NETO2 promotes melanoma progression via activation of the Ca^(2+)/CaMKⅡ signaling pathway

Melanoma is the most aggressive cutaneous tumor.Neuropilin and tolloid-like 2(NETO2)is closely related to tumorigenesis.However,the functional significance of NETO2 in melanoma progression remains unclear.Herein,we found that NETO2 expression was augmented in melanoma clinical tissues and associated with poor prognosis in melanoma patients.Disrupting NETO2 expression markedly inhibited melanoma proliferation,malignant growth,migration,and invasion by downregulating the levels of calcium ions(Ca^(2+))and the expression of key genes involved in the calcium signaling pathway.By contrast,NETO2 overexpression had the opposite effects.Importantly,pharmacological inhibition of CaMKII/CREB activity with the CaMKII inhibitor KN93 suppressed NETO2-induced proliferation and melanoma metastasis.Overall,this study uncovered the crucial role of NETO2-mediated regulation in melanoma progression,indicating that targeting NETO2 may effectively improve melanoma treatment.

Glutathione depleting drugs, antioxidants and intestinal calcium absorption

Glutathione （GSH） is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca2＋ absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K3, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca2＋ ab-sorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxida-tive/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca transport or the paracellular Ca route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca2＋ pathway are decreased. The favonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca2＋ absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca2＋ transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca2＋ absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety,pharmacokinetics and pharmacodynamics of them.

The ornithine-urea cycle involves fumaric acid biosynthesis in Aureobasidium pullulans var.aubasidani,a green and eco-friendly process for fumaric acid production

The current petroleum chemical methods for fumaric acid production can cause heavy pollution and global warming.In this study,the engineered strains of A.pullulans var.aubasidani were found to be suitable for green fumaric acid producer.Removal and complementation of the relevant genes showed only the ornithine-urea cycle(OUC)was involved in high level fumarate biosynthesis which was controlled by the Ca^(2+)signaling pathway.Removal of both the GOX gene encoding glucose oxidase and the PKS1 gene encoding the polyketide synthase for 3,5-dihydroxydecanoic acid biosynthesis and overexpression of the PYC gene encoding pyruvate carboxylase made the strain e-PYC produce 88.1±4.3 g/L of fumarate at flask level and 93.9±0.8 g/L of fumarate during the fed-batch fermentation.As a yeast-like fungal strain,it was very easy to cultivate A.pullulans var.aubasidani DH177 and their mutants in the bioreactor and to edit its genomic DNAs to enhance fumarate production.It was found that 2 mol of CO_(2) could be fixed during a maximal theoretical yield of 2 mol of fumarate per mole of glucose consumed in the OUC.Therefore,the OUC-mediated fumarate biosynthesis pathway in A.pullulans var.aubasidani was a green and eco-friendly process for the global sustainable development and carbon neutrality.

Pharmacodynamic Mechanism of Kuanxiong Aerosol for Vasodilation and Improvement of Myocardial Ischemia

Objective: To explore the effect of Kuanxiong Aerosol(KXA)on isoproterenol(ISO)-induced myocardial injury in rat models.Methods: Totally 24 rats were radomly divided into control,ISO,KXA low-dose and high-dose groups according to the randomized block design method,and were administered by intragastric administration for 10 consecutive days,and on the 9th and 10th days,rats were injected with ISO for 2 consecutive days to construct an acute myocardial ischemia model to evaluate the improvement of myocardial ischemia by KXA.In addition,the diastolic effect of KXA on rat thoracic aorta and its regulation of ion channels were tested by in vitro vascular tension test.The influence of KXA on the expression of calcium-CaM-dependent protein kinase Ⅱ(CaMK Ⅱ)/extracellular regulated protein kinases(ERK)signaling pathway has also been tested.Results: KXA significantly reduced the ISO-induced increase in ST-segment,interventricular septal thickness,cardiac mass index and cardiac tissue pathological changes in rats.Moreover,the relaxation of isolated thoracic arterial rings that had been precontracted using norepinephrine(NE)or potassium chloride(KCl)was increased after KXA treatment in an endothelium-independent manner,and was attenuated by preincubation with verapamil,but not with tetraethylammonium chloride,4-aminopyridine,glibenclamide,or barium chloride.KXA pretreatment attenuated vasoconstriction induced by CaCl_(2)in Ca^(2+)-free solutions containing K^(+) or NE.In addition,KXA pretreatment inhibited accumulation of Ca^(2+)in A7r5 cells mediated by KCl and NE and significantly decreased p-CaMK Ⅱ and p-ERK levels.Conclusion: KXA may inhibit influx and release of calcium and activate the CaMK Ⅱ/ERK signaling pathway to produce vasodilatory effects,thereby improving myocardial injury.