Comparing the effect of intravenous versus intracranial grafting of mesenchymal stem cells against parkinsonism in a rat model: Behavioral, biochemical, pathological and immunohistochemical studies.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Currently applied therapeutic protocols are limited to improve the motor functions of patients. Therefore, seeking alternative regimes with better therapeutic impact is crucial. This study aims to validate the therapeutic impact of mesenchymal stem cell injection using two delivery methods, intracranial administration and intravenous administration, on rotenone (ROT)-induced PD model in rats. Our work included behavioral, biochemical, histological, and molecular investigations. Open field test (OFT) and rotarod tests were applied. Important oxidative stress, antioxidant and proinflammatory markers were monitored. Substantia Nigra and Striatum tissues were examined histologically and the molecular expression of DOPA decarboxylase, Tyrosine hydroxylase, and α-synuclein in neurons in these tissues were investigated. Our results showed that MSC grafting improved motor and memory impairments and oxidative stress status that were observed after ROT administration. Additionally, BM-MSCs application restored SOD and CAT activities and the levels of DA, L-Dopa, IL6, IL1ß, and TNFα. Moreover, MSC grafting overwhelmed the pathological changes induced by ROT and normalized the expression of Tyrosine hydroxylase, DOPA decarboxylase, and α-synuclein towards the control values in the Nigral and Striatal tissues of male rats. Conclusively, both administration routes improved motor function, protection of the nigrostriatal system, and improved striatal dopamine release. The observed beneficial effect of applying MSCs suggests potential benefits in clinical applications. No significant differences in the outcomes of the treatment would favor a certain way of MSC application over the other. However, the intravenous delivery method seems to be safer and more feasible compared to the intrastriatal method.

Asprosin in health and disease, a new glucose sensor with central and peripheral metabolic effects.

Adipose tissue malfunction leads to altered adipokine secretion which might consequently contribute to an array of metabolic diseases spectrum including obesity, diabetes mellitus, and cardiovascular disorders. Asprosin is a novel diabetogenic adipokine classified as a caudamin hormone protein. This adipokine is released from white adipose tissue during fasting and elicits glucogenic and orexigenic effects. Although white adipose tissue is the dominant source for this multitask adipokine, other tissues also may produce asprosin such as salivary glands, pancreatic B-cells, and cartilage. Significantly, plasma asprosin levels link to glucose metabolism, lipid profile, insulin resistance (IR), and ß-cell function. Indeed, asprosin exhibits a potent role in the metabolic process, induces hepatic glucose production, and influences appetite behavior. Clinical and preclinical research showed dysregulated levels of circulating asprosin in several metabolic diseases including obesity, type 2 diabetes mellitus (T2DM), polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver (NAFLD), and several types of cancer. This review provides a comprehensive overview of the asprosin role in the etiology and pathophysiological manifestations of these conditions. Asprosin could be a promising candidate for both novel pharmacological treatment strategies and diagnostic tools, although developing a better understanding of its function and signaling pathways is still needed.

New chalcone-tethered 1,3,5-triazines potentiate the anticancer effect of cisplatin against human lung adenocarcinoma A549 cells by enhancing DNA damage and cell apoptosis.

In the pursuit of new compounds for co-treatment to enhance the anticancer efficacy of cisplatin against lung adenocarcinoma, a series of chalcone-tethered 1,3,5-triazines was designed and synthesized. MTT assay was used to evaluate the anticancer activity of the combinations in which two hybrids 10 and 12 were found to significantly inhibit A549 cancer cells viability and their IC50 values were 24.5 and 17 µM, respectively in reference to cisplatin (IC50 = 21.5 µM). The combined effect of cisplatin with each of 10 and 12 was analyzed according to Chou-Talalay method against both A549 and normal human fibroblast cells. Mechanistic studies employing MALDI-TOF MS and fluorescence spectroscopy using Evagreen probe inferred that 10 and 12 induced DNA double strand breaks in contrast to cisplatin which induces DNA interstrand cross-links. Also, DNA damage kinetics study demonstrated the difference in the rate of DNA damage induced by both 10 and 12 alone and in combination with cisplatin. Further Annexin V-FITC/propidium iodide dual staining assay provided evidence that 10 and 12 induced apoptosis via different pattern to cisplatin and their combination with cisplatin promoted more cells to enter late apoptosis and necrosis. Molecular docking of 10 and 12 in the active pocket of DNA dodecamer displayed their binding modes with higher number of stable hydrogen bond donor as well as π-H interactions in reference to the original ligand.

Sunset Yellow and Allura Red modulate Bcl2 and COX2 expression levels and confer oxidative stress-mediated renal and hepatic toxicity in male rats.

Studies on the adverse health effects caused by azo dyes are insufficient and quite contradictory. This work aims to investigate the possible toxic effect of two types of widely used food additives, Sunset Yellow and Allura Red, by assessing the physiological, histopathological and ultrastructural changes in the liver and kidney. Also, we investigated the genotoxic effect of both dyes on white blood cells. Thirty adult male albino rats were divided into three groups of 10 animals each: control (received water), Sunset Yellow-treated (2.5 mg/kg body weight) and Allura Red-treated (seven mg/kg body weight). The doses were orally applied for 4 weeks. Our results indicated an increase in the biochemical markers of hepatic and renal function (Aspartate aminotransferase, alanine aminotransferase, urea, uric acid and creatinine) in animals administered with the azo dyes. We also observed a noticeable increase in MDA and a marked decrease in total antioxidant levels in azo dye-treated animals compared to controls. Conversely, both dyes adversely affected the liver and kidney of albino rats and altered their histological and fine structure, with downregulation of Bcl2 and upregulation of COX2 expression. Our comet assay results showed a significant elevation in the fold change of tail moment in response to application of Sunset Yellow but not Allura Red. Collectively, we show that Sunset Yellow and Allura Red cause histopathological and physiological aberrations in the liver and kidney of male Wistar albino rats. Moreover, Sunset Yellow but not Allura Red induces a potential genotoxic effect.

Spatial competition constrains resistance to targeted cancer therapy.

Adaptive therapy (AT) aims to control tumour burden by maintaining therapy-sensitive cells to exploit their competition with resistant cells. This relies on the assumption that resistant cells have impaired cellular fitness. Here, using a model of resistance to a pharmacological cyclin-dependent kinase inhibitor (CDKi), we show that this assumption is valid when competition between cells is spatially structured. We generate CDKi-resistant cancer cells and find that they have reduced proliferative fitness and stably rewired cell cycle control pathways. Low-dose CDKi outperforms high-dose CDKi in controlling tumour burden and resistance in tumour spheroids, but not in monolayer culture. Mathematical modelling indicates that tumour spatial structure amplifies the fitness penalty of resistant cells, and identifies their relative fitness as a critical determinant of the clinical benefit of AT. Our results justify further investigation of AT with kinase inhibitors.

Tartrazine induces structural and functional aberrations and genotoxic effects in vivo.

Tartrazine is a synthetic organic azo dye widely used in food and pharmaceutical products. The current study aimed to evaluate the possible adverse effect of this coloring food additive on renal and hepatic structures and functions. Also, the genotoxic potential of tartrazine on white blood cells was investigated using comet assay. Twenty adult male Wistar rats were grouped into two groups of 10 each, control- and tartrazine-treated groups. The control group was administered orally with water alone. The experimental group was administered orally with tartrazine (7.5 mg/kg, b.wt.). Our results showed a marked increase in the levels of ALT, AST, ALP, urea, uric acid, creatinine, MDA and NO, and a decreased level of total antioxidants in the serum of rats dosed with tartrazine compared to controls. On the other hand, administration of tartrazine was associated with severe histopathological and cellular alterations of rat liver and kidney tissues and induced DNA damage in leucocytes as detected by comet assay. Taken together, the results showed that tartrazine intake may lead to adverse health effects.

CDK2 knockdown enhances head and neck cancer cell radiosensitivity.

PURPOSE: Cyclin-dependent kinase 2 (CDK2) is critically involved in cell cycling and has been proposed as a potential cancer target. It remains largely elusive whether CDK2 targeting alters the tumor cell radiosensitivity. MATERIALS AND METHODS: CDK2(-/-) and wild type (WT) mouse embryonic fibroblasts (MEF) as well as six human head and neck squamous cell carcinoma (HNSCC) cell lines (SAS, FaDu, Cal-33, HSC-4, UTSCC-5, UTSCC-8) were used. Upon CDK2 knockdown using small interfering technology, colony formation, DNA double-strand breaks (DSB), cell cycle distribution and expression and phosphorylation of major proteins regulating cell cycle and DNA damage repair were examined. RESULTS: CDK2(-/-) MEF and CDK2 HNSCC knockdown cell cultures were more radiosensitive than the corresponding controls. Repair of DSB was attenuated under CDK2 knockout or knockdown. In contrast to data in MEF, combined CDK2 knockdown with irradiation showed no cell cycling alterations in SAS and FaDu cultures. Importantly, CDK2 knockdown failed to radiosensitize SAS and FaDu when cultured in a more physiological three-dimensional (3D) extracellular matrix environment. CONCLUSIONS: Our findings suggest that targeting of CDK2 radiosensitizes HNSCC cells growing as monolayer. Additional studies performed under more physiological conditions are warranted to clarify the potential of CDK2 as target in radiotherapy.