Urinary transferrin and proinflammatory markers predict the earliest diabetic nephropathy onset.

AIM: This study aimed to determine the earliest markers of diabetic nephropathy (DN) onset with discriminative potentials from controlled diabetes (CD). METHODS: Sixty male Wistar rats were allocated into three groups (20/group), the two diabetic groups CD and DN received 45 and 65 mg/kg STZ in 0.1 mole/L citrate buffer, respectively, while the control group received only the vehicle. Serum/urinary levels of glomerular, tubular, oxidative and proinflammatory markers were weekly monitored. RESULTS: Each diabetic group showed a different pattern of inflammatory, oxidative and signs of nephropathy along the study period, but none had a discriminative power until the fourth week. At this time point, levels of urinary transferrin, serum/urinary IL-6 and TNF-α as well as urinary IL-18 were significantly higher in DN group compared to CD (p = 0.0217, <0.0001, 0.0005, 0.0004, 0.0006, 0.0019, respectively). Predictive thresholds of these markers were calculated by receiver operating characteristic (ROC) curve that showed area under curve (AUC) of 0.9375 for transferrin with cut-off value of 35.2 mg/dL and 1.000 for serum/urinary IL-6 and TNF-α and urinary IL-18 with cut-of values 224.1, 82.11, 6.596, 125.9 and 21.86 pg/mL, respectively. CONCLUSION: Urinary transferrin and the inflammatory endpoints proposed in this study might represent promising biomarkers for the early DN onset.

Co-administration of Ceratonia siliqua extract nanoparticles promotes the oral bioavailability and neurotherapeutic efficacy of donepezil in a dementia model.

BACKGROUND: This study aimed to assess the herb-drug interactions between crude/silver nanoparticle (SNP)-loaded carob extract (Car, NCar, respectively) and donepezil-HCl (DPZ) and their impact on neurotherapeutic outcomes in a dementia model. METHODS: Carob pods were subjected to ethanol extraction, and their phytoconstituents were chromatographically analysed. SNP-loaded extract was synthesized and characterized, and dementia-like symptoms were induced in Wistar rats by repeated dosing with 175 mg/kg AlCl3 for 60 days, after which the animals were treated with Car, NCar, DPZ, and combinations of Car/NCar-DPZ for 30 days. The effect of carob formulations on DPZ bioavailability was in-silico profiled and the herb-drug interactions were mathematically assessed as combination indices. RESULTS: Different formulations significantly improved cognitive/spatial memory functions, restored dysregulated brain redox and cholinergic functions, and markedly inhibited cholinesterase, as reflected by the reduction/absence of amyloid plaques and neurofibrillary tangles. In silico profiling of the major phytoconstituents revealed their non-P-glycoprotein substrate nature and CYP3A4, 2C19, and 2C9 inhibition, which might have improved the oral bioavailability of DPZ. The combination index calculations revealed strong synergy between DPZ and both carob formulations, with the strongest effect exhibited by the DPZ/NCar combination. CONCLUSION: The co-administration of carob extract/SNPs represents a promising approach for enhancing the neurotherapeutic efficacy of DPZ.

Portulaca oleracea L seed extracts counteract diabetic nephropathy through SDF-1/IL10/PPARγ-mediated tuning of keap1/Nrf2 and NF-κB transcription in Sprague Dawley rats.

BACKGROUND & OBJECTIVE: While oxidative stress is the key player driving diabetic nephropathy (DN), firm glycemic control remains the pillar prophylactic measure. Purslane was extensively described as a potent hypoglycemic and hypolipidemic agent owing to its rich content of antioxidants. Therefore, this report aimed to assess the renoprotective potentials of methanol (MO) and methylene chloride (MC) fixed oil extracts of purslane seeds in a diabetic nephropathy (DN) model. METHODS: Purslane seeds were extracted using absolute methanol and methylene chloride, and type-1 diabetes was induced with a single 55 mg/kg dose of Streptozotocin (STZ) dissolved in 100 mmol/L citrate buffer (pH 4.5), and then diabetic animals were received MO, MC, for 42 consecutive days to compare their antidiabetic effect relative to the reference drug "Losartan". Renal functions and DN biomarkers were weekly assessed, and the relative expression of different oxido-inflammatory mediators was quantified in diabetic kidneys by RT-PCR. Data were statistically analyzed using GraphPad Prism 9.0.2. RESULTS: The oral administration of MO and MC extracts (250 mg/kg/day) significantly ameliorated the body weight loss (P < 0.0001 / each), fasting blood glucose levels (FBG) (P < 0.0001 / each), urine volume (P < 0.0001 / each), as well as serum creatinine (P < 0.0001 / each), uric acid (P = 0.0022, 0.0052), and blood urea nitrogen (BUN) (P = 0.0265, 0.0338); respectively, compared with the untreated diabetic rats. In addition, both extracts restored the effectuality of antioxidative machinery in diabetic kidneys as indicated by a significant reduction of ROS accumulation and lipid peroxidation; higher GSH content, and promoted activity of glutathione reductase and superoxide dismutase antioxidant enzymes (P < 0.0001 / each). Histologically, both extracts alleviated the DN-structural alterations including the glomerular congestion and tubular degeneration, with MC-treated kidneys showing near to normal architecture. The transcription profiles of all treated kidneys revealed a significantly downregulated expression of TNF-α, IL-6, Keap1 and NF-κB genes, concomitant with a significant upregulation of SDF-1, IL-10, Nrf2, HO-1, and PPARγ gene expression (P < 0.0001 / all). CONCLUSION: These findings highlight the remarkable DN-prophylactic potentials of purslane extracts mediated by neutralizing the hyperglycemia-induced ROS accumulation, and circumventing the downstream inflammatory cascades, surpassing the reference angiotensin receptor blocker; i.e. Losartan.

Toxicological profiling of a de novo synthesized benzimidazole derivative with potent and selective proapoptotic potentials against breast cancer.

This study aimed to investigate the toxicological profile of 1-(6-(1H-benzo[d]imidazole-2-yl)-2-methylpyridin-3-yl) ethanone (BMPE), both in vitro and in vivo. The proapoptotic/necrotic and cell cycle arrest potentials of BMPE were assessed in MCF-7 cell line. The in vivo toxicology was assessed in female Balb/c mice by repeated dosing of 5, 25, and 50 mg/kg for 21 consecutive days, then different biochemical, inflammatory, and oxidative markers were assessed in sera/tissue homogenates of treated animals. The new derivative showed a potent selective cytotoxicity against malignant cell lines with IC50 value 0.2 µM/mL, while the cytotoxic effect on normal Wi-38 cells was observed at IC50 value 0.4 µM/mL; i.e. twofold the effective anticancer dose. BMPE exhibited an early DNA fragmentation-derived cell apoptosis observed at the G0/G1 checkpoint. In vivo, BMPE was biochemically/immunologically tolerable at a pharmacological dose range of 5-25 mg/kg, with no significant rates of mortality/morbidity and minimal-to-moderate histopathological alterations recorded. The new derivative represents an attractive therapeutic candidate for breast cancer, considering its noticeable modulatory effect on the oxidative-inflammatory axis that would relate to its potent antitumor effect.

Solvent polarity dictates the anti-inflammatory potency and mechanism of two purslane (Portulaca oleracea) seed extracts.

This study aimed to assess the effect of solvent polarity on anti-inflammatory potency and the underlying mechanisms of two purslane seed extracts. Methanol and dichloromethane extracts were prepared using Soxhlet extraction and chromatographically analyzed. Antioxidant activities were assessed by different assays, while the anti-inflammatory potentials were assessed in RAW 264.7 macrophage cells. Methanol extraction yielded 15.5% water-soluble extract while dichloromethane produced 3.74% fixed oil. Nineteen phenolic compounds were chromatographically identified in methanol extract compared with 16 in the fixed oil including omega fatty acids and phytosterols. Methanol extract showed significantly higher capacity in radical scavenging assays (p < .001), but the fixed oil showed higher total antioxidant capacity (p < .001). Both extracts demonstrated anti-inflammatory potentials with different mechanisms, where the phenol-rich methanol extract significantly reduced TNF-α (p = .0371) and IL-1ß (p = .0029) production through an antioxidant-mediated pathway, while the fixed oil inhibited COX1, COX2, and PGE2 gene expression through the upregulation of IL-10. PRACTICAL APPLICATIONS: Both purslane extracts presented herein demonstrated remarkable antioxidant/ anti-inflammatory potentials that could be safely utilized as natural antioxidants and inflammation remedies or as functional food products, particularly that they showed no cytotoxic effects.