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Author(s): Yu, Shu; Li, Michelle; Dubcovsky, Jorge; Tian, Li | Abstract: Grains of tetraploid wheat (Triticum turgidum L.) mainly accumulate the non-provitamin A carotenoid lutein-with low natural variation in provitamin A β-carotene in wheat accessions necessitating alternative strategies for provitamin A biofortification. Lycopene e-cyclase (LCYe) and β-carotene hydroxylase (HYD) function in diverting carbons from β-carotene to lutein biosynthesis and catalyzing the turnover of β-carotene to xanthophylls, respectively. However, the contribution of LCYe and HYD gene homoeologs to carotenoid metabolism and how they can be manipulated to increase β-carotene in tetraploid wheat endosperm (flour) is currently unclear. We isolated loss-of-function Targeting Induced Local Lesions in Genomes (TILLING) mutants of LCYe and HYD2 homoeologs and generated higher order mutant combinations of lcye-A, lcye-B, hyd-A2, and hyd-B2. Hyd-A2 hyd-B2, lcye-A hyd-A2 hyd-B2, lcye-B hyd-A2 hyd-B2, and lcye-A lcye-B hyd-A2 hyd-B2 achieved significantly increased β-carotene in endosperm, with lcye-A hyd-A2 hyd-B2 exhibiting comparable photosynthetic performance and light response to control plants. Comparative analysis of carotenoid profiles suggests that eliminating HYD2 homoeologs is sufficient to prevent β-carotene conversion to xanthophylls in the endosperm without compromising xanthophyll production in leaves, and that β-carotene and its derived xanthophylls are likely subject to differential catalysis mechanisms in vegetative tissues and grains. Carotenoid and gene expression analyses also suggest that the very low LCYe-B expression in endosperm is adequate for lutein production in the absence of LCYe-A. These results demonstrate the success of provitamin A biofortification using TILLING mutants while also providing a roadmap for guiding a gene editing-based approach in hexaploid wheat.

We report the efficient syntheses of chiral tetrahydroindole pyrazolinones by the asymmetric [3 + 2] cascade cyclizations (indolizations) of simple aniline derivatives with pyrazolinone ketimines as 2C synthons. The chiral phosphoric-acid-catalyzed system uses a concerted π-π interaction/dual H-bond control strategy to catalytically direct the asymmetric aniline, which undergoes a highly chemo-, regio-, and enantioselective [3 + 2] cascade annulation, furnishing a series of optically active tetra-hydroindole pyrazolinones with two contiguous chiral aza-quaternary carbon centers in excellent yields with excellent enantioselectivities. This method features a relatively broad substrate scope for amines and 2-naphthylamines and highlights the emerging value of direct chiral indolizations from simple amine sources in organic synthesis.

High-energy-density lithium (Li) metal batteries suffer from a short lifespan owing to apparently ceaseless inactive Li accumulation, which is accompanied by the consumption of electrolyte and active Li reservoir, seriously deteriorating the cyclability of batteries. Herein, a triiodide/iodide (I3- /I- ) redox couple initiated by stannic iodide (SnI4 ) is demonstrated to reclaim inactive Li. The reduction of I3- converts inactive Li into soluble LiI, which then diffuses to the cathode side. The oxidation of LiI by the delithiated cathode transforms cathode into the lithiation state and regenerates I3- , reclaiming Li ion from inactive Li. The regenerated I3- engages the further redox reactions. Furthermore, the formation of Sn mitigates the corrosion of I3- on active Li reservoir sacrificially. In working Li | LiNi0.5 Co0.2 Mn0.3 O2 batteries, the accumulated inactive Li is significantly reclaimed by the reversible I3- /I- redox couple, improving the lifespan of batteries by twice. This work initiates a creative solution to reclaim inactive Li for prolonging the lifespan of practical Li metal batteries.

The homeostasis of the ocular lens is maintained by a microcirculation system propagated through gap junction channels. It is well established that the intercellular communications of the lens become deteriorative during aging. However, the molecular basis for this change in human lenses has not been well defined. Here, we present evidence to show that over 90% of Cx46 and Cx50 are lost in the fiber cells of normal human lenses aged 50 and above. From transparent to cataractous lenses, while Cx43 was upregulated, both Cx46 and Cx50 were significantly down-regulated in the lens epithelia. During aging of mouse lenses, Cx43 remained unchanged, but both Cx46 and Cx50 were significantly downregulated. Under oxidative stress treatment, mouse lenses develop in vitro cataractogenesis. Associated with this process, Cx43 was significantly upregulated, in contrast, Cx46 and Cx50 were sharply downregulated. Together, our results for the first time reveal that downregulation in Cx46 and Cx50 levels appears to be the major reason for the diminished coupling conductance, and the aging-dependent loss of Cx46 and Cx50 promotes senile cataractogenesis.

Cynanchum paniculatum (Bge.) Kitag. (CP) is an important medicinal herb used in Chinese herbal medicine, with a variety of biological activities including anticancer property. In this study, we explored the water extract of CP, for its anticancer effects against breast cancer cells with different mutation types. Cells were grouped as untreated (Control); CP direct treatment (dir-CP); Conditioned medium from CP treated (sup-CP), and untreated cells (sup-Control). Effects of dir-CP and sup-CP were compared to corresponding untreated cells on cytotoxicity, cell migration, and protein expression (cleaved caspase-3, caspase-9, and MMP-2 and 9). CP treatment showed time-dependent decrease in cell number of MDA-MB-231 and SK-Br-3 (both ER(−) PR(−)), while the decrease in cell number was not as significant in MCF-7 and ZR-75-1 cells (both ER(+) PR(+)). sup-CP treatment inhibited the cell migration of MDA-MB-231 and MCF-7 (Her2(−)) in a 24 h scratch assay. Our data suggested that ER(−) PR(−) cells are more sensitive to the CP in terms of direct cytotoxicity, which is not regulated by caspase-3. CP inhibited the migration of the two Her2(−) cells, and this correlated with MMP-2 regulation. The migration of ER(−) PR(−) cells was more sensitive to conditioned medium with CP treatment than to direct CP, and this is not regulated by MMP-2. Our data suggested that CP has anticancer potential on various breast cancer cells through different mechanisms and is specifically effective in inhibiting the migration of the triple negative MDA-MB-231. Our data provide insight into the mechanism of CP against breast cancer progression and would benefit the medical practitioners in better management with CP usage.

Objective: We aim to investigate the anticancer effects and mechanisms of icaritin against breast cancer. Materials and Methods: Both estrogen receptor (ER) positive breast cancer cells MCF- 7 and ER-negative MDA-MB-231 cells were employed. We examined the effects of icaritin on the proliferation and migration by wound healing assay and transwell assay. Cell apoptosis and cell cycle of MCF-7 and MDA-MB-231 cells were analyzed using Flow cytometry. Cell autophagy of MCF-7 and MDA-MB-231 cells was assessed by western blotting, acridine orange staining and confocal microscopy. We also detected the expression of apoptosis-related genes by western blotting. In addition, an autophagy inhibitor was used to investigate whether cytoprotective autophagy was induced. Meanwhile, an ER inhibitor was utilized to explore whether ER was involved in autophagy. Results: Icaritin inhibited the proliferation and migration, and induced cell cycle arrest of both MDA-MB-231 and MCF-7 cells. Icaritin significantly induced apoptosis of MDA-MB- 231 cells by activating caspase-3. And icaritin stimulated autophagy in MCF-7 cells, as evidenced by increased LC3II/LC3I, enhanced p62 degradation, the accumulation of endogenous LC3 puncta formation, and the increased autophagy flux. Icaritin induced autophagy through upregulating the phosphorylation of AMPK and ULK1. Chloroquine, an autophagy inhibitor, increased icaritin-induced apoptosis and proliferation inhibition of MCF-7 cells. Meanwhile, tamoxifen, an ER inhibitor, reversed icaritin-induced autophagy and proliferation inhibition of MCF-7 cells. Conclusion: Our study demonstrated that the antitumor effects of icaritin against breast cancer are related to ER, which suggested that the status of ER should be considered in the clinical application of icaritin.

It has been a great challenge to optimize the growth conditions toward structure-controlled growth of single-wall carbon nanotubes (SWCNTs). Here, a high-throughput method combined with machine learning is reported that efficiently screens the growth conditions for the synthesis of high-quality SWCNTs. Patterned cobalt (Co) nanoparticles were deposited on a numerically marked silicon wafer as catalysts, and parameters of temperature, reduction time and carbon precursor were optimized. The crystallinity of the SWCNTs was characterized by Raman spectroscopy where the featured G/D peak intensity (IG/ID) was extracted automatically and mapped to the growth parameters to build a database. 1,280 data were collected to train machine learning models. Random forest regression (RFR) showed high precision in predicting the growth conditions for high-quality SWCNTs, as validated by further chemical vapor deposition (CVD) growth. This method shows great potential in structure-controlled growth of SWCNTs.

Although Cannabis sativa synthesizes a wide range of phytochemicals, much attention has been primarily given to two phytocannabinoids, Δ9-tetrahydocannabinol (THC) and cannabidiol (CBD), due to their distinctive activities in humans. These bioactivities can be further enhanced through the interaction of THC and CBD with other phytocannabinoids or non-phytocannabinoid chemicals, such as terpenes and flavonoids, a phenomenon that is termed the entourage effect. Flavonoid metabolism in C. sativa and the entourage effect are currently understudied. This mini-review examines recent advances in the biosynthesis and bioactivities of cannflavins, which are prenylated (C5) and geranylated (C10) flavones that are relatively unique to C. sativa. We also discuss the rapidly developing omics tools that enable discoveries in flavonoid metabolism in C. sativa and manipulation of flavonoid production through biotechnology. These advances set the stage for interrogating the health benefits of C. sativa flavonoids, deciphering the contribution of flavonoids to the entourage effect, and developing drugs.

Propylphosphonic anhydride, or T3P, is a commonly used reagent for amidation reactions with numerous examples of application on scale. One process-friendly aspect of the reagent is the ease of work...

Host–guest compounds based on crown ether are promising candidates for switchable dielectric materials, holding great potential in the fields of sensing, information storage, and electronics. However, their phase transition temperature (Tp) is commonly found to be very low, seriously limiting their further development. Herein, using the “momentum matching theory”, we have successfully designed a room-temperature crown ether based switchable dielectric material, 3-methoxyanilinium-18-crown-6 bis(trifluoromethanesulfonyl)ammonium ([(3-methoxyanilinium)(18-crown-6)][TFSA]) (1). Compared with [C7H10NO-(18-crown-6)][PF6] (Tp = 180 K), the introduction of the larger TFSA anion not only brings a new kind of C–H⋯O–S interaction between the host cations and ordered TFSA anions to affect the crystal stacking but also enhances the energy barrier of anionic movements, resulting in the occurrence of a phase transition at a higher temperature of about 308 K. Such a large Tp enhancement of 128 K has rarely been reported in a host–guest crown ether inclusion complex. The switchable dielectric behavior between high and low dielectric states suggests great potential for room-temperature bistable dielectric switches. This work paves the way towards the design of crown ether inclusion complex dielectric switches for a wide range of applications such as sensors and switches near room temperature.

A cobalt-catalyzed regio- and enantioselective γ-amination of β,γ-unsaturated N-acylpyrazoles that delivers the corresponding γ-amination products in good regio- and enantioselectivity has been established. Moreover, the nitrogen-containing compounds could be easily synthesized. DFT calculations have been provided to explain regio- and enantioselectivity for this γ-amination. The chiral γ-amination products were readily converted into the chiral γ-amino acid derivatives.

An expedient total synthesis of the title marine sponge alkaloids has been developed. The salient features of the synthesis are as follows: (i) preparation of the required 13- and 14-membered cyclic lactams with n + 4 ring-expansion strategy of cyclic β-keto esters and (ii) functional group manipulation of the resulted keto ester lactams. This approach used easily accessible and inexpensive materials/reagents, thus providing a promising alternative to the existing preparations.

Despite significant progress in the fabrication and application of semiconductor materials for optical emitters and sensors, few materials can cover the cyan-gap between 450 and 500 nm. We here introduce a robust and facile method to deposit amorphous Sb2S3 films with a bandgap of 2.8 eV. By exploiting the tunable functionality of graphene, a two-dimensional material, efficient deposition from a chemical was achieved. Ozone-generated defects in the graphene were shown to be required to enhance the morphology and quality of the material and comprehensive characterization of the seed layer and the Sb2S3 film were applied to design an optimal deposition process. The resulting material exhibits efficient carrier transport and high photodetector performance as evidenced by unprecedented responsivity and detectivity in semiconductor/graphene/glass vertical heterostructures. (112 A/W, 2.01 × 1012 Jones, respectively).

Z-scheme heterojunction research has become a hotspot in the field of photocatalysis owing to the strong oxidative and reductive capacity for driving photocatalytic reactions. In this work, for the first time, a Z-scheme ternary bismuth phosphate/reduced graphene oxide/protonated g-C3N4 (BiPO4/rGO/pg-C3N4) photocatalyst was fabricated for photocatalytic degradation of tetracycline (TC). The optimal mass ratios of rGO and pg-C3N4 were confirmed as 1.2 wt% and 40 wt%, respectively. This Z-scheme heterojunction exhibited an enhanced TC degrading ability with an 80.0% of TC decomposition after 50 min simulated solar light irradiation, which was 3.3 and 6.3 times that of pg-C3N4 and BiPO4, respectively. Importantly, the internal electric field forced Z-scheme charge transfer of BiPO4/rGO/pg-C3N4 composites, possessing higher charge separation efficiency. The formation of the Z-scheme heterojunction was substantiated by radical scavenging experiments and Mott–Schottky measurements, and it was beneficial for the photocatalytic reaction by accelerating the charge separation and improving the redox ability. Moreover, rGO as cocatalyst could not only provide TC adsorption and catalytic sites but also further promote the charge transfer.

An efficient and benign iron-catalyzed room-temperature method was developed for direct sequential C(sp3)–H/N–H annulation to construct pyrroloindole scaffolds. This strategy features cheap and rea...

The efficient total synthesis of lycojaponicumin A (1) has been accomplished for the first time. The remarkable features of this novel strategy include the following: (1) rapid construction of tricyclic intermediate 4 through a regio- and stereoselective semipinacol ring expansion, which simplified the construction of rings A and B of 1; (2) the subsequent regio- and stereoselective formation of the highly strained rings C-E of 1 through a tandem oxa-hetero [3 + 2] cycloaddition/N-cycloalkylation.

The coordination preference of different metal ions and ligands have an immense influence on the constructions of functional MOF materials. In this work, two new monometallic complexes, namely [Ag(HL)(bipy)0.5 ] (1) and {[Tb(L)1.5 (H2 O)]⋅4 H2 O}n (2) (bipy=4,4-bipyridine), have been synthesized successfully by employing a bifunctional 2-(imidazol-1-yl)terephthalic acid (H2 L) ligand. After that, two new different heterometallic-organic frameworks (HMOFs), namely {[TbAg(L)2 (H2 O)3 ]⋅H2 O}n (3) and [TbAg(L)2 (H2 O)]n (4), were obtained from complexes 1 and 2 as the precursors based on a rational stepwise construction strategy and the theory of hard and soft acids and bases (HSAB principle), respectively. The HMOFs bearing dual metallic catalytic sites (Tb and Ag) can be used as heterogeneous catalysts without losing performance for the chemical fixation of CO2 with epoxides including the sterically hindered epoxides, demonstrating some of the highest reported catalytic activity values. This work may provide a new synthetic route toward tailoring new HMOFs with excellent catalytic activity.

We have developed a novel π-π interaction and dual H-bond concerted control strategy to construct axially chiral naphthylamine heterocycles. With ortho-alkynyl-naphthylamines as the electrophile, indoles and 4-hydroxycoumarins were efficiently employed to construct axially chiral skeletons in good yields and with excellent enantioselectivities (up to 97% enantiomeric excess). Furthermore, the resulting products could be converted to potential squaramides featuring organic catalysts.

Flexible ultraviolet (UV) photodetectors (PDs) have gained increasing demand because of their widespread applications in wearable devices. However, difficulties associated with complicated fabrication technologies significantly limit their scope of application. Herein, via the development of a femtosecond laser direct writing (FsLDW) strategy, silicon carbide (SiC) nanoparticles are found to be assembled in a single microwire within 30 s. The surface of the deposited SiC microwire presents a three-dimensional porous structure, which is conducive to improving the responsivity of the device. The responsivity of a SiC-based microwire PD to UV light at 365 nm is found to be 55.89 A W−1 at a 1 V bias. The as-fabricated SiC microwire PDs on a glass substrate exhibit thermal stability at 350 °C, and the response speed of the PDs becomes notably faster at high temperatures, suggesting their promising applications in harsh conditions. Due to the low-temperature processing characteristics of this process, they can be prepared not only on glass substrates, but also on thermosensitive polymer substrates without an extra transfer process. Moreover, the SiC microwires prepared via FsLDW are directly deposited on the flexible substrate, and the prepared flexible SiC-based PDs can still work stably after being bent 2000 times. This research unveils a feasible way to fabricate a PD with excellent thermal stability and mechanical flexibility.

G9a (also known as EHMT2 - Euchromatin histone methyltransferase 2) is a protein lysine methyltransferase which introduces methylation modification in variety of proteins including histones. G9a catalyzes the dimethylation of lysine 9 on histone 3 (H3K9me2) which is a repressive epigenetic modification. H3K9me2 is associated with the silencing of several genes including tumor suppressor genes in many cancers and hence G9a is a well characterized drug target for cancer therapy. Here, we report the discovery of CSV0C018875 as a novel quinoline based G9a inhibitor through virtual screening strategy from a HTS database. Sub-structure querying based on the known G9a inhibitors, followed by docking based virtual screening, led to the identification of CSV0C018875 as G9a inhibitor. We found that CSV0C018875 inhibits the activity of G9a in both enzyme and cell based assays. Importantly, the toxicity of CSV0C018875 is much lesser than that of the well-studied G9a inhibitor, BIX-01294. Molecular dynamics simulations shows that CSV0C018875 binds deeper inside the active site cavity of G9a, which facilitates the tight binding and also increases the compounds residence time, which in turn reflects better G9a inhibition. The novel quinoline CSV0C018875 could be further optimized to improve the ADME as well pharmacodynamic property.

A mixed-ligand strategy has been used to construct stable luminescent coordination polymers (CPs). An ultra-stable Zn(ii) coordination polymer, [Zn(H3tpb)(Hbtc)]n (1) was hydrothermally synthesized by employing a new tripodal pyrazole ligand H3tpb and a classical carboxylic ligand H3btc (H3tpb = 1,3,5-tris(pyrazolyl)benzene, H3btc = 1,3,5-benzenetricarboxylic acid). Complex 1 exhibits a 2D sql network. Importantly, 1 not only possesses excellent thermal stability but also shows superior chemical stability in terms of water resistance, acid/base aqueous solutions tolerance (pH = 2-12), and organic solvents resistance. This excellent structural stability was further illustrated from the perspective of thermal decomposition kinetics. The luminescence properties were investigated, showing that complex 1 displays high sensitivity and selectivity for detecting Fe3+ and Cr2O72- ions in aqueous solutions via luminescence quenching effects.

The aim of this study was to investigate the effects of miR-210 abnormal expression on Porphyromonas gingivalis lipopolysaccharide (LPS)-treated primary human periodontal ligament cells (PDLCs). The miR-210 level was identified in gingival tissues from patients with chronic periodontitis (CP) and healthy subjects as well as LPS-treated PDLCs by qRT-PCR. Cell viability, apoptotic cells, expression of proteins associated with apoptosis, and release of inflammatory factors in LPS-treated PDLCs were measured using MTT assay, flow cytometry assay, western blotting and ELISA, respectively. Effects of miR-210 abnormal expression on cell viability, cell apoptosis and inflammation factors in LPS-treated PDLCs were evaluated. Afterwards, the target gene of miR-210 was identified, and the involvement of p38MAPK/NF-κB pathway with the effects of miR-210 was finally studied. The miR-210 level was significantly down-regulated in gingival tissues from CP patients as well as LPS-treated PDLCs. LPS-induced decrease of cell viability, increase of apoptosis, and release of TNF-α, IL-1β, IL-6 and IL-8 were attenuated by miR-210 overexpression. We found that hypoxia-inducible factor (HIF)-3α was a target of miR-210, and HIF-3α overexpression partly reversed the effects of miR-210 up-regulation on cell viability, cell apoptosis and inflammation factors expression in LPS-treated PDLCs. Moreover, the phosphorylation levels of key kinases in the NF-κB and p38MAPK pathways were reduced by miR-210 via targeting HIF-3α in LPS-treated PDLCs. MiR-210 attenuated LPS-induced periodontitis, and the LPS-induced activation of the NF-κB and p38MAPK pathways was attenuated by miR-210 via targeting HIF-3α in PDLCs.

Herein, we have reported a nickel-catalyzed cascade reductive thiolation of aryl halides with sulfinates driven by paired electrolysis. This protocol uses sulfinates as the sulfur source, and various thioethers could be synthesized under mild conditions. By mechanism exploration, we find that a cascade chemical step is allowed on the electrode interface and could alter the reaction pathway in paired electrolysis, whose findings could help the discovery of novel cascade reactions with unique reactivity.

Background Achyranthes bidentata polypeptide fraction k (ABPPk) has been shown to protect ischemic stroke and Parkinson's disease, and can inhibit neuroinflammation in lipopolysaccharide (LPS)-activated BV2 microglia. However, the effect of ABPPk responsible for alleviating microglial neurotoxicity remains unknown. Methods Primary microglia were cultured to investigate the effect of ABPPk on LPS-induced neuroinflammation. Microglia conditioned medium (MCM) was collected to stimulate primary cortical neurons and then the neuronal viability, lactate dehydrogenase (LDH) release, intracellular calcium influx, mitochondria membrane potential (MMP) were assessed, respectively. Postnatal day 5 Sprague-Dawley rat pups were intracerebral injected with LPS to establish an LPS-induced brain injury model. Double immunohistochemical staining for NeuN and Iba1 was performed to evaluate the effects of ABPPk on LPS-induced neuronal damage and microglial activation. TUNEL assay was conducted to detect cell apoptosis in LPS-injected brain. The effect of ABPPk on LPS-induced NADPH oxidase 2 (NOX2) expression and reactive oxygen species (ROS) production as well as the phosphorylation of protein kinase B (Akt) was detected. Moreover, LY294002 (a specific PI3K inhibitor) and SC79 (a specific Akt activator) were used to further reveal the underlying mechanism. Results ABPPk pretreatment inhibited LPS-induced NLRP3 and cleaved caspase 1 expressions as well as the mRNA levels of IL-1β and IL-18. Moreover, ABPPk inhibited glutamate release from LPS-activated microglia in a concentration-dependent manner. MCM stimulation resulted in characteristic neuronal toxicity including neuronal viability decrease, LDH release increase, calcium overload, and MMP drop. However, ABPPk pretreatment on microglia reduced the neurotoxicity of MCM. LPS intracerebral injection led to neuronal damage, microglial activation and cell apoptosis in the brain, while ABPPk preadministration significantly inhibited LPS-induced microglial activation and alleviated the brain injury. ABPPk pretreatment inhibited NOX2 expression and ROS production in LPS-activated primary microglia. Signaling pathway analysis showed that ABPPk promoted the phosphorylation of Akt in microglia and inhibited LPS-upregulated NOX2 expression, ROS production, and glutamate release, which can be eliminated by pharmacological inhibition of PI3K. Specific Akt activator could inhibit LPS-induced NOX2 expression, ROS production and glutamate release. Conclusions The present results suggested that ABPPk could alleviate neurotoxicity of LPS-activated microglia via PI3K/Akt dependent NOX2/ROS pathway.

Misplaced or excessive hypochlorous acid in lysosomes has a close association with lots of diseases, so monitoring hypochlorous acid in lysosomes is particularly necessary. In the present work, a novel lysosome-targetable fluorescent probe (Lyso-R-HClO) for hypochlorous acid based on a HClO-mediated cyclization reaction was developed. In the fluorescent probe, the morpholine unit and the site of a HClO-mediated cyclization reaction were, respectively, used as the lysosome-targetable group and the response group. The probe has high selectivity and high sensitivity to hypochlorous acid, with a linear range from 5.0 × 10

O-GlcNAcylation is a nutrient-driven post-translational modification known as a metabolic sensor that links metabolism to cellular function. Recent evidences indicate that the activation of O-GlcNAc pathway is a potential pro-survival pathway and that acute enhancement of this response is conducive to the survival of cells and tissues. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (SalA-4g), is a salidroside analogue synthesized in our laboratory by chemical structure-modification, with a phenyl ring containing a para-methoxy group and a sugar ring consisting of N-acetylglucosamine. We have previously shown that SalA-4g elevates levels of protein O-GlcNAc and improves neuronal tolerance to ischemia. However, the specific target of SalA-4g regulating O-GlcNAcylation remains unknown. To address these questions, in this study, we have focused on mitochondrial network homeostasis mediated by O-GlcNAcylation in SalA-4g’s neuroprotection in primary cortical neurons under ischemic-like conditions. O-GlcNAc-modified mitochondria induced by SalA-4g demonstrated stronger neuroprotection under oxygen glucose deprivation and reoxygenation stress, including the improvement of mitochondrial homeostasis and bioenergy, and inhibition of mitochondrial apoptosis pathway. Blocking mitochondrial protein O-GlcNAcylation with OSMI-1 disrupted mitochondrial network homeostasis and antagonized the protective effects of SalA-4g. Collectively, these data demonstrate that mitochondrial homeostasis mediated by mitochondrial protein O-GlcNAcylation is critically involved in SalA-4g neuroprotection.

Neuroinflammation plays a crucial role in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and anti-inflammation has been considered as a potential therapeutic strategy. Achyranthes bidentate polypeptide fraction k (ABPPk) was shown to protect neurons from death and suppress microglia and astrocyte activation in PD model mice. However, how ABPPk regulates neuroinflammation to exert a neuroprotective role remains unclear. Toxic Aβ oligomers (AβOs) can trigger inflammatory response and play an important role in the pathogenesis of AD. In the present study, for the first time, we investigated the effects and underlying mechanisms of ABPPk on neuroinflammation in AβOs-induced models of AD. In vitro, ABPPk pretreatment dose-dependently inhibited AβOs-induced pro-inflammatory cytokines mRNA levels in BV2 and primary microglia. ABPPk pretreatment also reduced the neurotoxicity of BV2 microglia-conditioned media on primary hippocampal neurons. Furthermore, ABPPk down-regulated the AβOs-induced phosphorylation of IκBα and NF-κB p65 as well as the expression of NLRP3 in BV2 microglia. In vivo, ABPPk pre-administration significantly improved locomotor activity, alleviated memory deficits, and rescued neuronal degeneration and loss in the hippocampus of AβOs-injected mice. ABPPk inhibited the activation of microglia in hippocampal CA3 region and suppressed the activation of NF-κB as well as the expression of NLRP3, cleaved caspase-1, and ASC in the brain after AβOs injection. ABPPk hindered the release of pro-inflammatory cytokines and promoted the release of anti-inflammatory cytokines in the brain. Notably, the polarization experiment on BV2 microglia demonstrated that ABPPk inhibited M1-phenotype polarization and promoted M2-phenotype polarization by activating the LPS- or AβOs-impaired autophagy in microglia. Taken together, our observations indicate that ABPPk can restore the autophagy of microglia damaged by AβOs, thereby promoting M2-phenotype polarization and inhibiting M1-phenotype polarization, thus playing a role in regulating neuroinflammation and alleviating neurotoxicity.

An inexpensive sulfur cathode with the highest possible charge storage capacity is attractive for the design of lithium-ion batteries with a high energy density and low cost. To promote existing lithium–sulfur battery technologies in the current energy storage market, it is critical to increase the electrochemical stability of the conversion-type sulfur cathode. Here, we present the adoption of a carbon nanofoam as an advanced current collector for the lithium–sulfur battery cathode. The carbon nanofoam has a conductive and tortuous network, which improves the conductivity of the sulfur cathode and reduces the loss of active material. The carbon nanofoam cathode thus enables the development of a high-loading sulfur cathode (4.8 mg cm−2) with a high discharge capacity that approaches 500 mA·h g−1 at the C/10 rate and an excellent cycle stability that achieves 90% capacity retention over 100 cycles. After adopting such an optimal cathode configuration, we superficially coat the carbon nanofoam with graphene and molybdenum disulfide (MoS2) to amplify the fast charge transfer and strong polysulfide-trapping capabilities, respectively. The highest charge storage capacity realized by the graphene-coated carbon nanofoam is 672 mA·h g−1 at the C/10 rate. The MoS2-coated carbon nanofoam features high electrochemical utilization attaining the high discharge capacity of 633 mA·h g−1 at the C/10 rate and stable cyclability featuring a capacity retention approaching 90%.

Increasing attention is being focused on the use of polypeptide-based N-methyl-d-aspartate (NMDA) receptor antagonists for the treatment of nervous system disorders. In our study on Achyranthes bidentata Blume, we identified an NMDA receptor subtype 2B (NR2B) antagonist that exerts distinct neuroprotective actions. This antagonist is a 33 amino acid peptide, named bidentatide, which contains three disulfide bridges that form a cysteine knot motif. We determined the neuroactive potential of bidentatide by evaluating its in vitro effects against NMDA-mediated excitotoxicity. The results showed that pretreating primary cultured hippocampal neurons with bidentatide prevented NMDA-induced cell death and apoptosis via multiple mechanisms that involved intracellular Ca2+ inhibition, NMDA current inhibition, and apoptosis-related protein expression regulation. These mechanisms were all dependent on bidentatide-induced inhibitory regulation of NR2B-containing NMDA receptors, thus, bidentatide may contribute to the development of neuroprotective agents that would likely possess the high selectivity and safety profiles inherent in peptide drugs.

SARS-CoV-2 genetic material has been detected in raw wastewater around the world throughout the COVID-19 pandemic and has served as a useful tool for monitoring community levels of SARS-CoV-2 infections. SARS-CoV-2 genetic material is highly detectable in a patient’s feces and the household wastewater for several days before and after a positive COVID-19 qPCR test from throat or sputum samples. Here, we characterize genetic material collected from raw wastewater samples and determine recovery efficiency during a concentration process. We find that pasteurization of raw wastewater samples did not reduce SARS-CoV-2 signal if RNA is extracted immediately after pasteurization. On the contrary, we find that signal decreased by approximately half when RNA was extracted 24-36 hours post-pasteurization and ∼90% when freeze-thawed prior to concentration. As a matrix control, we use an engineered enveloped RNA virus. Surprisingly, after concentration, the recovery of SARS-CoV-2 signal is consistently higher than the recovery of the control virus leading us to question the nature of the SARS-CoV-2 genetic material detected in wastewater. We see no significant difference in signal after different 24-hour temperature changes; however, treatment with detergent decreases signal ∼100-fold. Furthermore, the density of the samples is comparable to enveloped retrovirus particles, yet, interestingly, when raw wastewater samples were used to inoculate cells, no cytopathic effects were seen indicating that wastewater samples do not contain infectious SARS-CoV-2. Together, this suggests that wastewater contains fully intact enveloped particles.

Background and objective: soy protein and soy isoflavones have been suggested to be associated with improved cardiovascular risk factors (e.g., lipid profiles and uric acid (UA)), but few studies have been conducted among women with impaired glucose regulation (IGR). This study is aimed to evaluate the effect of isolated daidzein and genistein on lipid profiles, high sensitive C-reactive protein (hs-CRP), and uric acid (UA) among Chinese women with IGR. Methods and results: this randomized, double-blind, and placebo-controlled trial was conducted in 165 Chinese women aged 30–70 years with IGR. Participants were randomly assigned to one of the three groups: 0 mg of daidzein and genistein with 10 g soy protein (placebo group), 50 mg of daidzein with 10 g soy protein (daidzein group), or 50 mg of genistein with 10 g soy protein (genistein group) supplementation for 24 weeks. Fasting serum total cholesterol (TC), triacylglycerol (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), lipoprotein a (LP (a)), hs-CRP, and UA were assessed at baseline, 12, and 24 weeks after intervention. The results showed no significant differences in the changes (%) of TC, TG, HDL-C, LDL-C, LP (a), hs-CRP, and UA between the three treatment groups at weeks 12 or 24 (all P > 0.05). Conclusion: neither isolated daidzein nor genistein had a significant effect on cardiovascular health in Chinese women with IGR.

The dietary needs of humans for provitamin A carotenoids arise from their inability to synthesize vitamin A de novo. To improve the status of this essential micronutrient, special attention has been given to biofortification of staple foods, such as wheat grains, which are consumed in large quantities but contain low levels of provitamin A carotenoids. However, there remains an unclear contribution of metabolic genes and homoeologs to the turnover of carotenoids in wheat grains. To better understand carotenoid catabolism in tetraploid wheat, Targeting Induced Local Lesions in Genomes (TILLING) mutants of CCD4, encoding a Carotenoid Cleavage Dioxygenase (CCD) that cleaves carotenoids into smaller apocarotenoid molecules, were isolated and characterized. Our analysis showed that ccd4 mutations co-segregated with Poltergeist-like (pll) mutations in the TILLING mutants of A and B subgenomes, hence the ccd-A4 pll-A, ccd-B4 pll-B, and ccd-A4 ccd-B4 pll-A pll-B mutants were analyzed in this study. Carotenoid profiles are comparable in mature grains of the mutant and control plants, indicating that CCD4 homoeologs do not have a major impact on carotenoid accumulation in grains. However, the neoxanthin content was increased in leaves of ccd-A4 ccd-B4 pll-A pll-B relative to the control. In addition, four unidentified carotenoids showed a unique presence in leaves of ccd-A4 ccd-B4 pll-A pll-B plants. These results suggested that CCD4 homoeologs may contribute to the turnover of neoxanthin and the unidentified carotenoids in leaves. Interestingly, abnormal spike, grain, and seminal root phenotypes were also observed for ccd-A4 pll-A, ccd-B4 pll-B, and ccd-A4 ccd-B4 pll-A pll-B plants, suggesting that CCD4 and/or PLL homoeologs could function toward these traits. Overall, this study not only reveals the role of CCD4 in cleavage of carotenoids in leaves and grains, but also uncovers several critical growth traits that are controlled by CCD4, PLL, or the CCD4-PLL interaction.

Integrative medicine comprising a tumor-associated antigen vaccine and chemotherapeutic regimens has provided new insights into cancer therapy. In this study, the AB-type diblock copolymers poly(ethylene glycol)–polylactide (PEG–PLA) were subjected to the dispersion of poorly water-soluble molecules in aqueous solutions. The physicochemical behavior of the chemotherapeutic agent DBPR114 in the PEG–PLA-polymeric aqueous solution was investigated by dynamic light scattering (DLS) technology. In vitro cell culture indicated that replacing the organic solvent DMSO with PEG–PLA polymeric micelles could maintain the anti-proliferative effect of DBPR114 on leukemia cell lines. A murine tumor-associated antigen vaccine model was established in tumor-bearing mice to determine the effectiveness of these formulas in inducing tumor regression. The results demonstrated that the therapeutic treatments effectively reinforced each other via co-delivery of antitumor drug/antigen agents to synergistically integrate the efficacy of cancer therapy. Our findings support the potential use of polymeric micellar systems for aqueous solubilization and expansion of antitumor activity intrinsic to DBPR114 and tumor-associated antigen therapy.

Glioblastoma multiforme (GBM) is a malignant primary brain tumor. The 5-year relative survival rate of patients with GBM remains &lt, 30% on average despite aggressive treatments, and secondary therapy fails in 90% of patients. In chemotherapeutic failure, detoxification proteins are crucial to the activity of chemotherapy drugs. Usually, glutathione S-transferase (GST) superfamily members act as detoxification enzymes by activating xenobiotic metabolites through conjugation with glutathione in healthy cells. However, some overexpressed GSTs not only increase GST activity but also trigger chemotherapy resistance and tumorigenesis-related signaling transductions. Whether GSTM3 is involved in GBM chemoresistance remains unclear. In the current study, we found that T98G, a GBM cell line with pre-existing temozolomide (TMZ) resistance, has high glycolysis and GSTM3 expression. GSTM3 knockdown in T98G decreased glycolysis ability through lactate dehydrogenase A activity reduction. Moreover, it increased TMZ toxicity and decreased invasion ability. Furthermore, we provide next-generation sequencing–based identification of significantly changed messenger RNAs of T98G cells with GSTM3 knockdown for further research. GSTM3 was downregulated in intrinsic TMZ-resistant T98G with a change in the expression levels of some essential glycolysis-related genes. Thus, GSTM3 was associated with glycolysis in chemotherapeutic resistance in T98G cells. Our findings provide new insight into the GSTM3 mechanism in recurring GBM.

Protein sumoylation is one of the most important post-translational modifications regulating many biological processes (Flotho A & Melchior F. 2013. Ann Rev. Biochem. 82:357–85). Our previous studies have shown that sumoylation plays a fundamental role in regulating lens differentiation (Yan et al., 2010. PNAS, 107(49):21034-9.; Gong et al., 2014. PNAS. 111(15):5574–9). Whether sumoylation is implicated in lens pathogenesis remains elusive. Here, we present evidence to show that the protein inhibitor of activated STAT-1 (PIAS1), a E3 ligase for sumoylation, is implicated in regulating stress-induced lens pathogenesis. During oxidative stress-induced cataractogenesis, expression of PIAS1 is significantly altered at both mRNA and protein levels. Upregulation and overexpression of exogenous PIAS1 significantly enhances stress-induced apoptosis. In contrast, silence of PIAS1 with CRISPR/Cas9 technology attenuates stress-induced apoptosis. Mechanistically, different from other cells, PIAS1 has little effect to activate JNK but upregulates Bax, a major proapoptotic regulator. Moreover, Bax upregulation is derived from the enhanced transcription activity of the upstream transcription factor, p53. As revealed previously in other cells by different laboratories, our data also demonstrate that PIAS1 promotes SUMO1 conjugation of p53 at K386 residue in lens epithelial cells and thus enhances p53 transcription activity to promote Bax upregulation. Silence of Bax expression largely abrogates PIAS1-mediated enhancement of stress-induced apoptosis. Thus, our results demonstrated that PIAS1 promotes oxidative stress-induced apoptosis through positive control of p53, which specifically upregulates expression of the downstream proapoptotic regulator Bax. As a result, PIAS1-promoted apoptosis induced by oxidative stress is implicated in lens pathogenesis.