Pseudorabies virus inhibits progesterone-induced inactivation of TRPML1 to facilitate viral entry.

Viral infection is a significant risk factor for fertility issues. Here, we demonstrated that infection by neurotropic alphaherpesviruses, such as pseudorabies virus (PRV), could impair female fertility by disrupting the hypothalamus-pituitary-ovary axis (HPOA), reducing progesterone (P4) levels, and consequently lowering pregnancy rates. Our study revealed that PRV exploited the transient receptor potential mucolipin 1 (TRPML1) and its lipid activator, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), to facilitate viral entry through lysosomal cholesterol and Ca2+. P4 antagonized this process by inducing lysosomal storage disorders and promoting the proteasomal degradation of TRPML1 via murine double minute 2 (MDM2)-mediated polyubiquitination. Overall, the study identifies a novel mechanism by which PRV hijacks the lysosomal pathway to evade P4-mediated antiviral defense and impair female fertility. This mechanism may be common among alphaherpesviruses and could contribute significantly to their impact on female reproductive health, providing new insights for the development of antiviral therapies.

Polypyridyl Ru(II) or cyclometalated Ir(III) functionalized architectures for photocatalysis.

The chemistry of polypyridyl Ru(II) and cyclometalated Ir(III) derivatives provides long-lasting interest to researchers due to the inherent advantage of their triplet states in a variety of photoactivities. The introduction of Ru(N^N)3 and Ir(C^N)2(X^N) modules into well-defined architectures extends the research areas of both photoactive metal complexes and network chemistry, generating a lot of new opportunities with interesting structural aesthetics and profound functional possibilities. The rapid development of research in integrating Ru(II) or Ir(III) metallotecons into the architectures has been apparent in recent years which makes this a fascinating subject for reviewing. This review focuses on the design and syntheses of Ru(N^N)3 and Ir(C^N)2(X^N) functionalized architectures of metal-organic frameworks (MOFs), covalent-organic frameworks (COFs), metallasupramolecules, organic supramolecules and supramolecular organic frameworks (SOFs). Furthermore, the photocatalytic applications including the hydrogen evolution reaction (HER), carbon dioxide reduction reaction (CO2RR), photocatalytic oxidation and photoredox catalysis of organic transformation are also presented.

EGCG Restricts PRRSV Proliferation by Disturbing Lipid Metabolism.

Porcine reproductive and respiratory syndrome virus (PRRSV) infection leads to late-term reproductive failure and respiratory illness that affect the global swine industry. Epigallocatechin gallate (EGCG) is a polyphenolic compound from green tea that exerts antiviral activity against diverse viruses. This study aimed to report an uncharacterized mechanism of how EGCG restricted PRRSV proliferation. EGCG showed no significant effects on cell viability, cell cycle progression, and apoptosis in porcine alveolar macrophages and MARC-145 cells. The treatment of cells with EGCG attenuated the replication of both highly pathogenic and less pathogenic PRRSV in vitro. The viral life cycle analysis demonstrated that EGCG affected PRRSV replication and assembly, but not viral attachment, entry, or release. Interestingly, EGCG treatment abrogated the increased lipid droplets formation and lipid content induced by PRRSV infection. We further demonstrated that EGCG blocked PRRSV-stimulated expression of the key enzymes in lipid synthesis. In addition, EGCG attenuated PRRSV-induced autophagy that is critical for PRRSV proliferation. The supplementation of oleic acid restored PRRSV replication and assembly under EGCG treatment. Together, our results support that EGCG inhibits PRRSV proliferation through disturbing lipid metabolism. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) is an enveloped single-positive-stranded RNA virus that causes acute respiratory distress in piglets and reproductive failure in sows, resulting in huge economic losses to the global swine industry. Several lines of evidence have suggested the crucial roles of lipids in PRRSV proliferation. Our previous report demonstrated that PRRSV activated lipophagy to facilitate viral replication through downregulating the expression of N-Myc downstream-regulated gene 1. The manipulation of lipid metabolism may be a new perspective to prevent PRRSV spread. In the present study, we reported that epigallocatechin-3-gallate (EGCG), the major component of green tea catechins, significantly attenuated PRRSV infection through inhibiting lipid synthesis and autophagy. Given that natural products derived from plants have helped in the prevention and treatment of various infectious diseases, EGCG has a great potential to serve as a safe and environmentally friendly natural compound to treat PRRSV infection.

The Human-Specific STING Agonist G10 Activates Type I Interferon and the NLRP3 Inflammasome in Porcine Cells.

Pigs have anatomical and physiological characteristics comparable to those in humans and, therefore, are a favorable model for immune function research. Interferons (IFNs) and inflammasomes have essential roles in the innate immune system. Here, we report that G10, a human-specific agonist of stimulator of interferon genes (STING), activates both type I IFN and the canonical NLRP3 inflammasome in a STING-dependent manner in porcine cells. Without a priming signal, G10 alone transcriptionally stimulated Sp1-dependent p65 expression, thus triggering activation of the nuclear factor-κB (NF-κB) signaling pathway and thereby priming inflammasome activation. G10 was also found to induce potassium efflux- and NLRP3/ASC/Caspase-1-dependent secretion of IL-1ß and IL-18. Pharmacological and genetic inhibition of NLRP3 inflammasomes increased G10-induced type I IFN expression, thereby preventing virus infection, suggesting negative regulation of the NLRP3 inflammasome in the IFN response in the context of STING-mediated innate immune activation. Overall, our findings reveal a new mechanism through which G10 activates the NLRP3 inflammasome in porcine cells and provide new insights into STING-mediated innate immunity in pigs compared with humans.

An unprecedented polyhydroxycarboxylic acid ligand bridged multi-EuIII incorporated tellurotungstate and its luminescence properties.

The first polyhydroxycarboxylic acid ligand bridged multi-EuIII-incorporated tellurotungstate K14H10[Eu4(H2O)4W6(H2glu)4O12(B-α-TeW9O33)4]·60H2O (H6glu = d-gluconic acid) (1) was synthesized via an organic ligand-driven self-assembly strategy. The polyhydroxycarboxylic acid ligand bridged tetrameric polyoxoanion [Eu4(H2O)4W6(H2glu)4O12(B-α-TeW9O33)4]24- in 1 can be viewed as an aggregation of four trivacant Keggin [B-α-TeW9O33]8- fragments and an innovative heterometallic [Eu4(H2O)4W6(H2glu)4O12]8+ cluster, in which four high-coordinate polyhydroxy flexible H2glu4- ligands chelate W and Eu centers through carboxyl and hydroxyl groups, giving rise to a heterometallic cluster. The hexagonal packing of the tetrameric polyoxoanions in 1 along the c axis provides excellent porous channels, which greatly increases the specific surface area of the whole framework and may be of benefit for fluorescence sensing in aqueous solution. 1 can function as a "turn-off" luminescence sensor to detect Cu2+ ions in aqueous solution. The limit of detection (LOD) of the 1-sensor is 8.82 × 10-6 mM, which is the lowest among the reported polyoxometalate-based fluorescence sensors. As for the Cu2+-quenching system, it can function as an "off-on" sensor to detect cysteine in an aqueous system, affording a LOD of 1.75 × 10-4 mM. This work opens up an avenue to broaden the applications of polyoxometalate-based materials in the optical intelligence detection field.

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses.

Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.

Cyclic GMP-AMP synthase is essential for cytosolic double-stranded DNA and fowl adenovirus serotype 4 triggered innate immune responses in chickens.

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a predominant DNA sensor inducing the activation of the innate immune responses that produce proinflammatory cytokines and type I interferons, which has been well-investigated in mammals. However, chicken cGAS (chcGAS), which participates in avian innate immunity, has not been well-investigated. Here, we cloned the complete open reading frame sequence of chcGAS. Multiple sequence alignment and phylogenetic analysis revealed that chcGAS was homologous to mammalian cGAS. The chcGAS mRNA was highly expressed in the bone marrow and ileum. The subcellular localization of chcGAS was mainly in the cytoplasm, and partial co-localization was observed in the endoplasmic reticulum. Through overexpression and RNA interference, we demonstrated that chcGAS responded to exogenous dsDNA, HS-DNA, and poly(dA:dT), and to self dsDNA from the DNA damage response, thereby triggering the activation of STING/TBK1/IRF7-mediated innate immunity in both chicken embryonic fibroblasts and chicken liver cancer cells. Furthermore, downregulation of chcGAS enhanced the infection of fowl adenovirus serotype 4 in LMH cells. Our results demonstrated that chcGAS was an important cytosolic DNA sensor activating innate immune responses and may shed light on a strategy for preventing infectious diseases in the poultry industry.

Impact of the disclosure of diagnosis on posttraumatic stress and growth and quality of life in Chinese patients with hepatocellular carcinoma.

PURPOSE: To evaluate the impact of disclosure/nondisclosure of cancer diagnosis on patients' posttraumatic stress symptoms (PTSS), posttraumatic growth (PTG), and quality of life (QOL). METHODS: Patients with primary hepatocellular carcinoma (HCC) who were admitted for potentially curative treatments in a teaching hospital were recruited. Patients were interviewed at admission regarding their QOL and their attitude towards disclosure of diagnosis. They were interviewed again for QOL, PTSS, and PTG at discharge and at 1 month after discharge. RESULTS: There were 300 patients recruited, 88.3% of whom preferred disclosure of cancer diagnosis. In fact, 162 patients (54.0%) received disclosure of their cancer diagnosis before discharge (disclosed group). However, for the 138 patients whose diagnoses were concealed by their families (uninformed group), 116 patients (84.1%) had learned of their diagnosis of HCC independently within 1 month after discharge. Comparing the scores at 1 month after discharge with scores at discharge showed that the PTSS score significantly declined for patients in the disclosed group and the PTG score significantly decreased for the uninformed patients at 1 month after discharge (p < 0.001 for both comparisons). Additionally, compared with the uninformed group, patients in the disclosed group had lower scores for PTSS (p < 0.001), higher scores for PTG (p < 0.001), better emotional functioning (p < 0.001), and better global QOL (p = 0.006) at 1 month after discharge. CONCLUSIONS: Our findings indicate that concealing the diagnosis of cancer from patients is unlikely to succeed. Additionally, disclosure of diagnosis is beneficial for HCC patients in reducing PTSS and improving PTG and QOL.

Porcine IFITM1 is a host restriction factor that inhibits pseudorabies virus infection.

Interferon-inducible transmembrane proteins (IFITMs) restrict infection by several viruses, such as influenza A virus, West Nile virus and dengue virus. It has not been determined whether porcine IFITMs (pIFITMs) inhibit infection by pseudorabies virus (PRV), an enveloped, double-stranded DNA virus, which is the etiological agent of Aujeszky's disease in pigs. Here, we report that PRV infection elicited pIFITM1 expression in PK15 porcine kidney epithelial cells and 3D4/21 alveolar macrophages. pIFITM2 and pIFITM3 expression was only elevated in PK15 cells during PRV infection. Depletion of pIFITM1 using RNA interference, either in PK15 or in 3D4/21 cells, enhanced PRV infection while overexpression of pIFITM1 had the opposite effect. Knockdown of pIFITM2 and pIFITM3 did not influence PRV infection, suggesting that pIFITM2 and pIFITM3 are independent of PRV infection. PRV-induced pIFITM1 expression was dependent on the cGAS/STING/TBK1/IRF3 innate immune pathway and interferon-alpha receptor-1, suggesting that pIFITM1 is up-regulated by the type I interferon signaling pathway. The anti-PRV role of pIFITM1 was inhibited upon PRV entry. Our data demonstrate that pIFITM1 is a host restriction factor that inhibits PRV entry that may shed light on a strategy for prevention of PRV infection.

Ligand Substituent Effects on the Spin-Crossover Behaviors of Dinuclear Iron(II) Compounds.

Six analogue compounds with the general formula [Fe2( xL)5(NCS)4]· yMeOH ( x = o-Cl, y = 3 for compound 1; x = m-Cl, y = 5 for 2; x = p-Cl, y = 1 for 3; x = o-Me, y = 2 for 4; x = m-Me, y = 2 for 5; x = p-Me, y = 3 for 6; L = N-phenylmethylene-4-amino-1,2,4-triazole) were synthesized. The two Fe(II) ions are triply bridged by the triazole groups of three xL ligands and each Fe(II) is further capped with two NCS- groups and one more xL ligand. These compounds show regular patterns in their magnetic properties that depend on the positions the substituent groups (-Cl or -Me) ride, i.e., ortho-substituted compounds 1 and 4 undergo complete one-step spin crossover (SCO), while meta-substituted compounds 2 and 5 display incomplete one-step SCO with lower transition temperatures, and para-substituted compounds 3 and 6 are in the high-spin states in all temperature ranges. Structural analyses reveal that the molecular geometry and intermolecular interactions of these compounds, which should account for the differences in magnetic properties, are obviously depend on the positions of substituent groups (steric effect), despite them being electron-withdrawing chlorine or electron-donating methyl, whereas theoretical calculations confirm that the electronic effects of substituent groups exert no effect on the magnetic properties.

Myostatin knockout induces apoptosis in human cervical cancer cells via elevated reactive oxygen species generation.

Myostatin (Mstn) is postulated to be a key determinant of muscle loss and cachexia in cancer. However, no experimental evidence supports a role for Mstn in cancer, particularly in regulating the survival and growth of cancer cells. In this study, we showed that the expression of Mstn was significantly increased in different tumor tissues and human cancer cells. Mstn knockdown inhibited the proliferation of cancer cells. A knockout (KO) of Mstn created by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) 9 (CRISPR/Cas9) induced mitochondria-dependent apoptosis in HeLa cells. Furthermore, KO of Mstn reduced the lipid content. Molecular analyses demonstrated that the expression levels of fatty acid oxidation-related genes were upregulated and then increased rate of fatty acid oxidation. Mstn deficiency-induced apoptosis took place along with generation of reactive oxygen species (ROS) and elevated fatty acid oxidation, which may play a role in triggering mitochondrial membrane depolarization, the release of cytochrome c (Cyt-c), and caspase activation. Importantly, apoptosis induced by Mstn KO was partially rescued by antioxidants and etomoxir, thereby suggesting that the increased level of ROS was functionally involved in mediating apoptosis. Overall, our findings demonstrate a novel function of Mstn in regulating mitochondrial metabolism and apoptosis within cancer cells. Hence, inhibiting the production and function of Mstn may be an effective therapeutic intervention during cancer progression and muscle loss in cachexia.

PKM2 knockdown influences SREBP activation and lipid synthesis in bovine mammary-gland epithelial MAC-T cells.

OBJECTIVE: The purpose of the article is to evaluate the changes in lipid metabolism in bovine mammary-gland epithelial MAC-T cells after PKM2 knockdown. RESULTS: MAC-T cells stably expressing low levels of PKM2 were established with lentivirus-mediated small hairpin RNA. Although the knockdown of PKM2 had no effect on MAC-T cell growth, the reduced expression of PKM2 attenuated the mRNA and protein expression of key enzymes involved in sterol synthesis through the SREBP pathway. CONCLUSIONS: The downregulation of PKM2 significantly influenced lipid synthesis in bovine mammary-gland epithelial MAC-T cells. These findings extend our understanding of the crosstalk between glycolysis and lipid metabolism in bovine mammary-gland epithelial cells.

Maintenance of cyclic GMP-AMP homeostasis by ENPP1 is involved in pseudorabies virus infection.

In a previous study, we demonstrated that porcine cyclic GMP-AMP (cGAMP) synthase (cGAS) catalyzes cGAMP production and is an important DNA sensor for the pseudorabies virus (PRV)-induced activation of interferon ß (IFN-ß). Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) has recently been identified as the hydrolase of cGAMP in rodents, but its role in porcine cells is not clear. Our recent study demonstrated that porcine ENPP1 is responsible for the homeostasis of cGAMP and is critical for PRV infection. Porcine ENPP1 mRNA is predominantly expressed in muscle. PRV infection was enhanced by ENPP1 overexpression and attenuated by silencing of ENPP1. During PRV infection, the activation of IFN-ß and NF-κB was reduced in ENPP1 overexpressed cells and promoted in ENPP1 knockdown cells. Investigation of the molecular mechanisms of ENPP1 during PRV infection showed that ENPP1 hydrolyzed cGAMP in PRV-infected or cGAMP-transfected cells and inhibited IRF3 phosphorylation, reducing IFN-ß secretion. These results, combined with those for porcine cGAS, demonstrate that ENPP1 acts coordinately with cGAS to maintain the reservoir of cGAMP and participates in PRV infection.

A series of inorganic-organic hybrid cadmium borates with novel Cd-centred [Cd@B14O20(OH)6](2-) clusters.

Four novel inorganic-organic hybrid cadmium borates, namely [EAH]2{(py)2Cd@[B14O20-(OH)6]} (1, py = pyridine, EA = ethylamine), [PAH]2{(py)2Cd@[B14O20(OH)6]} (2, PA = propylamine), [pyH]2{(py)2Cd@[B14O20(OH)6]} (3) and {(AImH)2Cd@[B14O20(OH)6]} (4, AIm = 1-(3-aminopropyl)imidazole) have been solvothermally synthesized and characterized by elemental analysis, thermogravimetric analysis, IR spectroscopy, UV-Vis-NIR spectroscopy, fluorescence spectroscopy, powder X-ray diffraction, and single-crystal X-ray diffraction, respectively. They represent the first hybrid cadmium borates that exhibit 3D supramolecular open-frameworks with different topologies. All the networks are formed by the unprecedented Cd-centred cluster [Cd@B14O20(OH)6](2-), and further link each other via a multipoint H-bond system. UV-Vis-NIR spectral investigation reveals that these borates are wide-band-gap semiconductors. Moreover, they display strong fluorescence emission around 430 nm, making them excellent candidates for optoelectronic applications as blue materials.

Novel antitumor agent, trilacunary Keggin-type tungstobismuthate, inhibits proliferation and induces apoptosis in human gastric cancer SGC-7901 cells.

A new one-dimensional chain-like compound of tungstobismuthate, [(W(OH)2)2 (Mn(H2O)3)2(Na3(H2O)14)(BiW9O33)2](Himi)2·16H2O (1) (imi = iminazole), has been synthesized in aqueous solution. The structure of 1 was identified by elemental analysis, IR, thermogravimetry (TG), X-ray photoelectron spectroscopy (XPS), (183)W-NMR, and single crystal X-ray diffraction. To investigate the inhibitory effect of 1 on human gastric adenocarcinoma SGC-7901 cells, cell proliferation and apoptosis initiation were examined by MTT assay (MTT = 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide), flow cytometry, nuclear staining, transmission electron microscopy, single cell gel electrophoresis, DNA fragmentation, and Western blotting. The results showed that 1 inhibited cell proliferation and induced apoptosis in SGC-7901 cells in dose-dependent manner. In addition, 1 also decreased the expression of bcl-2 protein and nuclear factor-κB p65 protein in SGC-7901 cells. And expression of bcl-2 protein exhibits a decreasing trend with increase of concentration of 1. Thus, 1 possessed a potential antitumor activity in SGC-7901 cells. This suggests that polyoxotungstates will provide a promising and novel antitumor agent in prevention and treatment of gastric adenocarcinoma.

High-nuclearity Ni-substituted polyoxometalates: a series of poly(polyoxotungstate)s containing 20­22 nickel centers.

Three high-nuclearity Ni-substituted polyoxotungstates (POTs)--[Ni(enMe)2(H2O)2]2[Ni(H2O)6]2[Ni(enMe)2][Ni(H2O)2]1.5[HNi20X4W34(OH)4O136(H2O)6(enMe)8]·11 H2O (3), [Ni(en)2(H2O)]2[H8Ni21X4W34(OH)4O136(en)10(H2O)5]·22 H2O (4), and [Ni(enMe)2]2[H6Ni22X4W34(OH)4O136(H2O)6(enMe)10]·18 H2O (5), in which en = ethylenediamine, enMe = 1,2-diaminopropane, X = 0.5 P+0.5 Ge--were made under hydrothermal conditions and characterized by IR spectroscopy, elemental analysis, thermogravimetric analysis, powder X-ray diffraction, and single-crystal X-ray diffraction. The structures of 3­5 can be viewed as novel derivatives of [H6Ni20P4W34(OH)4O136(enMe)8(H2O)6]·12 H 2O (1) and [Ni(en)2(H2O)]2[H8Ni20P4W34(OH)4O136(en)9(H2O)4]·16 H 2O (2), which both contain 20 nickel ions per structural unit. Compound 3 is the first example of a 1D cluster chain constructed from Ni20-substituted polyanions [HNi20X4 W34(OH)4O136(H2O)6(enMe)8]11− and [Ni(enMe)2]2+ bridges. Compound 4 is a novel cluster­organic chain built by Ni21-substituted polyanions [H8Ni21X4W34(OH)4O136(en)10(H2O)5]4− and en molecule bridges. Compound 5 is a discrete POT with 22 Ni centers, and is not only the largest nickel-substituted POT, but also contains the highest number of nickel ions in one polyanion to date. Magnetic measurements illustrate that overall ferromagnetic interactions exist in 1­5. The magnetic behavior of 1 and 2 was theoretically simulated by the MAGPACK magnetic program package.

A series of luminescent lanthanide-cadmium-organic frameworks with helical channels and tubes.

Lanthanide (Ln) oxides and cadmium (Cd) salts as sources of metals provided the first series of luminescent Ln-Cd-organic frameworks, [LnCd(imdc)(SO4)(H2O)3].0.5H2O (Ln = Tb, Eu, Dy, Gd, Er, Yb, Y, Nd, Pr; H3imdc = 4,5-imidazoledicarboxylic acid), in which the Ln atoms are linked by imdc ligands with skew coordination orientation, resulting in novel hetero-metallic-organic frameworks with left-/right-handed helical tubes (L1/R1) and channels (L2/R2) along the b axis.