By using the Hirota bilinear form of the KP equation, twelve classes of lump–kink solutions are presented under the help of symbolic computations with Maple. Analyticity is naturally achieved by ...taking special choices of the involved parameters to guarantee a positive constant term. A key step in generating lump–kink solutions is to combine quadratic functions and the exponential function in the second-order logarithmic derivative transformation.
Ferulic acid (FA) has potential therapeutic effects in multiple diseases including cardiovascular diseases. However, the effect and molecular basis of FA in heart failure (HF) has not been thoroughly ...elucidated. Herein, we investigated the roles and mechanisms of FA in HF in isoproterenol (ISO)-induced HF rat model. Results found that FA ameliorated cardiac dysfunction, alleviated oxidative stress, reduced cell/myocardium injury-related enzyme plasma level, inhibited cardiocyte apoptosis in ISO-induced HF rat models. Moreover, FA reduced the co-localization of Keap1 and nuclear factor-E2-related factor 2 (Nrf2) in heart tissues of ISO-induced HF rats, and FA alleviated the inhibitory effects of ISO on expressions of p-Nrf2, heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1). Additionally, Nrf2 signaling pathway inhibitor ML385 showed adverse effects. FA weakened the effects of ML385 in ISO-induced HF rat models. Collectively, FA ameliorated HF by decreasing oxidative stress and inhibiting cardiocyte apoptosis via activating Nrf2 pathway in ISO-induced HF rats. Our data elucidated the underling molecular mechanism and provided a novel insight into the cardioprotective function of FA, thus suggested the therapeutic potential of FA in HF treatment.
Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel ...the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.
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•HCC-cell-derived ectosomal PKM2 induces monocyte-to-macrophage differentiation•Remodeling tumor microenvironment by ectosomal PKM2 promotes HCC progression•Sumoylation facilitates PKM2 sorting into ectosomes in an ARRDC1-dependent manner•Macrophage-secreted CCL1 reinforces PKM2 ectosomal excretion in a feedforward loop
Hou et al. demonstrate that sumoylation facilitates ectosomal excretion of PKM2 from HCC cells, which remodels the tumor microenvironment to promote HCC progression through inducing monocyte-to-macrophage differentiation. Macrophage-secreted CCL1 in tumor microenvironment further enhances ectosomal excretion of PKM2. The plasma ectosomal PKM2 is a potential early diagnostic marker for HCC.
A general catalytic hydrogen transfer‐mediated α‐functionalization of 1,8‐naphthyridines is reported for the first time that benefits from a hydrogen transfer‐mediated activation mode for ...non‐activated pyridyl cores. The pyridyl α‐site selectively couples with the C8‐site of various tetrahydroquinolines (THQs) to afford novel α‐functionalized tetrahydro 1,8‐naphthyridines, a class of synthetically useful building blocks and potential candidates for the discovery of therapeutic and bio‐active products. The utilization of THQs as inactive hydrogen donors (HDs) appears to be a key strategy to overcome the over‐hydrogenation barrier and address the chemoselectivity issue. The developed chemistry features operational simplicity, readily available catalyst and good functional group tolerance, and offers a significant basis for further development of new protocols to directly transform or functionalize inert N‐heterocycles.
Two become one: A general catalytic hydrogen‐transfer‐mediated α‐functionalization of 1,8‐naphthyridines is reported for the first time. The pyridyl α‐site selectively couples with the C8‐site of various tetrahydroquinolines to afford novel tetrahydro‐1,8‐naphthyridines (see scheme). The reaction features operational simplicity, a readily available catalyst and good functional group tolerance.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to ...suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.
Limb‐girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a specific LGMD caused by a gene mutation encoding the calcium‐dependent neutral cysteine protease calpain‐3 ...(CAPN3). In our study, the compound heterozygosity with two missense variants c.635 T > C (p.Leu212Pro) and c.2120A > G (p.Asp707Gly) was identified in patients with LGMDR1. However, the pathogenicity of c.635 T > C has not been investigated. To evaluate the effects of this novel likely pathogenic variant to the motor system, the mouse model with c.635 T > C variant was prepared by CRISPR/Cas9 gene editing technique. The pathological results revealed that a limited number of inflammatory cells infiltrated the endomyocytes of certain c.635 T > C homozygous mice at 10 months of age. Compared with wild‐type mice, motor function was not significantly impaired in Capn3 c. 635 T > C homozygous mice. Western blot and immunofluorescence assays further indicated that the expression levels of the Capn3 protein in muscle tissues of homozygous mice were similar to those of wild‐type mice. However, the arrangement and ultrastructural alterations of the mitochondria in the muscular tissues of homozygous mice were confirmed by electron microscopy. Subsequently, muscle regeneration of LGMDR1 was simulated using cardiotoxin (CTX) to induce muscle necrosis and regeneration to trigger the injury modification process. The repair of the homozygous mice was significantly worse than that of the control mice at day 15 and day 21 following treatment, the c.635 T > C variant of Capn3 exhibited a significant effect on muscle regeneration of homozygous mice and induced mitochondrial damage. RNA‐sequencing results demonstrated that the expression levels of the mitochondrial‐related functional genes were significantly downregulated in the mutant mice. Taken together, the results of the present study strongly suggested that the LGMDR1 mouse model with a novel c.635 T > C variant in the Capn3 gene was significantly dysfunctional in muscle injury repair via impairment of the mitochondrial function.
A novel missense variants c.635 T > C (p.Leu212Pro) was identified in patients with LGMDR1. The mouse model with c.635 T > C variant was prepared by CRISPR/Cas9 gene editing technique. Muscle regeneration of LGMDR1 was simulated using cardiotoxin (CTX) to induce muscle necrosis and regeneration to trigger the injury modification process. The repair of the mouse model was significantly worse at day 21 days following treatment, the c.635 T > C variant of Capn3 exhibited a significant effect on muscle regeneration and induced mitochondrial damage. RNA‐sequencing results demonstrated that the expression levels of the mitochondrial‐related functional genes were significantly downregulated in the mu‐tant mice. Taken together, the results of the present study strongly suggested that the LGMDR1 mouse model with a novel c.635 T > C variant in the Capn3 gene was significantly dysfunctional in muscle injury repair via impairment of the mitochondrial function.
Gluconeogenesis, an essential metabolic process for hepatocytes, is downregulated in hepatocellular carcinoma (HCC). Here we show that the nuclear receptor Nur77 is a tumour suppressor for HCC that ...regulates gluconeogenesis. Low Nur77 expression in clinical HCC samples correlates with poor prognosis, and a Nur77 deficiency in mice promotes HCC development. Nur77 interacts with phosphoenolpyruvate carboxykinase (PEPCK1), the rate-limiting enzyme in gluconeogenesis, to increase gluconeogenesis and suppress glycolysis, resulting in ATP depletion and cell growth arrest. However, PEPCK1 becomes labile after sumoylation and is degraded via ubiquitination, which is augmented by the p300 acetylation of ubiquitin-conjugating enzyme 9 (Ubc9). Although Nur77 attenuates sumoylation and stabilizes PEPCK1 via impairing p300 activity and preventing the Ubc9-PEPCK1 interaction, Nur77 is silenced in HCC samples due to Snail-mediated DNA methylation of the Nur77 promoter. Our study reveals a unique mechanism to suppress HCC by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation.
The development of nontoxic and stable all-inorganic perovskite nanocrystals (NCs) represents a major challenge to unlock widely practical applications in photoelectric fields. It is an effective ...strategy to discover nontoxic metal perovskite nanocrystals (NCs) with excellent optical properties. In addition, it has been proved that alkali metals such as rubidium (Rb) and potassium (K) have a good influence on improving the optical performance of perovskites. Hence, we reported new lead-free perovskite Rb7Bi3Cl16 single crystals, which displayed a zero-dimensional cluster structure and were composed of two kinds of octahedra with different distortions. At the same time, we synthesized its NCs, which showed a blue emission at 437 nm with a PLQY of 28.43% and presented a good optical and moisture stability for one month. The excellent moisture-stability might be attributed to their much higher ratio of Rb atoms and the ideal BiCl63− octahedra on the surface, which are beneficial to form an inorganic BiOCl shell to protect the Rb7Bi3Cl16 NCs from moisture attack.
Organoids hold inestimable therapeutic potential in regenerative medicine and are increasingly serving as an in vitro research platform. Still, their expanding applications are critically restricted ...by the canonical culture matrix and system. Synthesis of a suitable bioink of bioactivity, biosecurity, tunable stiffness, and printability to replace conventional matrices and fabricate customized culture systems remains challenging. Here, we envisaged a novel bioink formulation based on decellularized extracellular matrix (dECM) from porcine small intestinal submucosa for organoids bioprinting, which provides intestinal stem cells (ISCs) with niche‐specific ECM content and biomimetic microstructure. Intestinal organoids cultured in the fabricated bioink exhibited robust generation as well as a distinct differentiation pattern and transcriptomic signature. This bioink established a new co‐culture system able to study interaction between epithelial homeostasis and submucosal cells and promote organoids maturation after transplantation into the mesentery of immune‐deficient NODSCID‐gamma (NSG) mice. In summary, the development of such photo‐responsive bioink has the potential to replace tumor‐derived Matrigel and facilitate the application of organoids in translational medicine and disease modeling.
The development of nontoxic and stable all-inorganic perovskite nanocrystals (NCs) represents a major challenge to unlock widely practical applications in photoelectric fields. It is an effective ...strategy to discover nontoxic metal perovskite nanocrystals (NCs) with excellent optical properties. In addition, it has been proved that alkali metals such as rubidium (Rb) and potassium (K) have a good influence on improving the optical performance of perovskites. Hence, we reported new lead-free perovskite Rb7Bi3Cl16 single crystals, which displayed a zero-dimensional cluster structure and were composed of two kinds of octahedra with different distortions. At the same time, we synthesized its NCs, which showed a blue emission at 437 nm with a PLQY of 28.43% and presented a good optical and moisture stability for one month. The excellent moisture-stability might be attributed to their much higher ratio of Rb atoms and the ideal BiCl63- octahedra on the surface, which are beneficial to form an inorganic BiOCl shell to protect the Rb7Bi3Cl16 NCs from moisture attack.
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