Electroactive Carbazole-Based Polycyclic Aromatic Hydrocarbons: Synthesis, Photophysical Properties, and Computational Studies.

Herein, we explored the oxidative coupling reactions of carbazole-based polycyclic aromatic hydrocarbons using traditional Scholl reactions and electrochemical oxidation. Our findings indicate that the oxidation predominantly occurs at the carbazole functional group. The underlying reaction mechanisms were also clarified through theoretical investigations, highlighting that the primary oxidation pathway involves the 3,6-positions of the carbazole moiety, which is attributable to its high electron density.

ATF2/BAP1 Axis Mediates Neuronal Apoptosis After Subarachnoid Hemorrhage via P53 Pathway.

BACKGROUND: Neuronal apoptosis plays an essential role in the pathogenesis of brain injury after subarachnoid hemorrhage (SAH). BAP1 (BRCA1-associated protein 1) is considered to exert pro-apoptotic effects in multiple diseases. However, evidence supporting the effect of BAP1 on the apoptotic response to SAH is lacking. Therefore, we aimed to confirm the role of BAP1 in SAH-induced apoptosis. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to detect BAP1 expression in the cerebrospinal fluid. Endovascular perforation was performed in mice to induce SAH. Lentiviral short hairpin RNA targeting BAP1 mRNA was transduced into the ipsilateral cortex of mice with SAH to investigate the role of BAP1 in neuronal damage. Luciferase and coimmunoprecipitation assays were performed to investigate the mechanism through which BAP1 participates in hemin-induced SAH. RESULTS: First, BAP1 expression was upregulated in the cerebrospinal fluid of patients with SAH and positively associated with unfavorable outcomes. ATF2 (activating transcription factor-2) then regulated BAP1 expression by binding to the BAP1 promoter. In addition, BAP1 overexpression enhanced P53 activity and stability by reducing P53 proteasome-mediated degradation. Subsequently, elevated P53 promoted neuronal apoptosis via the P53 pathway. Inhibition of the neuronal BAP1/P53 axis significantly reduced neurological deficits and neuronal apoptosis and improved neurological dysfunction in mice after SAH. CONCLUSIONS: Our results suggest that the neuronal ATF2/BAP1 axis exerts a brain-damaging effect by modulating P53 activity and stability and may be a novel therapeutic target for SAH.

Construction of S-scheme CuInS2/ZnIn2S4 heterostructures for enhanced photocatalytic activity towards Cr(VI) removal and antibiotics degradation.

The efficient and ecofriendly removal of pharmaceutical antibiotics and heavy metal Cr(VI) from water sources is a crucial challenge in current environmental management. Photocatalysis presents a viable environmentally friendly solution for eliminating organic contaminants and heavy-metal ions. In this study, a novel S-scheme CuInS2/ZnIn2S4 (CIS/ZIS) heterojunction was developed using a one-pot solvothermal method. The optimized CIS/ZIS heterojunction exhibited considerably improved photocatalytic activity for the removal of antibiotics and Cr(VI), achieving over 90% removal for both tetracycline hydrochloride (TC) (20 mg/L) and Cr(VI) (20 mg/L) under visible light irradiation. The study also delved into the effect of coexisting inorganic anions and assessed the cyclic stability of the composite photocatalysts. This enhancement mechanism can be delineated into three key elements. First, the incorporation of the narrow-gap semiconductor CuInS2 effectively augmented the photoabsorption capacity. Second, the inclusion of ZnIn2S4 caused an increase in surface active sites. Most importantly, the internal electric field at the interface between CuInS2 and ZnIn2S4 expedited the separation of photogenerated carriers. Furthermore, the results revealed that superoxide radical and photogenerated holes are the primary active substance responsible for TC removal, while photogenerated electrons play a central role in the photoreduction of Cr(VI). To gain insights into the transport pathways of photogenerated carriers, we conducted experiments with nitrotetrazolium blue chloride (NBT) and photodeposited gold. This study offers an innovative approach to enhancing the photocatalytic performance of ternary In-based materials by constructing S-scheme heterojunctions.

Enhancing Near-Infrared Absorption in Terpyridyl Ru/Os Complexes with Ancillary Ligands to Activate Spin-Forbidden Transitions in Dye-Sensitized Solar Cells: A TDDFT Investigation.

Dye sensitizers with wideband absorption covering the near-IR region have long been of interest because they potentially harvest a wide range of solar energies essential to promote photocurrent power conversion efficiencies. In this study, we used time-dependent density functional theory with spin-orbit (SO) interactions to theoretically explore the long-wavelength absorptions and spin-forbidden triplet transitions activated by SO interactions for terpyridyl ruthenium/osmium complex dyes. These dyes feature a Ru(II) sensitizer coordinated with a phosphine ligand and are exemplified by DX1, denoted as [trans-dichloro-(phenyldimethoxyphosphine)(2,2';6',2″-terpyridyl-4,4',4″-tricarboxylic)Ru]. We found that ancillary ligands significantly affected the longest wavelength spin-allowed absorption, with NCS- ligands yielding longer wavelength S1 transitions than halides. High atomic number halide ligands caused blue shifts in the S1 transition. Os complexes consistently exhibited longer wavelength S1 transitions than Ru complexes with identical ligands. In Ru/Os complexes, ancillary ligands with higher atomic numbers have a more pronounced effect in activating spin-forbidden triplet transitions through spin-orbit coupling (SOC) than those with lower atomic numbers. The absorption wavelength of the SOC-activated transition primarily depended on the energy of lower lying triplet states. Some complexes exhibited T1 states activated by SOC, leading to longer wavelength absorption than that of SOC-activated T2 states. Our study revealed the significance of ancillary ligands and SOC interactions in Ru/Os complexes, offering insights for optimizing materials with enhanced long-wavelength absorption properties, particularly in the near-IR range, for photovoltaic and optoelectronic applications.

Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with cognitive dysfunction as its major clinical symptom. However, there is no disease-modifying small molecular medicine to effectively slow down progression of the disease. Here, we show an optimized asparagine endopeptidase (AEP, also known as δ-secretase) inhibitor, #11 A, that displays an orderly in vivo pharmacokinetics/pharmacodynamics (PK/PD) relationship and robustly attenuates AD pathologies in a sporadic AD mouse model. #11 A is brain permeable with great oral bioavailability. It blocks AEP cleavage of APP and Tau dose-dependently, and significantly decreases Aß40 and Aß42 and p-Tau levels in APP/PS1 and Tau P301S mice after oral administration. Notably, #11 A strongly inhibits AEP and prevents mouse APP and Tau fragmentation by AEP, leading to reduction of mouse Aß42 (mAß42), mAß40 and mouse p-Tau181 levels in Thy1-ApoE4/C/EBPß transgenic mice in a dose-dependent manner. Repeated oral administration of #11 A substantially decreases mAß aggregation as validated by Aß PET assay, Tau pathology, neurodegeneration and brain volume reduction, resulting in alleviation of cognitive impairment. Therefore, our results support that #11 A is a disease-modifying preclinical candidate for pharmacologically treating AD.

FSH and ApoE4 contribute to Alzheimer's disease-like pathogenesis via C/EBPß/δ-secretase in female mice.

Alzheimer's disease (AD) is the most common dementia. It is known that women with one ApoE4 allele display greater risk and earlier onset of AD compared with men. In mice, we previously showed that follicle-stimulating hormone (FSH), a gonadotropin that rises in post-menopausal females, activates its receptor FSHR in the hippocampus, to drive AD-like pathology and cognitive impairment. Here we show in mice that ApoE4 and FSH jointly trigger AD-like pathogenesis by activating C/EBPß/δ-secretase signaling. ApoE4 and FSH additively activate C/EBPß/δ-secretase pathway that mediates APP and Tau proteolytic fragmentation, stimulating Aß and neurofibrillary tangles. Ovariectomy-provoked AD-like pathologies and cognitive defects in female ApoE4-TR mice are ameliorated by anti-FSH antibody treatment. FSH administration facilitates AD-like pathologies in both young male and female ApoE4-TR mice. Furthermore, FSH stimulates AD-like pathologies and cognitive defects in ApoE4-TR mice, but not ApoE3-TR mice. Our findings suggest that in mice, augmented FSH in females with ApoE4 but not ApoE3 genotype increases vulnerability to AD-like process by activating C/EBPß/δ-secretase signalling.

Polarization-Insensitive Metasurface Cloak for Dynamic Illusions with an Electromagnetic Transparent Window.

Artificial camouflage has garnered long-standing interest in both academia and industry. The metasurface-based cloak has attracted much attention due to the powerful capability of manipulating the electromagnetic wave, convenient multifunctional integration design, and easy fabrication. However, existing metasurface-based cloaks tend to be passive and of single function and monopolarization, which cannot meet the requirement of applications in ever-changing environments. So far, it is still challenging to realize a reconfigurable full-polarization metasurface cloak with multifunctional integration. Herein, we proposed an innovative metasurface cloak, which can simultaneously realize dynamic illusion effects at lower frequencies (e.g., 4.35 GHz) and specific microwave transparency at higher frequencies (e.g., X band) for communication with the outside environment. These electromagnetic functionalities are demonstrated by both numerical simulations and experimental measurements. The simulation and measurement results agree well with each other, indicating that our metasurface cloak can generate various electromagnetic illusions for full polarizations as well as a polarization-insensitive transparent window for the signal transmission to enable the communication between the cloaked device and the outside environment. It is believed that our design can offer powerful camouflage tactics to address the stealth problem in ever-changing environments.

Effect of regio-specific arylamine substitution on novel π-extended zinc salophen complexes: density functional and time-dependent density functional study on DSSC applications.

A series of π-extended salophen-type Schiff-base zinc(ii) complexes, e.g., zinc-salophen complexes (ZSC), were investigated toward potential applications for dye-sensitized solar cells. The ZSC dyes adopt linear-, X-, or π-shaped geometries either with the functionalization of 1 donor/1 acceptor or 2 donors/2 acceptors to achieve a push-pull type molecular structure. The frontier molecular orbitals, light-harvesting properties as well as charge transfer characters against regio-specific substitution of donor/acceptor groups were studied by using density functional theory (DFT) and time-dependent density functional theory (TDDFT). The results reveal that all ZSC dyes of D-ZnS-π-A geometry (where D, S, and A denote to donor, salophen ligand, and acceptor, respectively) exhibit relatively lower HOMO energy compared to the structurally resembled porphyrin dye YD2-o-C8. Natural transition orbital (NTO) and electron-hole separation (EHS) approaches clearly differentiate the linear type YD-series dyes from CL-, AJ1-, and AJ2-series dyes because of poor charge transfer (CT) properties. In contrast, the π-shaped AJ2-series and X-shaped AJ1-series dyes outperform the others in a manner of stronger CT characteristics, broadened UV-vis absorption as well as tunable bandgap simply via substitution of p-ethynylbenzoic acids (EBAs) and arylamine donors at salophen 7,8- and 2,3,12,13-positions, respectively. Both EHS and calculated exciton binding energies suggest the strength of CT character for ZSC dyes with an amino donor in the trend TPA > AN > DPA. This work has provided clear illustration toward molecular design of efficient dyes featuring a zinc-salophen backbone.

Diabetes or calcium channel blocker contribute to cerebral hemodynamics after bypass surgery in adult patients with moyamoya disease.

Background: Moyamoya disease (MMD) is a teratogenic and lethal disease. However, existing studies do not sufficiently indicate the impact factors. Therefore, we investigated the different impact factors on cerebral hemodynamics after revascularization in patients with MMD. Methods: We retrospectively collected the clinical data of 233 adult patients with MMD who underwent revascularization surgery in the Department of Neurosurgery, Renmin Hospital of Wuhan University, from January 2015 to June 2021 for this retrospective cohort study. We analyzed the effects on hemodynamic improvement of age, sex, stroke type, early symptoms, Suzuki stage, history of hypertension, history of diabetes, and history of hyperlipidemia in patients with MMD. We also evaluated the efficacy of different revascularization strategies and we verified the effect of computed tomography perfusion (CTP) in evaluating cerebral hemodynamics. Results: The CTP values demonstrated that δ cerebral blood volume (CBV) values were significantly higher in the combined group [1.01 (0.87-1.75)] relative to those in the indirect group [1.34 (1.01-1.63); P=0.027]. There was no statistical significance in the improvement of clinical symptoms and clinical prognosis between the indirect and combined groups. Patients with MMD with diabetes [δ mean transit time (MTT), 0.49 (0.35-0.70) vs. 0.72 (0.52-0.87); P<0.001] or calcium channel blocker (CCB) [δCBV, 1.46 (1.10-1.83) vs. 1.12 (0.93-1.54); P=0.001] had better cerebral hemodynamics than patients in non-diabetic group or non-CCB group after revascularization. Conclusions: We didn't find differences in clinical outcome between indirect and combined revascularization in patients with MMD. we demonstrated that CTP values can be used as a way to detect postoperative cerebral hemodynamic changes in MMD patients. Interestingly, we found that MMD patients with diabetes or CCB showed better cerebral perfusion after revascularization.

A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin.

Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) are expressed in human osteoblasts and mediate fracture healing. BDNF/TrkB signaling activates Akt that phosphorylates and inhibits asparagine endopeptidase (AEP), which regulates the differentiation fate of human bone marrow stromal cells (hBMSC) and is altered in postmenopausal osteoporosis. Here we show that R13, a small molecular TrkB receptor agonist prodrug, inhibits AEP and promotes bone formation. Though both receptor activator of nuclear factor kappa-Β ligand (RANK-L) and osteoprotegerin (OPG) induced by ovariectomy (OVX) remain comparable between WT and BDNF+/- mice, R13 treatment significantly elevates OPG in both mice without altering RANKL, blocking trabecular bone loss. Strikingly, both R13 and anti-RANK-L exhibit equivalent therapeutic efficacy. Moreover, OVX increases RANK-L and OPG in WT and AEP KO mice with RANK-L/OPG ratio lower in the latter than the former, attenuating bone turnover. 7,8-DHF, released from R13, activates TrkB and its downstream effector CREB, which is critical for OPG augmentation. Consequently, 7,8-DHF represses C/EBPß/AEP pathway, inhibiting RANK-L-induced RAW264.7 osteoclastogenesis. Therefore, our findings support that R13 exerts its therapeutic efficacy toward osteoporosis via inhibiting AEP and escalating OPG.

A Dynamic Thermal Camouflage Metadevice with Microwave Scattering Reduction.

With rapid development of radar and infrared (IR) surveillance technologies, the need for microwave-IR compatible camouflage is now more than ever. Here, a novel multispectral metadevice is proposed to simultaneously achieve microwave scattering reduction, dynamic IR camouflage, and low IR reflection. This metadevice is constructed by the coding thermoelectric elements with the properly designed phase arrangement, and the incident microwave energy can be redirected to the nonthreatening directions for specular reflection reduction. The dynamic IR camouflage with low IR reflection is realized by using the thermoelectric cooling and heating effect and high-IR-absorptivity surface. The above three functionalities are demonstrated by experimental measurement. The 10 dB scattering reduction can be realized at the microwave band of 10-16.1 GHz. In the IR region, the designed metadevice can not only dynamically modulate the surface temperature for matching different background temperatures, but also realize the pixel temperature control for adapting to a spatially varying thermal background. In addition, it reflects almost no surrounding thermal signals compared with the traditional low-emissivity IR stealth material. This study paves an effective way to achieve microwave-IR compatible camouflage, which may inspire the future researches and applications in multispectral camouflage and stealth fields.

Synthesis of a robust, water-stable, and biodegradable pulp foam by poly-lactic acid coating towards a zero-plastic earth.

Biodegradable cellulosic pulp foams with robustness and water resistance are urgently needed in nowadays to replace petroleum-based plastic foams for environmental sustainability. In this work, a facile protocol to fabricate robust poly-lactic acid (PLA) coated cellulose foams (PCCF) was developed through a combined water-based foaming and PLA melt-coating process using pulp as the raw material. In the synthesis, the so-called PLA coating was realized through melting PLA powders dispersed between fibers by an in-situ heating and post cooling process. Performance tests revealed that the incorporation of PLA coating significantly enhances mechanical strength, water stability, and biodegradability of the synthesized PCCF samples compared with conventional cellulosic foams. Specifically, the low-density PCCF were observed with mechanical strength up to 81.24 kPa, high water stability, and more than 95% degradation in 56 days. As the fabrication process is simple and pulp is highly cost competitive, our proposed synthesis strategy makes the PCCF a promising substitute for petroleum-based plastic foams at large-scale production.

Effect of Thiophene Insertion on X-Shaped Anthracene-Based Hole-Transporting Materials in Perovskite Solar Cells.

In this work, two novel tetra-substituted X-shaped molecules X1 and X2 that were constructed with anthracene as the central core and arylamine as the donor groups have been synthesized. The HTMs X1 and X2 were synthesized in two steps from industrially accessible and moderately reasonable beginning reagents. These new HTMs are described in terms of utilization of light absorption, energy level, thermal properties, hole mobility (µh), and film-forming property. The photovoltaic performances of these HTMs were effectively assessed in perovskite solar cells (PSCs). The devices based on these HTMs accomplished an overall efficiency of 16.10% for X1 and 10.25% for X2 under standard conditions (AM 1.5 G and 100 mW cm-2). This precise investigation provides another perspective on the use of HTMs in PSCs with various device configurations.

C/EBPß/AEP signaling couples atherosclerosis to the pathogenesis of Alzheimer's disease.

Atherosclerosis (ATH) and Alzheimer's disease (AD) are both age-dependent inflammatory diseases, associated with infiltrated macrophages and vascular pathology and overlapping molecules. C/EBPß, an Aß or inflammatory cytokine-activated transcription factor, and AEP (asparagine endopeptidase) are intimately implicated in both ATH and AD; however, whether C/EBPß/AEP signaling couples ATH to AD pathogenesis remains incompletely understood. Here we show that C/EBPß/AEP pathway mediates ATH pathology and couples ATH to AD. Deletion of C/EBPß or AEP from primary macrophages diminishes cholesterol load, and inactivation of this pathway reduces foam cell formation and lesions in aorta in ApoE-/- mice, fed with HFD (high-fat-diet). Knockout of ApoE from 3xTg AD mouse model augments serum LDL and increases lesion areas in the aorta. Depletion of C/EBPß or AEP from 3xTg/ApoE-/- mice substantially attenuates these effects and elevates cerebral blood flow and vessel length, improving cognitive functions. Strikingly, knockdown of ApoE from the hippocampus of 3xTg mice decreases the cerebral blood flow and vessel length and aggravates AD pathologies, leading to cognitive deficits. Inactivation of C/EBPß/AEP pathway alleviates these events and restores cognitive functions. Hence, our findings demonstrate that C/EBPß/AEP signaling couples ATH to AD via mediating vascular pathology.

Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation.

OBJECTIVE: This study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer's disease (AD) pathogenesis. DESIGN: We analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors. RESULTS: Microbial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-ß plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients' gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPß/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors' microbiota transplants. CONCLUSIONS: These findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.

Proliferating cell nuclear antigen clamp associated factor, a potential proto-oncogene with increased expression in malignant gastrointestinal tumors.

Gastrointestinal (GI) cancers, including malignancies in the gastrointestinal tract and accessory organs of digestion, represent the leading cause of death worldwide due to the poor prognosis of most GI cancers. An investigation into the potential molecular targets of prediction, diagnosis, prognosis, and therapy in GI cancers is urgently required. Proliferating cell nuclear antigen (PCNA) clamp associated factor (PCLAF), which plays an essential role in cell proliferation, apoptosis, and cell cycle regulation by binding to PCNA, is a potential molecular target of GI cancers as it contributes to a series of malignant properties, including tumorigenesis, epithelial-mesenchymal transition, migration, and invasion. Furthermore, PCLAF is an underlying plasma prediction target in colorectal cancer and liver cancer. In addition to GI cancers, PCLAF is also involved in other types of cancers and autoimmune diseases. Several pivotal pathways, including the Rb/E2F pathway, NF-κB pathway, and p53-p21 cascade, are implicated in PCLAF-mediated diseases. PCLAF also contributes to some diseases through dysregulation of the p53 pathway, WNT signal pathway, MEK/ERK pathway, and PI3K/AKT/mTOR signal cascade. This review mainly describes in detail the role of PCLAF in physiological status and GI cancers. The signaling pathways involved in PCLAF are also summarized. Suppression of the interaction of PCLAF/PCNA or the expression of PCLAF might be potential biological therapeutic strategies for GI cancers.

lnc-NLC1-C inhibits migration, invasion and autophagy of glioma cells by targeting miR-383 and regulating PRDX-3 expression.

Long non-coding RNAs (lncRNAs) serve an important role in tumor progression, and their abnormal expression is associated with tumor development. The lncRNA narcolepsy candidate region 1 gene C (lnc-NLC1-C) is involved in numerous types of cancer, but its biological function in glioma remains unknown. In the present study, lnc-NLC1-C expression was detected using reverse transcription-quantitative (RT-q)PCR in U251, SHG44, U87MG and U118MG glioma cells. U87MG cells were transfected with lnc-NLC1-C overexpression or interference vectors. Cell proliferation was detected using a Cell Counting Kit-8 assay. Cell migration and invasion were examined using a Transwell assay, while apoptosis, cell cycle and reactive oxygen species production were evaluated using flow cytometry, and the expression levels of lnc-NLC1-C, microRNA (miR)-383 and peroxiredoxin 3 (PRDX-3) were measured using western blotting and RT-qPCR. Rescue experiments were performed to verify the function of the lnc-NLC1-C/miR-383/PRDX-3 axis. The highest expression levels of lnc-NLC1-C were identified in U87MG glioma cells. Overexpression of lnc-NLC1-C expression promoted cell proliferation, G1 phase blocking, migration and invasion, while inhibiting apoptosis and autophagy in U87MG cells. Mechanistically, miR-383 could bind to lnc-NLC1-C to regulate PRDX-3 expression and improve its oncogenic effect. Rescue experiments confirmed that the lnc-NLC1-C/miR-383/PRDX-3 axis was involved in the molecular mechanism of glioma progression. Therefore, lnc-NLC1-C may be a tumor promoter that affects multiple biological functions, such as migration, invasion and autophagy, in glioma cells.

Targeting both BDNF/TrkB pathway and delta-secretase for treating Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementia, and no disease-modifying therapeutic agents are currently available. BDNF/TrkB signaling is impaired in AD and is associated with prominent delta-secretase (δ-secretase, also known as asparaginyl endopeptidase or legumain) activation, which simultaneously cleaves both APP and Tau and promotes Aß production and neurofibrillary tangles (NFT) pathologies. Here we show that the optimized δ-secretase inhibitor (#11a) or TrkB receptor agonist (CF3CN) robustly blocks δ-secretase activity separately, and their combination synergistically blunts δ-secretase, exhibiting promising therapeutic efficacy in 3xTg AD mouse model. The optimal δ-secretase inhibitor reveals demonstrable brain exposure and oral bioavailability, suppressing APP N585 and Tau N368 cleavage by δ-secretase. Strikingly, CF3CN treatment evidently escalates BDNF levels. Both #11a and CF3CN display strong in vivo PK/PD properties and ability to suppress δ-secretase activity in the brain. Orally administrated CF3CN strongly activates TrkB that triggers active Akt to phosphorylate δ-secretase T322, preventing its proteolytic activation and mitigating AD pathologies. #11a or CF3CN significantly diminishes AD pathogenesis and improves cognitive functions with the combination exhibiting the maximal effect. Thus, our data support that these derivatives are strong pharmaceutical candidates for the treatment of AD.

C/EBPß/AEP Signaling Regulates the Oxidative Stress in Malignant Cancers, Stimulating the Metastasis.

Solid tumors start as a local disease, but some are capable of metastasizing to the lymph nodes and distant organs. The hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating cancer progression and metastasis. However, the molecular mechanisms mediating the disseminated cancer cell metastasis remain incompletely understood. Here, we show that C/EBPß/AEP signaling that is upregulated in breast cancers mediates oxidative stress and lung metastasis, and inactivation of asparagine endopeptidase (AEP, also known as legumain) robustly regulates breast cancer reactive oxygen species (ROS) and metastasis. AEP, a protease activated in acidic conditions, is overexpressed in numerous types of cancer and promotes metastasis. Employing a breast cancer cell line MDA-MD-231, we show that C/EBPß, an oxidative stress or inflammation-activated transcription factor, and its downstream target AEP mediate ROS production as well as migration and invasion in cancer cells. Deficiency of AEP in the MMTV-PyMT transgenic breast cancer mouse model significantly regulates oxidative stress and suppresses lung metastasis. Administration of an innovative AEP inhibitor substantially mitigates ROS production and cancer metastasis. Hence, our study demonstrates that pharmacologic inhibition of AEP activity might provide a disease-modifying strategy to suppress cancer metastasis.

Optimized TrkB Agonist Ameliorates Alzheimer's Disease Pathologies and Improves Cognitive Functions via Inhibiting Delta-Secretase.

BDNF/TrkB neurotropic pathway, essential for neural synaptic plasticity and survival, is deficient in neurodegenerative diseases including Alzheimer's disease (AD). Our previous works support that BDNF diminishes AD pathologies by inhibiting delta-secretase, a crucial age-dependent protease that simultaneously cleaves both APP and Tau and promotes AD pathologies, via Akt phosphorylation. Small molecular TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) binds and activates the receptor and its downstream signaling, exerting therapeutic efficacy toward AD. In the current study, we optimize 7,8-DHF pharmacokinetic characteristics via medicinal chemistry to obtain a synthetic derivative CF3CN that interacts with the TrkB LRM/CC2 domain. CF3CN possesses improved druglike features, including oral bioavailability and half-life, compared to those of the lead compound. CF3CN activates TrkB neurotrophic signaling in primary neurons and mouse brains. Oral administration of CF3CN blocks delta-secretase activation, attenuates AD pathologies, and alleviates cognitive dysfunctions in 5xFAD. Notably, chronic treatment of CF3CN reveals no demonstrable toxicity. Hence, CF3CN represents a promising preclinical candidate for treating the devastating neurodegenerative disease.