"Affimer" synthetic protein scaffolds block oxidized LDL binding to the LOX-1 scavenger receptor and inhibit ERK1/2 activation.

In multicellular organisms, a variety of lipid-protein particles control the systemic flow of triacylglycerides, cholesterol, and fatty acids between cells in different tissues. The chemical modification by oxidation of these particles can trigger pathological responses, mediated by a group of membrane proteins termed scavenger receptors. The lectin-like oxidized low-density lipoprotein (LOX-1) scavenger receptor binds to oxidized low-density lipoprotein (oxLDL) and mediates both signaling and trafficking outcomes. Here, we identified five synthetic proteins termed Affimers from a phage display library, each capable of binding recombinant LOX-1 extracellular (oxLDL-binding) domain with high specificity. These Affimers, based on a phytocystatin scaffold with loop regions of variable sequence, were able to bind to the plasma membrane of HEK293T cells exclusively when human LOX-1 was expressed. Binding and uptake of fluorescently labeled oxLDL by the LOX-1-expressing cell model was inhibited with subnanomolar potency by all 5 Affimers. ERK1/2 activation, stimulated by oxLDL binding to LOX-1, was also significantly inhibited (p < 0.01) by preincubation with LOX-1-specific Affimers, but these Affimers had no direct agonistic effect. Molecular modeling indicated that the LOX-1-specific Affimers bound predominantly via their variable loop regions to the surface of the LOX-1 lectin-like domain that contains a distinctive arrangement of arginine residues previously implicated in oxLDL binding, involving interactions with both subunits of the native, stable scavenger receptor homodimer. These data provide a new class of synthetic tools to probe and potentially modulate the oxLDL/LOX-1 interaction that plays an important role in vascular disease.

Isoliquiritigenin ameliorates paroxetine-induced sexual dysfunction in male albino mice.

Paroxetine (PRX), a widely prescribed antidepressant, often leads to sexual dysfunction. The available management options such as sildenafil (SDF), are associated with side effects. The present study investigates the fertility-boosting properties of isoliquiritigenin (ISL) on PRX-induced sexual dysfunction in male mice. We allocated fertile mice into six different groups (n = 5): group I- DMSO; group II- PRX; group III- co-administered PRX and SDF; group IV- ISL alone; group V- co-administered PRX and ISL (low dose); and, group VI- co-administered PRX and ISL (high dose). 14 days post treatment, animals were sacrificed, and the weights of the testis and epididymis were evaluated. Furthermore, sperm parameters, testicular and epididymal antioxidant levels, serum testosterone and nitric oxide (NO) levels, histoarchitecture of testis and epididymis, and markers of cellular toxicity were assessed. Results revealed that the PRX administration reduced organ weights, sperm count, intact acrosome, catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), serum testosterone, and NO levels, and increased sperm abnormalities and MDA levels (a biomarker for lipid peroxidation). Additionally, we observed damage in the testis and epididymis. The toxicity biomarker study revealed a higher concentration of SGOT, SGPT, and ALP enzymes in the PRX-treated group. However, the co-administration of PRX with ISL ameliorated the adverse effect of PRX on the parameters mentioned above. The PRX+ISL (high) results were almost at par with the PRX+SDF group. The group that received ISL alone showed overall improvements. In conclusion, our comprehensive panel of tests indicates that ISL could be helpful in managing sexual dysfunction.

VEGFR endocytosis: Implications for angiogenesis.

The binding of vascular endothelial growth factor (VEGF) superfamily to VEGF receptor tyrosine kinases (VEGFRs) and co-receptors regulates vasculogenesis, angiogenesis and lymphangiogenesis. A recurring theme is that dysfunction in VEGF signaling promotes pathological angiogenesis, an important feature of cancer and pro-inflammatory disease states. Endocytosis of basal (resting) or activated VEGFRs facilitates signal attenuation and endothelial quiescence. However, increasing evidence suggest that activated VEGFRs can continue to signal from intracellular compartments such as endosomes. In this chapter, we focus on the evolving link between VEGFR endocytosis, signaling and turnover and the implications for angiogenesis. There is much interest in how such understanding of VEGFR dynamics can be harnessed therapeutically for a wide range of human disease states.

Xanthohumol from Hop: Hope for cancer prevention and treatment.

Cancer is a major public health concern due to high mortality and poor quality of life of patients. Despite the availability of advanced therapeutic interventions, most treatment modalities are not efficacious, very expensive, and cause several adverse side effects. The factors such as drug resistance, lack of specificity, and low efficacy of the cancer drugs necessitate developing alternative strategies for the prevention and treatment of this disease. Xanthohumol (XN), a prenylated chalcone present in Hop (Humulus lupulus), has been found to possess prominent activities against aging, diabetes, inflammation, microbial infection, and cancer. Thus, this manuscript thoroughly reviews the literature on the anti-cancer properties of XN and its various molecular targets. XN was found to exert its inhibitory effect on the growth and proliferation of cancer cells via modulation of multiple signaling pathways such as Akt, AMPK, ERK, IGFBP2, NF-κB, and STAT3, and also modulates various proteins such as Notch1, caspases, MMPs, Bcl-2, cyclin D1, oxidative stress markers, tumor-suppressor proteins, and miRNAs. Thus, these reports suggest that XN possesses enormous therapeutic potential against various cancers and could be potentially used as a multi-targeted anti-cancer agent with minimal adverse effects.