Design, Synthesis, and Biological Evaluation of Pyridazinone-Containing Derivatives As Novel Protoporphyrinogen IX Oxidase Inhibitor.

Protoporphyrinogen IX oxidase (PPO, E.C. 1.3.3.4) plays a pivotal role in chlorophyll biosynthesis in plants, making it a prime target for herbicide development. In this study, we conducted an investigation aimed at discovering PPO-inhibiting herbicides. Through this endeavor, we successfully identified a series of novel compounds based on the pyridazinone scaffold. Following structural optimization and biological assessment, compound 10ae, known as ethyl 3-((6-fluoro-5-(6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)benzo[d]thiazol-2-yl)thio)propanoate, emerged as a standout performer. It exhibited robust activity against Nicotiana tabacum PPO (NtPPO) with an inhibition constant (Ki) value of 0.0338 µM. Concurrently, we employed molecular simulations to obtain further insight into the binding mechanism with NtPPO. Additionally, another compound, namely, ethyl 2-((6-fluoro-5-(5-methyl-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)benzo[d]thiazol-2-yl)thio)propanoate (10bh), demonstrated broad-spectrum and highly effective herbicidal properties against all six tested weeds (Leaf mustard, Chickweed, Chenopodium serotinum, Alopecurus aequalis, Poa annua, and Polypogon fugax) at the dosage of 150 g a.i./ha through postemergence application in a greenhouse. This work identified a novel lead compound (10bh) that showed good activity in vitro and excellent herbicidal activity in vivo and had promising prospects as a new PPO-inhibiting herbicide lead.

GATA3 functions downstream of BRCA1 to promote DNA damage repair and suppress dedifferentiation in breast cancer.

BACKGROUND: Inadequate DNA damage repair promotes aberrant differentiation of mammary epithelial cells. Mammary luminal cell fate is mainly determined by a few transcription factors including GATA3. We previously reported that GATA3 functions downstream of BRCA1 to suppress aberrant differentiation in breast cancer. How GATA3 impacts DNA damage repair preventing aberrant cell differentiation in breast cancer remains elusive. We previously demonstrated that loss of p18, a cell cycle inhibitor, in mice induces luminal-type mammary tumors, whereas depletion of either Brca1 or Gata3 in p18 null mice leads to basal-like breast cancers (BLBCs) with activation of epithelial-mesenchymal transition (EMT). We took advantage of these mutant mice to examine the role of Gata3 as well as the interaction of Gata3 and Brca1 in DNA damage repair in mammary tumorigenesis. RESULTS: Depletion of Gata3, like that of Brca1, promoted DNA damage accumulation in breast cancer cells in vitro and in basal-like breast cancers in vivo. Reconstitution of Gata3 improved DNA damage repair in Brca1-deficient mammary tumorigenesis. Overexpression of GATA3 promoted homologous recombination (HR)-mediated DNA damage repair and restored HR efficiency of BRCA1-deficient cells. Depletion of Gata3 sensitized tumor cells to PARP inhibitor (PARPi), and reconstitution of Gata3 enhanced resistance of Brca1-deficient tumor cells to PARP inhibitor. CONCLUSIONS: These results demonstrate that Gata3 functions downstream of BRCA1 to promote DNA damage repair and suppress dedifferentiation in mammary tumorigenesis and progression. Our findings suggest that PARP inhibitors are effective for the treatment of GATA3-deficient BLBCs.

Effects of different treatment modalities on cardiovascular disease in ARR-positive hypertensive patients.

Data on the prognosis of clinically undiagnosed hypertensive patients who are aldosterone-to-renin ratio (ARR) positive are still scarce. Therefore, we investigated the clinical characteristics of clinically undiagnosed hypertensive patients who were ARR-positive and the influence of their different treatments on the occurrence and development of complications. A total of 285 hypertensive patients data with ARR ≥ 3.8 in the Second People's Hospital of Huai'an from January 2019 to December 2021 were collected, and 135 undiagnosed hypertensive patients were ultimately included in the analysis. According to their treatment strategy in various clinical departments, 135 patients were divided into the operation, spironolactone and control groups. Then, the clinical characteristics and the occurrence and development of complications in the three groups were compared. The results suggested that: (1) Only 34 (11.9%) of 285 hypertensive patients with ARR ≥ 3.8 were clearly diagnosed with Primary aldosteronism (PA) through functional tests, and the blood pressure (BP) compliance rate was only 50.30% during follow-up. (2) Based on exclusion criteria, 135 undiagnosed hypertensive patients were eventually included in the analysis. Patients in the surgery group had lower blood potassium levels and higher aldosterone levels than those in the other two groups, and their risk of new cerebrovascular complications was lower than that of the patients in the spironolactone group. (3) The risk of new cerebrovascular complications in the spironolactone group was 9.520 times higher than that of the control group, and this risk mainly occurred in patients with ARR values of 3.8-5.7. On the whole, surgery remains a good option for hypertensive patients with severe hyperaldosteronism and hypokalemia and those unable to undergo confirmatory tests; however, spironolactone therapy in patients with clinically undiagnosed hypertension, especially those with 3.8 ≤ ARR < 5.7, confered a higher risk of new cerebrovascular complications.

FASN Inhibition Decreases MHC-I Degradation and Synergizes with PD-L1 Checkpoint Blockade in Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICI) transformed the treatment landscape of hepatocellular carcinoma (HCC). Unfortunately, patients with attenuated MHC-I expression remain refractory to ICIs, and druggable targets for upregulating MHC-I are limited. Here, we found that genetic or pharmacologic inhibition of fatty acid synthase (FASN) increased MHC-I levels in HCC cells, promoting antigen presentation and stimulating antigen-specific CD8+ T-cell cytotoxicity. Mechanistically, FASN inhibition reduced palmitoylation of MHC-I that led to its lysosomal degradation. The palmitoyltransferase DHHC3 directly bound MHC-I and negatively regulated MHC-I protein levels. In an orthotopic HCC mouse model, Fasn deficiency enhanced MHC-I levels and promoted cancer cell killing by tumor-infiltrating CD8+ T cells. Moreover, the combination of two different FASN inhibitors, orlistat and TVB-2640, with anti-PD-L1 antibody robustly suppressed tumor growth in vivo. Multiplex IHC of human HCC samples and bioinformatic analysis of The Cancer Genome Atlas data further illustrated that lower expression of FASN was correlated with a higher percentage of cytotoxic CD8+ T cells. The identification of FASN as a negative regulator of MHC-I provides the rationale for combining FASN inhibitors and immunotherapy for treating HCC. SIGNIFICANCE: Inhibition of FASN increases MHC-I protein levels by suppressing its palmitoylation and lysosomal degradation, which stimulates immune activity against hepatocellular carcinoma and enhances the efficacy of immune checkpoint inhibition.

Coordination Self-Assembled AuTPyP-Cu Metal-Organic Framework Nanosheets with pH/Ultrasound Dual-Responsiveness for Synergistically Triggering Cuproptosis-Augmented Chemotherapy.

Reactive oxygen species (ROS) mediated tumor cell death is a powerful anticancer strategy. Cuproptosis is a copper-dependent and ROS-mediated prospective tumor therapy strategy. However, the complex tumor microenvironment (TME), low tumor specificity, poor therapy efficiency, and lack of imaging capability impair the therapy output of current cuproptosis drugs. Herein, we designed a dual-responsive two-dimensional metal-organic framework (2D MOF) nanotheranostic via a coordination self-assembly strategy using Au(III) tetra-(4-pyridyl) porphine (AuTPyP) as the ligand and copper ions (Cu2+) as nodes. The dual-stimulus combined with the protonation of the pyridyl group in AuTPyP and deep-penetration ultrasound (US) together triggered the controlled release in an acidic TME. The ultrathin structure (3.0 nm) of nanotheranostics promoted the release process. The released Cu2+ was reduced to Cu+ by depleting the overexpressed glutathione (GSH) in the tumor, which not only activated the Ferredoxin 1 (FDX1)-mediated cuproptosis but also catalyzed the overexpressed hydrogen peroxide (H2O2) in the tumor into reactive oxygen species via Fenton-like reaction. Simultaneously, the released AuTPyP could specifically bind with thioredoxin reductase and activate the redox imbalance of tumor cells. These together selectively induced significant mitochondrial vacuoles and prominent tumor cell death but did not damage the normal cells. The fluorescence and magnetic resonance imaging (MRI) results verified this nanotheranostic could target the HeLa tumor to greatly promote the self-enhanced effect of chemotherapy/cuproptosis and tumor inhibition efficiency. The work helped to elucidate the controlled assembly of multiresponsive nanotheranostics and the high-specificity ROS regulation for application in anticancer therapy.

Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer's disease.

BACKGROUND: Patients with Alzheimer's disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial. METHODS: Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated. RESULTS: APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV+ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice. CONCLUSION: Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.

Microemulsion-Assisted Self-Assembly of Indium Porphyrin Photosensitizers with Enhanced Photodynamic Therapy.

Designing and constructing supramolecular photosensitizer nanosystems with highly efficient photodynamic therapy (PDT) is vital in the nanomedical field. Despite recent advances in forming well-defined superstructures, the relationship between molecular arrangement in nanostructures and photodynamic properties has rarely been involved, which is crucial for developing stable photosensitizers for highly efficient PDT. In this work, through a microemulsion-assisted self-assembly approach, indium porphyrin (InTPP) was used to fabricate a series of morphology-controlled self-assemblies, including nanorods, nanospheres, nanoplates, and nanoparticles. They possessed structure-dependent 1O2 generation efficiency. Compared with the other three nanostructures, InTPP nanorods featuring strong π-π stacking, J-aggregation, and high crystallinity proved to be much more efficient at singlet oxygen (1O2) production. Also, theoretical modeling and photophysical experiments verified that the intermolecular π-π stacking in the nanorods could cause a decreased singlet-triplet energy gap (ΔEST) compared with the monomer. This played a key role in enhancing intersystem crossing and facilitating 1O2 generation. Both in vitro and in vivo experiments demonstrated that the InTPP nanorods could trigger cell apoptosis and tumor ablation upon laser irradiation (635 nm, 0.1 W/cm2) and exhibited negligible dark toxicity and high phototoxicity. Thus, the supramolecular self-assembly strategy provides an avenue for designing high-performance photosensitizer nanosystems for photodynamic therapy and beyond.

PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis.

Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary epithelial cells (MECs) to hormone signaling is key to avoiding breast cancer development. Here, we show that lactogenic differentiation of murine MECs requires silencing of genes encoding ribosomal RNA (rRNA) by the antisense transcript PAPAS. Accordingly, knockdown of PAPAS derepresses rRNA genes, attenuates the response to lactogenic hormones, and induces malignant transformation. Restoring PAPAS levels in breast cancer cells reduces tumorigenicity and lung invasion and activates many interferon-regulated genes previously linked to metastasis suppression. Mechanistically, PAPAS transcription depends on R-loop formation at the 3' end of rRNA genes, which is repressed by RNase H1 and replication protein A (RPA) overexpression in breast cancer cells. Depletion of PAPAS and upregulation of RNase H1 and RPA in human breast cancer underpin the clinical relevance of our findings.

A Review on the Application of Hospice Care in Patients with Advanced Cancer.

Hospice care is to improve the quality of life and help patients die comfortably, peacefully and dignified by controlling pain and discomfort symptoms and providing physical, psychological and spiritual care and humanistic care in the final stage of the patient's life. Hospice care clients were primarily cancer patients at first and then slowly extended to other critically patients. Hospice care can alleviate the physical, psychosocial and mental problems of patients with advanced cancer, meet the diversified and multi-level health service needs of patients, improve the quality of life of patients and their families, and also save medical expenditure and improve the efficiency of medical resources. At present, there were few studies on hospice care for Chinese patients with advanced cancer. In this study, the needs of hospice care for patients with advanced cancer were reviewed from physical comfort and pain reduction, dignity maintenance, social support, and help calm death, and specific screening and evaluation tools for hospice care for patients with advanced cancer. And this study was summarized to review the influencing factors of hospice care in order to provide a reference for clinical hospice care practice for patients with advanced cancer in China.

Conditional knockout of AIM2 in microglia ameliorates synaptic plasticity and spatial memory deficits in a mouse model of Alzheimer's disease.

AIMS: Synaptic dysfunction is a hallmark pathology of Alzheimer's disease (AD) and is strongly associated with cognitive impairment. Abnormal phagocytosis by the microglia is one of the main causes of synapse loss in AD. Previous studies have shown that the absence of melanoma 2 (AIM2) inflammasome activity is increased in the hippocampus of APP/PS1 mice, but the role of AIM2 in AD remains unclear. METHODS: Injection of Aß1-42 into the bilateral hippocampal CA1 was used to mimic an AD mouse model (AD mice). C57BL/6 mice injected with AIM2 overexpression lentivirus and conditional knockout of microglial AIM2 mice were used to confirm the function of AIM2 in AD. Cognitive functions were assessed with novel object recognition and Morris water maze tests. The protein and mRNA expression levels were evaluated by western blotting, immunofluorescence staining, and qRT-PCR. Synaptic structure and function were detected by Golgi staining and electrophysiology. RESULTS: The expression level of AIM2 was increased in AD mice, and overexpression of AIM2 induced synaptic and cognitive impairments in C57BL/6 mice, similar to AD mice. Elevated expression levels of AIM2 occurred in microglia in AD mice. Conditional knockout of microglial AIM2 rescued cognitive and synaptic dysfunction in AD mice. Excessive microglial phagocytosis activity of synapses was decreased after knockout of microglial AIM2, which was associated with inhibiting complement activation. CONCLUSION: Our results demonstrated that microglial AIM2 plays a critical role in regulating synaptic plasticity and memory deficits associated with AD, providing a new direction for developing novel preventative and therapeutic interventions for this disease.

Structure-based discovery of pyrazole-benzothiadiazole hybrid as human HPPD inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine catabolism. Only one commercial drug, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), clinically treat type I tyrosinemia, but show some severe side effects in clinical application. Here, we determined the structure of human HPPD-NTBC complex, and developed new pyrazole-benzothiadiazole 2,2-dioxide hybrids from the binding of NTBC. These compounds showed improved inhibition against human HPPD, among which compound a10 was the most active candidate. The Absorption Distribution Metabolism Excretion Toxicity (ADMET) predicted properties suggested that a10 had good druggability, and was with lower toxicity than NTBC. The structure comparison between inhibitor-bound and ligand-free form human HPPD showed a large conformational change of the C-terminal helix. Furthermore, the loop 1 and α7 helix were found adopting different conformations to assist the gating of the cavity, which explains the gating mechanism of human HPPD.

Synthesis and Biological Activity Evaluation of Benzoxazinone-Pyrimidinedione Hybrids as Potent Protoporphyrinogen IX Oxidase Inhibitor.

Protoporphyrinogen IX oxidase (PPO/Protox, E.C. 1.3.3.4) is recognized as one of the most important targets for herbicide discovery. In this study, we report our ongoing research efforts toward the discovery of novel PPO inhibitors. Specifically, we identified a highly potent new compound series containing a pyrimidinedione moiety and bearing a versatile building block-benzoxazinone scaffold. Systematic bioassays resulted in the discovery of compound 7af, ethyl 4-(7-fluoro-6-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate, which exhibited broad-spectrum and excellent herbicidal activity at the dosage of 37.5 g a.i./ha through postemergence application. The inhibition constant (Ki) value of 7af to Nicotiana tabacum PPO (NtPPO) was 14 nM, while to human PPO (hPPO), it was 44.8 µM, indicating a selective factor of 3200, making it the most selective PPO inhibitor to date. Moreover, molecular simulations further demonstrated the selectivity and the binding mechanism of 7af to NtPPO and hPPO. This study not only identifies a candidate that showed excellent in vivo bioactivity and high safety toward humans but also provides a paradigm for discovering PPO inhibitors with improved performance through molecular simulation and structure-guided optimization.

Dual-Site Förster Resonance Energy Transfer Route of Upconversion Nanoparticles-Based Brain-Targeted Nanotheranostic Boosts the Near-Infrared Phototherapy of Glioma.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with low survival, primarily due to the blood-brain barrier (BBB) and high infiltration. Upconversion nanoparticles (UCNPs)-based near-infrared (NIR) phototherapy with deep penetration is a promising therapy method against glioma but faces low photoenergy utilization that is induced by spectral mismatch and single-site Förster resonance energy transfer (FRET). Herein, we designed a brain-targeting NIR theranostic system with a dual-site FRET route and superior spectral matching to maximize energy utilization for synergistic photodynamic and photothermal therapy of glioma. The system was fabricated by Tm-doped UCNPs, zinc tetraphenylporphyrin (ZnTPP), and copper sulfide (CuS) nanoparticles under multioptimized modulation. First, the Tm-doping ratio was precisely adjusted to improve the relative emission intensity at 475 nm of UCNPs (11.5-fold). Moreover, the J-aggregate of ZnTPP increased the absorption at 475 nm (163.5-fold) of monomer; both together optimize the FRET matching between UCNPs and porphyrin for effective NIR photodynamic therapy. Simultaneously, the emission at 800 nm was utilized to magnify the photothermal effect of CuS nanoparticles for photothermal therapy via the second FRET route. After being modified by a brain-targeted peptide, the system efficiently triggers the synergistic phototherapy ablation of glioma cells and significantly prolongs the survival of orthotopic glioma-bearing mice after traversing the BBB and targeting glioma. This success of advanced spectral modulation and dual-site FRET strategy may inspire more strategies to maximize the photoenergy utilization of UCNPs for brain diseases.

A metabolomics-based analysis of the metabolic pathways associated with the regulation of branched-chain amino acids in rats fed a high-fructose diet.

Previous studies have shown that the elevated levels of circulating branched-chain amino acids (BCAAs) are associated with the development of insulin resistance and its complications, including obesity, type 2 diabetes, cardiovascular disease and some cancers. However, animal models that can mimic the metabolic state of chronically elevated BCAAs in humans are rare. Therefore, the aim of this study was to establish the above animal model and analyse the metabolic changes associated with high BCAA levels. Sixteen 8-week-old Sprague-Dawley (SD) rats were randomly divided into two groups and given either a high fructose diet or a normal diet. BCAA levels as well as blood glucose and lipid levels were measured at different time points of feeding. The mRNA expression levels of two key enzymes of BCAA catabolism, ACAD (acyl-CoA dehydrogenase) and BCKDH (branched-chain α-keto acid dehydrogenase), were measured by qPCR, and the protein expression levels of these two enzymes were analysed by immunohistochemistry. Finally, the metabolite expression differences between the two groups were analysed by Q300 metabolomics technology. Our study confirms that defects in the catabolic pathways of BCAAs lead to increased levels of circulating BCAAs, resulting in disorders of glucose and lipid metabolism characterized by insulin resistance by affecting metabolic pathways associated with amino acids and bile acids.

p18INK4C and BRCA1 inhibit follicular cell proliferation and dedifferentiation in thyroid cancer.

Only 3% of thyroid cancers are medullary thyroid carcinomas (MTCs), the rest are follicular epithelial cell derived non-MTCs (NMTCs). A dysfunctional INK4-CDK4-RB pathway is detected in most of NMTCs. DNA repair defects and genome instability are associated with NMTC dedifferentiation and aggressiveness. Whether inactivation of the INK4-CDK4-RB pathway induces NMTCs and how differentiation of NMTC cells is controlled remain elusive. In this study, we generated p18Ink4c and Brca1 singly and doubly deficient mice as well as p16Ink4a and Brca1 singly and doubly deficient mice. By using these mice and human thyroid carcinoma cell lines, we discovered that loss of p18Ink4c, not p16Ink4a, in mice stimulated follicular cell proliferation and induced NMTCs. Depletion of Brca1 alone or both p16Ink4a and Brca1 did not induce thyroid tumor. Depletion of Brca1 in p18Ink4c null mice results in poorly differentiated and aggressive NMTCs with epithelial-mesenchymal transition (EMT) features and enhanced DNA damage. Knockdown of BRCA1 in thyroid carcinoma cells activated EMT and promoted tumorigenesis whereas overexpression of BRCA1 inhibited EMT. BRCA1 and EMT marker expression were inversely related in human thyroid cancers. Our finding, for the first time, demonstrates that inactivation of INK4-CDK4-RB pathway induces NMTCs and that Brca1 deficiency promotes dedifferentiation of NMTC cells. These results suggest that BRCA1 and p18INK4C collaboratively suppress thyroid tumorigenesis and progression and CDK4 inhibitors will be effective for treatment of INK4-inactivated or cyclin D-overexpressed thyroid carcinomas.

Loss of function of GATA3 regulates FRA1 and c-FOS to activate EMT and promote mammary tumorigenesis and metastasis.

Basal-like breast cancers (BLBCs) are among the most aggressive cancers, partly due to their enrichment of cancer stem cells (CSCs). Breast CSCs can be generated from luminal-type cancer cells via epithelial-mesenchymal transition (EMT). GATA3 maintains luminal cell fate, and its expression is lost or reduced in BLBCs. However, deletion of Gata3 in mice or cells results in early lethality or proliferative defects. It is unknown how loss-of-function of GATA3 regulates EMT and CSCs in breast cancer. We report here that haploid loss of Gata3 in mice lacking p18Ink4c, a cell cycle inhibitor, up-regulates Fra1, an AP-1 family protein that promotes mesenchymal traits, and downregulates c-Fos, another AP-1 family protein that maintains epithelial fate, leading to activation of EMT and promotion of mammary tumor initiation and metastasis. Depletion of Gata3 in luminal tumor cells similarly regulates Fra1 and c-Fos in activation of EMT. GATA3 binds to FOSL1 (encoding FRA1) and FOS (encoding c-FOS) loci to repress FOSL1 and activate FOS transcription. Deletion of Fra1 or reconstitution of Gata3, but not reconstitution of c-Fos, in Gata3 deficient tumor cells inhibits EMT, preventing tumorigenesis and/or metastasis. In human breast cancers, GATA3 expression is negatively correlated with FRA1 and positively correlated with c-FOS. Low GATA3 and FOS, but high FOSL1, are characteristics of BLBCs. Together, these data provide the first genetic evidence indicating that loss of function of GATA3 in mammary tumor cells activates FOSL1 to promote mesenchymal traits and CSC function, while concurrently repressing FOS to lose epithelial features. We demonstrate that FRA1 is required for the activation of EMT in GATA3 deficient tumorigenesis and metastasis.

Discovery of a Subnanomolar Inhibitor of Protoporphyrinogen IX Oxidase via Fragment-Based Virtual Screening.

Protoporphyrinogen IX oxidase (PPO, E.C. 1.3.3.4), a key functional enzyme existing in various organisms, is acknowledged to be one of the most important action targets in the development of herbicides due to its pivotal roles in chlorophyll and heme biosynthesis pathways. As our persistent research work on the discovery of novel PPO-inhibiting herbicides, a new compound methyl 2-((5-(3-chloro-4,5,6,7-tetrahydro-2H-indazol-2-yl)-6-fluorobenzo[d]thiazol-2-yl)thio)acetate (8aj, Ki = 16 nM) was screened out as a hit compound via a fragment-based virtual screening method performed in the Auto Core Fragment in silico Screening web server. Subsequently, through a fused process of "hit-to-lead" optimization guided by molecular simulation, a total of 30 3-chloro-4,5,6,7-tetrahydro-2H-indazol-benzo[d]thiazole derivatives were synthesized and characterized. The results of the enzymatic inhibition bioassay showed that more than half of the newly synthesized compounds displayed higher activity against Nicotiana tabacum PPO (NtPPO) than oxadiazon, a commercial PPO-inhibiting herbicide. In particular, compound 8ab, a subnanomolar inhibitor with a Ki value of 380 pM against NtPPO, was discovered, which showed to be 71-fold more active than the commercial control oxadiazon (Ki = 27 nM), and was proven to be the most potent PPO inhibitor so far. Furthermore, the greenhouse assay demonstrated that most of the synthetic compounds showed good herbicidal activity toward the tested weeds. Especially, compound 8ad (Ki = 670 pM) showed the most promising post-emergence herbicidal activity with a broad spectrum of weed control even at a concentration as low as 37.5 g a.i./ha and relatively safe to rice at a dosage of 150 g a.i./ha, indicating that 8ad has the greatest potential to be developed as a new herbicide for weed control in paddy fields. This work provides a paradigm for the rational design and discovery of a novel PPO-inhibiting herbicide guided by the fragment-based drug design.

Cystofilobasidium josepaulonis sp. nov., a novel basidiomycetous yeast species.

A yeast strain belonging to the basidiomycetous yeast genus Cystofilobasidium was isolated from a marine sediment sample collected in an intertidal zone in Shandong province, PR China. The results of phylogenetic analyses based on sequences of the D1/D2 domain of the 26S ribosomal RNA gene and the internal transcribed spacer (ITS) region indicate that this strain, together with three other strains isolated from basal ice collected in Norway, the gut of an insect and an alga collected in Russia, represent a novel species of the genus, for which the name Cystofilobasidium josepaulonis sp. nov. (holotype strain CGMCC 2.6672T) is proposed. The novel species differs from the known species of the genus Cystofilobasidium by 1.7 %-4.1 and 11.3 %-17.1 % mismatches in the D1/D2 domain and the ITS region, respectively. This species forms teliospores on potato dextrose agar (PDA) and 10 % V8 juice agar, but teliospore germination with basidia was not observed.

Absent in melanoma 2 mediates aging-related cognitive dysfunction by acting on complement-dependent microglial phagocytosis.

Pattern separation (PS) dysfunction is a type of cognitive impairment that presents early during the aging process, and this deficit has been attributed to structural and functional alterations in the dentate gyrus (DG) of the hippocampus. Absent in melanoma 2 (AIM2) is an essential component of the inflammasome. However, whether AIM2 plays a role in aging-associated cognitive dysfunction remains unclear. Here, we found that PS function was impaired in aging mice and was accompanied by marked synaptic loss and increased expression of AIM2 in the DG. Subsequently, we used an AIM2 overexpression virus and mice with AIM2 deletion to investigate the role of AIM2 in regulating PS function and synaptic plasticity and the mechanisms involved. Our study revealed that AIM2 regulates microglial activation during synaptic pruning in the DG region via the complement pathway, leading to impaired synaptic plasticity and PS function in aging mice. These results suggest a critical role for AIM2 in regulating synaptic plasticity and PS function and provide a new direction for ameliorating aging-associated cognitive dysfunction.

Preparation of Naphthalenediimide-Decorated Electron-Deficient Photochromic Lanthanide (III)-MOF and Paper Strip as Multifunctional Recognition and Ratiometric Luminescent Turn-On Sensors for Amines and Pesticides.

Detecting toxic amine and pesticide contamination in the environment is one of the most pressing issues for environmental sustainability. In this work, two 3D Ln-BINDI complexes [Ln = Eu (1), Sm (2); H4BINDI (N, N'-bis(5-isophthalic acid)-1,4,5,8-naphthalenediimide)] have been designed and synthesized. Crystal structure of [Eu2(BINDI) (NO3)2(DMA)4]·2DMA (complex 1) featuring the lvt topology was determined by X-ray single-crystal diffraction. A multi-functional ratiometric luminescence sensor benefitting from π-electron-deficient NDI moieties and f-f transition characteristics of lanthanide Eu3+ ions for complex 1 has been investigated. Markedly, complex 1 exhibit completely different selective fluorescence ratiometric turn-on responses and pretty high sensitivity behaviors to aromatic amines (OPD), aliphatic amines (n-BA), and pesticides (TBZ), respectively, which are driven by interactions between the electron-donating amino group and acceptor NDI site, contributing to complex 1 as a potential ratiometric luminescent turn-on sensor for practical environmental applications. A PVA/1@paper strip can be used as a potential size selectivity sensor for the practical detection of aliphatic amine vapors in the environment through visual chromic fluorescence enhancement. Because NDIs can undergo one-electron reduction to form stable NDI· free radicals, solid complex 1 can visually distinguish different kinds of amines by selective amine-specific color changes and has the photochromic property of erasable inkless printing.