A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

Loss of FUT8 in renal tubules ameliorates ischemia-reperfusion injury-induced renal interstitial inflammation transition to fibrosis via the TLR3-NF-κB pathway.

Renal ischemia-reperfusion injury (IRI) is a common reason of acute kidney injury (AKI). AKI can progress to chronic kidney disease (CKD) in some survivors. Inflammation is considered the first-line response to early-stage IRI. We previously reported that core fucosylation (CF), specifically catalyzed by α-1,6 fucosyltransferase (FUT8), exacerbates renal fibrosis. However, the FUT8 characteristics, role, and mechanism in inflammation and fibrosis transition remain unclear. Considering renal tubular cells are the trigger cells that initiate the fibrosis in the AKI-to-CKD transition in IRI, we targeted CF by generating a renal tubular epithelial cell (TEC)-specific FUT8 knockout mouse and measured FUT8-driven and downstream signaling pathway expression and AKI-to-CKD transition. During the IRI extension phase, specific FUT8 deletion in the TECs ameliorated the IRI-induced renal interstitial inflammation and fibrosis mainly via the TLR3 CF-NF-κB signaling pathway. The results firstly indicated the role of FUT8 in the transition of inflammation and fibrosis. Therefore, the loss of FUT8 in TECs may be a novel potential strategy for treating AKI-CKD transition.

3, 14, 19-Triacetyl Andrographolide alleviates the cognitive dysfunction of 3 × Tg-AD mice by inducing initiation and promoting degradation process of autophagy.

The present study aims to investigate the cognition-enhancing effect of 3, 14, 19-Triacetyl andrographolide (ADA) on learning and memory deficits in 3 × Tg-AD mice and to explore its underlying mechanism. Eight-month-old 3 × Tg-AD mice and C57BL/6J mice were randomly divided into three groups, namely wild-type group, 3 × Tg-AD group, and 3 × Tg-AD+ADA group (5 mg/kg, for 21 days, i.p.). We found that ADA significantly improved learning and cognition impairment, inhibited the loss of Nissl body, and reduced Aß load in the brains of 3 × Tg-AD mice. In addition, ADA enhanced the levels of PSD95 and SYP, which were closely associated with synaptic plasticity. Accumulated autophagosomes, LC3II, and P62 in hippocampus and cortex of 3 × Tg-AD mice were decreased by ADA treatment. Furthermore, ADA administration further down-regulated the expressions of p-AKT and p-mTOR, reduced the level of CTSB, and increased the co-localization of LC3 and LAMP1 in the brains of 3 × Tg-AD mice, implying that ADA-induced autophagy initiation and also promoted the degradation process. In Aß25-35 -induced HT22 cells, ADA displayed similar effects on autophagy flux as observed in 3 × Tg-AD mice. Our finding verified that ADA could improve synaptic plasticity and cognitive function, which is mainly attributed to the key roles of ADA in autophagy induction and degradation.

Transcriptome Dynamics of Brassica juncea Leaves in Response to Omnivorous Beet Armyworm (Spodoptera exigua, Hübner).

Cruciferous plants manufacture glucosinolates (GSLs) as special and important defense compounds against insects. However, how insect feeding induces glucosinolates in Brassica to mediate insect resistance, and how plants regulate the strength of anti-insect defense response during insect feeding, remains unclear. Here, mustard (Brassica juncea), a widely cultivated Brassica plant, and beet armyworm (Spodoptera exigua), an economically important polyphagous pest of many crops, were used to analyze the changes in GSLs and transcriptome of Brassica during insect feeding, thereby revealing the plant-insect interaction in Brassica plants. The results showed that the content of GSLs began to significantly increase after 48 h of herbivory by S. exigua, with sinigrin as the main component. Transcriptome analysis showed that a total of 8940 DEGs were identified in mustard challenged with beet armyworm larvae. The functional enrichment results revealed that the pathways related to the biosynthesis of glucosinolate and jasmonic acid were significantly enriched by upregulated DEGs, suggesting that mustard might provide a defense against herbivory by inducing JA biosynthesis and then promoting GSL accumulation. Surprisingly, genes regulating JA catabolism and inactivation were also activated, and both JA signaling repressors (JAZs and JAMs) and activators (MYCs and NACs) were upregulated during herbivory. Taken together, our results indicate that the accumulation of GSLs regulated by JA signaling, and the regulation of active and inactive JA compound conversion, as well as the activation of JA signaling repressors and activators, collectively control the anti-insect defense response and avoid over-stunted growth in mustard during insect feeding.

Luteolin alleviates cognitive impairment in Alzheimer's disease mouse model via inhibiting endoplasmic reticulum stress-dependent neuroinflammation.

Luteolin is a flavonoid in a variety of fruits, vegetables, and herbs, which has shown anti-inflammatory, antioxidant, and anti-cancer neuroprotective activities. In this study, we investigated the potential beneficial effects of luteolin on memory deficits and neuroinflammation in a triple-transgenic mouse model of Alzheimer's disease (AD) (3 × Tg-AD). The mice were treated with luteolin (20, 40 mg · kg-1 · d-1, ip) for 3 weeks. We showed that luteolin treatment dose-dependently improved spatial learning, ameliorated memory deficits in 3 × Tg-AD mice, accompanied by inhibiting astrocyte overactivation (GFAP) and neuroinflammation (TNF-α, IL-1ß, IL-6, NO, COX-2, and iNOS protein), and decreasing the expression of endoplasmic reticulum (ER) stress markers GRP78 and IRE1α in brain tissues. In rat C6 glioma cells, treatment with luteolin (1, 10 µM) dose-dependently inhibited LPS-induced cell proliferation, excessive release of inflammatory cytokines, and increase of ER stress marker GRP78. In conclusion, luteolin is an effective agent in the treatment of learning and memory deficits in 3 × Tg-AD mice, which may be attributable to the inhibition of ER stress in astrocytes and subsequent neuroinflammation. These results provide the experimental basis for further research and development of luteolin as a therapeutic agent for AD.

Theoretical Investigation of the Excited-State Dynamics Mechanism of the Asymmetric Two-Way Proton Transfer Molecule BTHMB.

An asymmetric two-way proton transfer molecule 3-(benzo[d]-thiazol-2-yl)-2-hydroxy-5-methoxybenzaldehyde (BTHMB) with the function of white-light emission was synthesized in a recent experiment (Bhattacharyya, A.; Mandal, S. K.; Guchhait, N. J. Phys. Chem. A 2019, 123, 10246). The particularity of this molecule is that there are two possible forms, one of which contained a six-membered H-bonded network toward a N atom (BTHMB-NH) present in the molecule as a proton acceptor and the other was toward an O atom (BTHMB-OH). Unfortunately, the experimental work lacked the theoretical explanation about the determination of the BTHMB-NH form and its excited-state intramolecular proton transfer (ESIPT) process under different solvents. Therefore, this study has explored these two points by means of the time-dependent density functional theory (TDDFT) method. The calculated relative energy and potential energy profile (PEP) of the transformation between BTHMB-NH and BTHMB-OH forms illustrated that BTHMB-NH was more stable, and the transfer from BTHMB-NH to BTHMB-OH was almost impossible at both S0 and S1 states under all solvents due to high potential energy barriers (PEBs) (11.67-21.59 kcal/mol). These calculated results provided the theoretical explanation and verification for the conclusion that the BTHMB molecule exists in the BTHMB-NH form in the experiment. Subsequently, the constructed PEPs of the ESIPT process for BTHMB-NH have proved that it was prone to the ESIPT process due to low PEBs (0.11-0.28 kcal/mol) at the S1 state. In particular, as the solvent polarity increased, the intensity of the intramolecular hydrogen bond (IHB) (O3-H4···N5) increased and the ESIPT process was more likely to occur. In addition, the twisted intramolecular charge-transfer (TICT) process was studied to explore the possible fluorescence quenching pathway of BTHMB-NH. Based on the PEPs of BTHMB-NH-T as a function of the N5-C6-C7-C8 dihedral angle at the S0 and S1 states, it is seen that the S0 state TICT process was inhibited due to the large PEBs (16.45-23.93 kcal/mol). Although the S1 state PEBs have been greatly reduced, they were still maintained at about 3.60 kcal/mol (3.60-3.84 kcal/mol), and hence, this process was still relatively difficult to occur. Due to the fact that BTHMB can be regarded as a standard in future designs involving red light and solvent-specific white-light emitters, a certain amount of investigative work on the ESIPT process was done in detail, and it paved the way for future research on the directionality of ESIPT in double ESIPT probes.

XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence.

XAB2 is a multi-functional protein participating processes including transcription, splicing, DNA repair and mRNA export. Here, we report POLR2A, the largest catalytic subunit of RNA polymerase II, as a major target gene down-regulated after XAB2 depletion. XAB2 depletion led to severe splicing defects of POLR2A with significant intron retention. Such defects resulted in substantial loss of POLR2A at RNA and protein levels, which further impaired global transcription. Treatment of splicing inhibitor madrasin induced similar reduction of POLR2A. Screen using TMT-based quantitative proteomics identified several proteins involved in mRNA surveillance including Dom34 with elevated expression. Inhibition of translation or depletion of Dom34 rescued the expression of POLR2A by stabilizing its mRNA. Immuno-precipitation further confirmed that XAB2 associated with spliceosome components important to POLR2A expression. Domain mapping revealed that TPR motifs 2-4 and 11 of XAB2 were critical for POLR2A expression by interacting with SNW1. Finally, we showed POLR2A mediated cell senescence caused by XAB2 deficiency. Depletion of XAB2 or POLR2A induced cell senescence by up-regulation of p53 and p21, re-expression of POLR2A after XAB2 depletion alleviated cellular senescence. These data together support that XAB2 serves as a guardian of POLR2A expression to ensure global gene expression and antagonize cell senescence.

Dynamic Excited-State Intramolecular Proton Transfer Mechanisms of Two Novel 3-Hydroxyflavone-Based Chromophores in Two Different Surroundings.

The dynamic excited-state intramolecular proton transfer (ESIPT) mechanisms of two novel 3-hydroxyflavone-based chromophores (1 and 2) in different surroundings (nonpolar cyclohexane and polar acetonitrile solvents), which are reported in the recent work (Chou et al. J. Phys. Chem. A. 2010, 114, 10412), are explored in terms of the density functional theory (DFT) and time-dependent DFT theoretical methods. The computational absorption and emission spectra for the work rendered here were in reasonable agreement with the relevant experiment. In order to present the molecular-level exposition of the ESIPT reactions for these compounds in two different solvents, we calculated the hydrogen bond (HB) parameters, corresponding infrared vibrational frequencies, frontier molecular orbitals, and maps of electron density difference between the S0 and S1 states, and the HB strengthening tendency in S1 states was verified, giving the probability of ESIPT reactions. In addition, to definitely expose the ESIPT mechanisms of compounds 1 and 2, we built the potential energy curves and potential energy surfaces in the S0 and S1 states. Calculated results exhibited that the ESIPT reaction of compound 1 in nonpolar cyclohexane solvent was more susceptible than that in polar acetonitrile solvent. For the asymmetric compound 2, only single-ESIPT processes could occur in both the solvents, and double-ESIPT processes were prohibitive due to high potential energy barriers. Moreover, the single-ESIPT processes [I (6.26 kcal/mol) and II (6.62 kcal/mol)] in cyclohexane were more susceptible than that [I' (6.91 kcal/mol) and II' (6.90 kcal/mol)] in acetonitrile. Furthermore, the single-ESIPT process I had a little advantage over the process II in cyclohexane, while the probabilities of processes I' and II' were roughly the same in acetonitrile.

Activator Protein-2ß Promotes Tumor Growth and Predicts Poor Prognosis in Breast Cancer.

BACKGROUND/AIMS: Activator protein-2 (AP-2) transcription factors have been proved to be essential in maintaining cellular homeostasis and regulating the transformation from normal growth to neoplasia. However, the role of AP-2ß, a key member of AP-2 family, in breast cancer is rarely reported. METHODS: The effect of AP-2 on cell growth, migration and invasion in breast cancer cells were measured by MTT, colony formation, wound-healing and transwell assays, respectively. The expression levels of AP-2ß and other specific markers in breast cancer cell lines and tissue microarrays from the patients were detected using RT-PCR, Western blot and immunohistochemical staining. The regulation of AP-2ß on tumor growth in vivo was analyzed in a mouse xenograft model. RESULTS: We demonstrated the tumor-promoting function of AP-2ß in breast cancer. AP-2ß was found to be highly expressed in breast cancer cell lines and tumor tissues of breast cancer patients. The shRNA-mediated silencing of AP-2ß led to the dramatic inhibition of cell proliferation, colony formation ability, migration and invasiveness in breast cancer cells accompanied by the down-regulated expression of some key proteins involved in cancer progression, including p75, MMP-2, MMP-9, C-Jun, p-ERK and STAT3. Overexpression of AP-2ß markedly up-regulated the levels of these proteins. Consistent with the in vitro study, the silencing or overexpression of AP-2ß blocked or promoted tumor growth in the mice with xenografts of breast cancers. Notably, the high AP-2ß expression levels was correlated with poor prognosis and advanced malignancy in patients with breast cancer. CONCLUSIONS: Our study demonstrates that AP-2ß promotes tumor growth and predicts poor prognosis, and may represent a potential therapeutic target for breast cancer.

Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways.

5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in colon cancer treatment, but has a narrow therapeutic index limited by its toxicity. Melatonin exerts antitumor activity in various cancers, but it has never been combined with 5-FU as an anticolon cancer treatment to improve the chemotherapeutic effect of 5-FU. In this study, we assessed such combinational use in colon cancer and investigated whether melatonin could synergize the antitumor effect of 5-FU. We found that melatonin significantly enhanced the 5-FU-mediated inhibition of cell proliferation, colony formation, cell migration and invasion in colon cancer cells. We also found that melatonin synergized with 5-FU to promote the activation of the caspase/PARP-dependent apoptosis pathway and induce cell cycle arrest. Further mechanism study demonstrated that melatonin synergized the antitumor effect of 5-FU by targeting the PI3K/AKT and NF-κB/inducible nitric oxide synthase (iNOS) signaling. Melatonin in combination with 5-FU markedly suppressed the phosphorylation of PI3K, AKT, IKKα, IκBα, and p65 proteins, promoted the translocation of NF-κB p50/p65 from the nuclei to cytoplasm, abrogated their binding to the iNOS promoter, and thereby enhanced the inhibition of iNOS signaling. In addition, pretreatment with a PI3K- or iNOS-specific inhibitor synergized the antitumor effects of 5-FU and melatonin. Finally, we verified in a xenograft mouse model that melatonin and 5-FU exerted synergistic antitumor effect by inhibiting the AKT and iNOS signaling pathways. Collectively, our study demonstrated that melatonin synergized the chemotherapeutic effect of 5-FU in colon cancer through simultaneous suppression of multiple signaling pathways.

Bufalin Inhibits hTERT Expression and Colorectal Cancer Cell Growth by Targeting CPSF4.

BACKGROUND/AIMS: Bufalin can induce apoptosis in certain human cancer cell lines, but bufalin has not yet been thoroughly evaluated in colorectal cancer cells. Cleavage and polyadenylation specific factor 4 (CPSF4) and human telomerase reverse transcriptase (hTERT) play important roles in colorectal cancer growth. The aim of this study was to investigate the roles and interactions of bufalin, CPSF4 and hTERT and the effects of bufalin in human colorectal cancer. METHODS: We treated LoVo and SW620 cells with bufalin to investigate the effect of bufalin on proliferation, apoptosis and migration. We verified the relationship between CPSF4 and hTERT using pulldown assays, luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays. RESULTS: Bufalin inhibited the proliferation and migration of and induced apoptosis in LoVo and SW620 cells. We identified CPSF4 as an hTERT promoter-binding protein in colorectal cancer cells. CONCLUSION: Our study identified bufalin as a potential small molecule inhibitor for cancer therapy.

A polarizable dipole-dipole interaction model for evaluation of the interaction energies for N-H···O=C and C-H···O=C hydrogen-bonded complexes.

In this article, a polarizable dipole-dipole interaction model is established to estimate the equilibrium hydrogen bond distances and the interaction energies for hydrogen-bonded complexes containing peptide amides and nucleic acid bases. We regard the chemical bonds N-H, C=O, and C-H as bond dipoles. The magnitude of the bond dipole moment varies according to its environment. We apply this polarizable dipole-dipole interaction model to a series of hydrogen-bonded complexes containing the N-H···O=C and C-H···O=C hydrogen bonds, such as simple amide-amide dimers, base-base dimers, peptide-base dimers, and ß-sheet models. We find that a simple two-term function, only containing the permanent dipole-dipole interactions and the van der Waals interactions, can produce the equilibrium hydrogen bond distances compared favorably with those produced by the MP2/6-31G(d) method, whereas the high-quality counterpoise-corrected (CP-corrected) MP2/aug-cc-pVTZ interaction energies for the hydrogen-bonded complexes can be well-reproduced by a four-term function which involves the permanent dipole-dipole interactions, the van der Waals interactions, the polarization contributions, and a corrected term. Based on the calculation results obtained from this polarizable dipole-dipole interaction model, the natures of the hydrogen bonding interactions in these hydrogen-bonded complexes are further discussed.

The PRX-1/TLR4 axis promotes hypoxia-induced radiotherapy resistance in non-small cell lung cancer by targeting the NF-κB/p65 pathway.

Hypoxic lung cancer cells are highly resistant to radiation. Peroxiredoxin-1 (PRX-1), a transcriptional coactivator that enhances the DNA-binding activity of serum reactive factor, has been identified as a target for radiotherapy sensitization, but the underlying molecular mechanism remains unclear. This study aimed to investigate the influence of PRX-1 on radiotherapy sensitivity in hypoxic tumors. Hypoxic lung cancer cells exhibited radiotherapy-resistant phenotypes after irradiation, including increased proliferation, DNA damage repair, cell migration, invasion and stemness. Radio-resistant hypoxic lung cancer cells showed high expression levels of PRX-1. Furthermore, we observed that PRX-1 bound to the promoter region of TRL4 (-300 to -600) and promoted its transcription and expression and that PRX-1/TRL4 activated the NF-κB/p65 signaling pathway. Increased radiotherapy resistance of hypoxic lung cancer cells increased their ability to proliferate, migrate, and maintain stemness in vivo and in vitro. These findings suggest that PRX-1/TRL4 could be used as a target for the treatment of radiotherapy-resistant lung cancer cells and further provide a theoretical basis for the clinical treatment of hypoxic lung cancer cells.

The complete chloroplast genome sequence of Plectranthus hadiensis (Lamiaceae) and phylogenetic analysis.

Plants of the genus Plectranthus are used for the treatment of digestive problems, skin diseases, and allergies, with a wide variety of uses. Here, the complete chloroplast genome sequence of Plectranthus hadiensis (Benth. ex E.Mey) Codd. 1788 was assembled and characterized for the first time. The full length of the chloroplast genome is 152,484 bp, consisting of a small single-copy region of 17,686 bp, a large single-copy region of 83,380 bp, and a pair of inverted repeats of 51,418 bp. The overall GC content is 37.73%. The chloroplast genome contains 131 unique genes, including 87 protein-coding genes, 36 transfer RNA genes, and eight ribosomal RNA genes. Phylogenetic tree construction based on the complete chloroplast genome sequences of 25 species (23 Nepetoideae, two Ajugoideae) of the Lamiaceae family showed that P. hadiensis exhibited the closest relationship with Isodon.

Baicalein ameliorates Alzheimer's disease via orchestration of CX3CR1/NF-κB pathway in a triple transgenic mouse model.

Alzheimer's disease (AD) is a common chronic neurodegenerative disease. Some studies have suggested that dysregulation of microglia activation and the resulting neuroinflammation play an important role in the development of AD pathology. Activated microglia have both M1 and M2 phenotypes and inhibition of M1 phenotype while stimulating M2 phenotype has been considered as a potential treatment for neuroinflammation-related diseases. Baicalein is a class of flavonoids with anti-inflammatory, antioxidant and other biological activities, but its role in AD and the regulation of microglia are limited. The purpose of this study was to investigate the effect of baicalein on the activation of microglia in AD model mice and the related molecular mechanism. Our results showed that baicalein significantly improved the learning and memory ability and AD-related pathology of 3 × Tg-AD mice, inhibited the level of pro-inflammatory factors TNF-α, IL-1ß and IL-6, promoted the production of anti-inflammatory factors IL-4 and IL-10, and regulated the microglia phenotype through CX3CR1/NF-κB signaling pathway. In conclusion, baicalein can regulate the phenotypic transformation of activated microglia and reduce neuroinflammation through CX3CR1/NF-κB pathway, thereby improving the learning and memory ability of 3 × Tg-AD mice.

Tetra-kis(nitrato-κ(2)O,O')[N,N'-1,4-phenyl-enebis(pyridine-4-carboxamide)-κN(1)](4-{[4-(pyridine-4-carboxamido-κN(1))phen-yl]carbamo-yl}pyridin-1-ium)neodymium(III).

In the title compound, [Nd(NO(3))(4)(C(18)H(15)N(4)O(2))(C(18)H(14)N(4)O(2))], the Nd(III) centre is located on a twofold axis and exhibits a ten-coordinated distorted bicapped square-anti-prismatic geometry. The pyridinium NH H atom is disordered over the two ligands. Adjacent mononuclear clusters are linked through N-H⋯O and N-H⋯N hydrogen-bonding inter-actions, generating layers in the (102) plane.

Cornuside Is a Potential Agent against Alzheimer's Disease via Orchestration of Reactive Astrocytes.

Cornuside is an iridoid glycoside from Cornus officinalis, with the activities of anti-inflammatory, antioxidant, anti-mitochondrial dysfunction, and neuroprotection. In the present research, a triple-transgenic mice model of AD (3 × Tg-AD) was used to explore the beneficial actions and potential mechanism of cornuside on the memory deficits. We found that cornuside prominently alleviated neuronal injuries, reduced amyloid plaque pathology, inhibited Tau phosphorylation, and repaired synaptic damage. Additionally, cornuside lowered the release of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), lowered the level of malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD) and the level of glutathione peroxidase (GSH-Px). Cornuside also significantly reduced the activation of astrocytes and modulated A1/A2 phenotypes by the AKT/Nrf2/NF-κB signaling pathway. We further confirmed that LY294002 and Nrf2 silencing could block the cornuside-mediated phenotypic switch of C6 cells induced by microglia conditioned medium (MCM) in response to lipopolysaccharide (LPS), which indicated that the effects of cornuside in astrocyte activation are dependent on AKT/Nrf2/NF-κB signaling. In conclusion, cornuside may regulate the phenotypic conversion of astrocytes, inhibit neuroinflammation and oxidative stress, improve synaptic plasticity, and alleviate cognitive impairment in mice through the AKT/Nrf2/NF-κB axis. Our present work provides an experimental foundation for further research and development of cornuside as a candidate drug for AD management.

SPT6 recruits SND1 to co-activate human telomerase reverse transcriptase to promote colon cancer progression.

Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism-based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull-down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem-like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human-derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co-control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6-SND1-hTERT axis may create a therapeutic vulnerability in CRC.

CRSP8 promotes thyroid cancer progression by antagonizing IKKα-induced cell differentiation.

CRSP8 plays an important role in recruiting mediators to genes through direct interaction with various DNA-bound transactivators. In this study, we uncovered the unique function of CRSP8 in suppressing thyroid cancer differentiation and promoting thyroid cancer progression via targeting IKKα signaling. CRSP8 was highly expressed in human thyroid cancer cells and tissues, especially in anaplastic thyroid cancer (ATC). Knockdown of CRSP8 suppressed cell growth, migration, invasion, stemness, and induced apoptosis and differentiation in ATC cells, while its overexpression displayed opposite effects in differentiated thyroid cancer (DTC) cells. Mechanistically, CRSP8 downregulated IKKα expression by binding to the IKKα promoter region (-257 to -143) to negatively regulate its transcription. Knockdown or overexpression of IKKα significantly reversed the expression changes of the differentiation and EMT-related markers and cell growth changes mediated by CRSP8 knockdown or overexpression in ATC or DTC cells. The in vivo study also validated that CRSP8 knockdown inhibited the growth of thyroid cancer by upregulating IKKα signaling in a mouse model of human ATC. Furthermore, we found that CRSP8 regulated the sensitivity of thyroid cancer cells to chemotherapeutics, including cisplatin and epirubicin. Collectively, our results demonstrated that CRSP8 functioned as a modulator of IKKα signaling and a suppressor of thyroid cancer differentiation, suggesting a potential therapeutic strategy for ATC by targeting CRSP8/IKKα pathway.

Unveiling the effect of solvent polarity on the excited state intramolecular proton transfer mechanism of new 3-hydroxy-4-pyridylisoquinoline compound.

The new 3-hydroxy-4-pyridylisoquinoline compound is attractive and promising lead structure in drug discovery. The pronounced sensitivity of its emission property toward solvent polarity effect was presented in experiment (J. Org. Chem, 2019, 84, 3011). Nevertheless, the experiment was lack of solvent polarity effect on the excited state intramolecular proton transfer (ESIPT) mechanism in detail. In this study, the ESIPT process of this molecule in different polarity solvents were comprehensively expounded by density functional theory (DFT) and time-dependent DFT (TDDFT) methods. In order to ensure the accuracy of the experiment and roundly explore in theoretical level, two ESIPT pathways (1 and 2) based on the N1 and N2 forms of studied molecule were proposed, among which the ESIPT pathway 1 was derived from experiment. The calculated electronic spectrum of both N1 and N2 forms were rather comparable with the experiment. The calculated intramolecular hydrogen bond (IHB) parameters and infrared (IR) vibration spectra determined the enhancement of IHBs at the S1 state under different solvents for both N1 and N2 forms. The frontier molecular orbitals (FMOs) analysis proved that the intramolecular charge transfer (ICT) taken place during photoexcitation. The potential energy curves (PECs) at the S0 and S1 states were constructed to illustrate the solvent polarity effect on ESIPT mechanism. According to potential energy barriers (PEBs) on the PECs at S1 state, it is concluded that the ESIPT pathway 1 was forbidden with exceedingly high PEBs (24.585-25.322 kcal/mol), while the ESIPT pathway 2 was feasible with enough low PEBs (0.100-0.510 kcal/mol), which suggested the inconsequence of the experiment. Based on the PEBs of ESIPT pathway 2 in different solvent, the effect of solvent polarity on ESIPT mechanism was depicted. The results are as follows: the S1 state IHB intensity was enhanced with increasing solvent polarity; the extent of ICT was decreased with the increment of solvent polarity; the S1 state PEB was decreased as the solvent polarity increased. Indeed in short, the ESIPT reaction became more and more likely as the solvent polarity enhanced. We believe that this investigation will be useful to the utilization and development of property for such photochemical substances.