Current Issue : October-December Volume : 2021 Issue Number : 4 Articles : 5 Articles
HER2 is a prognostic and predictive marker widely used in breast cancer. Lapatinib is a tyrosine kinase inhibitor that works by blocking the phosphorylation of the receptor HER2. Its use is related to relatively good results in the treatment of women with HER2+ breast cancer. Thus, this study aimed to verify the effects of lapatinib on four canine primary mammary gland carcinoma cell cultures and two paired metastatic cell cultures. Cultures were treated with lapatinib at concentrations of 100, 500, 1000 and 3000 nM for 24 h and the 50% inhibitory concentration (IC50) for each cell culture was determined. In addition, a transwell assay was performed to assess the ability of lapatinib to inhibit cell migration. Furthermore, we verified HER2 expression by RT-qPCR analysis of cell cultures and formalin-fixed paraffin-embedded tissues from samples corresponding to those used in cell culture. Lapatinib was able to inhibit cell proliferation in all cell cultures, but it was not able to inhibit migration in all cell cultures. The higher the expression of HER2 in a culture, the more sensitive the culture was to treatment. This relationship may be an indication that the expression of HER2 may be a predictive factor and opens a new perspective for the treatment of primary and metastatic mammary gland cancer....
Neuroinflammation is an integral part of epilepsy pathogenesis and other convulsive conditions, and non-steroidal anti-inflammatory drugs (NSAIDs) present a potent tool for the contemporary search and design of novel anticonvulsants. In the present paper, evaluation of the anticonvulsant activity of the potential NSAID dual COX-2/5-LOX inhibitor darbufelone methanesulfonate using an scPTZ model in mice in dose 100 mg/kg is reported. Darbufelone possesses anticonvulsant properties in the scPTZ model and presents interest for in-depth studies as a possible anticonvulsant multi-target agent with anti-inflammatory activity. The series of 4-thiazolidinone derivatives have been synthesized following the analogue-based drug design and hybrid-pharmacophore approach using a darbufelone matrix. The synthesized derivatives showed a significant protection level for animals in the scPTZ model and are promising compounds for the design of potential anticonvulsants with satisfactory drug-like parameters....
Diminished ovarian reserve (DOR) is an increasingly emerging reproductive disorder that disturbs reproductive-aged women, which is closely linked with inflammation. In clinic, moxibustion has already been applied for reproductive problems. In the present study, we examined the involvement of inflammation in DOR and investigated the effect of moxibustion for its antiinflammatory activities. Methods. DOR rat model was established using tripterygium glycosides A tablets (TGs) suspension by intragastric administration and was then treated with either moxibustion or hormone replacement therapy (HRT), respectively. Estrus cycles were observed through vaginal cytology. Ovarian morphological alterations were observed by HE staining. -e serum levels of follicle-stimulating hormone (FSH), estradiol (E2), anti-M¨ullerian hormone (AMH), tumor necrosis factor alpha (TNF-α), and interleukin-10 (IL-10) were measured through ELISA. -e expression levels of Nrf2, HO-1, and NLRP3 were detected using immunohistochemistry. Nrf2, HO-1, and NLRP3 mRNA were examined by RT-PCR. Results. Moxibustion improved estrus cycles, FSH, E2, and AMH levels relative to DOR rats as well as HRT, while also inhibiting ovarian tissue injury. Anti-inflammatory cytokine IL-10 in peripheral blood was upregulated, and proinflammatory factor TNF-α was decreased after treatment with moxibustion. Moxibustion enhanced the expression of mRNA and protein of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1); in the mean time, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) was suppressed. Conclusions. We demonstrated that moxibustion could ameliorate the ovarian reserve in rats induced by TGs. Overall, the effect of moxibustion was comparable to that of HRT. -e underlying mechanism could be attributed to the anti-inflammatory effects of moxibustion, which suppressed NLRP3 activation by upregulating Nrf2/HO-1 signaling pathway....
Multiple sclerosis (MS) is an immune-mediated inflammatory disease that leads to demyelination and neuronal loss in the central nervous system. Immune cells of lymphoid and myeloid origin play a significant role in the initiation and amplification of neuronal inflammation in MS. STAT3 signaling plays a pivotal role in both myeloid and lymphoid immune cells, such as neutrophils and CD4+ T cells, through regulation of their inflammatory potential. Dysregulation in STAT3 signaling in myeloid and lymphoid cell compartments has been reported in MS. In this report, we attempted to investigate the effect of a small molecular inhibitor of STAT3, i.e., Stattic, in a relapsing–remitting (RR) model of experimental autoimmune encephalomyelitis (EAE). The effect of Stattic was investigated for clinical features, oxidative stress parameters, and Th17-related signaling in both the periphery and brain of SJL/J mice. Our data report that p-STAT3 expression is elevated in granulocytes, CD4+ T cells, and brain tissue in myelin proteolipid protein (PLP)-immunized SJL/J mice, which is associated with the presence of clinical symptoms and upregulation of inflammatory markers in these cells/tissues. Treatment with Stattic leads to the amelioration of disease symptoms and attenuation of inflammatory markers in neutrophils (iNOS/nitrotyrosine/IL-1 ), CD4+ T cells (IL-17A/IL-23R), and brain tissue (IL-17A/iNOS/IL-1 /MPO activity/lipid peroxides) in mice with EAE. These data suggest that the blockade of STAT3 signaling in cells of lymphoid and myeloid origin may cause the attenuation of systemic and neuronal inflammation, which could be responsible for the amelioration of disease symptoms in an RR model of EAE...................
The peptide transporter PEPT-1 (SLC15A1) plays a major role in nutritional supply with amino acids by mediating the intestinal influx of dipeptides and tripeptides generated during food digestion. Its role in the uptake of small bioactive peptides and various therapeutics makes it an important target for the investigation of the systemic absorption of small peptide-like active compounds and prodrug strategies of poorly absorbed therapeutics. The dipeptide glycyl-sarcosine (Gly-Sar), which comprises an N-methylated peptide bond that increases stability against enzymatic degradation, is widely utilized for studying PEPT-1-mediated transport. To support experiments on PEPT-1 inhibitor screening to identify potential substrates, we developed a highly sensitive Gly-Sar quantification assay for Caco-2 cell lysates with a dynamic range of 0.1 to 1000 ng/mL (lower limit of quantification 0.68 nM) in 50 L of cell lysate. The assay was validated following the applicable recommendations for bioanalytic method validation of the FDA and EMA. Sample preparation and quantification were established in 96-well cell culture plates that were also used for the cellular uptake studies, resulting in a rapid and robust screening assay for PEPT-1 inhibitors. This sample preparation principle, combined with the high sensitivity of the UPLC-MS/MS quantification, is suitable for screening assays for PEPT-1 inhibitors and substrates in high-throughput formats and holds the potential for automation. Applicability was demonstrated by IC50 determinations of the known PEPT-1 inhibitor losartan, the known substrates glycyl-proline (Gly-Pro), and valaciclovir, the prodrug of aciclovir, which itself is no substrate of PEPT-1 and consequently showed no inhibition in our assay....
Loading....