Mirabegron, dependent on ß3-adrenergic receptor, alleviates mercuric chloride-induced kidney injury by reversing the impact on the inflammatory network, M1/M2 macrophages, and claudin-2.

The ß3-adrenergic receptor (ß3-AR) agonism mirabegron is used to treat overactive urinary bladder syndrome; however, its role against acute kidney injury (AKI) is not unveiled, hence, we aim to repurpose mirabegron in the treatment of mercuric chloride (HgCl2)-induced AKI. Rats were allocated into normal, normal + mirabegron, HgCl2 untreated, HgCl2 + mirabegron, and HgCl2 + the ß3-AR blocker SR59230A + mirabegron. The latter increased the mRNA of ß3-AR and miR-127 besides downregulating NF-κB p65 protein expression and the contents of its downstream targets iNOS, IL-4, -13, and -17 but increased that of IL-10 to attest its anti-inflammatory capacity. Besides, mirabegron downregulated the protein expression of STAT-6, PI3K, and ERK1/2, the downstream targets of the above cytokines. Additionally, it enhanced the transcription factor PPAR-α but turned off the harmful hub HNF-4α/HNF-1α and the lipid peroxide marker MDA. Mirabegron also downregulated the CD-163 protein expression, which besides the inhibited correlated cytokines of M1 (NF-κB p65, iNOS, IL-17) and M2 (IL-4, IL-13, CD163, STAT6, ERK1/2), inactivated the macrophage phenotypes. The crosstalk between these parameters was echoed in the maintenance of claudin-2, kidney function-related early (cystatin-C, KIM-1, NGAL), and late (creatinine, BUN) injury markers, besides recovering the microscopic structures. Nonetheless, the pre-administration of SR59230A has nullified the beneficial effects of mirabegron on the aforementioned parameters. Here we verified that mirabegron can berepurposedto treat HgCl2-induced AKI by activating the ß3-AR. Mirabegron signified its effect by inhibiting inflammation, oxidative stress, and the activated M1/M2 macrophages, events that preserved the proximal tubular tight junction claudin-2 via the intersection of several trajectories.

Anandamide modulates WNT-5A/BCL-2, IP3/NFATc1, and HMGB1/NF-κB trajectories to protect against mercuric chloride-induced acute kidney injury.

Endocannabinoid anandamide (AEA) has a physiological role in regulating renal blood flow, whereas its analogs ameliorated renal ischemia/reperfusion injury. Nonetheless, the role of AEA against mercuric chloride (HgCl2)-induced renal toxicity has not been unraveled. Rats were allocated into control, HgCl2, and HgCl2/AEA treated groups. The administration of AEA quelled the HgCl2-mediated increase in inositol trisphosphate (IP3) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). The endocannabinoid also signified its anti-inflammatory potential by turning off the inflammatory cascade evidenced by the suppression of high mobility group box protein-1 (HMGB1), receptor of glycated end products (RAGE), nuclear factor-κB p65 (NF-κB), and unexpectedly PPAR-γ. Additionally, the aptitude of AEA to inhibit malondialdehyde and boost glutathione points to its antioxidant capacity. Moreover, AEA by enhancing the depleted renal WNT-5A and reducing cystatin-C and KIM-1 (two kidney function parameters) partly verified its anti-apoptotic capacity, confirmed by inhibiting caspase-3 and increasing B-cell lymphoma-2 (BCL-2). The beneficial effect of AEA was mirrored by the improved architecture and kidney function evidenced by the reduction in cystatin-C, KIM-1, creatinine, BUN, and caspase1-induced activated IL-18. In conclusion, our results verify the reno-protective potential of AEA against HgCl2-induced kidney injury by its anti-inflammatory, antioxidant, and anti-apoptotic capacities by modulating WNT-5A/BCL-2, IP3/NFATC1, HMGB-1/RAGE/NF-κB, caspase-1/IL-18, and caspase-3/BCL-2 cues.

A comparative study to optimize experimental conditions of pentylenetetrazol and pilocarpine-induced epilepsy in zebrafish larvae.

A common way to investigate epilepsy and the effect of antiepileptic pharmaceuticals is to analyze the movement patterns of zebrafish larvae treated with different convulsants like pentylenetetrazol (PTZ), pilocarpine, etc. Many articles have been written on this topic, but the research methods and exact settings are not sufficiently defined in most. Here we designed and executed a series of experiments to optimize and standardize the zebrafish epilepsy model. We found that during the light and the dark trials, the zebrafish larvae moved significantly more in the light, independent of the treatment, both in PTZ and pilocarpine-treated and the control groups. As expected, zebrafish larvae treated with convulsants moved significantly more than the ones in the control group, although this difference was higher between the individuals treated with PTZ than pilocarpine. When examining the optimal observation time, we divided the half-hour period into 5-minute time intervals, and between these, the first 5 minutes were found to be the most different from the others. There were fewer significant differences in the total movement of larvae between the other time intervals. We also performed a linear regression analysis with the cumulative values of the distance moved during the time intervals that fit the straight line. In conclusion, we recommend 30 minutes of drug pretreatment followed by a 10-minute test in light conditions with a 5-minute accommodation time. Our result paves the way toward improved experimental designs using zebrafish to develop novel pharmaceutical approaches to treat epilepsy.

Not Every Fat-Containing Lesion on Mammogram is a Benign Finding: Case Report and Review of Breast Malignant Phyllodes Tumor with Heterologous Liposarcomatous Differentiation.

Phyllodes tumors (PTs) are a rare fibroepithelial tumor of the breast. Histopathological confirmation of stromal and epithelial component is required for making the diagnosis of PT, and stromal component carries an increased risk of sarcomatous transformation. We present imaging findings of a histologically proven case of malignant PT with heterologous liposarcomatous transformation of the breast.

Nontraumatic emergencies of inflammatory paranasal sinus disease.

Inflammatory disease of the paranasal sinuses is extremely common and the course is often innocuous. However, when extrasinus spread of disease occurs life-threatening complications can arise. Intraorbital and intracranial involvement can progress rapidly either by hematogenous spread or in the case of fungal sinusitis via angioinvasion. An understanding of anatomy and appropriate imaging protocols is critical when these complications arise. The knowledge of imaging features of the different disease processes and prompt diagnosis is essential to improve patient outcomes and positively impact patient care.