This report details the design and synthesis of a novel chalcone-trimethoxycinnamide hybrid (7), constructed from the combined subunits of two previously identified potent antiproliferative compounds, CM-M345 (1) and BP-M345 (2), both products of our research group's prior work. A novel collection of seven analogues was developed and synthesized with the goal of expanding structure-activity relationship (SAR) understanding. A study on the antitumor efficacy of all compounds involved testing against melanoma (A375-C5), breast adenocarcinoma (MCF-7), colorectal carcinoma (HCT116) cell lines, and the non-tumor HPAEpiC cell lines. Significant antiproliferative activity was observed in the newly synthesized compounds 6, 7, and 13, primarily targeting colorectal tumor cells (GI50 = 266-326 M), displaying a hybrid selectivity toward these tumor cells. We investigated the molecular mechanisms by which compounds might interfere with the p53 pathway, particularly the p53-MDM2 interaction and cell mitosis in HCT116 cells. The antiproliferative activity of the compounds, untethered to p53, was established. By interfering with the mitotic process, Compound 7 effectively arrested colorectal tumor cell division, resulting in cell death.
Immunocompromised patients experiencing colorectal cancer are sometimes linked to the parasitic diarrheal disease, cryptosporidiosis. While the FDA-approved drug nitazoxanide (NTZ) initially demonstrated a temporary effect, relapses were unfortunately observed. The leaves of Annona muricata are extensively utilized in traditional medicine, demonstrating efficacy in addressing a variety of ailments, such as antiparasitic and anticancer properties. Annona muricata leaf extract was evaluated for its antiparasitic and anticancer effects on Cryptosporidium parvum (C. parvum), using NTZ as a comparative standard. Acute and chronic parvum infections were observed in immunosuppressed mice. Molecular docking analysis was applied to determine the effectiveness of selected bioactive compounds, representative of the pharmacological properties present in Annona muricata leaf-rich extract, towards C. parvum lactate dehydrogenase, in contrast to the performance of NTZ. The in vivo study, using eighty immunosuppressed albino mice, sorted them into four groups: group I, infected and given *A. muricata* treatment; group II, infected and treated with nitazoxanide; group III, infected without treatment; and group IV, which remained uninfected and untreated. Additionally, in groups I and II, half of the mice received the medications on day 10 post-infection, and the other half were treated on the 90th day post-infection. A thorough assessment encompassing parasitological, histopathological, and immunohistochemical examinations was conducted. Docking analysis showed the estimated lowest free energies of binding of annonacin, casuarine, L-epigallocatechin, p-coumaric acid, and ellagic acid against C. parvum LDH to be -611, -632, -751, -781, and -964 kcal/mol, respectively; NTZ demonstrated a binding energy of -703 kcal/mol. learn more Groups I and II displayed a considerably higher mean count of Cryptosporidium parvum oocysts than group III (p<0.0001), as determined through parasitological assessment. Notably, group I achieved the highest efficacy. Group I's histopathological and immunohistochemical results revealed the return of a typical villous structure, demonstrating no signs of dysplasia or malignancy. Using compelling evidence, this paper argues that the substance is a promising antiparasitic, and that it can prevent the development of tumors associated with Cryptosporidium.
Chlorogenic acid, or CHA, exhibits a range of biological activities, including anti-inflammatory, antioxidant, and anti-cancer properties. Still, the pharmaceutical effect of CHA on neuroblastoma is not currently understood. A type of cancer, neuroblastoma, originates in undifferentiated sympathetic ganglion cells. This study proposes to evaluate CHA's capacity to inhibit neuroblastoma growth and to investigate its mechanism of action related to cell differentiation.
Neuroblastoma cell lines, Be(2)-M17 and SH-SY5Y, served as models for confirming the differentiation phenotype. The antitumor activity of CHA was additionally assessed using xenograft mouse models, encompassing subcutaneous and orthotopic types. To determine the impact of CHA and its target ACAT1 on mitochondrial metabolic pathways, seahorse assays and metabolomic analyses were subsequently performed.
CHA facilitated the differentiation of both Be(2)-M17 and SH-SY5Y neuroblastoma cells, a phenomenon noted in live subjects and in vitro conditions. CHA's effect on mitochondrial ACAT1, causing its knockdown, also produced noticeable differentiation characteristics both in living subjects (in vivo) and in laboratory-grown cells (in vitro). Through a metabolomic examination, thiamine metabolism was identified as crucial to the differentiation of neuroblastoma cells.
CHA's anti-neuroblastoma action, as evidenced by these results, is linked to the induction of differentiation, a process mediated by the ACAT1-TPK1-PDH pathway. Neuroblastoma treatment may find a potential drug candidate in CHA.
These results provide compelling evidence of CHA's antitumor efficacy against neuroblastoma, specifically through the induction of differentiation, as mediated by the ACAT1-TPK1-PDH pathway. Neuroblastoma therapy may find a potential drug candidate in CHA.
A significant number of bone graft substitute materials are currently under development in the field of bone tissue engineering, aiming to regenerate new bone tissue while maintaining similarities to native bone. Currently, the problem of insufficient scaffold degradation acts as a major limitation on tuning the rate of bone formation turnover. In vivo degradation rate improvements are studied using novel scaffold compositions composed of chitosan (CS), hydroxyapatite (HAp), and fluorapatite (FAp) at varying proportions. Reports from previous investigations indicated the P28 peptide displayed comparable, or potentially improved, performance in the stimulation of new bone formation compared to the native bone morphogenetic protein-2 (BMP-2) in live organisms to promote osteogenesis. In order to accommodate different experimental conditions, various P28 concentrations were incorporated into the CS/HAp/FAp scaffolds for implantation within a living system. After eight weeks, H&E staining demonstrates a notable decrease in scaffold material within the majority of the created defects, indicating the scaffolds' improved in vivo biodegradability. The HE stain revealed a thickened periosteum, signifying new bone growth within the scaffolds, as evidenced by CS/HAp/FAp/P28 75 g and CS/HAp/FAp/P28 150 g demonstrating cortical and trabecular thickening. CS/HAp/FAp 11 P28 150 g scaffolds exhibited a more pronounced calcein green fluorescence signal, lacking xylenol orange staining, suggesting that mineralization and remodeling processes were inactive four days before the specimens were sacrificed. In contrast, dual labeling was evident in the CS/HAp/FAp 11 P28 25 g and CS/HAp/FAp/P28 75 g samples, signifying the persistence of mineralization ten and four days pre-sacrifice, respectively. In femoral condyle defects, consistent osteoinduction was evident in CS/HAp/FAp 11, carrying P28 peptides and labeled with HE and fluorochrome following implantation. The results demonstrate this customized formulation's capacity to enhance scaffold degradation, crucial for bone regeneration, and provide a cost-effective alternative to BMP-2.
This study explored the protective properties of the microalgae Halamphora sp. Using Wistar rats, the nutraceutical and pharmacological natural product, HExt, was evaluated for its impact on lead-intoxicated human liver and kidney cells, through in vitro and in vivo experiments. In the course of the in vitro investigation, the human hepatocellular carcinoma cell line HepG2 and the human embryonic kidney cell line HEK293 were instrumental. The GC/MS method was employed to analyze the fatty acid methyl esters in the extract sample. Following a pretreatment with HExt at a concentration of 100 grams per milliliter, the cells were then treated with varying concentrations of lead acetate, from 25 to 200 micromolars, over a period of 24 hours. Cultures were incubated in an atmosphere of 5% CO2 at a temperature of 37°C for a total time of 24 hours. Four groups, comprising six rats each, were subjected to the in vivo experiment. median filter A daily dose of 5 mg kg-1 b.w. of lead acetate was used for a subchronic treatment period on the rats. HepG2 and HEK293 cells pretreated with the extract (100 g/mL) exhibited a significant (p < 0.005) reduction in cytotoxicity induced by lead. To evaluate the in vivo experiment's biochemical effects, serum malondialdehyde (MDA) levels, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were quantified in the supernatant of organ homogenates. Palmitic acid (29464%) and palmitoleic acid (42066%) were the principal fatty acids found within HExt. Hext cotreatment, both in vitro and in vivo, safeguarded liver and kidney cell structures in rats, significantly maintaining normal antioxidant and biochemical parameters. The research uncovered a possible protective mechanism of HExt, potentially advantageous for Pb-poisoned cells.
From native black beans, this work aimed to produce and evaluate the characteristics of anthocyanin-rich extracts (ARE), including their antioxidant and anti-inflammatory properties. Supercritical fluids (RE) were employed to initially extract the substance, which was subsequently purified using Amberlite XAD-7 resin (PE). Countercurrent chromatography was used to fractionate RE and PE, isolating four fractions: REF1 and REF2 from RE, and PEF1 and PEF2 from PE. The subsequent steps involved the characterization of ARE and the fractions and evaluating their biological potential. From 79 to 1392 mg C3GE/L, ABTS IC50 values were observed, followed by DPPH IC50 values between 92 and 1172 mg C3GE/L, and finally NO IC50 values from 0.6 to 1438 mg C3GE/L (p < 0.005). Medidas posturales COX-1 IC50 exhibited a range of 0.01 to 0.09 mg C3GE/L, while COX-2 IC50 spanned 0.001 to 0.07 mg C3GE/L and iNOS IC50 ranged from 0.09 to 0.56 mg C3GE/L, indicating a statistically significant difference (p < 0.005).