Biological evaluation of combinations of tyrosine kinase inhibitors with Inecalcitol as novel treatments for human chronic myeloid leukemia.

Background: The use of tyrosine kinase inhibitors (TKIs) as a treatment for chronic myeloid leukemia (CML) has improved the natural history of the disease and increased the duration of survival. Tyrosine kinase inhibitors represent the success of target therapies that work on molecular targets, although some patients still have therapy failure. Vitamin D has antiproliferative, pro-apoptotic, and anti-angiogenic effects on cells, therefore it can be considered as a potential cancer preventative and treatment agent. Inecalcitol (TX-522) is the 14-epi-analogue of Calcitriol (1,25(OH)2-vitamin D3), and inhibits cancer cell proliferation more effectively than Calcitriol. This study was conducted to evaluate the antiproliferative and synergistic effects of the anticancer drugs Imatinib and Dasatinib in combinations with Inecalcitol on human chronic myeloid leukemia K-562 cells. Method: The growth inhibitory activities of Inecalcitol, Imatinib, Dasatinib, and different combinations of one of the two drugs (Imatinib and Dasatinib) with Inecalcitol, were determined in vitro using MTT assay against K-562 cell line. Results: Inecalcitol, Imatinib, and Dasatinib showed potent antiproliferative activities against K-562 cells with GI50 values of 5.6 µM, 0.327 µM, and 0.446 nM, respectively. Combinations of Imatinib or Dasatinib with different concentrations of Inecalcitol increased significantly the antiproliferative activities and potencies of both drugs (****p < 0.0001), with optimal GI50 values of 580 pM (Imatinib) and 0.51 pM (Dasatinib). Furthermore, the combination treatments showed synergistic interaction between the antileukemic drugs and Inecalcitol, with combination indices (CI) < 1. Conclusion: The study demonstrated that the human chronic myeloid leukemia K-562 cells were subjected to a synergistic growth inhibitory impact when antileukemic drugs (Imatinib or Dasatinib) were combined with Inecalcitol, therefore, it is recommended that these combinations be viewed as promising novel antileukemic medications and used in place of individual medications with lower dosages and negligible side effects in the treatment of CML.

Anti-S and Anti-N Antibody Responses of COVID-19 Vaccine Recipients.

The long-term immunoglobulin responses of COVID-19 vaccinations is important to determine the efficacy of these vaccinations. This study aimed to investigate and compare the long-term immunoglobulin response of COVID-19 vaccination recipients, using anti-S IgG, anti-N IgG, and IgM titer levels. This study included 267 participants, comprising individuals who tested positive for COVID-19 through PCR testing (n = 125), and those who received the Pfizer (n = 133), Sinopharm (n = 112), AstraZeneca (n = 20), or Sputnik (n = 2) vaccines. Female participants comprised the largest share of this study (n = 147, 55.1%). This study found that most participants had positive IgG antibodies, with 96.3% having anti-S IgG and 75.7% having anti-N IgG. Most participants (90.3%) tested negative for anti-N IgM antibodies. Sinopharm-vaccinated individuals exhibited a notably lower rate of positive anti-S IgG (93.8%) and a significantly higher rate of positive anti-N IgG antibodies (91%). Anti-N IgG levels were significantly correlated with the number of prior COVID-19 infections (p = 0.015). Specifically, individuals with a history of four COVID-19 infections had higher anti-N IgG titers (14.1 ± 1.4) than those with only one experience of COVID-19 infection (9.4 ± 7.2). Individuals who were infected with COVID-19 after receiving the vaccine demonstrated higher levels of anti-N IgG, exhibiting a 25% increase in mean titer levels compared to those who were infected prior to vaccination. There was a statistically significant association between anti-N IgG positivity with age (p = 0.034), and smoking status (p = 0.006) of participants. Participants younger than 20 and older than 60 showed the highest positivity rate of anti-N (>90%). Smokers had a low positivity rate of anti-N (68.8%) compared to nonsmokers (83.6%). In conclusion, this study demonstrated that most COVID-19 vaccination recipients had positive IgG antibodies, with differences in the long-term immunoglobulin response depending on the type of vaccine administered and occurrence of COVID-19 infection.

Immunoglobulins response of COVID-19 patients, COVID-19 vaccine recipients, and random individuals.

BACKGROUND: The development of specific immunoglobulins to COVID-19 after natural infection or vaccination has been proposed. The efficacy and dynamics of this response are not clear yet. AIM: This study aims to analyze the immunoglobulins response among COVID-19 patients, COVID-19 vaccine recipients and random individuals. METHODS: A total of 665 participants including 233 COVID-19 patients, 288 COVID-19 vaccine recipients, and 144 random individuals were investigated for anti-COVID-19 immunoglobulins (IgA, IgG, IgM). RESULTS: Among COVID-19 patients, 22.7% had detectable IgA antibodies with a mean of 27.3±57.1 ng/ml, 29.6% had IgM antibodies with a mean of 188.4±666.0 BAU/ml, while 59.2% had IgG antibodies with a mean of 101.7±139.7 BAU/ml. Pfizer-BioNTech vaccine recipients had positive IgG in 99.3% with a mean of 515.5±1143.5 BAU/ml while 85.7% of Sinopharm vaccine recipients had positive IgG with a mean of 170.0±230.0 BAU/ml. Regarding random individuals, 54.9% had positive IgG with a mean of 164.3±214 BAU/ml. The peak IgM response in COVID-19 patients was detected early at 15-22 days, followed by IgG peak at 16-30 days, and IgA peak at 0-60 days. IgM antibodies disappeared at 61-90 days, while IgG and IgA antibodies decreased slowly after the peak and remained detectable up to 300 days. The frequency of IgG positivity among patients was significantly affected by increased age, admission department (inpatient or outpatient), symptoms, need for oxygen therapy, and increased duration between positive COVID-19 RT PCR test and serum sampling (p˂0.05). Positive correlations were noted between different types of immunoglobulins (IgG, IgM, and IgA) among patients. CONCLUSIONS: Natural infection and COIVD-19 vaccines provide IgG-mediated immunity. The class, positivity, mean, efficacy, and duration of immunoglobulins response are affected by the mechanism of immunity and host related variables. Random community individuals had detectable COVID-19 IgG at ~55%, far from reaching herd immunity levels.

Comparative Phytochemical Profile and Biological Activity of Four Major Medicinal Halophytes from Qassim Flora.

Four halophytic plants, Lycium shawii, Anabasis articulata, Rumex vesicarius, and Zilla spinosa, growing in the central Qassim area, Saudi Arabia, were phytochemically and biologically investigated. Their hydroalcoholic extracts' UPLC-ESIQ-TOF analyses demonstrated the presence of 44 compounds of phenolic acids, flavonoids, saponins, carbohydrates, and fatty acids chemical classes. Among all the plants' extracts, L. shawii showed the highest quantities of total phenolics, and flavonoids contents (52.72 and 13.01 mg/gm of the gallic acid and quercetin equivalents, respectively), along with the antioxidant activity in the TAA (total antioxidant activity), FRAP (ferric reducing antioxidant power), and DPPH-SA (2,2-diphenyl-1-picryl-hydrazyl-scavenging activity) assays with 25.6, 56.68, and 19.76 mg/gm, respectively, as Trolox equivalents. The hydroalcoholic extract of the L. shawii also demonstrated the best chelating activity at 21.84 mg/gm EDTA equivalents. Among all the four halophytes, the hydroalcoholic extract of L. shawii exhibited the highest antiproliferative activity against MCF7 and K562 cell lines with IC50 values at 194.5 µg/mL and 464.9 µg/mL, respectively. The hydroalcoholic extract of A. articulata demonstrated better cytotoxic activity amongst all the tested plants' extracts against the human pancreatic cancer cell lines (PANC1) with an IC50 value of 998.5 µg/mL. The L. shawii induced apoptosis in the MCF7 cell lines, and the percentage of the necrotic cells changed to 28.1% and 36.5% for the IC50 and double-IC50 values at 22.9% compared with the untreated groups. The hydroalcoholic extract of L. shawii showed substantial antibacterial activity against Bacillus cereus ATCC 10876 with a MIC value of 12.5 mg/mL. By contrast, the A. articulata and Z. spinosa exhibited antifungal activities against Aspergillus niger ATCC 6275 with MIC values at 12.5 and 50 mg/mL, respectively. These findings suggested that the L. shawii is a potential halophyte with remarkable biological properties, attributed to its contents of phenolics and flavonoid classes of compounds in its extract.

Chemical Profile, Antioxidant, Antimicrobial, and Anticancer Activities of the Water-Ethanol Extract of Pulicaria undulata Growing in the Oasis of Central Saudi Arabian Desert.

Pulicaria undulata (L.) C. A. Mey has multiple uses as part of the traditional medicament, and several biological activities of the plant have been corroborated in the scientific literature. The current work evaluates the phytochemical constituents and biological properties of the water-ethanol extract of the P. undulata growing in Qassim, the central arid regions of the Kingdom of Saudi Arabia. Qualitative UPLC-ESIQ-TOF analysis identified 27 compounds belonging to the phenolics, flavonoids, triterpenes, coumarins, and of fatty acids chemical classes. The quantitative analysis exhibited 33.3 mg/g GAE (Gallic Acid Equivalents), and 10.8 mg/g QE (Quercetin Equivalents) of the phenolics and flavonoids in the plant's concentrated (to dryness) water-ethanol extract. The trace elements analysis of the plant's dry powder established the presence of copper (20.13 µg/kg), and zinc (68.2 µg/kg) in the higher levels of occurrences. In terms of the antioxidant potential of the plant's extract, the ferric-reducing, and free-radicals scavenging activities were recorded at 47.11 mg/g, and 19.13 mg/g equivalents of the concentrated to dryness water-ethanol extract of the plant. The water-ethanol extract of P. undulata also exhibited antimicrobial activity against the tested Gram-positive bacteria, while no activity was observed against the tested Gram-negative bacteria, or the fungi. The MIC (minimum inhibitory concentration) values were in the range of 49 to 1563 µg/mL, whereas the MBC (minimum bactericidal concentration) values ranged from 49 to 3125 µg/mL, against the tested Gram-positive bacteria. The P. undulata water-ethanol extract also exhibited potent cytotoxic effects with the IC50 value at 519.2 µg/mL against the MCF-7 breast cancer cell-lines, followed by the anticancer activity of erythroleukemic cell-lines, K562 at 1212 µg/mL, and pancreatic cell-lines, PANC-1, at 1535 µg/mL, as compared to the normal fibroblast cells (4048 µg/mL). The Annexin-V assay demonstrated that, as the P. undulata extract's dose increased from IC50 to twice of the IC50, the percentage of the necrosis was found to be increased in the late apoptosis stage of the cancer cells. These data confirmed the P. undulata extract's ability to inhibit several human cancer cell lines' growth in comparison to other local halophytes. The antimicrobial activity of the plant was also confirmed.

Antioxidant potential and hypolipidemic effect of whey protein against gamma irradiation induced damages in rats.

PURPOSE: Evaluation of the efficacy of whey protein as antioxidant against γ-irradiation induced oxidative stress and dyslipidemia in male rats. METHOD: Rats were divided into groups; group 1 (control), rats in group 2 & 3 were exposed to γ-irradiation 5 & 10Gy respectively and rats in group 4 & 5 were orally administrated with whey protein after γ-irradiation. The antioxidant status (glutathione (GSH), Superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC) and malondialdehyde (MDA), lipid profile (total cholesterol (TC), triglyceride (TG) and high-density lipoprotein (HDL) as well as the hematological parameters were determined. RESULTS: γ-irradiation had depletion in GSH, SOD, CAT and TAC levels and elevation in MDA. Moreover, an increase in TC & TG coupled with decrease in HDL after γ-irradiation. The hematological parameters decreased after γ-irradiation. Treated rats with whey protein improved the antioxidant status and minimized the alterations of lipid and blood cells induced by γ-irradiation. CONCLUSION: whey protein has a positive effect on lipid and antioxidant status to minimize the oxidative stress due to exposure to γ-irradiation.

Radioprotective effect of green tea and grape seed extracts mixture on gamma irradiation induced immune suppression in male albino rats.

PURPOSE: Green tea extract (GTE) and grape seed extract (GSE) have antioxidant and radioprotective effects. The current study aimed to investigate the radioprotective effect of GTE and GSE mixture on radiation-induced immune suppression in rats. METHOD: A total of 35 male albino rats were divided into five groups: group 1 (control rats). The 2nd and 3rd groups rats were exposed to a single dose of gamma radiation (5 and 10 Gy), respectively. The 4th and 5th groups of rats were gamma-irradiated with 5 and 10 Gy, respectively, then administrated by gavage with GTE and GSE mixture (100 mg: 200 mg/kg BW), respectively, for 14 consecutive days. RESULTS: Gamma irradiation induced hematological, immunological and biochemical effects in rats. Treated rats with GTE and GSE mixture (1:2) showed an increase in concentrations of immune cells including CD4 and CD8. The level of pro-inflammatory cytokines Tumor necrosis factor-α and C-reactive protein elevated after γ-irradiation and significantly decreased by mixture administration. Moreover, groups treated with antioxidant mixture showed a significant increase in all hematological parameters and a significant decrease in cholesterol and triglyceride levels. CONCLUSION: GTE and GSE mixture is a good radioprotector and immune modulator compound, indicating its possible use as an adjuvant during radiotherapy.