ABSTRACT
OBJECTIVES: Diabetic nephropathy (DN) is one of the most prevalent secondary complications associated with diabetes mellitus. Decades of research have implicated multiple pathways in the etiology and pathophysiology of diabetic nephropathy. There has been no reliable predictive biomarkers for the onset or progression of DN and no successful treatments are available. METHODS: In the present study, we explored the datasets of RNA sequencing data from patients with Type II diabetes mellitus (T2DM)-induced nephropathy to identify a novel gene signature. We explored the target bioactive compounds identified from Azanza garckeana, a medicinal plant commonly used by the traditional treatment of diabetes nephropathy. RESULTS: Our analysis identified lymphotoxin beta (LTB), SRY-box transcription factor 4 (SOX4), SOX9, and WAP four-disulfide core domain protein 2 (WFDC2) as novel signatures of T2DM-induced nephropathy. Additional analysis revealed the pathological involvement of the signature in cell-cell adhesion, immune, and inflammatory responses during diabetic nephropathy. Molecular docking and dynamic simulation at 100 ns conducted studies revealed that among the three compounds, Terpinen-4-ol exhibited higher binding efficacies (binding energies (ΔG) = -3.9~5.5 kcal/mol) against the targets. The targets, SOX4, and SOX9 demonstrated higher druggability towards the three compounds. WFDC2 was the least attractive target for the compounds. CONCLUSION: The present study was relevant in the diagnosis, prognosis, and treatment follow up of patients with diabetes induced nephropathy. The study provided an insight into the therapeutic application of the bioactive principles from Azanza garckeana. Continued follow-up invitro validations study are ongoing in our laboratory.
ABSTRACT
Papillary thyroid carcinoma (PTC) is the most prevalent endocrine malignancy with a steadily increasing global incidence in recent decades. The pathogenesis of PTC is poorly understood, and the present diagnostic protocols are deficient. Thus, identifying novel prognostic biomarkers to improve our understanding of the mechanisms of pathogenesis, diagnosis, and designing therapeutic strategies for PTC is crucial. In this study, we integrated 27 PTC transcriptomic datasets and identified overlapping differentially expressed genes (DEGs) and differentially expressed microRNAs, collectively known as thyroid tumor-enriched proteins (TTEPs), and TTEmiRs, respectively. Our integrated bioinformatics analysis revealed that TTEPs were associated with tumor stages, poor surgical outcomes, distant metastasis, and worse prognoses in PTC cohorts. In addition, TTEPs were found to be associated with tumor immune infiltrating cells and immunosuppressive phenotypes of PTC. Enrichment analysis suggested the association of TTEPs with epithelial-to-mesenchymal transition (EMT), cell-matrix remodeling, and transcriptional dysregulation, while the TTEmiRs (miR-146b-5p and miR-21-5p) were associated with the modulation of the immune response, EMT, migration, cellular proliferation, and stemness. Molecular docking simulations were performed to evaluate binding affinities between TTEPs and antrocinnamomin, antcin, and antrocin, the bioactive compounds from one of the most reputable Taiwan indigenous medicinal plants (Antrodia camphorata). Our results revealed that antcin exhibited higher binding efficacies toward FN1, ETV5, and NRCAM, whereas antrocin demonstrated the least. Among the targets, fibronectin (FN1) demonstrated high ligandability potential for the compounds whereas NRCAM demonstrated the least. Collectively, our results hinted at the potential of antcin for targeting TTEPs. In conclusion, this comprehensive bioinformatics analysis strongly suggested that TTEPs and TTEmiRs could be used as potential diagnostic biomarker signatures and be exploited as potential targets for therapeutics development.
ABSTRACT
BACKGROUND: Sterculia tragacantha is a medicinal plant commonly used in the western part of Nigeria, for managing diabetes mellitus. However, there is a dearth of scientific information on the antidiabetic and neuroprotective properties of the plant. METHODS: The in silico, in vitro and in vivo models were used to evaluate the antioxidants, antidiabetic, anti-inflammatory and neuroprotective potential of aqueous extract of Sterculia tragacantha leaf (AESTL) in streptozotocin (STZ)-induced diabetic rats. Thirty (30) male albino rats (155.34±6.33 g) were intraperitoneal injected with 40 mg/kg of freshly prepared streptozotocin and were divided into 5 groups (A-E) of 6 animals each. Groups A-D were treated with 0, 150 and 300 mg/kg of AESTL, and 200 mg/kg body weight of metformin respectively, while group E serve as the normal control. RESULTS: The results of in vitro analysis revealed dose-dependent antioxidant activities; ABTS (IC50 = 63.03±2.57 µg/mL), DPPH (117.49±2.35 µg/mL), FRAP (15.19±0.98 mmol/100g), TAC (43.38±0.96 mg/100g), hypoglycaemic effect; α-amylase (IC50 = 77.21±4.35 µg/mL) and α-glucosidase (IC50 = 443.25±12.35), and anti-cholinesterase; AChE (IC50 = 113.07±3.42 µg/mL) and BChE (IC50 = 87.50±4.32 µg/mL) activities of AESTL. In vivo study revealed dose-dependent hypoglycemic effect and body weight improvement in rats treated with the AESTL. In addition, AESTL improved the antioxidant status and attenuated STZ-induced dysregulations of Na+-K+-ATPase, cholinesterases and neurotransmitters in the brain tissue of experimental rats. The results also demonstrated that AESTL could regulate anti-inflammatory response via inhibition of COX-2/NO signaling axis in the brain of diabetic rats. Molecular docking analysis revealed that epicatechin and procyanidin B2, the bioactive compounds from AESTL, docked well to the binding cavities of acetylcholinesterase, butyrylcholinesterase, α-amylase and α-glucosidase with binding affinities ranges between -8.0 and -11.4 kcal/mol, suggesting that these compounds are the bioactive component that could be responsible for the antidiabetic and neuroprotective activities of AESTL. CONCLUSION: The results of the present study strongly suggested that the AESTL extract could be very useful for halting diabetes progression and its associated neuroinflammation complications.
