miR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression.

The complexity of the mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 is elevated in the livers of humans and mice with NAFLD and that its deletion in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including steatosis and inflammation, limiting the progression to non-alcoholic steatohepatitis (NASH), fibrosis and HCC. Mechanistically, hepatic miR-33 deletion reduces lipid synthesis and promotes mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 alters the expression of several known miR-33 target genes involved in metabolism and results in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of NAFLD, NASH, and HCC in obesity.

Regulating band structure, charge transfer and separation, oxygen adsorption and activation by surface ion modification.

As a most promising environmental technology, the substantial enhancement of photocatalytic efficiency is still a big challenge for practical applications. In this work, the surface of Bi2O2CO3 (BOC) nanotubes are modified by Cl and I. The as-obtained samples at different hydrothermal temperatures (T) are designated as T-X-BOC (X = Cl, I). X-ray diffraction (XRD), energy dispersive X-ray (EDX) spectroscopy and X-ray photoelectron spectroscopy (XPS) prove that Cl and I merely chemically adsorb on the BOC surface, rather than dope into the crystal lattice. The surface modification of Cl and I slightly increases light absorption range, while significantly promotes the photoelectron migration from bulk to the surface that greatly enhances the carrier separation efficiency. Density functional theory (DFT) calculations further prove that surface Cl and I have adjusted band structure and surface charge distribution. Besides, the surface Cl and I favor the O2 adsorption and trap the surface photoelectrons, thus promoting the formation of •O2-; while the surface Cl and I impede the surface adsorption of H2O, thus refraining the generation of •OH. In the degradation of rhodamine B (RhB), holes and •O2- radicals play the crucial role. Under ultraviolet light irradiation (λ < 420 nm) for 45 min, the RhB degradation ratios over 150-Cl-BOC (94%) and 150-I-BOC (85%) are 4.2 and 3.7 times higher than that of original BOC (18%), respectively. This work demonstrates that the simple surface halogenation modification greatly improves the photocatalytic activity.

Effect of multi-interface electron transfer on water splitting and an innovative electrolytic cell for synergistic hydrogen production and degradation.

The cleaning and utilization of industry wastewater are still a big challenge. In this work, we mainly investigate the effect of electron transfer among multi-interfaces on water electrolysis reaction. Typically, the CoS2, Co3S4/CoS2 (designated as CS4-2) and Co3S4/Co9S8/CoS2 (designated as CS4-8-2) samples are prepared on a large scale by one-step molten salt method. It is found that because of the different work functions (designated as WF; WF(Co3S4) = 4.48eV, WF(CoS2) = 4.41eV, WF(Co9S8) = 4.18 eV), the effective heterojunctions at the multi-interfaces of CS4-8-2 sample, which obviously improve interface charge transfer. Thus, the CS4-8-2 sample shows an excellent oxygen evolution reaction (OER) activity (134 mV/10 mA cm-2, 40 mV dec-1). The larger double-layer capacitance (Cdl = 17.1 mF cm-2) of the CS4-8-2 sample indicates more electrochemical active sites, compared to the CoS2 and CS4-2 samples. Density functional theory (DFT) calculation proves that due to interface polarization under electric field, the multi-interfaces effectively promote electron transfer and regulate electron structure, thus promoting the adsorption of OH- and dissociation of H2O. Moreover, an innovative norfloxacin (NFX) electrolytic cell (EC) is developed through introducing NFX into the electrolyte, in which efficient NFX degradation and hydrogen production are synergistically achieved. To reach 50 mA cm-2, the required cell voltage of NFX-EC has decreased by 35.2%, compared to conventional KOH-EC. After 2h running at 1 V, 25.5% NFX was degraded in the NFX EC. This innovative NFX-EC is highly energy-efficient, which is promising for the synergistic cleaning and utilization of industry wastewater.

Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage.

Midlobular hepatocytes are proposed to be the most plastic hepatic cell, providing a reservoir for hepatocyte proliferation during homeostasis and regeneration. However, other mechanisms beyond hyperplasia have been little explored and the contribution of other hepatocyte subpopulations to regeneration has been controversial. Thus, re-examining hepatocyte dynamics during regeneration is critical for cell therapy and treatment of liver diseases. Using a mouse model of hepatocyte- and non-hepatocyte- multicolor lineage tracing, we demonstrate that midlobular hepatocytes also undergo hypertrophy in response to chemical, physical, and viral insults. Our study shows that this subpopulation also combats liver impairment after infection with coronavirus. Furthermore, we demonstrate that pericentral hepatocytes also expand in number and size during the repair process and Galectin-9-CD44 pathway may be critical for driving these processes. Notably, we also identified that transdifferentiation and cell fusion during regeneration after severe injury contribute to recover hepatic function.

Replacing cholesterol with asiatic acid to prolong circulation and enhance anti-metastatic effects of non-PEGylated liposomes.

Cholesterol is an indispensable component of most liposomes, heavily influencing their physical and surface properties. In this study, cholesterol in non-PEGylated liposomes was replaced by its analog, asiatic acid (AA), to generate liposomes with an alternative composition. These AA liposomes are generally smaller and more rigid than conventional liposomes, circulate longer in the body, and accumulate more in primary tumors and lung metastases in vivo. On the other hand, as an active ingredient, AA can decrease TGF-ß secretion to inhibit the epithelial-mesenchymal transition (EMT) process, increase the sensitivity of tumor cells to doxorubicin (DOX), and synergize with DOX to enhance the immune response, thus improving their antitumor and anti-metastasis efficiency. Based on this rationale, DOX-loaded AA liposomes were fabricated and tested against triple-negative breast cancer (TNBC). Results showed that compared with conventional liposomes, the DOX-AALip provided approximately 28.4% higher tumor volume reduction with almost no metastatic nodules in the mouse model. Our data demonstrate that AA liposomes are safe, simple, and efficient, and thus in many situations may be used instead of conventional liposomes, having good potential for further clinical translational development.

Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice.

Blood vessels are continually exposed to circulating lipids, and elevation of ApoB-containing lipoproteins causes atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FAs) into triglyceride-rich (TG-rich) lipid droplets (LDs) is not known. In this study, we showed that deletion of the enzyme adipose TG lipase (ATGL) in the endothelium led to neutral lipid accumulation in vessels and impaired endothelial-dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress-induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD affects endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state.

Tool Frame Calibration for Robot-Assisted Ultrasonic Testing.

Tool frame calibration has been widely used in robot-assisted printing, welding, and grinding, but it is not suitable for ultrasonic testing because the robot is submerged in water. The purpose of this paper is to present a tool frame calibration method, which is suitable for improving the precision of ultrasonic testing. In uniform mediums, sound travels along a straight line like ray. A reflector is fixed in water to reflect ultrasound, which makes it possible to measure distances between incidence points on a reflector and tool center point (TCP) on an ultrasound transducer. In addition, the positions and poses of the end flange are recorded through a robot controller. Finally, an optimization method is applied to calculate the position and pose errors of the tool frame relative to the end flange according to such records. The presented method was implemented in an ultrasonic testing system. We selected 100 incidence points on the reflector to calculate the assembly errors of the transducer. The pulse amplitude rose obviously after calibration, which verifies that this is an effective method. Considering that ultrasonic transducers can be used as a measuring tool, this paper proposes a tool frame calibration method for ultrasonic testing robots without introducing other measuring devices, which draws the conclusion that tool frame can be calibrated through ultrasound.

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome.

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

Three-Dimensional Carbon Foam Modified with Mg3N2 for Ultralong Cyclability of a Dendrite-Free Li Metal Anode.

Uncontrolled growth of lithium dendrites and huge volume change during the lithium plating/stripping process as well as poor mechanical properties of the solid electrolyte interphase (SEI) are key obstacles to the development of a stable Li metal anode. Here, an ultralight Mg3N2-modified carbon foam (CF-Mg3N2) was fabricated as a collector to address these issues. The calculated results show that the CF-Mg3N2 composite is relatively stable in terms of energy. Based on the synergistic effect of the three-dimensional skeleton and the lithiophilic nature of Mg3N2, homogeneous lithium deposition/stripping was realized around the foam carbon skeleton with an extremely low nucleation overpotential (∼9.3 mV) and high retention of Coulombic efficiency (99.3%) as well as long cyclability (700 cycles and 3000 h in half and symmetrical cells, respectively). Meanwhile, Mg3N2-CF@Li//LiFePO4 full cells also showed better rate capability and more stable cycling capability than CF@Li//LiFePO4 and Li//LiFePO4 cells, exhibiting extreme practicality. Accordingly, the design concept mentioned in this work provides a far-reaching influence on the development of a stable Li metal anode.

Comparison of two methods for tumour-targeting peptide modification of liposomes.

Liposomes decorated with tumour-targeting cell-penetrating peptides can enhance specific drug delivery at the tumour site. The TR peptide, c(RGDfK)-AGYLLGHINLHHLAHL(Aib)HHIL, is pH-sensitive and actively targets tumour cells that overexpress integrin receptor αvß3, such as B16F10 melanoma cells. Liposomes can be modified with the TR peptide by two different methods: utilization of the cysteine residue on TR to link DSPE-PEG2000-Mal contained in the liposome formula (LIPTR) or decoration of TR with a C18 stearyl chain (C18-TR) for direct insertion into the liposomal phospholipid bilayer through electrostatic and hydrophobic interactions (LIPC18-TR). We found that both TR and C18-TR effectively reversed the surface charge of the liposomes when the systems encountered the low pH of the tumour microenvironment, but LIPC18-TR exhibited a greater increase in the charge, which led to higher cellular uptake efficiency. Correspondingly, the IC50 values of PTX-LIPTR and PTX-LIPC18-TR in B16F10 cells in vitro were 2.1-fold and 2.5-fold lower than that of the unmodified PTX-loaded liposomes (PTX-LIP), respectively, in an acidic microenvironment (pH 6.3). In B16F10 tumour-bearing mice, intravenous administration of PTX-LIPTR and PTX-LIPC18-TR (8 mg/kg PTX every other day for a total of 4 injections) caused tumour reduction ratios of 39.4% and 56.1%, respectively, compared to 20.8% after PTX-LIP administration. Thus, we demonstrated that TR peptide modification could improve the antitumour efficiency of liposomal delivery systems, with C18-TR presenting significantly better results. After investigating different modification methods, our data show that selecting an adequate method is vital even when the same molecule is used for decoration.