Effect of safflower injection on endoplasmic reticulum stress-induced apoptosis in rats with hypoxic pulmonary hypertension

Objective To explore the effects of safflower injection on prevention and treatment of hypoxic pulmonary hypertension and clarify the function of the endoplasmic reticulum stress apoptosis pathway during the process.Methods Thirty male SD rats were randomly grouped as normal control group,hypoxiahypercapnia group and hypoxia+safflower group.The latter two groups were put in the cabin with oxygen concentration ranged from 9% to 11% and carbon dioxide concentration from 5% to 6%.The pulmonary artery pressure and the index of right ventricular hypertrophy were determined after hypoxia exposure(8 h/d×28 d).Changes in morphology of lung tissue were observed by electron microscopy.To explore the possible mechanisms,we also detected apoptosis and apoptosis-related genes/proteins in lung tissue by TUNEL reactivity and PCR and Western blot.Results Compared with the normal control group,pulmonary artery pressure and the index of right ventricular hypertrophy in hypoxia group were 45% and 33.4% higher,respectively.Tiny blood vessel wall of lungs was thickened and edema,and proliferation of collagen fibers was obvious under the electron microscope.TUNEL staining of apoptotic cells in lung tissues showed more high brightness green fluorescence(+～++),but less green fluorescence showed in the pulmonary vascular smooth muscle cell layer,and apoptosis index(AI) value was 150% higher;gene and protein expression levels of endoplasmic reticulum stress pathway were increased.Compared with hypoxia-hypercapnia group,pulmonary artery pressure and the index of right ventricular hypertrophy in the hypoxia+safflower group were 18% and 15.6% lower,respectively;collagen fibers were decreased,and smooth muscle cells and epithelial cells were got apoptotic-like changes under the electron microscope.TUNEL staining of apoptotic cells in lung tissues showed brighter green fluorescence(++～+++);the high brightness green fluorescence showed in pulmonary vascular smooth muscle cell layer,and apoptotic index(AI) value was 40% higher;gene and protein expressions of endoplasmic reticulum stress pathway were significantly upregulated.Conclusion Our findings demonstrate that safflower injection could activate endoplasmic reticulum stressinduced apoptosis and especially promote apoptosis in pulmonary vascular smooth muscle cells.

Synergetic treatment of oxygen microcapsules and lenvatinib for enhanced therapy of HCC by alleviating hypoxia condition and activating anti-tumor immunity

Hypoxia is a typical characteristic of hepatocellular carcinoma(HCC), which causes tremendous obstacles to tumor treatments. Current first-line treatment may further deteriorate tumor hypoxia. For example,Lenvatinib, a receptor tyrosine kinase inhibitor(RTKI), suppresses tumor growth via blocking vascular endothelial growth factor(VEGF) signaling, and can also inhibit angiogenesis, thus limiting oxygen supply to tumor sites. Therefore, alleviating tumor microenvironment(TME) hypoxia holds great potential for enhancing the therapeutic effect of RTKI. Here, nanoparticle-stabilized oxygen microcapsules, a stable and biocompatible oxygen-loaded delivery system, are successfully prepared through interfacial polymerization of polydopamine nanoparticles. The microcapsules with a large loading capacity of oxygen in the core show excellent bioavailability and dispersity, which could effectively improve the hypoxic TME when they serve as oxygen delivery vehicles. Synergetic treatments of Lenvatinib and oxygen microcapsules could induce the transition of “cold tumor” in an immune-suppressed state to “hot tumor” in an immune-activated state by improving tumor hypoxic TME and reducing angiogenesis in HCC. It is revealed that combined treatments of oxygen microcapsules and Lenvatinib could polarize tumor-associated macrophages(TAMs) to anti-tumor M1 cells and activate T cell-mediated anti-tumor immune responses.The results suggest that synergetic therapy using oxygen microcapsules and Lenvatinib could alleviate the hypoxic TME and enhance the therapeutic performance of RTKI, demonstrating a promising anti-tumor strategy for enhanced therapy of HCC.

Gabapentin inhibits central sensitization during migraine

Peripheral and central sensitizations are phenomena that occur during migraine. The role of gabapentin, a migraine preventive drug, on central sensitization remains unclear. In this study, a rat model of migraine was established by electrical stimulation of the trigeminal ganglion, and the animals were given intragastric gabapentin. Changes in amino acid content in the cerebrospinal fluid and protein kinase C membrane translocation in the spinal trigeminal nucleus were examined to clarify the mechanisms underlying the efficacy of gabapentin in the treatment of central sensiti- zation during migraine. Electrophysiology, liquid chromatography-mass spectrometry and western blot analysis results revealed that gabapentin reduces neuronal excitability in the spinal nucleus in the trigeminal nerve, decreases excitatory amino acid content and inhibits the activation of protein kinase C. This provides evidence that excitatory amino acids and protein kinase C are involved in the formation and maintenance of central sensitization during migraine. Gabapentin inhibits mi- graine by reducing excitatory amino acid content in the cerebrospinal fluid and inhibiting protein kinase C activation.