Genetic deletion of zinc transporter ZnT3 induces progressive cognitive deficits in mice by impairing dendritic spine plasticity and glucose metabolism.

Zinc transporter 3 (ZnT3) is abundantly expressed in the brain, residing in synaptic vesicles, where it plays important roles in controlling the luminal zinc levels. In this study, we found that ZnT3 knockout in mice decreased zinc levels in the hippocampus and cortex, and was associated with progressive cognitive impairments, assessed at 2, 6, and 9-month of age. The results of Golgi-Cox staining demonstrated that ZnT3 deficiency was associated with an increase in dendritic complexity and a decrease in the density of mature dendritic spines, indicating potential synaptic plasticity deficit. Since ZnT3 deficiency was previously linked to glucose metabolism abnormalities, we tested the expression levels of genes related to insulin signaling pathway in the hippocampus and cortex. We found that the Expression of glucose transporters, GLUT3, GLUT4, and the insulin receptor in the whole tissue and synaptosome fraction of the hippocampus of the ZnT3 knockout mice were significantly reduced, as compared to wild-type controls. Expression of AKT (A serine/threonine protein kinase) and insulin-induced AKT phosphorylation was also reduced in the hippocampus of ZnT3 knockout mice. We hypothesize that the ZnT3 deficiency and reduced brain zinc levels may cause cognitive impairment by negatively affecting glycose metabolism via decreased expression of key components of insulin signaling, as well as via changes in synaptic plasticity. These finding may provide new therapeutic target for treatments of neurodegenerative disorders.

Construction of emulsion gel based on the interaction of anionic polysaccharide and soy protein isolate: Focusing on structural, emulsification and functional properties.

In this study, the effects on the structures and emulsion gels of carrageenan (CA) and gum arabic (GA) with soybean protein isolate (SPI) were investigated. The results showed that CA and GA exposed hydrophobic groups to SPI, and formed complexes through non-covalent interactions to improve the stability of the complexes. Furthermore, the emulsion gels based on the emulsions exhibited that CA formed emulsion-filled gels with higher elasticity, stronger gel strength, and thermal reversibility, whereas GA formed emulsion-aggregated gels with higher viscosity, and a weak-gel network. The results of digestion showed that, CA was more helpful to slow down the release of free fatty acids and protect vitamin E during digestion. Compared with SPI-GA emulsion gel, SPI-CA emulsion gel had better physicochemical properties and stronger network structure. The results of this study may be useful in the development of anionic polysaccharides that interact with SPI, and they may provide new insights on the preparation of emulsion gels that slowly release fat-soluble nutrients.

Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity.

Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.

Spatial Distribution of Parvalbumin-Positive Fibers in the Mouse Brain and Their Alterations in Mouse Models of Temporal Lobe Epilepsy and Parkinson's Disease.

Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson's disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.

Impact of left atrial appendage occlusion device position on potential determinants of device-related thrombus: a patient-specific in silico study.

BACKGROUND: Device-related thrombus (DRT) after left atrial appendage occlusion (LAAO) is potentially linked to adverse events. Although clinical reports suggest an effect of the device type and position on the DRT risk, in-depth studies of its mechanistic basis are needed. This in silico study aimed to assess the impact of the position of non-pacifier (Watchman) and pacifier (Amulet) LAAO devices on surrogate markers of DRT risk. METHODS: The LAAO devices were modeled with precise geometry and virtually implanted in different positions into a patient-specific left atrium. Using computational fluid dynamics, the following values were quantified: residual blood, wall shear stress (WSS) and endothelial cell activation potential (ECAP). RESULTS: In comparison to an ostium-fitted device position, deep implantation led to more residual blood, lower average WSS and higher ECAP surrounding the device, especially on the device's atrial surface and the surrounding tissue, suggesting increased risk for potential thrombus. For the non-pacifier device, an off-axis device orientation resulted in even more residual blood, higher ECAP and similar average WSS as compared to an ostium-fitted device position. Overall, the pacifier device showed less residual blood, higher average WSS and lower ECAP, compared to the non-pacifier device. CONCLUSIONS: In this in silico study, both LAAO device type and implant position showed an impact on potential markers of DRT in terms of blood stasis, platelet adhesion and endothelial dysfunction. Our results present a mechanistic basis for clinically observed risk factors of DRT and the proposed in silico model may aid in the optimization of device development and procedural aspects.

FeNiCrCoMn High-Entropy Alloy Nanoparticles Loaded on Carbon Nanotubes as Bifunctional Oxygen Catalysts for Rechargeable Zinc-Air Batteries.

An efficient and stable bifunctional oxygen catalyst is necessary to complete the application of the rechargeable zinc-air battery. Herein, an economical and convenient process was adopted to successfully coat high-entropy alloy Fe12Ni23Cr10Co55-xMnx nanoparticles on carbon nanotubes (CNTs). In 0.1 M KOH solution, with a bifunctional oxygen overpotential (ΔE) of only 0.7 V, the catalyst Fe12Ni23Cr10Co30Mn25/CNT exhibits excellent bifunctional oxygen catalytic performance, exceeding most catalysts reported so far. In addition, the air electrode assembled with this catalyst exhibits high specific capacity (760 mA h g-1) and energy density (865.5 W h kg-1) in a liquid zinc-air battery, with a long-term cycle stability over 256 h. The density functional theory calculation points out that changing the atomic ratio of Co/Mn can change the adsorption energy of the oxygen intermediate (*OOH), which allows the ORR catalytic process to be accelerated in the alkaline environment, thereby increasing the ORR catalytic activity. This article has important implications for the progress of commercially available bifunctional oxygen catalysts and their applications in zinc-air batteries.

Diagnostic performance of angiography-derived fractional flow reserve analysis based on bifurcation fractal law for assessing hemodynamic significance of coronary stenosis.

OBJECTIVES: Blood flow into the side branch affects the calculation of coronary angiography-derived fractional flow reserve (FFR), called Angio-FFR. Neglecting or improperly compensating for the side branch flow may decrease the diagnostic accuracy of Angio-FFR. This study aims to evaluate the diagnostic accuracy of a novel Angio-FFR analysis that considers the side branch flow based on the bifurcation fractal law. METHODS: A one-dimensional reduced-order model based on the vessel segment was used to perform Angio-FFR analysis. The main epicardial coronary artery was divided into several segments according to the bifurcation nodes. Side branch flow was quantified using the bifurcation fractal law to correct the blood flow in each vessel segment. In order to verify the diagnostic performance of our Angio-FFR analysis, two other computational methods were taken as control groups: (i) FFR_s: FFR calculated by delineating the coronary artery tree to consider side branch flow, (ii) FFR_n: FFR calculated by just delineating the main epicardial coronary artery and neglecting the side branch flow. RESULTS: The analysis of 159 vessels from 119 patients showed that our Anio-FFR calculation method had comparable diagnostic accuracy to FFR_s and provided significantly higher diagnostic accuracy than that of FFR_n. In addition, using invasive FFR as a reference, the Pearson correlation coefficients of Angio-FFR and FFRs were 0.92 and 0.91, respectively, while that of FFR_n was only 0.85. CONCLUSIONS: Our Angio-FFR analysis has demonstrated good diagnostic performance in assessing the hemodynamic significance of coronary stenosis by using the bifurcation fractal law to compensate for side branch flow. CLINICAL RELEVANCE STATEMENT: Bifurcation fractal law can be used to compensate for side branch flow during the Angio-FFR calculation of the main epicardial vessel. Compensating for side branch flow can improve the ability of Angio-FFR to diagnose stenosis functional severity. KEY POINTS: • The bifurcation fractal law could accurately estimate the blood flow from the proximal main vessel into the main branch, thus compensating for the side branch flow. • Angiography-derived FFR based on the bifurcation fractal law is feasible to evaluate the target diseased coronary artery without delineating the side branch.

Design, Synthesis, and Anti-tumor Activity of Novel 2-Aryl Benzimidazole Compounds.

BACKGROUND: Combretastatin A-4 (CA-4) is a natural product isolated from the bark of the South African bush willow tree Combretum caffrum, which exerts tubulin inhibition, but its clinical application is limited due to poor stability and water solubility. 2-aryl benzimidazoles are excellent pharmacological skeletons with many activities, especially in tumor inhibition, and better pharmacokinetic properties. Several scaffold CA-4 analogs have been synthesized to date possessing antitumor activities. OBJECTIVE: The benzimidazole was applied as the core moiety to replace the B ring and unstable linkage of CA-4, and the 5-aryl acetenyl group was introduced to improve the antitumor activity. MCF-7, A549, Caco-2, Siha, and Eca-109 tumor cell lines were used to study inhibition by these agents in vitro. METHODS: The benzimidazole structure was constructed from the oxidation of o-nitroaniline and aldehyde and the following schemes, and the structural characterization was carried out. The antitumor effects were evaluated in vitro through MTT assay, cell cycle arrest, and apoptosis assay. Molecular docking with tubulin (Protein ID: 1SA0) was analyzed for the structure-activity relationship. RESULTS: Among these derivatives, 4a-4h series (with 6-methoxy group) compounds inhibited the tumor cell lines much stronger than the CA-4 and cisplatin, especially compound 4f showed prominently inhibitory activity in Siha cell with IC50 value as 0.61 µmol/L. The further assay showed that the cell cycle was arrested at the G0/G1 phase as well verified in apoptosis assay. Molecular docking indicated that 4f had stronger affinity energy and hydrogen bond than CA-4. CONCLUSION: The compound 4f has the potency to be used as an anti-tubulin agent and the 2-trimethoxyphenyl benzimidazole skeleton deserves further study as an antitumor structure.

Intracellular zinc protects Kv7 K+ channels from Ca2+/calmodulin-mediated inhibition.

Zinc (Zn) is an essential trace element; it serves as a cofactor for a great number of enzymes, transcription factors, receptors, and other proteins. Zinc is also an important signaling molecule, which can be released from intracellular stores into the cytosol or extracellular space, for example, during synaptic transmission. Amongst cellular effects of zinc is activation of Kv7 (KCNQ, M-type) voltage-gated potassium channels. Here, we investigated relationships between Kv7 channel inhibition by Ca2+/calmodulin (CaM) and zinc-mediated potentiation. We show that Zn2+ ionophore, zinc pyrithione (ZnPy), can prevent or reverse Ca2+/CaM-mediated inhibition of Kv7.2. In the presence of both Ca2+ and Zn2+, the Kv7.2 channels lose most of their voltage dependence and lock in an open state. In addition, we demonstrate that mutations that interfere with CaM binding to Kv7.2 and Kv7.3 reduced channel membrane abundance and activity, but these mutants retained zinc sensitivity. Moreover, the relative efficacy of ZnPy to activate these mutants was generally greater, compared with the WT channels. Finally, we show that zinc sensitivity was retained in Kv7.2 channels assembled with mutant CaM with all four EF hands disabled, suggesting that it is unlikely to be mediated by CaM. Taken together, our findings indicate that zinc is a potent Kv7 stabilizer, which may protect these channels from physiological inhibitory effects of neurotransmitters and neuromodulators, protecting neurons from overactivity.

Co-Delivery System of Vitamin B12 and Vitamin E Using a Binary W/O/W Emulsion Based on Soybean Isolate Protein-Xanthan Gum/Carrageenan: Emulsification Properties, Rheological Properties, Structure, Stability, and Digestive Characteristics.

In this study, the soybean protein isolate (SPI)-xanthan gum (XG) or carrageenan (CA) W/O/W emulsions for the co-delivery of vitamin B12 and vitamin E were prepared. The effects of XG and CA concentrations on the physicochemical properties and digestive characteristics of the emulsions were also investigated. The addition of XG and CA improved the SPI aggregation and increased its electrostatic repulsion so that more SPI was adsorbed at the phase interface. The emulsifying activity index and emulsifying stability index increased to 24.09 (XG 0.4%) and 14.00 (CA 0.5%) and 151.08 (XG 0.4%) and 135.34 (CA 0.5%), respectively. The adsorbed protein content increased to 88.90% (XG 0.4%) and 88.23% (CA 0.5%), respectively. Moreover, the encapsulation efficiencies of vitamin B12 and vitamin E were increased to 86.72% (XG 0.4%) and 86.47 (CA 0.5%) and 86.31% (XG 0.4%) and 85.78% (CA 0.5%), respectively. The bioaccessibility of vitamin B12 and vitamin E increased to 73.53% (XG 0.4%) and 71.32% (CA 0.5%) and 68.86% (XG 0.4%) and 68.74% (CA 0.5%). The best properties of the emulsions were obtained at a 0.4% concentration of XG and 0.5% of CA. This study offers a novel system for delivering bioactive substances, which is favorable for the advancement of food with delivery capability in food processing.

Recent Progress in Blue Thermally Activated Delayed Fluorescence Emitters and Their Applications in OLEDs: Beyond Pure Organic Molecules with Twist D-π-A Structures.

Thermally activated delayed fluorescence (TADF) materials, which can harvest all excitons and emit light without the use of noble metals, are an appealing class of functional materials emerging as next-generation organic electroluminescent materials. Triplet excitons can be upconverted to the singlet state with the aid of ambient thermal energy under the reverse inter-system crossing owing to the small singlet-triplet splitting energy (ΔEST). This results from a specific molecular design consisting of minimal overlap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, due to the spatial separation of the electron-donating and electron-releasing part. When a well-designed device structure is applied, high-performance blue-emitting TADF organic light-emitting diodes can be realized with an appropriate molecular design. Unlike the previous literature that has reviewed general blue-emitting TADF materials, in this paper, we focus on materials other than pure organic molecules with twist D-π-A structures, including multi-resonance TADF, through-space charge transfer TADF, and metal-TADF materials. Cutting-edge molecules with extremely small and even negative ΔEST values are also introduced as candidates for next-generation TADF materials. In addition, OLED structures used to exploit the merits of the abovementioned TADF emitters are also described in this review.

Piezo2 channel in nodose ganglia neurons is essential in controlling hypertension in a pathway regulated directly by Nedd4-2.

Baroreflex plays a crucial role in regulation of arterial blood pressure (BP). Recently, Piezo1 and Piezo2, the mechanically-activated (MA) ion channels, have been identified as baroreceptors. However, the underlying molecular mechanism for regulating these baroreceptors in hypertension remains unknown. In this study, we used spontaneously hypertensive rats (SHR) and NG-Nitro-l-Arginine (L-NNA)- and Angiotensin II (Ang II)-induced hypertensive model rats to determine the role and mechanism of Piezo1 and Piezo2 in hypertension. We found that Piezo2 was dominantly expressed in baroreceptor nodose ganglia (NG) neurons and aortic nerve endings in Wistar-Kyoto (WKY) rats. The expression of Piezo2 not Piezo1 was significantly downregulated in these regions in SHR and hypertensive model rats. Electrophysiological results showed that the rapidly adapting mechanically-activated (RA-MA) currents and the responsive neuron numbers were significantly reduced in baroreceptor NG neurons in SHR. In WKY rats, the arterial BP was elevated by knocking down the expression of Piezo2 or inhibiting MA channel activity by GsMTx4 in NG. Knockdown of Piezo2 in NG also attenuated the baroreflex and increased serum norepinephrine (NE) concentration in WKY rats. Co-immunoprecipitation experiment suggested that Piezo2 interacted with Neural precursor cell-expressed developmentally downregulated gene 4 type 2 (Nedd4-2, also known as Nedd4L); Electrophysiological results showed that Nedd4-2 inhibited Piezo2 MA currents in co-expressed HEK293T cells. Additionally, Nedd4-2 was upregulated in NG baroreceptor neurons in SHR. Collectively, our results demonstrate that Piezo2 not Piezo1 may act as baroreceptor to regulate arterial BP in rats. Nedd4-2 induced downregulation of Piezo2 in baroreceptor NG neurons leads to hypertension in rats. Our findings provide a novel insight into the molecular mechanism for the regulation of baroreceptor Piezo2 and its critical role in the pathogenesis of hypertension.

BF12, a Novel Benzofuran, Exhibits Antitumor Activity by Inhibiting Microtubules and the PI3K/Akt/mTOR Signaling Pathway in Human Cervical Cancer Cells.

BF12 [(2E)-3-[6-Methoxy-2-(3,4,5-trimethoxybenzoyl)-1-benzofuran-5-yl]prop-2-enoic acid], a novel derivative of combretastatin A-4 (CA-4), was previously found to inhibit tumor cell lines, with a particularly strong inhibitory effect on cervical cancer cells. In this study, we investigated the microtubule polymerization effects and apoptosis signaling mechanism of BF12. BF12 showed a potent efficiency against cervical cancer cells, SiHa and HeLa, with IC50 values of 1.10 and 1.06 µm, respectively. The cellular mechanism studies revealed that BF12 induced G2/M phase arrest and apoptosis in SiHa and HeLa cells, which were associated with alterations in the expression of the cell G2/M cycle checkpoint-related proteins (cyclin B1 and cdc2) and alterations in the levels of apoptosis-related proteins (P53, caspase-3, Bcl-2, and Bax) of these cells, respectively. Western blot analysis showed that BF12 inhibited the PI3 K/Akt/mTOR signaling pathway and induced apoptosis in human cervical cancer cells. BF12 was identified as a tubulin polymerization inhibitor, evidenced by the effective inhibition of tubulin polymerization and heavily disrupted microtubule networks in living SiHa and HeLa cells. By inhibiting the PI3 K/Akt/mTOR signaling pathway and inducing apoptosis in human cervical cancer cells, BF12 shows promise for use as a microtubule inhibitor.

Transient Receptor Potential Cation Channel Subfamily Vanilloid 4 and 3 in the Inner Ear Protect Hearing in Mice.

The transient receptor potential cation channel, vanilloid type (TRPV) 3, is a member of the TRPV subfamily that is expressed predominantly in the skin, hair follicles, and gastrointestinal tract. It is also distributed in the organ of Corti of the inner ear and colocalizes with TRPV1 or TRPV4, but its role in auditory function is unknown. In the present study, we demonstrate that TRPV3 is expressed in inner hair cells (HCs) but mainly in cochlear outer HCs in mice, with expression limited to the cytoplasm and not detected in stereocilia. We compared the number of HCs as well as distortion product otoacoustic emissions (DPOAE) and auditory brainstem response (ABR) thresholds between TRPV3 knockout (V3KO) and wild-type (V3WT) mice and found that although most mutants (72.3%) had normal hearing, a significant proportion (27.7%) showed impaired hearing associated with loss of cochlear HCs. Compensatory upregulation of TRPV4 in HCs prevented HC damage and kanamycin-induced hearing loss and preserved normal auditory function in most of these mice. Thus, TRPV4 and TRPV3 in cochlear HCs protect hearing in mice; moreover, the results suggest some functional redundancy in the functions of TRPV family members. Our findings provide novel insight into the molecular basis of auditory function in mammals that can be applied to the development of strategies to mitigate hearing loss.

Mechanosensitive ion channel Piezo1 promotes prostate cancer development through the activation of the Akt/mTOR pathway and acceleration of cell cycle.

Prostate cancer is one of the most common types of cancer affecting men worldwide; however, its etiology and pathological mechanisms remain poorly understood. Mechanical stimulation plays a key role in prostate cancer development. Piezo type mechanosensitive ion channel component 1 (Piezo1), which functions as a cell sensor and transducer of mechanical stimuli, may have a crucial role in the development of prostate cancer. In the present study, the expression of the Piezo1 channel was demonstrated to be significantly elevated in prostate cancer cell lines and in human prostate malignant tumor tissues. Downregulation of Piezo1 significantly suppressed the viability, proliferation and migration of prostate cancer cells in vitro, and inhibited prostate tumor growth in vivo. The activation of the Akt/mTOR pathway or acceleration of cell cycle progression from G0/G1 to S phase may downstream consequences of Piezo 1 signal pathway activation. Downregulation of Piezo1 considerably suppressed Ca2+ signal increments, inhibited the phosphorylation of Akt and mTOR and arrested the cell cycle of prostate cancer cells at G0/G1 phase in while inhibiting the activation of CDK4 and cyclin D1. Taken together, these findings suggest that Piezo1 channels have a crucial role in prostate cancer development and may, therefore, be a novel therapeutic target in the treatment of prostate cancer.

Deep sea water improves exercise and inhibits oxidative stress in a physical fatigue mouse model.

Physical fatigue is extremely common and occurs daily, and is considered to be associated with oxidative stress. The diverse functions of deep sea water (DSW) have recently gained increasing attention. Previous studies have emphasized the anti-fatigue effect of DSW, but the intrinsic mechanism behind the effect remains to be elucidated. In the imprinting control region (ICR) mice model, DSW delayed the exhaustive swimming time. In addition, DSW decreased the area under the blood lactate (BLA) curve, which was associated with the area under the BLA curve of pre-swimming, post-swimming and post-rest. Furthermore, DSW reduced the basal levels of malondialdehyde and the post-swimming concentration of blood urea nitrogen, lactate dehydrogenase and creatine kinase after swimming, along with an increase in the normal level of antioxidant enzyme activity such as superoxide dismutase and glutathione peroxidase. However, no significant effect on body weight, hepatic glycogen and muscle glycogen was observed between any group. In conclusion, DSW can improve the athletic ability and alleviate physical fatigue of ICR mice. This effect is achieved by enhancing the antioxidant capacity.