FMS-like tyrosine kinase 3 (FLT3) gene mutations have been found in more than one-third of Acute Myeloid Leukemia (AML) cases. The most common point mutation in FLT3 occurs at the 835th residue (D835A/E/F/G/H/I/N/V/Y), in the activation loop region. The D835 residue is critical in maintaining FLT3 inactive conformation; these mutations might influence the interaction with clinically approved AML inhibitors used to treat the AML. The molecular mechanism of each of these mutations and their interactions with AML inhibitors at the atomic level is still unknown. In this manuscript, we have investigated the structural consequence of native and mutant FLT-3 proteins and their molecular mechanisms at the atomic level, using molecular dynamics simulations (MDS). In addition, we use the molecular docking method to investigate the binding pattern between the FLT-3 protein and AML inhibitors upon mutations. This study apparently elucidates that, due to mutations in the D835, the FLT-3 structure loses its conformation and becomes more flexible compared to the native FLT3 protein. These structural changes are suggested to contribute to the relapse and resistance responses to AML inhibitors. Identifying the effects of FLT3 at the molecular level will aid in developing a personalized therapeutic strategy for treating patients with FLT-3-associated AML.

Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1–242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.

Two novel samples of nanoparticles based on chitosan were greenly synthesized using pomegranate peel extract. The extract served as a nanoparticle precursor, facilitating the precipitation of nanosized chitosan through the ionic gelation method. Additionally, by mixing the green chitosan nanoparticles with copper ions, a nanoscale composite of chitosan and copper oxide was also produced. Structural and morphological investigations (FTIR, XRD, SEM, EDX, and TGA analyses) were performed for greenly synthesized chitosan nanoparticles and their copper oxide composite to determine all the significant characteristics of those nanoparticles. In addition, both samples were tested using some biological investigations, such as antimicrobial activity and hematological effects. The antimicrobial tests yielded promising results for both the green chitosan nanoparticles and the CuO composite when tested using two bacterial strains and two fungal strains. Moreover, the results showed that using a similar concentration of both green-based chitosan samples resulted in a slightly larger inhibition zone and a lower minimum inhibition concentration (MIC) for the copper oxide chitosan composite compared to the chitosan nanoparticles for all microorganisms included in the test. The mean count of blood components (RBCs and platelets), clotting time, and cholesterol levels in three different blood samples were used to indicate the hematological activity of both greenly synthesized nanoparticles. The results verified a slight reduction in blood component count after the addition of green chitosan nanoparticles, but the chitosan copper oxide composite did not have a noticeable effect on the three blood samples. The chitosan nanoparticles were able to cause a considerable reduction in clotting time and cholesterol levels for all blood samples, thus acting as procoagulants. However, the mixing of CuO with chitosan nanoparticles prolonged the rate of clotting in blood samples from hypercholesteremic individuals, and thus, the mixture acted as an anticoagulant agent.

Background Currently natural products are of great interest in drug discovery. Natural products contains novel molecules that are been developed as potent therapeutic agents. Fibrosis is the most common disease observed in females. Emblica officinalis (Amla) is the most traditional agent used from decades and lot of research is going on to explore its therapeutic efficacy. Objective The objective of present study is to evaluate the effect of Emblica officinalis(Amla) on Monosodium Glutamate (MSG) induced uterine fibroids in wistar rats. Method Twenty four female wistar rats weighing 180-300g were divided into group of four. Group A was the no treatment group (Control). Groups B and C and D were treated with Monosodium glutamate (inducer), Emblica officinalis (test drug) and combined contraceptive pill (Standard drug). Treatment with MSG was conducted for 30 days followed by Amla after which total protein, plasma cholesterol and estradiol were determined. The animals in group is in control receives of 5.0ml distilled water via gastric incubation. And in another groups of 2 and 3 the animals treated with 100mg MSG/Kg with combination of 10 mg/kg Amla and in a total volume of 5.0 ml vehicle. Where, however the animals were treated with MSG only for 30 day before the commencement of treatment with Emblica officinalis (Amla) extracts and these experiment lasted for 60 days. Result Results demonstrated that the level of estradiol, cholesterol and total serum protein level was ameliorated indicating antifibrotic effect of Emblica officinalis. Interpretation and Conclusion Emblica officinalis contains uterine fibroid protective phytochemicals and may be useful in preventing uterine fibroids induced by MSG. This activity can be attributed to phenolic and other constituents and one of the mechanisms could be by balancing of oxidative stress, acting as anti-oxidant.

Mixed infections with two or more species of Plasmodium are frequently reported due to vector factors, parasite factors (formation of hypnozoites) and host factors (residing in endemic areas, travel to endemic areas, inadequately treated previous infection, lack of compliance to therapy). Here we report a case of a 33-year-old Saudi female who had a significant travel history, and a peripheral blood smear (PBS) revealed mixed infection with P. falciparum and P. vivax. The case was successfully treated with a combination therapy of artemisinin and primaquine with follow up testing at three, seven, 14, and 28 days. Mixed malaria infections are especially reported in travelers to endemic areas. Hence, adequate diagnosis and appropriate treatment of the cases contributes majorly to preventing relapse and controlling the disease. Travel consultations should be given to all travelers before their trips to endemic countries.