Inhibition of Wnt Signaling by Atovaquone Inhibits Gastric Cancer and Enhances Chemotherapy Effectiveness Through Activation of Casein Kinase 1α.

Abnormal activation of the Wnt/ß-catenin signaling pathway is a driving force behind the progression of gastric cancer. Atovaquone, known as an antimalarial drug, has emerged as a potential candidate for anti-cancer therapy. This study investigated atovaquone's effects on gastric cancer and its underlying mechanisms. Using gastric cancer cell lines, we found that atovaquone, at concentrations relevant to clinical use, significantly reduced their viability. Notably, atovaquone exhibited a lower effectiveness in reducing the viability of normal gastric cells compared to gastric cancer cells. We further demonstrated that atovaquone inhibited gastric cancer growth and colony formation. Mechanism studies revealed that atovaquone inhibited mitochondrial respiration and induced oxidative stress. Experiments using ρ0 cells, deficient in mitochondrial respiration, indicated a slightly weaker effect of atovaquone on inducing apoptosis compared to wildtype cells. Atovaquone increased phosphorylated ß-catenin at Ser45 and Ser33/37/Thr41, elevated Axin, and reduced ß-catenin. The inhibitory effects of atovaquone on ß-catenin were reversed upon depletion of CK1α. Furthermore, the combination of atovaquone with paclitaxel suppressed gastric cancer growth and improved overall survival in mice. Given that atovaquone is already approved for clinical use, these findings suggest its potential as a valuable addition to the drug arsenal available for treating gastric cancer.

FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling.

Reducing casein kinase 1α (CK1α) expression inhibits the growth of multiple cancer cell lines, making it a potential therapeutic target for cancer. Herein, we evaluated the antitumor activity of FPFT-2216-a novel low molecular weight compound-in lymphoid tumors and elucidated its molecular mechanism of action. In addition, we determined whether targeting CK1α with FPFT-2216 is useful for treating hematopoietic malignancies. FPFT-2216 strongly degraded CK1α and IKAROS family zinc finger 1/3 (IKZF1/3) via proteasomal degradation. FPFT-2216 exhibited stronger inhibitory effects on human lymphoma cell proliferation than known thalidomide derivatives and induced upregulation of p53 and its transcriptional targets, namely, p21 and MDM2. Combining FPFT-2216 with an MDM2 inhibitor exhibited synergistic antiproliferative activity and induced rapid tumor regression in immunodeficient mice subcutaneously transplanted with a human lymphoma cell line. Nearly all tumors in mice disappeared after 10 days; this was continuously observed in 5 of 7 mice up to 24 days after the final FPFT-2216 administration. FPFT-2216 also enhanced the antitumor activity of rituximab and showed antitumor activity in a patient-derived diffuse large B-cell lymphoma xenograft model. Furthermore, FPFT-2216 decreased the activity of the CARD11/BCL10/MALT1 (CBM) complex and inhibited IκBα and NFκB phosphorylation. These effects were mediated through CK1α degradation and were stronger than those of known IKZF1/3 degraders. In conclusion, FPFT-2216 inhibits tumor growth by activating the p53 signaling pathway and inhibiting the CBM complex/NFκB pathway via CK1α degradation. Therefore, FPFT-2216 may represent an effective therapeutic agent for hematopoietic malignancies, such as lymphoma. SIGNIFICANCE: We found potential vulnerability to CK1α degradation in certain lymphoma cells refractory to IKZF1/3 degraders. Targeting CK1α with FPFT-2216 could inhibit the growth of these cells by activating p53 signaling. Our study demonstrates the potential therapeutic application of CK1α degraders, such as FPFT-2216, for treating lymphoma.

Yck3 casein kinase-mediated phosphorylation determines Ivy1 localization and function at endosomes and the vacuole.

The Saccharomyces cerevisiae casein kinase protein Yck3 is a central regulator at the vacuole that phosphorylates several proteins involved in membrane trafficking. Here, we set out to identify novel substrates of this protein. We found that endogenously tagged Yck3 localized not only at the vacuole, but also on endosomes. To disable Yck3 function, we generated a kinase-deficient mutant and thus identified the I-BAR-protein Ivy1 as a novel Yck3 substrate. Ivy1 localized to both endosomes and vacuoles, and Yck3 controlled this localization. A phosphomimetic Ivy1-SD mutant was found primarily on vacuoles, whereas its non-phosphorylatable SA variant strongly localized to endosomes, similar to what was observed upon deletion of Yck3. In vitro analysis revealed that Yck3-mediated phosphorylation strongly promoted Ivy1 recruitment to liposomes carrying the Rab7-like protein Ypt7. Modeling of Ivy1 with Ypt7 identified binding sites for Ypt7 and a positively charged patch, which were both required for Ivy1 localization. Strikingly, Ivy1 mutations in either site resulted in more cells with multilobed vacuoles, suggesting a partial defect in its membrane biogenesis. Our data thus indicate that Yck3-mediated phosphorylation controls both localization and function of Ivy1 in endolysosomal biogenesis.

Structure-Based Development of Isoform-Selective Inhibitors of Casein Kinase 1ε vs Casein Kinase 1δ.

Specific inhibition of a single kinase isoform is a challenging task due to the highly conserved nature of ATP-binding sites. Casein kinase 1 (CK1) δ and ε share 97% sequence identity in their catalytic domains. From a comparison of the X-ray crystal structures of CK1δ and CK1ε, we developed a potent and highly CK1ε-isoform-selective inhibitor (SR-4133). The X-ray co-crystal structure of the CK1δ-SR-4133 complex reveals that the electrostatic surface between the naphthyl unit of SR-4133 and CK1δ is mismatched, destabilizing the interaction of SR-4133 with CK1δ. Conversely, the hydrophobic surface area resulting from the Asp-Phe-Gly motif (DFG)-out conformation of CK1ε stabilizes the binding of SR-4133 in the ATP-binding pocket of CK1ε, leading to the selective inhibition of CK1ε. The potent CK1ε-selective agents display nanomolar growth inhibition of bladder cancer cells and inhibit the phosphorylation of 4E-BP1 in T24 cells, which is a direct downstream effector of CK1ε.

Casein Kinase 1α as a Novel Factor Affects Thyrotropin Synthesis via PKC/ERK/CREB Signaling.

Casein kinase 1α (CK1α) is present in multiple cellular organelles and plays various roles in regulating neuroendocrine metabolism. Herein, we investigated the underlying function and mechanisms of CK1α-regulated thyrotropin (thyroid-stimulating hormone (TSH)) synthesis in a murine model. Immunohistochemistry and immunofluorescence staining were performed to detect CK1α expression in murine pituitary tissue and its localization to specific cell types. Tshb mRNA expression in anterior pituitary was detected using real-time and radioimmunoassay techniques after CK1α activity was promoted and inhibited in vivo and in vitro. Relationships among TRH/L-T4, CK1α, and TSH were analyzed with TRH and L-T4 treatment, as well as thyroidectomy, in vivo. In mice, CK1α was expressed at higher levels in the pituitary gland tissue than in the thyroid, adrenal gland, or liver. However, inhibiting endogenous CK1α activity in the anterior pituitary and primary pituitary cells significantly increased TSH expression and attenuated the inhibitory effect of L-T4 on TSH. In contrast, CK1α activation weakened TSH stimulation by thyrotropin-releasing hormone (TRH) by suppressing protein kinase C (PKC)/extracellular signal-regulated kinase (ERK)/cAMP response element binding (CREB) signaling. CK1α, as a negative regulator, mediates TRH and L-T4 upstream signaling by targeting PKC, thus affecting TSH expression and downregulating ERK1/2 phosphorylation and CREB transcriptional activity.

Glutaredoxin 1 protects lens epithelial cells from epithelial-mesenchymal transition by preventing casein kinase 1α S-glutathionylation during posterior capsular opacification.

Oxidative stress drives protein S-glutathionylation, which regulates the structure and function of target proteins and is implicated in the pathogenesis of many diseases. Glutaredoxin 1 (Grx1), a cytoplasmic deglutathionylating enzyme, maintains a reducing environment within the cell under various conditions by reversing S-glutathionylation. Grx1 performs a wide range of antioxidant activities in the lens and prevents protein-thiol mixed disulfide accumulation, reducing protein-protein aggregation, insolubilization, and apoptosis of lens epithelial cells. Oxidative stress is related to epithelial-mesenchymal transition (EMT) during posterior capsular opacification (PCO). However, whether Grx1-regulated protein S-glutathionylation plays an essential role in PCO remains unclear. In this study, we revealed that Grx1 expression was decreased in mice following cataract surgery. Furthermore, the absence of Grx1 elevated oxidative stress and protein S-glutathionylation and aggravated EMT in both in vitro and in vivo models. Concurrently, these results could be reversed by Grx1 overexpression. Notably, liquid chromatography-tandem mass spectrometry results showed that casein kinase 1α (CK1α) was susceptible to S-glutathionylation under oxidative stress, and CK1α S-glutathionylation (CK1α-SSG) was mediated at Cys249. The absence of Grx1 upregulated CK1α-SSG, subsequently decreasing the CK1α-induced phosphorylation of ß-catenin at Ser45. The consequential downregulation of degradative ß-catenin and upregulation of its nuclear translocation activated the Wnt/ß-catenin signaling pathway and aggravated EMT. In conclusion, the downregulated expression of Grx1 in mice following cataract surgery aggravated EMT by upregulating the extent of CK1α-SSG. To the best of our knowledge, our study is the first to report how S-glutathionylation regulates CK1α activity under oxidative stress.

Targeting the Maladaptive Effects of Binge Drinking on Circadian Gene Expression.

Previous studies (1) support a role of circadian genes in regulating alcohol intake, and (2) reveal that harmful alcohol use alters circadian rhythms. However, there is minimal knowledge of the effects of chronic alcohol processes on rhythmic circadian gene expression across brain regions important for circadian biology and alcohol intake. Therefore, the present study sought to test the effects of chronic binge-like drinking on diurnal circadian gene expression patterns in the master circadian pacemaker (SCN), the ventral tegmental area (VTA), and the nucleus accumbens (NAc) in High Drinking in the Dark-1 (HDID-1) mice, a unique genetic risk model for drinking to intoxication. Consistent with earlier findings, we found that 8 weeks of binge-like drinking reduced the amplitude of several core circadian clock genes in the NAc and SCN, but not the VTA. To better inform the use of circadian-relevant pharmacotherapies in reducing harmful drinking and ameliorating alcohol's effects on circadian gene expression, we tested whether the casein kinase-1 inhibitor, PF-67046, or the phosphodiesterase type-4 (an upstream regulator of circadian signalling) inhibitor, apremilast, would reduce binge-like intake and mitigate circadian gene suppression. PF-67046 did not reduce intake but did have circadian gene effects. In contrast, apremilast reduced drinking, but had no effect on circadian expression patterns.

An order-to-disorder structural switch regulates HIF-1 transcription through S247 phosphorylation in the HIF1α PAS-B domain.

Hypoxia-inducible factor 1 (HIF-1), a transcriptional activator that mediates cellular responses to hypoxic stress, is essential for tumor progression. It is a heterodimer comprising HIF1α and HIF1ß, with multiple interfaces among their PAS-A, PAS-B, and bHLH domains. HIF1ß is also known as aryl hydrocarbon receptor nuclear translocator (ARNT). Casein kinase 1δ-dependent phosphorylation of the solvent-front residue S247 on the HIF1α PAS-B domain interrupts HIF1α-ARNT complex formation and reduces HIF-1 transcription activity. However, S247 is involved in neither HIF1α-ARNT complex formation nor stabilization of the relative orientation between the HIF1α PAS-A and PAS-B domains. To uncover the underlying allosteric mechanism, we conducted Gaussian accelerated molecular dynamics simulations and identified two distinct conformations of the pS247-carrying HIF1α PAS-B domain: H291-in and H291-out. The H291-in structure can associate with the HIF1α PAS-A domain and form a V-shaped pouch to accommodate the ARNT PAS-A domain, but it cannot associate with the ARNT PAS-B domain. By contrast, the H291-out structure can bind to the ARNT PAS-B domain, but its association with the HIF1α PAS-A domain leads to an unsuitable relative orientation to accommodate the ARNT PAS-A domain. Both conformations were also collected in parallel simulations of the unphosphorylated PAS-B domain. Both structures manage to associate with the ARNT PAS-B and HIF1α PAS-A domains; thus, they are adequate for HIF1α-ARNT complex formation. The domain-domain contact pattern in a phosphorylated variant is shuffled by an order-to-disorder structural switch, triggered by the newly formed K251-pS247 interaction.

The conserved C-terminal residues of FAM83H are required for the recruitment of casein kinase 1 to the keratin cytoskeleton.

The casein kinase 1 (CK1) family of serine/threonine protein kinases is involved in diverse cellular events at discrete subcellular compartments. FAM83H acts as a scaffold protein that recruits CK1 to the keratin cytoskeleton or to the nuclear speckles, which are storage sites for splicing factors. We determined the amino acid region of FAM83H required for recruiting CK1 to the keratin cytoskeleton. The subcellular localization of mutant FAM83H proteins with deletions of amino acid residues at different positions was evaluated via immunofluorescence. FAM83H mutants with deleted C-terminal residues 1134-1139, which are conserved among vertebrates, lost the ability to localize and recruit CK1 to the keratin cytoskeleton, suggesting that these residues are required for recruiting CK1 to the keratin cytoskeleton. The deletion of these residues (1134-1139) translocated FAM83H and CK1 to the nuclear speckles. Amino acid residues 1 to 603 of FAM83H were determined to contain the region responsible for the recruitment of CK1 to the nuclear speckles. Our results indicated that FAM83H recruits CK1 preferentially to the keratin cytoskeleton and alternatively to the nuclear speckles.

Casein kinase CK2 structure and activities in plants.

Casein kinase CK2 is a highly conserved serine/threonine protein kinase and exists in all eukaryotes. It has been demonstrated to be widely involved in the biological processes of plants. The CK2 holoenzyme is a heterotetramer consisting of two catalytic subunits (α and/or α') and two regulatory subunits (ß). CK2 in plants is generally encoded by multiple genes, with monomeric and oligomeric forms present in the tissue. Various subunit genes of CK2 have been cloned and characterized from Arabidopsis thaliana, tobacco, maize, wheat, tomato, and other plants. This paper reviews the structural features of CK2, provides a clear classification of its physiological functions and mechanisms of action, and elaborates on the regulation of CK2 activity to provide a knowledge base for subsequent studies of CK2 in plants.

Neurospora casein kinase 1a recruits the circadian clock protein FRQ via the C-terminal lobe of its kinase domain.

Timing by the circadian clock of Neurospora is associated with hyperphosphorylation of frequency (FRQ), which depends on anchoring casein kinase 1a (CK1a) to FRQ. It is not known how CK1a is anchored so that approximately 100 sites in FRQ can be targeted. Here, we identified two regions in CK1a, p1 and p2, that are required for anchoring to FRQ. Mutation of p1 or p2 impairs progressive hyperphosphorylation of FRQ. A p1-mutated strain is viable but its circadian clock is non-functional, whereas a p2-mutated strain is non-viable. Our data suggest that p1 and potentially also p2 in CK1a provide an interface for interaction with FRQ. Anchoring via p1-p2 leaves the active site of CK1a accessible for phosphorylation of FRQ at multiple sites.

Hsa_circ_0001550 facilitates colorectal cancer progression through mediating microRNA-4262/nuclear casein kinase and cyclin-dependent kinase substrate 1 cascade.

BACKGROUND: Circular RNAs (circRNAs) play important roles in various malignancies, such as colorectal cancer (CRC). However, the function of hsa_circ_0001550 in CRC remains to be elucidated. METHODS: The expression levels of hsa_circ_0001550, microRNA (miR)-4262, and nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) were determined by real-time qPCR. Cell biological behaviors were evaluated via colony formation assay, transwell assay, flow cytometry, and sphere formation assays. The target relationship was validated via dual-luciferase reporter and RNA pull-down assays. Protein expression was analyzed by western blot. Xenograft tumor model was adopted to evaluate hsa_circ_0001550 function in vivo. RESULTS: Hsa_circ_0001550 enrichment was enhanced in CRC tissue specimens and cell lines. Hsa_circ_0001550 absence hindered CRC cell proliferation, metastasis, stemness, and caused apoptosis. Hsa_circ_0001550 targeted miR-4262, and hsa_circ_0001550 absence-caused impacts were diminished by anti-miR-4262. MiR-4262 targeted NUCKS1. Hsa_circ_0001550 had positive regulation on NUCKS1 expression. NUCKS1 overexpression overturned the influences of hsa_circ_0001550 silencingon CRC cell progression. Hsa_circ_0001550 interference notably blocked in vivo xenograft tumor growth. CONCLUSION: Hsa_circ_0001550 facilitated CRC progression by binding to miR-4262 to positively regulate NUCKS1 abundance.

Differential immunohistochemical expression of DEC1, CK­1ε, and CD44 in oral atypical squamous epithelium and carcinoma in situ.

Presence of nuclear atypia during histological investigation is often a cause of concern for pathologists while identifying tumor and non­tumor cells in a biopsy sample of oral mucosa. Nuclear atypia is observed in severe inflammation, ulcers and reactive changes. Therefore, additional methods, such as immunohistochemistry, may help precise diagnosis. When the atypia is suggestive of tumorous or reactive origin, the lesion is diagnosed as atypical squamous epithelium (ASE). When there is severe nuclear atypia in the mucosa, such as in disorders of nuclear polarity, large nuclei, and clear nucleolus, the lesion is diagnosed as carcinoma in situ (CIS). However, it is not easy to distinguish ASE and CIS using hematoxylin and eosin staining. The present study aimed to distinguish ASE from CIS using immunohistochemistry. A total of 32 biopsy samples of either ASE or CIS cases were selected and the level of casein kinase 1ε (CK­1ε), differentiated embryonic chondrocyte gene 1 (DEC1), proliferating cell nuclear antigen (PCNA) and CD44, which are four protein markers which have been previously linked to cancer progression, were analyzed. CK­1ε and CD44 expression was higher in CIS samples than in ASE samples. However, DEC1 expression was lower in CIS samples than in ASE samples. PCNA expression was not markedly different between the two groups. Additionally, it was found that DEC1­overexpressing cells had decreased levels of CK­1ε and CD44 compared with control cells, while CK­1ε­overexpressing cells had relatively unchanged levels of CD44, DEC1 and PCNA. These results suggested that DEC1 negatively regulates the expression of CK­1ε and CD44. Thus, DEC1, CK­1ε, and CD44 were identified as mechanistically linked and clinically relevant protein biomarkers, which could help distinguish ASE and CIS.

Differentiation of mouse fetal lung alveolar progenitors in serum-free organotypic cultures.

Lung epithelial progenitors differentiate into alveolar type 1 (AT1) and type 2 (AT2) cells. These cells form the air-blood interface and secrete surfactant, respectively, and are essential for lung maturation and function. Current protocols to derive and culture alveolar cells do not faithfully recapitulate the architecture of the distal lung, which influences cell fate patterns in vivo. Here, we report serum-free conditions that allow for growth and differentiation of mouse distal lung epithelial progenitors. We find that Collagen I promotes the differentiation of flattened, polarized AT1 cells. Using these organoids, we performed a chemical screen to investigate WNT signaling in epithelial differentiation. We identify an association between Casein Kinase activity and maintenance of an AT2 expression signature; Casein Kinase inhibition leads to an increase in AT1/progenitor cell ratio. These organoids provide a simplified model of alveolar differentiation and constitute a scalable screening platform to identify and analyze cell differentiation mechanisms.

The rice blast fungus MoRgs1 functioning in cAMP signaling and pathogenicity is regulated by casein kinase MoCk2 phosphorylation and modulated by membrane protein MoEmc2.

GTP-binding protein (G-protein) and regulator of G-protein signaling (RGS) mediated signal transduction are critical in the growth and virulence of the rice blast pathogen Magnaporthe oryzae. We have previously reported that there are eight RGS and RGS-like proteins named MoRgs1 to MoRgs8 playing distinct and shared regulatory functions in M. oryzae and that MoRgs1 has a more prominent role compared to others in the fungus. To further explore the unique regulatory mechanism of MoRgs1, we screened a M. oryzae cDNA library for genes encoding MoRgs1-interacting proteins and identified MoCkb2, one of the two regulatory subunits of the casein kinase (CK) 2 MoCk2. We found that MoCkb2 and the sole catalytic subunit MoCka1 are required for the phosphorylation of MoRgs1 at the plasma membrane (PM) and late endosome (LE). We further found that an endoplasmic reticulum (ER) membrane protein complex (EMC) subunit, MoEmc2, modulates the phosphorylation of MoRgs1 by MoCk2. Interestingly, this phosphorylation is also essential for the GTPase-activating protein (GAP) function of MoRgs1. The balance among MoRgs1, MoCk2, and MoEmc2 ensures normal operation of the G-protein MoMagA-cAMP signaling required for appressorium formation and pathogenicity of the fungus. This has been the first report that an EMC subunit is directly linked to G-protein signaling through modulation of an RGS-casein kinase interaction.

Mut9p-LIKE KINASE Family Members: New Roles of the Plant-Specific Casein Kinase I in Plant Growth and Development.

: Casein kinase I (CK1), a ubiquitous serine/threonine (Ser/Thr) protein kinase in eukaryotes, plays pivotal roles in a wide spectrum of cellular functions including metabolism, cell cycle progression, developmental control and stress responses. Plant CK1 evolves a lineage expansion, resulting in a unique branch of members exclusive to the kingdom. Among them, Arabidopsis Mut9p-LIKE KINASEs (MLKs) target diverse substrates including histones and the key regulatory proteins involving in physiological processes of light signaling, circadian rhythms, phytohormone and plant defense. Deregulation of the kinase activity by mutating the enzyme or the phosphorylation sites of substrates causes developmental disorders and susceptibility to adverse environmental conditions. MLKs have evolved as a general kinase that modifies transcription factors or primary regulatory proteins in a dynamic way. Here, we summarize the current knowledge of the roles of MLKs and MLK orthologs in several commercially important crops.

Wnt3a Stimulation Promotes Primary Ciliogenesis through ß-Catenin Phosphorylation-Induced Reorganization of Centriolar Satellites.

Primary cilium is an antenna-like microtubule-based cellular sensing structure. Abnormal regulation of the dynamic assembly and disassembly cycle of primary cilia is closely related to ciliopathy and cancer. The Wnt signaling pathway plays a major role in embryonic development and tissue homeostasis, and defects in Wnt signaling are associated with a variety of human diseases, including cancer. In this study, we provide direct evidence of Wnt3a-induced primary ciliogenesis, which includes a continuous pathway showing that the stimulation of Wnt3a, a canonical Wnt ligand, promotes the generation of ß-catenin p-S47 epitope by CK1δ, and these events lead to the reorganization of centriolar satellites resulting in primary ciliogenesis. We have also confirmed the application of our findings in MCF-7/ADR cells, a multidrug-resistant tumor cell model. Thus, our data provide a Wnt3a-induced primary ciliogenesis pathway and may provide a clue on how to overcome multidrug resistance in cancer treatment.

Protective effects of two novel nitronyl nitroxide radicals on heart failure induced by hypobaric hypoxia.

AIMS: Hypobaric hypoxia (HH), linked to oxidative stress, impairs cardiac function. We synthesized a novel nitronyl nitroxide radical, an HPN derivative (HEPN) and investigated the protective effects of HEPN and HPN against HH-induced heart injury in mice and the underlying mechanisms of action. MAIN METHODS: Mice were administered with HPN (200 mg/kg) or HEPN (200 mg/kg) 30 min before exposed to HH. The cardiac function was measured. Serum AST, CK, LDH and cTnI were estimated. Heart tissue oxidase activity, SOD, CAT, GSH-Px, ROS and MDA were estimated. ATP content, Na+/K+-ATPase and Ca2+/Mg2+-ATPase activity was measured. The expression of HIF-1, VEGF, Nrf2, HO-1, Bax, Bcl-2, Caspase-3 was estimated. KEY FINDINGS: Results showed that pretreatment with HEPN or HPN led to a dramatic decrease in the activity of biochemical markers AST, CK, LDH and cTnI in murine serum. They increased the activity of SOD, CAT and GSH-Px and reduced the level of ROS and MDA in the hearts of mice. HEPN and HPN could increase the expression of Nrf2 and OH-1. They could maintain the ATPase activity. The Bax and Caspase-3 expression as well as the ratio of Bax/Bcl-2 were significantly downregulated and the Bcl-2 expression was upregulated by HPN or HEPN compared to the HH group. They may attenuate the HH-induced oxidant stress via free radical scavenging activity. SIGNIFICANCE: The present study showed that the nitronyl nitroxide radical HEPN and HPN may be potential therapeutic agents for treatment of HH-induced cardiac dysfunction.

New responsibilities for aged kinases in B-lymphomas.

The knowledge accumulated over the last decade on B-cell-derived non-Hodgkin lymphoma (B-NHL) pathogenesis has led to the identification of several molecular abnormalities, opening new perspectives in the design of novel therapies. Indeed, drugs targeting specific biochemical pathways critical for B-NHL cell survival, proliferation, and fitness within the malignant microenvironment are now available to the clinician: the B-cell receptor signaling inhibitors of BTK, PI3Kδ, ζ, γ, and SYK or the pro-apoptotic BH3-mimetics are clear examples of it. Moreover, it is emerging that malignant B-cell growth is sustained not only by mutations in oncogenes/tumor suppressors but also by the "addiction" to nononcogene (ie, nonstructurally altered) molecules. In this regard, a consistent body of data has established that the Ser/Thr kinases CK1, CK2, and GSK3 are involved in malignant lymphocyte biology and act as pro-survival and signaling-boosting molecules, both in precursor and mature B-cell tumors. Currently, an experimental and clinical groundwork is available, upon which to design CK1-, CK2-, and GSK3-directed antilymphoma/leukemia therapies. In this review, we have examined the main features of CK1, CK2, and GSK3 kinases, summarized the data in B-NHL supporting them as suitable therapeutic targets, and proposed a perspective on potential future research development.

Efficacy of Shenqi Pollen Capsules for High-Altitude Deacclimatization Syndrome via Suppression of the Reoxygenation Injury and Inflammatory Response.

High-altitude deacclimatization syndrome (HADAS) is involved in hypoxia-reoxygenation injury and inflammatory response, induced a series of symptoms, and has emerged as a severe public health issue. Here, we investigated the mechanism as well as potential means to prevent HADAS using Shenqi pollen capsules (SPCs) in subjects with HADAS in a multicenter, double-blinded, randomized, placebo-controlled study. All subjects were at the same high altitude (3650 m) for 4-8 months before returning to lower altitudes. Subjects (n = 288) in 20 clusters were diagnosed with mild or moderate HADAS on the third day of the study. We randomly allocated 20 clusters of subjects (1 : 1) to receive SPCs or a placebo for 7 weeks, and they were then followed up to the 14th week. The primary endpoints were subjects' HADAS scores recorded during the 14 weeks of follow-up. Compared with the placebo, SPC treatment significantly decreased the subjects' HADAS scores and reduced the incidence of symptom persistence. SPC therapy also reduced the serum levels of CK, CK-MB, LDH, IL-17A, TNF-α, and miR-155 and elevated IL-10 and miR-21 levels. We thus demonstrate that SPCs effectively ameliorated HADAS symptoms in these subjects via suppression of the hypoxia-reoxygenation injury and inflammatory response.