Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.

Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.

Inhibition of TRPV4 remodels single cell polarity and suppresses the metastasis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor, frequently causing both intrahepatic and extrahepatic metastases. The overall prognosis of patients with metastatic HCC is poor. Recently, single-cell (sc) polarity is proved to be an innate feature of some tumor cells in liquid phase, and directly involved in the cell adhesion to blood vessel and tumor metastasis. Here, we characterize the maintained sc polarity of HCC cells in a suspension culture, and investigate its roles and regulatory mechanisms during metastasis. We demonstrate that transient receptor potential vanilloid 4 (TRPV4) is a promoting regulator of sc polarity via activating Ca2+-dependent AMPK/MLC/ERM pathway. This attenuates the adhesion of metastatic HCC cells to vascular endothelial cells. The reduction of cancer metastases can result from TRPV4 inhibition, which not only impacts the migration and invasion of tumor cells, but also prevents the adhesion to vascular endothelial cells. Additionally, we discover a brand-new TRPV4 inhibitor called GL-V9 that modifies the degree of sc polarization and significantly decreases the metastatic capacity of HCC cells. Taken together, our data shows that TRPV4 and calcium signal are significant sc polarity regulators in metastatic HCC, and that the pharmacological intervention that results in HCC cells becoming depolarized suggests a promising treatment for cancer metastasis.

AFP deletion leads to anti-tumorigenic but pro-metastatic roles in liver cancers with concomitant CTNNB1 mutations.

HCC remains one of the most prevalent and deadliest cancers. Serum AFP level is a biomarker for clinical diagnosis of HCC, instead the contribution of AFP to HCC development is clearly highly complex. Here, we discussed the effect of AFP deletion in the tumorigenesis and progression of HCC. AFP deletion in HepG2 cells inhibited the cell proliferation by inactivating PI3K/AKT signaling. Surprisingly, AFP KO HepG2 cells appeared the increasing metastatic capacity and EMT phenotype, which was attributed to the activation of WNT5A/ß-catenin signal. Further studies revealed that the activating mutations of CTNNB1 was closely related with the unconventional pro-metastatic roles of AFP deletion. Consistently, the results of DEN/CCl4-induced HCC mouse model also suggested that AFP knockout suppressed the growth of HCC primary tumors, but promoted lung metastasis. Despite the discordant effect of AFP deletion in HCC progression, a drug candidate named OA showed the potent suppression of HCC tumor growth by interrupting AFP-PTEN interaction and, importantly, reduced the lung metastasis of HCC via angiogenesis suppression. Thus, this study demonstrates an unconventional effect of AFP in HCC progression, and suggests a potent candidate strategy for HCC therapy.

Fragmentation Dynamics of a Carbon Dioxide Dication Produced by Ion Impact.

The response of carbon dioxide to radiolysis is crucial for understanding the atmospheric chemistry of planets. Here, we present a combined experimental and theoretical investigation of the three-body fragmentation dynamics of CO22+ to C+ + O+ + O initiated by 1 keV/u Ar2+ impact. Taking advantage of the kinematic complete measurement employing a reaction microscope, three dissociation mechanisms are distinguished, and their branching ratios are determined. The concerted fragmentation with two C-O bonds breaking simultaneously is dominant, while the sequential pathway with CO+ as the intermediate also makes a significant contribution. Also, a novel isomerization pathway with transitory formation of O2+ is identified. The identified mechanisms can contribute to O+ and O escaping from the Martian atmosphere, since the kinetic energies of most of the fragments are observed to be higher than the escape energy of oxygen.

Uncertainties in Atomic Data for Modeling Astrophysical Charge Exchange Plasmas.

Relevant uncertainties of theoretical atomic data are vital to determining the accuracy of plasma diagnostics in a number of areas, including, in particular, the astrophysical study. We present a new calculation of the uncertainties on the present theoretical ion-impact charge exchange atomic data and X-ray spectra, based on a set of comparisons with the existing laboratory data obtained in historical merged-beam, cold-target recoil-ion momentum spectroscopy, and electron beam ion traps experiments. The average systematic uncertainties are found to be 35-88% on the total cross sections, and 57-75% on the characteristic line ratios. The model deviation increases as the collision energy decreases. The errors on total cross sections further induce a significant uncertainty to the calculation of ionization balance for low-temperature collisional plasmas. Substantial improvements of the atomic database and dedicated laboratory measurements are needed to obtain the current models, ready for the X-ray spectra from the next X-ray spectroscopic mission.

The spatially heterogeneous response of aerosol properties to anthropogenic activities and meteorology changes in China during 1980-2018 based on the singular value decomposition method.

The unsustainable and rapid economy development brings air pollution prominently in China. In the last decade, the haze weather and its influencing mechanism across China have received increasingly attention. Although previous research has extensively focused on the characteristics of aerosols, better understanding of long-term variation in aerosols and their determinants since the Reform and Opening-up still lack in China. Furthermore, the previous studies exploring the influencing mechanism behind haze episodes by using statistical method only reflect correlation between pollutant concentration and indicators at single station, which cannot consider the remote influences resulting from atmosphere transport. In this research, we investigated the spatiotemporal pattern of aerosol optical depth (AOD) and aerosol species in China during 1980-2018 and explored the spatially heterogeneous response of AOD and aerosol component to meteorological conditions and urbanization based on singular value decomposition (SVD) method. The results indicated that AOD exhibited an upward trend in nearly 40 years, especially in eastern China with the fastest growth of sulfate aerosol. The heterogeneity of determinants revealed a great gap in anthropogenic activities and meteorological influences on aerosol varing regions. In eastern China, anthropogenic activities should be closely monitored. Besides, scientific desert governance and urban construction exert positive impact on air pollution in Xinjiang province.

Structural characterization of modular supramolecular architectures in solution.

Structures of modular supramolecular architectures consisting of a hexameric, diphenylethyne-linked porphyrin macrocyclic array and the corresponding host-guest complex formed by inclusion of a tripyridyl guest molecule were characterized in solution using high-angle X-ray scattering. Scattering measurements made to 6 A resolution coupled with pair distance function (PDF) analyses demonstrated that (1) the porphyrin architectures are not rigid but are distributed across a conformational ensemble with a mean diameter that is 1.5 A shorter than the diameter of a symmetric, energy-minimized model structure, (2) the conformational envelope has limits of 3 A positional dispersion and full rotational freedom for all six porphyrin groups, and (3) insertion of the tripyridyl guest molecule expands the diameter of the host conformer by 0.6 A and decreases the configurational dispersion by approximately 2-fold. These results validate the molecular design, provide a new measure of conformational ensembles in solution that cannot be obtained by other techniques, and establish a structural basis for understanding the photophysical and guest-hosting functions of the hexameric porphyrin architectures in liquids.

Protein conformations explored by difference high-angle solution X-ray scattering: oxidation state and temperature dependent changes in cytochrome C.

We demonstrate the use of high-angle X-ray scattering to explore protein conformational states in solution by resolving oxidation state- and temperature-dependent changes in the conformation of horse heart cytochrome c. Several detailed models exist for oxidation-dependent changes in mitochondrial class I c cytochromes determined by X-ray crystallography and solution NMR techniques. These models differ in the magnitude and locations of structural change. Our scattering measurements show that high-angle X-ray scattering can discriminate between these models, and that the experimental scattering data for horse cytochrome c can be best reconciled with selected NMR models for the same protein. These results demonstrate the ability to use high-angle X-ray scattering to resolve conformational states of proteins in solution, and to relate these measurements to detailed structural models. Furthermore, temperature-dependent changes are found in the high angle scattering patterns for horse cytochrome c, illustrating the sensitivity of these measurements to dynamic aspects of protein structure. These results demonstrate the ability to use difference high angle scattering as a quantitative monitor of reaction-linked changes in protein conformation and structural dynamics. Synchrotron-based high-angle scattering holds promise as a widely applicable, high throughput technique for exploring conformational states linked to physiological protein function, for resolving configurational differences between protein structures in solution and crystalline states, and for bridging the gap between solution NMR and crystallographic structure techniques.