The selenoenzyme glutathione peroxidase 4 (GPx4) has been described to control specific cyclooxygenases (COXs) and lipoxygenases (LOXs) that exert substantiated functions in tumor growth and angiogenesis. Therefore, we hypothesized a putative regulatory role of GPx4 during tumor progression and created transformed murine embryonic fibroblasts with inducible disruption of GPx4. GPx4 inactivation caused rapid cell death in vitro, which could be prevented either by lipophilic antioxidants or by 12/15-LOX-specific inhibitors, but not by inhibitors targeting other LOX isoforms or COX. Surprisingly, transformed GPx4(+/-) cells did not die when grown in Matrigel but gave rise to tumor spheroids. Subcutaneous implantation of tumor cells into mice resulted in knockout tumors that were indistinguishable in volume and mass in comparison to wild-type tumors. However, further analysis revealed a strong vascular phenotype. We observed an increase in microvessel density as well as a reduction in the number of large diameter vessels covered by smooth muscle cells. This phenotype could be linked to increased 12/15-LOX activity that was accompanied by an up-regulation of basic fibroblast growth factor and down-regulation of vascular endothelial growth factor A protein expression. Indeed, pharmacological inhibition of 12/15-LOX successfully reversed the tumor phenotype and led to "normalized" vessel morphology. Thus, we conclude that GPx4, through controlling 12/15-LOX activity, is an important regulator of tumor angiogenesis as well as vessel maturation.

Objective: Exposure to loud noise can impair cochlear microcirculation and cause noise-induced hearing loss (NIHL). TNF-α signaling has been shown to be activated in NIHL and to control spiral modiolar artery vasoconstriction that regulates cochlear microcirculation. It was the aim of this experimental study to analyse the effects of the TNF-α inhibitor etanercept on cochlear microcirculation and hearing threshold shift in NIHL in vivo. Design: After assessment of normacusis using ABR, loud noise (106 dB SPL, 30 minutes) was applied on both ears in guinea pigs. Etanercept was administered systemically after loud noise exposure while control animals received a saline solution. In vivo fluorescence microscopy of strial capillaries was performed after surgical exposure of the cochlea for microcirculatory analysis. ABR measurements were derived from the contralateral ear. Study sample: Guinea pigs (n = 6, per group). Results: Compared to controls, cochlear blood flow in strial capillary segments was significantly increased in etanercept-treated animals. Additionally, hearing threshold was preserved in animals receiving the TNF-α inhibitor in contrast to a significant threshold raising in controls. Conclusions: TNF-α inhibition using etanercept improves cochlear microcirculation and protects hearing levels after loud noise exposure and appears as a promising treatment strategy for human NIHL.

Background: The Indian Ayurvedic herbal formula Triphala (TPL) is known for its pharmacological properties for immunomodulation, anti-inflammation, antioxidant, and anti-cancer. This study aimed to investigate the acute and chronic toxicities of the Triphala recipe in a rat model. Methods: To assess the acute toxicities, 5000 mg/kg of TPL was orally administered to Sprague-Dawley rats. For chronic toxicities, different dose levels of TPL at 600, 1200, and 2400 mg/kg/day were given daily for 270 days. General health and behaviors and the body and organ weights of the rats were monitored. At the end of the experiment, blood samples were evaluated for hematology and biochemistry profiles. The evaluation of the internal organs’ appurtenance and necropsy was performed to confirm the tissue histopathology. Results: The results showed that there was no sign of acute toxicity in the TPL group with a decrease in sex organ weights. No significant differences in the rats’ behaviors, physical health, body, or organ weights were found between the controls and the rats receiving the 270/day of oral Triphala at 600, 1200, and 2400 mg/kg/day. However, some alterations in blood chemistries and hematology, including glucose, BUN, red blood cells, Hb, HCT, and MCV, were observed without abnormalities in histopathology. Conclusions: It has been demonstrated that the long-term use of TPL in rat models is safe. No toxic effects were found, suggesting possible safety for long-term use in humans.

Background: Onion has antiallergic activity but lack of evidence for shallot.Objectives: To determine whether shallot owns similar antiallergic activity to onion and its therapeutic effects in allergic rhinitis when added to standard treatmentMethods: In-vitro beta-hexosaminidase inhibitory activities of shallot was compared with onion on RBL-2H3 cells. In clinical study, a randomized, double-blind, placebo-controlled trial was performed. Sixteen AR patients were randomized equally into the controls who received cetirizine 10 mg once daily and placebo capsules for 4 weeks, and the treatment who received 3 g of oral shallot per day (equivalent to 1 1/2 bulbs) and cetirizine. Visual analog scores of overall symptoms (VAS), total nasal and ocular symptom scores (TNSS and TOSS), nasal airway resistance (NAR), and adverse events were assessed.Results: Shallot extract at 200 mu g/mL had an average beta-hexosaminidase inhibition rate of 97% while onion extract had 73%. HPLC chromatograms (lambda = 290 nm) of both plants showed nearly identical patterns of quercetin compounds, such as quercetin 3,4'-diglucoside, quercetin 4'-glucoside, and quercetin. After 4-week of treatment, 62.5% of patients in shallot group and 37.5% of patients in control group showed improvement of post-treatment VAS. TNSS were significantly reduced in both groups, however no difference between groups (P = 0.18). TOSS were significantly improved only in the shallot group (P = 0.01). Adverse events from shallot were not different from placebo.Conclusions: Shallot had antiallergic activity and similar quercetin compounds to onion. The shallot oral supplement and cetirizine was shown to improve the overall AR symptoms more than cetirizine alone.