION: Vitamin D insufficiency is common in critically ill patients (69%); it is associated with more severity of illness, but it is not an independent risk factor for longer ICU stay or mortality.