In this study, new thieno2,3-dpyrimidine derivatives that could have potential anticancer activity by inhibiting the VEGFR-2 receptor have been designed, synthesized, and investigated. The ...thieno2,3-dpyrimidine derivatives showed strong in vitro abilities to inhibit VEGFR-2 and to prevent cancer cell growth in two different types of cancer cells, MCF-7 and HepG2. Particularly, compound 22 showed the most potent anti-VEGFR-2 activity with an IC50 value of 0.58 µM. Additionally, compound 22 exhibited good anti-proliferative activity against both MCF-7 and HepG2 cancer cell lines, with IC50 values of 11.32 ± 0.32 and 16.66 ± 1.22 µM, respectively. Further investigations revealed that compound 22 induced cell cycle arrest at the G2/M phase and promoted both early and late apoptosis in the MCF-7 cancer cells. Compound 22 also increased the level of BAX (2.8-fold), and reduced the level of Bcl-2 (2.2-fold), hence increasing the rate of apoptosis. Compound 22 also revealed 2.9-fold and 2.8-fold higher levels of caspase-8 and caspase-9, respectively, in the treated MCF-7 cancer cells compared to the control cell lines. The MD simulations showed that the VEGFR-2-22 complex was structurally and energytically stable over 100 ns, while the MM-GBSA study indicated its stable thermodynamic behavior. The bi-dimensional projection analysis confirmed the proper binding of the VEGFR-2-22 complex, while the DFT studies provided optimized geometry, charge distribution, FMO, ESP, the total density of state, and QTAIM maps of compound 22. Finally, computational ADMET studies were performed to assess the drug development potential of the thieno2,3-dpyrimidine derivatives. Overall, this study suggests that compound 22 has the potential as an anticancer lead compound by inhibiting VEGFR-2, which may be a guide for future drug design and development.
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•A new series of thieno2,3-dpyrimidine derivatives has been designed and synthesized as VEGFR-2 inhibitors.•VEGFR-2 inhibitory activity and cytotoxic effect were assessed.•The effect on cell cycle and apoptosis was determined.•The effect of the most active compound against caspase-8, caspase-9, Bax, BcL2, TNF-α and IL-2 was assessed.•In silico docking, MD simulation, ADMET, and toxicity studies were carried out.
Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to ...modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in MIA PaCa-2 cells (using siRNA) reduced cytosolic Ca
(Ca
) clearance, cell migration, and sensitized cells to apoptosis, without affecting cell growth. Knocking down PMCA4 had minimal effects on numerous metabolic parameters (as assessed using the Seahorse XF analyzer). In summary, this study provides the first evidence that PMCA4 is over-expressed in PDAC and plays a role in cell migration and apoptotic resistance in MIA PaCa-2 cells. This suggests that PMCA4 may offer an attractive novel therapeutic target in PDAC.
Febrile Convulsions in Anemic Children: A Review Mohamed, Hassan Tag Elkhatim; Alruwaili, Ibtisam Khulaif; Alenazi, Maisa Hamad Freaj ...
Journal of Pharmaceutical Research International,
09/2021
Journal Article
Open access
Febrile convulsions are the most common type of convulsions that affect children aged 6 months to 5 years old. Iron deficiency anemia could be a risk factor for febrile convulsions as was suggested ...by some studies, for the reason that febrile convulsions is common in children under 5 years and iron deficiency anemia is also more common in children in the same age bracket. The prevalence of febrile convulsions is 2-5% of the total number of children. Studies discussing the association of iron deficiency anemia and febrile convulsions are contradictory. Management of cases is of great importance as there are special guidelines. Prevention is also vital as it plays a role in evading the occurrence of the convulsions.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancer. It is well known that cancer cell prefers glycolysis as its main metabolic pathway (Warburg effect). In our ...previous studies, we found that this switch is critical for cancer cells to maintain their intracellular calcium homeostasis because glycolytic ATP is important for fueling PMCA. However, one of the main characteristics of PDAC cells is that it has an abundant stroma. There is an accumulation of evidence suggesting a metabolic cross-talk between cancer cells and their stoma (revere Warburg effect). In this project, we have investigated the effects of cancer-stromal interaction with a focus on pancreatic cancer cell metabolism and metabolic regulation of Ca2+i homeostasis by co-culturing PDAC cells (MiaPaCa-2) with pancreatic stellate cells (hPSCs). This has been achieved by testing the relative effect of metabolic inhibitors on cellular ATP and fura-2 Ca2+ overload for both cells in co-culture. Moreover, their metabolic phenotype in co-culture has been determined by using Seahorse flux analyzer. Our results are showing that there was no change in the calcium homeostasis regulation in PDAC cells in co-culture. However, we have found significant changes in their metabolism (increase mitochondrial respiration; decrease glycolysis). We next have identified that citrate is the main metabolite that is secreted by hPSCs to fuel PDAC cells mitochondria and decrease glycolysis by performing a footprint metabolomic analysis of the condition media collected from hPSCs. We have further confirmed that citrate can be taken up and consumed by PDAC cell. More importantly, we have tested the effect of citrate in PDAC cells metabolism and found that it mimics the PDAC cells response in co-culture. These findings elucidate a novel metabolic interaction between PDAC cells and hPSCs where citrate plays a major role in such interaction.
Sphingosine‐1‐phosphate (S1P) is an endogenous metabolite derived from ceramide as part of the sphingomyelin cycle. It is a potent molecular messenger which exerts its function both intracellularly ...and extracellularly. Intracellularly, S1P acts as a second messenger regulating calcium mobilization, and cellular proliferation and survival. Extracellularly, S1P acts as a ligand of the G‐protein‐coupled S1P receptors (S1PRs) and mediates a variety of physiological and pathological processes. Levels of S1P and other sphingosine metabolites are maintained in a delicate balance through the action of two enzymes, sphingosine kinase (SK) and sphingosine‐1‐phosphate lyase (SPL). Our previous studies showed that exogenously administered S1P (concentration: 1 µM) exhibited synergistic effects with chemotherapy drugs in human breast cancer MCF7 and MDA‐MB‐361 cells 1, 2. Herein, we report other cell lines and mouse xenograf study results on the antitumor activity of S1P.
Sphingosine-1-phosphate (S1P) is an important sphingolipid metabolite regulating key physiological and pathophysiological processes such as cell growth and survival and tumor angiogenesis. ...Significant research evidence links elevated cellular S1P concentration to cancer cell proliferation, migration and angiogenesis. Physiological levels of S1P are tightly regulated and maintained at the low nanomolar level. In cancer, S1P may exist well beyond the low nanomolar level. Recently, we reported that S1P selectively induces cell apoptosis of the breast cancer MCF7 cell line at concentrations higher than 1 µM and co-administration of 1 µM S1P significantly increased the cytotoxicity of chemotherapy drug docetaxel. In this study, we show that S1P caused minor increases in cell proliferation or apoptosis, in a concentration-dependent manner, yet co-administration of 10 µM S1P exhibited a significant synergistic effect with chemotherapy drugs docetaxel, doxorubicin and cyclophosphamide. S1P increased the cytotoxic potential of each drug by 2-fold, 3-fold, and 10-fold, respectively, against the breast cancer metastatic cell line MDA-MB-361. This synergism may suggest improved anticancer drug therapy by co-administration of exogenous S1P.
Background: Foot ulcers may be complicated to toe amputation or limb amputation which can be prevented by patient education on self-management and appropriate foot care procedures.
Study Objectives: ...The objective of this study is to determine the awareness of diabetic foot and its risk factors among the general population of Arar city, Northern Saudi Arabia.
Methods: An analytical cross-sectional study was carried out in primary health care centers in Arar, Northern Saudi Arabia, during the period from 1st September to 10th October 2021. Data was collected by personal interview with the attendees of the primary health care center, using a predesigned questionnaire.
Results: Almost 60% of participants have knowledge about diabetic foot. The Source of information about diabetic foot was doctors and nurses in 13% and 11.9% social media in our study population. 62.7% know that diabetic foot risk may be reduced by controlling blood sugar level, 13% by checking the feet every day and several times a day, and 9.2% reported wearing shoes and socks on a daily basis. 65.6%, 66.7%, 48.4%, 82.6% and 62.1% knew that skin infections, foot abscess, bone infections, gangrene, and foot deformity are complications of diabetic foot respectively. Good knowledge of diabetic foot was significantly associated with age and educational level but not with marital status.
Conclusion: The level of knowledge of diabetic foot and its related complications is relatively average. Due to the high incidence of diabetes mellitus (DM) in Saudi Arabia, it is vital that the population has appropriate information and awareness about this illness to enable continued promotion of public health measures to limit its prevalence. It is also crucial for DM patients to understand the medication and lifestyle modifications that may enable them to better regulate their blood glucose and prevent the complications.
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