Nogo-A Drives Alzheimer's Disease Progression by Inducing Tauopathy Vulnerability.

Tauopathies, a group of neurodegenerative disorders, are characterized by disrupted homeostasis of the microtubule binding protein tau. Nogo-A mainly hinders axonal growth and development in neurons, but the underlying mechanism of tau vulnerability has not been determined. Here, to gain more comprehensive insights into the impact of Nogo-A on tau protein expression, we showed that Nogo-A induces tau hyperphosphorylation, synapse loss and cognitive dysfunction. Consistent with the biological function of tau hyperphosphorylation, Nogo-A-induced tau hyperphosphorylation altered microtubule stability, which causes synaptic dysfunction. Mechanistically, Nogo-A-induced tau hyperphosphorylation was abolished by the Nogo-A antagonist NEP1-40 in primary neurons. Surprisingly, downregulation of Nogo-A in the hippocampus of AD mice (hTau. P301S) inhibited tau hyperphosphorylation at the AT8, Thr181, The231 and Ser404 sites and rescued synaptic loss and cognitive impairment in AD mice. Our findings exhibit a strong degree of consistency with Nogo-A-induced tauopathy vulnerability, reinforcing the coherence and reliability of our research. Furthermore, in mice, Nogo-A increases tauopathy vulnerability to exacerbate AD progression via ROCK/AKT/GSK3ß signaling. Together, our findings provide new insight into the function of Nogo-A in regulating tau hyperphosphorylation and reveal an effective treatment strategy for tauopathies.

Small-molecule Molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma.

Glioblastoma (GBM), one of the most malignant brain tumors in the world, has limited treatment options and a dismal survival rate. Effective and safe disease-modifying drugs for glioblastoma are urgently needed. Here, we identified a small molecule, Molephantin (EM-5), effectively penetrated the blood-brain barrier (BBB) and demonstrated notable antitumor effects against GBM with good safety profiles both in vitro and in vivo. Mechanistically, EM-5 not only inhibits the proliferation and invasion of GBM cells but also induces cell apoptosis through the reactive oxygen species (ROS)-mediated PI3K/Akt/mTOR pathway. Furthermore, EM-5 causes mitochondrial dysfunction and blocks mitophagy flux by impeding the fusion of mitophagosomes with lysosomes. It is noteworthy that EM-5 does not interfere with the initiation of autophagosome formation or lysosomal function. Additionally, the mitophagy flux blockage caused by EM-5 was driven by the accumulation of intracellular ROS. In vivo, EM-5 exhibited significant efficacy in suppressing tumor growth in a xenograft model. Collectively, our findings not only identified EM-5 as a promising, effective, and safe lead compound for treating GBM but also uncovered its underlying mechanisms from the perspective of apoptosis and mitophagy.

Inhibition of melanoma by survivin-specific lymphocytes combined with CCL17 and granulocyte-macrophage colony-stimulating factor in a mouse syngeneic model.

As a new generation of treatment, tumor immunotherapy targeting tumor-associated antigens (TAA) has attracted widespread attention. The survivin antigen belongs to TAA. It is a key inhibitor of apoptosis and a key regulator of cell cycle progression; furthermore, it may be a candidate target for tumor therapy. In addition, studies have confirmed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and CCL17 significantly affect local anti-tumor immunity in the tumor microenvironment. The mouse survivin gene was screened by BIMAS and SYFPEITHI to obtain the highest scored mouse survivin epitope peptide, which was synthesized into a peptide vaccine to immunize normal mice. Subsequently, spleen lymphocytes were isolated to induce survivin-specific cytotoxic T lymphocytes (CTL). Next, genetic engineering was used to construct the B16F10 cell line that stably expressed CCL17 and GM-CSF genes. A mouse melanoma model was used to observe the effects of the combination of the three on tumor volume and tumor weight. In-vitro survivin-specific CTL combined with CCL17 gene had a stronger inhibitory effect on B16F10 cells, while combined GM-CSF gene did not enhance the inhibitory effect of CTL on B16F10 cells. In-vivo experiments demonstrated that survivin-specific CTL combined with GM-CSF and CCL17 genes can inhibit the growth of mouse melanoma. HE staining and immunohistochemistry showed that the tumor had more necrotic cells and more infiltrating lymphocytes. The results showed that survivin-specific CTL combined with CCL17 and GM-CSF genes could inhibit tumor growth better.

Benzophenones from Mango Leaves Exhibit α-Glucosidase and NO Inhibitory Activities.

Mango (Mangifera indica L.) is a succulent tropical fruit. Bioactive phytochemical investigation has been carried out to the leaves of mango. Three new benzophenone glycosides, along with 14 known compounds, were purified and identified. The novel benzophenones were elucidated to be 2,4,4',6-tetrahydroxy-3'-methoxybenzophenone-3-C-ß-d-glucopyranoside (1), 4,4',6-trihydroxybenzophenone-2-O-α-l-arabinofuranoside (7), and 4',6-dihydroxy-4-methoxybenzophenone-2-O-(2″),3-C-(1″)-1″-desoxy-α-l-fructofuranoside (11). The α-glucosidase inhibitory, NO production inhibitory, and antioxidant activities were assessed for the purified benzophenones and triterpenoids. Some benzophenones showed moderate α-glucosidase and NO inhibitory activities. The IC50 value of the α-glucosidase inhibitory of isolated compounds 1, 13, and 14 were 284.93 ± 20.29, 239.60 ± 25.00, and 297.37 ± 8.12 µM, respectively. Most compounds showed moderate effects to reduce the NO content in 50 and 100 µM. The above results of bioactivity powerfully demonstrated the phytochemicals from mango, especially benzophenones, probably partially rational for its antidiabetes and anti-inflammatory.