Application of calcium overload-based ion interference therapy in tumor treatment: strategies, outcomes, and prospects.

Low selectivity and tumor drug resistance are the main hinderances to conventional radiotherapy and chemotherapy against tumor. Ion interference therapy is an innovative anti-tumor strategy that has been recently reported to induce metabolic disorders and inhibit proliferation of tumor cells by reordering bioactive ions within the tumor cells. Calcium cation (Ca2+) are indispensable for all physiological activities of cells. In particular, calcium overload, characterized by the abnormal intracellular Ca2+ accumulation, causes irreversible cell death. Consequently, calcium overload-based ion interference therapy has the potential to overcome resistance to traditional tumor treatment strategies and holds promise for clinical application. In this review, we 1) Summed up the current strategies employed in this therapy; 2) Described the outcome of tumor cell death resulting from this therapy; 3) Discussed its potential application in synergistic therapy with immunotherapy.

Identification of pimavanserin tartrate as a potent Ca2+-calcineurin-NFAT pathway inhibitor for glioblastoma therapy.

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor, and 95% of patients die within 2 years after diagnosis. In this study, aiming to overcome chemoresistance to the first-line drug temozolomide (TMZ), we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy. To accelerate the drug's clinical application, we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors. After screening a set of 93 FDA-approved drugs with simple structures, we identified pimavanserin tartrate (PIM), an effective 5-HT2A receptor inverse agonist used for the treatment of Parkinson's disease-associated psychiatric symptoms, as having the most potent inhibitory activity against the NFAT signaling pathway. Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry (SOCE) and subsequent NFAT activity. In cellula, PIM significantly suppressed the proliferation, migration, division, and motility of U87 glioblastoma cells, induced G1/S phase arrest and promoted apoptosis. In vivo, the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM. Unbiased omics studies revealed the novel molecular mechanism of PIM's antitumor activity, which included suppression of the ATR/CDK2/E2F axis, MYC, and AuroraA/B signaling. Interestingly, the genes upregulated by PIM were largely associated with cholesterol homeostasis, which may contribute to PIM's side effects and should be given more attention. Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.

Nanocrystallized Oleanolic Acid Better Inhibits Proliferation, Migration and Invasion in Intracranial Glioma via Caspase-3 Pathway.

Glioma associates with high malignancy and poor prognosis for traditional treatment. Oleanolic acid (OA) has been confirmed to have an inhibitory effect on different kinds of tumors, while accompanying with low efficiency because of its large molecular mass and low solubility. Nanoliposome is an appropriate drug delivery system that can compensate for the limitations of traditional insoluble drugs, involving improvement of their solubility, stability and lipophilicity. In the present study, we comprised of OA covered with nanoliposomes, named OAnano, to observe antitumor effects on U87 glioma cells. The results showed that OAnano raised the solubility and oil-water partition coefficient. OAnano suppressed proliferation of U87 glioma cells, and also had an anticancer effect on U87 glioma cells, which was found to be higher than that of OA. Moreover, treatment with OAnano induced apoptosis and degraded migration ability by caspase-3 pathway. In conclusion, our results demonstrated that OA covered with nanoliposomes led to enhanced anticancer effects by suppressing proliferation, migration and invasion abilities. The findings may provide a reliable reference for development of new anti-cancer drugs.

3D Metallic Ti@Ni0.85 Se with Triple Hierarchy as High-Efficiency Electrocatalyst for Overall Water Splitting.

In this study, Ti@Ni0.85 Se electrodes with a triple hierarchy architecture were designed, and their applications in electrocatalytic water splitting were studied. The 3D electrode is comprised of three types of structures including the bottom square Ti mesh structure as the conductive substrate, a vertical and uniform Ni0.85 Se nanosheet arrays structure in the intermediate section, and the topmost Ni0.85 Se flower structure. This triple hierarchy architecture is binder-free, conductive, and has a particular feature of enlarged surface areas, exposing more active sites, promoting mass- and charge-transfer, and accelerating dissipation of gases generated during water electrolysis. Moreover, DFT calculations confirmed that the Ni0.85 Se possesses metallic character, which further promotes the charge transfer of the electrocatalyst. Benefiting from this special structure and metallic character, the electrode displays a superior activity of 10 mA cm-2 at 120 mV hydrogen evolution reaction overpotential and 30 mA cm-2 at 270 mV oxygen evolution reaction overpotential. By using this electrode as a bifunctional electrocatalyst, an alkali electrolyzer affords a water splitting current of 10 mA cm-2 at a cell voltage of 1.66 V.

Surface oxygen vacancy induced solar light activity enhancement of a CdWO4/Bi2O2CO3 core-shell heterostructure photocatalyst.

A CdWO4/Bi2O2CO3 core-shell heterostructure photocatalyst was fabricated via a facile two-step hydrothermal process. Flower-like Bi2O2CO3 was synthesized and functioned as the cores on which CdWO4 nanorods were coated as the shells. Photoluminescence (PL) spectra and electron paramagnetic resonance (EPR) demonstrate that the CdWO4/Bi2O2CO3 core-shell heterostructure photocatalyst possesses a large amount of oxygen vacancies, which induce defect levels in the band gap and help to broaden light absorption. The photocatalyst exhibits enhanced photocatalytic activity for Rhodamine B (RhB), methylene blue (MB), methyl orange (MO), and colorless contaminant phenol degradation under solar light irradiation. The heterostructured CdWO4/Bi2O2CO3 core-shell photocatalyst shows drastically enhanced photocatalytic properties compared to the pure CdWO4 and Bi2O2CO3. This remarkable enhancement is attributed to the following three factors: (1) the presence of oxygen vacancies induces defect levels in the band gap and increases the visible light absorption; (2) intimate interfacial interactions derived from the core-shell heterostructure; and (3) the formation of the n-n junction between the CdWO4 and Bi2O2CO3. The mechanism is further explored by analyzing its heterostructure and determining the role of active radicals. The construction of high-performance photocatalysts with oxygen vacancies and core-shell heterostructures has great potential for degradation of refractory contaminants in water with solar light irradiation.

Associations of Unilateral Whisker and Olfactory Signals Induce Synapse Formation and Memory Cell Recruitment in Bilateral Barrel Cortices: Cellular Mechanism for Unilateral Training Toward Bilateral Memory.

Somatosensory signals and operative skills learned by unilateral limbs can be retrieved bilaterally. In terms of cellular mechanism underlying this unilateral learning toward bilateral memory, we hypothesized that associative memory cells in bilateral cortices and synapse innervations between them were produced. In the examination of this hypothesis, we have observed that paired unilateral whisker and odor stimulations led to odorant-induced whisker motions in bilateral sides, which were attenuated by inhibiting the activity of barrel cortices. In the mice that showed bilateral cross-modal responses, the neurons in both sides of barrel cortices became to encode this new odor signal alongside the innate whisker signal. Axon projections and synapse formations from the barrel cortex, which was co-activated with the piriform cortex, toward its contralateral barrel cortex (CBC) were upregulated. Glutamatergic synaptic transmission in bilateral barrel cortices was upregulated and GABAergic synaptic transmission was downregulated. The associative activations of the sensory cortices facilitate new axon projection, glutamatergic synapse formation and GABAergic synapse downregulation, which drive the neurons to be recruited as associative memory cells in the bilateral cortices. Our data reveal the productions of associative memory cells and synapse innervations in bilateral sensory cortices for unilateral training toward bilateral memory.

Expression and purification of soluble porcine cystatin 11 in Pichia pastoris.

Cystatin 11 (CST11) belongs to the cystatin type 2 family of cysteine protease inhibitors and exhibits antimicrobial activity in vitro. In this study, we describe the expression and purification of recombinant porcine CST11 in the Pichia pastoris system. We then assess its antimicrobial activity against Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus subtilis by liquid growth inhibition assay. Kinetic studies indicate that the recombinant porcine CST11 has high potency against E. coli and S. aureus. Scanning electronic microscope analysis showed that CST11 might be targeting the bacterial membrane and, thus, could potentially be developed as a therapeutic agent for inhibiting microbe infection without the risk of antibiotic resistance.