Busting the Breast Cancer with AstraZeneca's Gefitinib.

Breast cancer is the most common cancer diagnosed in women, and in 2020, there were 684, 996 deaths due to this disease. Epidermal growth factor receptors (EGFRs) and their respective ligands have been blamed for the pathogenesis and resistance to treatment in specific breast cancer cases. With EGFR having four homologues: EGFR1, EGFR2, EGFR3, and EGFR4, in-depth understanding of EGFR biology led to the discovery of small-molecule inhibitors and antibodies against this receptor. Gefitinib (GEF), a tyrosine kinase inhibitor of EGFR1, possesses a vast potential for treatment against breast cancer and is supported by a multiplicity of experiments. Unfortunately, in clinical trials, GEF did not show the outcomes expected with complete response and disease progress. This is due to incomplete understanding of the molecular mechanisms involved in EGFR signaling and endocrine sensitivity. Hence, additional in-depth experiments are needed regarding various molecular pathways and crosstalk pathways to comprehend GEF's action mechanism thoroughly in breast cancer patients. In this review, the role of EGFR in the development and pathogenesis of breast cancer and the pharmacokinetics and pharmacotherapy of GEF for the treatment of breast cancer have been elaborated. Nanomedicines synthesized with GEF have shown positive experimental response, paving a promising path for GEF against breast cancer.

Roles of Sodium Hydrogen Exchanger (NHE1) and Anion Exchanger (AE2) across Chondrocytes Plasma Membrane during Longitudinal Bone Growth.

Mammalian long bone growth occurs through endochondral ossification, majorly regulated by the controlled enlargement of chondrocytes at the growth plate (GP). This study aimed to investigate the roles of Na+/H+ (sodium hydrogen exchanger (NHE1)) and HCO3− (anion exchanger [AE2]) during longitudinal bone growth in mammals. Bones from P10 SpragueDawley rat pups were cultured exvivo in the presence or absence of NHE1 and AE2 inhibitors to determine their effect on long bone growth. Gross morphometry, histomorphometry, and immunohistochemistry were used to assess the bone growth. The results revealed that the culture of the bones in the presence of NHE1 and AE2 inhibitors reduces bone growth significantly (p < 0.05) by approximately 11%. The inhibitor significantly (p < 0.05) reduces bone growth velocity and the length of the hypertrophic chondrocyte zone without any effect on the total GP length. The total GP chondrocyte density was significantly (p < 0.05) reduced, but hypertrophic chondrocyte densities remained constant. NHE1 fluorescence signaling across the GP length was higher than AE2, and their localization was significantly (p < 0.05) inhibited at the hypertrophic chondrocytes zone. The GP lengthening was majorly driven by an increase in the overall GP chondrocyte and hypertrophic chondrocyte densities apart from the regulatory volume phenomenon. This may suggest that NHE1 and AE2 could have a regulatory role in long bone growth.

Synthesis and Characterization of Gefitinib and Paclitaxel Mono and Dual Drug-Loaded Blood Cockle Shells (Anadara granosa)-Derived Aragonite CaCO3 Nanoparticles.

Calcium carbonate has slowly paved its way into the field of nanomaterial research due to its inherent properties: biocompatibility, pH-sensitivity, and slow biodegradability. In our efforts to synthesize calcium carbonate nanoparticles (CSCaCO3NP) from blood cockle shells (Anadara granosa), we developed a simple method to synthesize CSCaCO3NP, and loaded them with gefitinib (GEF) and paclitaxel (PTXL) to produce mono drug-loaded GEF-CSCaCO3NP, PTXL-CSCaCO3NP, and dual drug-loaded GEF-PTXL-CSCaCO3NP without usage of toxic chemicals. Fourier-transform infrared spectroscopy (FTIR) results reveal that the drugs are bound to CSCaCO3NP. Scanning electron microscopy studies reveal that the CSCaCO3NP, GEF-CSCaCO3NP, PTXL-CSCaCO3NP, and GEF-PTXL-CSCaCO3NP are almost spherical nanoparticles, with a diameter of 63.9 ± 22.3, 83.9 ± 28.2, 78.2 ± 26.4, and 87.2 ± 26.7 (nm), respectively. Dynamic light scattering (DLS) and N2 adsorption-desorption experiments revealed that the synthesized nanoparticles are negatively charged and mesoporous, with surface areas ranging from ~8 to 10 (m2/g). Powder X-ray diffraction (PXRD) confirms that the synthesized nanoparticles are aragonite. The CSCaCO3NP show excellent alkalinization property in plasma simulating conditions and greater solubility in a moderately acidic pH medium. The release of drugs from the nanoparticles showed zero order kinetics with a slow and sustained release. Therefore, the physico-chemical characteristics and in vitro findings suggest that the drug loaded CSCaCO3NP represent a promising drug delivery system to deliver GEF and PTXL against breast cancer.

Systematic review and meta-analyses of vitamin E (alpha-tocopherol) supplementation and blood lipid parameters in patients with diabetes mellitus.

BACKGROUND AND AIMS: The studies have shown that α-tocopherol supplementation could improve lipid profile in diabetes mellitus (DM) patients. Nonetheless, the result remains inconsistent. Therefore, this meta-analysis was performed to evaluate the efficacy of α-tocopherol supplement on lipid parameters in DM patients. METHODS: We conducted an extensive search via Cochrane Library, PubMed, Scopus, and Web of Science databases to acquire the reported RCTs up to October 2020. RESULTS: The results showed no effects of α-tocopherol supplementation on lipid profile in DM patients except when used ≥12 weeks. CONCLUSIONS: α-tocopherol supplementation in DM patients had no significant effect on lipid profiles.

The Therapeutic Effect and In Vivo Assessment of Palmitoyl-GDPH on the Wound Healing Process.

The standard treatment of open wounds via the direct usage of therapeutic agents is not without limitations with respect to healing. Small peptides can create a favorable milieu for accelerating the healing of wounds. This study presents the potential of a novel fatty acid conjugated tetrapeptide (palmitic acid-glycine-aspartic acid-proline-histidine; Palmitoyl-GDPH) in alleviating wound healing. Tetracycline was employed as a standard control drug following its significance in wound healing including biologically active and antimicrobial effects. The peptide in liquid form was applied on to a 4 cm2 full thickness wound surgically induced at the dorsum of Sprague Dawley (SD) rats. The in vivo wound treatment with Palmitoyl-GDPH for eighteen days, histologically demonstrated an almost perfect healing exhibited by increased re-epithelialization, enhanced collagen deposition, and diminished scar formation compared to the controls. In addition, the well-developed epidermal-dermal junction and ultimate stimulation of hair follicle-growth in the Palmitoyl-GDPH treated group indicated the wound to have healed as functionally viable tissues. In general, the much lower hemogram values in the Palmitoyl-GDPH group indicated that the ongoing healing is en route to an earlier recovery. Additionally, the liver, kidney, and pancreas function biomarkers being within normal limits indicated the relatively non-toxic nature of Palmitoyl-GDPH at the used dosage. These results indisputably supported the great potential of this newly synthesized Palmitoyl-GDPH to be used as an effective therapeutic agent for wound healing (this actually means creating a new wound).

The effects of carnitine supplementation on clinical characteristics of patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The beneficial effects of carnitine supplementation on nonalcoholic fatty liver disease are unclear. We conducted a systematic review and meta-analysis to evaluate the effects of carnitine supplementation on liver function, lipid profile, body mass index, body weight, and homeostasis model assessment of insulin resistance in patients with nonalcoholic fatty liver disease. METHODS: A comprehensive search of PubMed, Web of Science, Scopus, Cochrane Library, and Google Scholar databases were performed. Only randomized placebo-controlled human studies that examined the effects of carnitine supplementation on liver function, lipid profile, body mass index, body weight, and homeostasis model assessment of insulin resistance up to September 2019 were included. Fixed effects or random-effects models were applied to compute the pooled effect size. Heterogeneity assessments were performed using Cochran's Q test and I-squared statistics. The quality of the studies was assessed using the Jaded scale. RESULTS: A total of 5 articles were selected, including 334 individuals (167 in control and 167 in intervention groups). The results demonstrated that carnitine supplementation significantly reduced homeostasis model assessment of insulin resistance (HOMA-IR) (WMD: -0.91; 95 % CI: -1.11, -0.72; p < 0.001, I2 = 0.0 %) and the levels of aspartate aminotransferase (AST) (WMD: -16.62; 95 % CI: -28.11, -5.14; IU/l; p = 0.005, I2 = 93.5 %), alanine aminotransferase (ALT) (WMD: -33.39; 95 % CI: -45.13, -21.66; IU/l; p < 0.001, I2 = 93.4 %), and triglycerides (TG) (WMD: -22.13; 95 % CI: -38.91, -5.34; mg/dl; p = 0.01; I2 = 0.0 %). However, the results of the pooled effect size did not show any significant effect of carnitine supplementation on body mass index (BMI) (WMD: 0.07; 95 % CI: -0.15, 0.29; p = 0.55; I2 = 0.0 %), body weight (WMD: -0.28; 95 % CI: -2.23, 1.68; p = 0.78; I2 = 45.7 %), the levels of gamma-glutamyl transferase (γGT) (WMD: -11.31; 95 % CI: -24.35, 1.73; IU/l; p = 0.09, I2 = 61.1 %), cholesterol (WMD: -13.58; 95 % CI: -46.77, 19.60; mg/dl; p = 0.42; I2 = 94.9 %), high-density lipoprotein-cholesterol (HDL-C) (WMD: 1.36; 95 % CI: -0.96, 3.68; mg/dl; p = 0.25; I2 = 64.7 %), and low density lipoprotein-cholesterol (LDL-C) (WMD: -14.85; 95 % CI: -45.43, 15.73; mg/dl; p = 0.34; I2 = 96.4 %). CONCLUSIONS: This analysis shows that carnitine supplementation for patients with nonalcoholic fatty liver disease demonstrates a reduction in AST, ALT, TG levels and HOMA-IR. However, no significant effect of carnitine supplementation was observed on BMI, body weight, the levels of γGT, TC, HDL-cholesterol and LDL-cholesterol.

In vivo evaluation of anticancer efficacy of drug loaded cockle shell-derived aragonite nanoparticles.

Doxorubicin (DOX) is an effective and commonly used anthracycline anticancer drug for the treatment of osteosarcoma (OS). However, its antitumor effect is hampered by the nonspecific distribution and significant adverse effects. Nanoparticles based drug delivery systems are promising approaches to maximize the anticancer efficacy while decrease the side effects. In this study, biogenic aragonite nanoparticles (ANPs) were developed from cockle shells and loaded with DOX. An orthotopic rat OS model was induced by UMR-106 cells tibia cavity injection. The anticancer efficacy study included five groups: normal control group, OS model group, free DOX group (2 mg/kg), DOX-ANPs 1 group (2 mg of equivalent DOX/kg) and DOX-ANPs 2 group (1.5 mg of equivalent DOX/kg). This study demonstrates that the DOX-ANPs treatment groups can significantly reduce the tumor volume and increase the surviving ratio as compared to the OS model group. In addition, these two DOX-ANPs groups showed less toxicity to the normal organs compared to the free DOX group. Furthermore, DOX-ANPs 2 group showed the similar anticancer efficacy as DOX-ANPs 1 group, which suggested that DOX loaded onto the ANPs may allow the reduction of chemotherapy doses. These results highlight the promising application of ANPs derived from cockle shells as an effective drug delivery system for a successful chemotherapy against OS. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1898-1907, 2019.

Optimization of a closed rat tibial fracture model.

BACKGROUND: The use of a closed fracture model has become the preferred model to study the fracture healing process, given that the periosteum and the soft tissue surrounding the fracture site play an important role in the fracture healing process. Some techniques like osteotomy, drilling the long bones and the use of the guillotine-like apparatus to induce fracture are characterized by some undesirable effects and complications. The aim of this study is to optimize and evaluate an in vivo fracture model using three-point bending pliers that can be used to study secondary bone fracture healing in rats. METHODS: Modified three-point bending pliers were used as a device to create the closed rat tibial bone fracture that was prefixed with an intramedullary pin (23 G × 11/2″) in rats. The exact location of the induced closed fracture was along the long bone. The presence of bone comminution, and the fracture bone alignment were immediately examined after the induction of the fracture until the 6th week. RESULTS: All fractures induced were transverse, located in the middle to proximal one third of the tibia, and they all healed without complications. Bone union as shown radiographically occurred within 2-3 weeks postoperative. The average angle of the fracture line with the axis of the tibia was 89.41 ± 2.11°. The lateral and anterio-posterior pin angulation views were 167.33 ± 3.67° and 161.60 ± 4.87° respectively. The average length of proximal end of the fractured bone in comparison with the whole length of intact bone was 41.02 ± 3.27%. There was a significant difference in percentage of the gross callus area and gross callus index, while there was no significant difference in X-ray callus index. There was no significant difference of the gross callus area between slight comminution (n = 4) and non comminution (n = 21). CONCLUSION: The optimized rat tibial fracture model resulted in mainly transverse tibial mid-shaft fractures with minimal bone comminution and absence of surrounding soft tissue damage. The size area of consequent soft callus formation and the extent to which the closed fracture model was reproducible are very good outcomes making it feasible for in vivo laboratory research use.