The Photosensitising Clinical Agent Verteporfin Is an Inhibitor of SPAK and OSR1 Kinases

STE20/SPS1‐related proline/alanine‐rich kinase (SPAK) and oxidative‐stress‐responsive kinase 1 (OSR1) are two serine/threonine protein kinases that play key roles in regulating ion homeostasis. Various SPAK and OSR1 mouse models exhibited reduced blood pressure. Herein, the discovery of verteporfin, a photosensitising agent used in photodynamic therapy, as a potent inhibitor of SPAK and OSR1 kinases is reported. It is shown that verteporfin binds the kinase domains of SPAK and OSR1 and inhibits their catalytic activity in an adenosine triphosphate (ATP)‐independent manner. In cells, verteporfin was able to suppress the phosphorylation of the ion co‐transporter NKCC1; a downstream physiological substrate of SPAK and OSR1 kinases. Kinase panel screening indicated that verteporfin inhibited a further eight protein kinases more potently than that of SPAK and OSR1. Although verteporfin has largely been studied as a modifier of the Hippo signalling pathway, this work indicates that the WNK‐SPAK/OSR1 signalling cascade is also a target of this clinical agent. This finding could explain the fluctuation in blood pressure noted in patients and animals treated with this drug.     

The TRPC1 Channel Forms a PI3K/CaM Complex and Regulates Pancreatic Ductal Adenocarcinoma Cell Proliferation in a Ca2+-Independent Manner

Dysregulation of the transient receptor canonical ion channel (TRPC1) has been found in several cancer types, yet the underlying molecular mechanisms through which TRPC1 impacts pancreatic ductal adenocarcinoma (PDAC) cell proliferation are incompletely understood. Here, we found that TRPC1 is upregulated in human PDAC tissue compared to adjacent pancreatic tissue and this higher expression correlates with low overall survival. TRPC1 is, as well, upregulated in the aggressive PDAC cell line PANC-1, compared to a duct-like cell line, and its knockdown (KD) reduced cell proliferation along with PANC-1 3D spheroid growth by arresting cells in the G1/S phase whilst decreasing cyclin A, CDK2, CDK6, and increasing p21^CIP1 expression. In addition, the KD of TRPC1 neither affected Ca²⁺ influx nor store-operated Ca²⁺ entry (SOCE) and reduced cell proliferation independently of extracellular calcium. Interestingly, TRPC1 interacted with the PI3K-p85α subunit and calmodulin (CaM); both the CaM protein level and AKT phosphorylation were reduced upon TRPC1 KD. In conclusion, our results show that TRPC1 regulates PDAC cell proliferation and cell cycle progression by interacting with PI3K-p85α and CaM through a Ca²⁺-independent pathway.     

The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer’s Disease

Neuropathological lesions in Alzheimer’s disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aβ accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.     

Suppression of NtZIP4A/B Changes Zn and Cd Root-to-Shoot Translocation in a Zn/Cd Status-Dependent Manner

In tobacco, the efficiency of Zn translocation to shoots depends on Zn/Cd status. Previous studies pointed to the specific contribution of root parts in the regulation of this process, as well as the role of NtZIP4A/B (from the ZIP family; Zrt Irt-like Proteins). Here, to verify this hypothesis, NtZIP4A/B RNAi lines were generated. Then, in plants exposed to combinations of Zn and Cd concentrations in the medium, the consequences of NtZIP4A/B suppression for the translocation of both metals were determined. Furthermore, the apical, middle, and basal root parts were examined for accumulation of both metals, for Zn localization (using Zinpyr-1), and for modifications of the expression pattern of ZIP genes. Our results confirmed the role of NtZIP4A/B in the control of Zn/Cd-status-dependent transfer of both metals to shoots. Furthermore, they indicated that the middle and basal root parts contributed to the regulation of this process by acting as a reservoir for excess Zn and Cd. Expression studies identified several candidate ZIP genes that interact with NtZIP4A/B in the root in regulating Zn and Cd translocation to the shoot, primarily NtZIP1-like in the basal root part and NtZIP2 in the middle one.     

CDK4, CDK6/cyclin-D1 Complex Inhibition and Radiotherapy for Cancer Control: A Role for Autophagy

The expanding clinical application of CDK4- and CDK6-inhibiting drugs in the managements of breast cancer has raised a great interest in testing these drugs in other neoplasms. The potential of combining these drugs with other therapeutic approaches seems to be an interesting work-ground to explore. Even though a potential integration of CDK4 and CDK6 inhibitors with radiotherapy (RT) has been hypothesized, this kind of approach has not been sufficiently pursued, neither in preclinical nor in clinical studies. Similarly, the most recent discoveries focusing on autophagy, as a possible target pathway able to enhance the antitumor efficacy of CDK4 and CDK6 inhibitors is promising but needs more investigations. The aim of this review is to discuss the recent literature on the field in order to infer a rational combination strategy including cyclin-D1/CDK4-CDK6 inhibitors, RT, and/or other anticancer agents targeting G1-S phase cell cycle transition.     

A novel high entropy perovskite oxide with co-substitution in A and B sites (Ca1/3Sr1/3Ba1/3)(Y1/4Zr1/2Nb1/4)O3 design,synthesis and structural characterization

A novel high-entropy perovskite oxide (HEPO) (Ca_1/3Sr_1/3Ba_1/3)(Y_1/4Zr_1/2Nb_1/4)O₃ (CSBYZN) was designed and synthesized by solid-state reaction method by the use of CaCO₃, SrCO₃, BaCO₃, Y₂O₃, ZrO₂ and Nb₂O₅. Due to the substitution of the cations at both the A and B sites, the configuration entropy of CSBYZN was higher than that of other HEPOs with only one Wyckoff site (A or B site) substituted with 5 elements. The crystal structure of CSBYZN was identified as a cubic structure of the Pm-3m space group by Rietveld refinement. The measured lattice constant a = 4.1242 Å is similar to the value obtained by using the empirical formula (a_cal = 4.1229 Å). It was proved that the lattice constant of HEPOs can be predicted by the empirical formula. This study provides a new thought for the design of novel HEPOs.     

B位氧化物预合成法制备(1-x)Pb(Fe1/4Sc1/4Nb1/2)O3-xPbTiO3铁电陶瓷及其性能研究

利用传统的陶瓷工艺、通过B位氧化物预合成法制备了高质量、钙钛矿结构的(1-x)Pb(Fe1/4Sc1/4Nb1/2)O3-xPbTiO3(PFSN-PT)铁电陶瓷.结构测定和性能测试表明,1180℃烧结2h制备的PFSN-PT陶瓷呈现相当均匀的显微结构和良好的电学性能,同时具有较高的致密度(约95%),只有PbTiO3(PT)物质的量分数为40%、60%的陶瓷致密度略低(约91%).随着PT含量的增加,PFSN-PT从三方相结构转变为四方相结构,并伴随着晶胞体积的减小(从PFSN的6.6676×10-2 nm3下降到0.2PFSN-0.8PT的6.3555×10-2 nm3)和钙钛矿结构四方性的增大(从0.6PFSN-0.4PT的1.0242增加到0.2PFSN-0.8PT的1.0488).PFSN-PT陶瓷的介电常数最大值(εm)及其峰值温度(Tm)也随着PT含量的增加呈线性增大.介电性能测试和热滞行为研究表明,随着PT含量的增加,PFSN-PT的铁电-顺电相变从弛豫铁电体的弥散型铁电相变向正常铁电体的一级铁电相变转变.     

Temozolomide Induces the Acquisition of Invasive Phenotype by O6-Methylguanine-DNA Methyltransferase (MGMT)+ Glioblastoma Cells in a Snail-1/Cx43-Dependent Manner

Glioblastoma multiforme (GBM) recurrences after temozolomide (TMZ) treatment result from the expansion of drug-resistant and potentially invasive GBM cells. This process is facilitated by O6-Methylguanine-DNA Methyltransferase (MGMT), which counteracts alkylating TMZ activity. We traced the expansion of invasive cell lineages under persistent chemotherapeutic stress in MGMT^low (U87) and MGMT^high (T98G) GBM populations to look into the mechanisms of TMZ-induced microevolution of GBM invasiveness. TMZ treatment induced short-term, pro-invasive phenotypic shifts of U87 cells, in the absence of Snail-1 activation. They were illustrated by a transient induction of their motility and followed by the hypertrophy and the signs of senescence in scarce U87 sub-populations that survived long-term TMZ stress. In turn, MGMT^high T98G cells reacted to the long-term TMZ treatment with the permanent induction of invasiveness. Ectopic Snail-1 down-regulation attenuated this effect, whereas its up-regulation augmented T98G invasiveness. MGMT^low and MGMT^high cells both reacted to the long-term TMZ stress with the induction of Cx43 expression. However, only in MGMT^high T98G populations, Cx43 was directly involved in the induction of invasiveness, as manifested by the induction of T98G invasiveness after ectopic Cx43 up-regulation and by the opposite effect after Cx43 down-regulation. Collectively, Snail-1/Cx43-dependent signaling participates in the long-term TMZ-induced microevolution of the invasive GBM front. High MGMT activity remains a prerequisite for this process, even though MGMT-related GBM chemoresistance is not necessary for its initiation.     

配合物Ni(C_6H_6NO_3S)_2(H_2O)_4的合成、表征及热稳定性

用常温挥发法合成了一个新颖的单核配合物Ni(C6H6NO3S)2(H2O)4,并利用红外光谱、元素分析、热重分析及X-射线单晶衍射法对其结构进行了表征。结果表明,该配合物晶体属于单斜晶系,P121/n1空间群,晶胞参数为:a=1.191 2 nm,b=0.633 nm,c=1.224 nm,β=108.936°,Z=2,R1=0.027 1,wR2=0.100 7。在标题配合物中,每个Ni2+与4个H2O分子的氧原子及来自两个邻氨基苯磺酸的两个氮原子配位,形成一个畸变的八面体构型。在该配合物中,磺酸基的氧原子没有配位,这表明在该体系下,H2O的配位性能优于磺酸基氧原子。     

含取代吡唑基的1,2,4-三唑并[3,4-b]-1,3,4-噻二唑类化合物的合成与波谱表征

通过3-烷基／芳基-4-氨基-5-巯基-1,2,4-三唑与1-苯基-3-甲基-5-氯吡唑甲醛进行分子内的Mannich反应,合成了12个标题化合物,并经元素分析、红外光谱、核磁共振氢谱确证结构,讨论了,其波谱性质。     

The PagKNAT2/6b-PagBOP1/2a Regulatory Module Controls Leaf Morphogenesis in Populus

Leaf morphogenesis requires precise regulation of gene expression to achieve organ separation and flat-leaf form. The poplar KNOTTED-like homeobox gene PagKNAT2/6b could change plant architecture, especially leaf shape, in response to drought stress. However, its regulatory mechanism in leaf development remains unclear. In this work, gene expression analyses of PagKNAT2/6b suggested that PagKNAT2/6b was highly expressed during leaf development. Moreover, the leaf shape changes along the adaxial-abaxial, medial-lateral, and proximal-distal axes caused by the mis-expression of PagKNAT2/6b demonstrated that its overexpression (PagKNAT2/6b OE) and SRDX dominant repression (PagKNAT2/6b SRDX) poplars had an impact on the leaf axial development. The crinkle leaf of PagKNAT2/6b OE was consistent with the differential expression gene PagBOP1/2a (BLADE-ON-PETIOLE), which was the critical gene for regulating leaf development. Further study showed that PagBOP1/2a was directly activated by PagKNAT2/6b through a novel cis-acting element “CTCTT”. Together, the PagKNAT2/6b-PagBOP1/2a module regulates poplar leaf morphology by affecting axial development, which provides insights aimed at leaf shape modification for further improving the drought tolerance of woody plants.     

Discovery of ordered tetragonal and cubic phases in the morphotropic phase boundary region of (1-x)Bi(Mg3/4W1/4)O3-xPbTiO3 piezoceramics

Studies on (1-x)[Bi(Mg_3/4W_1/4)O₃]-xPbTiO₃ ceramics across morphotropic phase boundary have been done to investigate the crystal structure and structure-property correlations. Rietveld structure refinement reveals that the structure of the morphotropic phase boundary compositions consists of coexisting ordered tetragonal and cubic phases for 0.55 < x < 0.72, not reported earlier. The structure is B-site ordered cubic (space group Fm-3m) for the compositions with x ≤ 0.55, B-site ordered tetragonal (space group I4/m) for x ≥ 0.72. The structure gradually transforms into disordered tetragonal phase (space group P4mm) for higher concentrations (x) of PbTiO₃. Raman studies also confirm the B-site ordered structure for the compositions close to morphotropic phase boundary. For all the compositions investigated, two peaks are observed in the temperature dependence of the permittivity, originating due to dielectric relaxation and structural transition from tetragonal (I4/m) to cubic (Fm-3m) phase. A new phase diagram of the solid solution is established.     

Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

Alport syndrome (AS) is a hereditary renal disorder with no etiological therapy. In the preclinical Col4a3^-/- model of AS, disease progression and severity vary depending on mouse strain. The sodium-glucose cotransporter 2 (SGLT2) is emerging as an attractive therapeutic target in cardiac/renal pathologies, but its application to AS remains untested. This study investigates cardiorespiratory function and SGLT2 renal expression in Col4a3^-/- mice from three different genetic backgrounds, 129x1/SvJ, C57Bl/6 and Balb/C. male Col4a3^-/- 129x1/SvJ mice displayed alterations consistent with heart failure with preserved ejection fraction (HFpEF). Female, but not male, C57Bl/6 and Balb/C Col4a3^-/- mice exhibited mild changes in systolic and diastolic function of the heart by echocardiography. Male C57Bl/6 Col4a3^-/- mice presented systolic dysfunction by invasive hemodynamic analysis. All strains except Balb/C males demonstrated alterations in respiratory function. SGLT2 expression was significantly increased in AS compared to WT mice from all strains. However, cardiorespiratory abnormalities and SGLT2 over-expression were significantly less in AS Balb/C mice compared to the other two strains. Systolic blood pressure was significantly elevated only in mutant 129x1/SvJ mice. The results provide further evidence for strain-dependent cardiorespiratory and hypertensive phenotype variations in mouse AS models, corroborated by renal SGLT2 expression, and support ongoing initiatives to develop SGLT2 inhibitors for the treatment of AS.     

Peroxiredoxin 1 Controls Ovulation and Ovulated Cumulus–Oocyte Complex Activity through TLR4-Derived ERK1/2 Signaling in Mice

Peroxiredoxins (PRDXs) are expressed in the ovary and during ovulation. PRDX1 activity related to the immuno-like response during ovulation is unknown. We investigated the roles of Prdx1 on TLR4 and ERK1/2 signaling from the ovulated cumulus–oocyte complex (COC) using Prdx1-knockout (K/O) and wild-type (WT) mice. Ovulated COCs were collected 12 and 16 h after pregnant mare serum gonadotropin/hCG injection. PRDX1 protein expression and COC secretion factors (Il-6, Tnfaip6, and Ptgs2) increased 16 h after ovulated COCs of the WT mice were obtained. We treated the ovulated COCs in mice with LPS (0.5 μg/mL) or hyaluronidase (Hya) (10 units/mL) to induce TLR4 activity. Intracellular reactive oxygen species (ROS), cumulus cell apoptosis, PRDX1, TLR4/P38/ERK1/2 protein expression, and COC secretion factors’ mRNA levels increased in LPS- and Hya-treated COCs. The ERK inhibitor (U0126) and Prdx1 siRNA affected TLR4/ERK1/2 expression. The number and cumulus expansion of ovulated COCs by ROS were impaired in Prdx1 K/O mice but not in WT ones. Prdx1 gene deletion induced TLR4/P38/ERK1/2 expression and cumulus expansion genes. These results show the controlling roles of PRDX1 for TLR4/P38/ERK1/2 signaling activity in ovulated mice and the interlink of COCs with ovulation.     

The characteristics of a copper-exchanged natural zeolite for NO reduction by NH3 and C3H6

The catalytic performance of the natural zeolite mined from Youngil, Korea was investigated when two types of reductant such as NH₃ and hydrocarbons were employed for the reduction of NO. The determination of the structure of the natural zeolite has also been made to identify the type of zeolite and to examine its use as a catalytic material for NO removal reaction. The elementary analysis and electron probe microanalysis of the zeolite revealed that it typically consisted of an aluminosilicate. Although it mainly contains mordenite-type zeolite, heulandite was also included as well as the phases of quartz and feldspar as an impurity in the zeolite. This result could be also confirmed by the X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses. It should be noted that the acid treatment of the natural zeolite for its use as a catalytic material is essential for the high performance of NO reduction by selective catalytic reduction (SCR) technology. Copper ion-exchanged natural zeolite catalyst (CuNZA) exhibits a competitive NO reducing activity for the reduction of NO by NH₃ as well as hydrocarbons. It can be regarded as a promising catalytic system by NH₃ and hydrocarbons for the removal of NO_x from stationary and mobile sources.     

Correlations between the crystal structure and microwave dielectric properties in Ce2[Zr1-xMx]3(MoO4)9 (M = Mn1/3Nb2/3, Mn1/3Ta2/3) solid-solution ceramics

Ce₂[Zr_1-xM_x]₃(MoO₄)₉ (M = Mn_1/3Nb_2/3, Mn_1/3Ta_2/3; x = 0.02, 0.04, 0.06, 0.08 and 0.10) (abbreviated as CZ_1-xN_x and CZ_1-xT_x) ceramics were prepared through the solid-state reaction method. Effects of (Mn_1/3Nb_2/3)⁴⁺ and (Mn_1/3Ta_2/3)⁴⁺ ions on the sintering characteristics, crystal structures, microwave dielectric properties and infrared vibrational modes were studied in detail. X-ray diffraction (XRD) results reveal the formation of solid solutions for all components. Based on the chemical bond theory and Rietveld refinement, intrinsic structure parameters including the polarizability (P), the packing fraction (P.F.) and the octahedral distortion (Δ_octa.), and bond parameters including the lattice energy (U), bond energy (E) and thermal expansion coefficient (α) were calculated. Interestingly, the Ce–O bond plays a major role in the bond ionicity (f_i), while Mo–O bond dominates the contributions in the lattice energy (U), bond energy (E) and thermal expansion coefficient (α). In addition, these parameters are used to explain the variations of the microwave dielectric properties of ceramics either changing the doping contents or replacing different ions at x = 0.06. Furthermore, far infrared (FIR) spectra uncover that the phonon modes provide the major polarization contribution of 68.59% in the CZ_0.9T_0.1 ceramic, implying that the main contribution to ε_r stems from the ionic polarization instead of the electronic polarization. Typically, the optimum microwave dielectric properties are achieved for the CZ_0.9N_0.1 and CZ_0.9T_0.1 ceramics with ε_r = 10.76, Q × f = 85,893 GHz (at 9.52 GHz), τ_f = −14.83 ppm °C⁻¹ and ε_r = 10.72, Q × f = 87,355 GHz (at 9.81 GHz) and τ_f = −8.68 ppm °C⁻¹, respectively. Notably, the CZ_0.9T_0.1 ceramic has a markedly increased Q × f while maintaining a good τ_f = −8.68 ppm °C⁻¹ and a low sintering temperature of 700 °C.     

Competitive nanocrystallization of Na3ScF6 and NaYbF4 in aluminosilicate glass and optical spectroscopy of Ln3+ dopants

The precipitation of monoclinic Na₃ScF₆ nanocrystals from aluminosilicate glass with specially designed compositions of SiO₂-Al₂O₃-Na₂O-NaF-ScF₃-YbF₃ was achieved for the first time. Impressively, competitive nanocrystallization of cubic NaYbF₄ and monoclinic Na₃ScF₆ has been evidenced to be dependent on Na⁺ content and F/Na ratio in glass. Adopting Er³⁺ and Eu³⁺ dopants as structural probes, optical spectroscopic analyses verified that these emissive centers preferred to partition into NaYbF₄ nanocrystals rather than Na₃ScF₆ ones.