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Due to the poor stability and adverse effects of chemotherapy drugs, such as gemcitabine, the current effectiveness of traditional chemotherapy is minimal. Some patients also show a low response rate to immunotherapy. Therefore, a novel material PD‐L1‐GEMs is designed and synthesized with targeted specificity. PD‐L1‐GEMs specifically bind to bladder cancer cells. Free gemcitabine cleaved by a phosphatase enters bladder cancer cells through the macropinocytosis pathway and induces cytotoxicity. PD‐L1‐GEMs show good stability, binding specificity, and significant inhibitory effects in vitro. Two bladder tumor models (subcutaneous model and in situ model) show inhibition of growth and progression in PD‐L1‐GEMs treatment, as well as good biosafety in vivo. The PD‐L1 aptamer blocks the binding of PD‐L1 on the tumor cell surface to PD‐1 on T lymphocytes, restoring their immune function, inducing cytokine production and aggregation, and exerting an immune killing role on bladder cancer cells. PD‐L1‐GEMs represent a successful chemotherapy–immunotherapy strategy for bladder cancer. [ABSTRACT FROM AUTHOR]

T‐lymphokine‐activated killer cell‐originated protein kinase (TOPK) is a serine–threonine kinase that is overexpressed in gastric cancer (GC) and promotes tumor progression. Polyphyllin VII (PPVII), a pennogenin isolated from the rhizomes of Paris polyphylla, shows anticancer effects. Here, we explored the antitumor activity and mechanism of PPVII in GC. Ferroptosis was detected by transmission electron microscope, malondialdehyde, and iron determination assays. Autophagy and its upstream signaling pathway were detected by Western blot, and gene alterations. The binding of PPVII and TOPK was examined through microscale thermophoresis and drug affinity responsive target stability assays. An in vivo mouse model was performed to evaluate the therapeutic of PPVII. PPVII inhibits GC by inducing autophagy‐mediated ferroptosis. PPVII promotes the degradation of ferritin heavy chain 1, which is responsible for autophagy‐mediated ferroptosis. PPVII activates the Unc‐51‐like autophagy‐activating kinase 1 (ULK1) upstream of autophagy. PPVII inhibits the activity of TOPK, thereby weakening the inhibition of downstream ULK1. PPVII stabilizes the dimer of the inactive form of TOPK by direct binding. PPVII inhibits tumor growth without causing obvious toxicity in vivo. Collectively, this study suggests that PPVII is a potential agent for the treatment of GC by targeting TOPK to activate autophagy‐mediated ferroptosis. [ABSTRACT FROM AUTHOR]

Cardiomyopathy is a common disease of cardiac muscle that negatively affects cardiac function. HDAC3 commonly functions as corepressor by removing acetyl moieties from histone tails. However, a deacetylase‐independent role of HDAC3 has also been described. Cardiac deletion of HDAC3 causes reduced cardiac contractility accompanied by lipid accumulation, but the molecular function of HDAC3 in cardiomyopathy remains unknown. We have used powerful genetic tools in Drosophila to investigate the enzymatic and nonenzymatic roles of HDAC3 in cardiomyopathy. Using the Drosophila heart model, we showed that cardiac‐specific HDAC3 knockdown (KD) leads to prolonged systoles and reduced cardiac contractility. Immunohistochemistry revealed structural abnormalities characterized by myofiber disruption in HDAC3 KD hearts. Cardiac‐specific HDAC3 KD showed increased levels of whole‐body triglycerides and increased fibrosis. The introduction of deacetylase‐dead HDAC3 mutant in HDAC3 KD background showed comparable results with wild‐type HDAC3 in aspects of contractility and Pericardin deposition. However, deacetylase‐dead HDAC3 mutants failed to improve triglyceride accumulation. Our data indicate that HDAC3 plays a deacetylase‐independent role in maintaining cardiac contractility and preventing Pericardin deposition as well as a deacetylase‐dependent role to maintain triglyceride homeostasis. [ABSTRACT FROM AUTHOR]

G protein pathway suppressor 2 (GPS2) is expressed in most human tissues, including the stomach. However, the biological functions of GPS2 in cancer, as well as the underlying molecular mechanisms, remain poorly understood. Here, we report that GPS2 expression was aberrantly downregulated in gastric cancer (GC) tissues compared with control tissues. Clinicopathologic analysis showed that low GPS2 expression was significantly correlated with pathological grade, lymph node stage, and invasive depth. Kaplan‐Meier analysis indicated that patients with low GPS2 expression showed poorer overall survival rates than those with high GPS2 expression. Moreover, GPS2 overexpression decreased GC cell proliferation, colony formation, tumorigenesis, and invasion. Overexpression of GPS2 reduced the protein expression of epidermal growth factor receptor (EGFR) and inhibited its downstream signaling in GC cells. Interestingly, GPS2 decreased EGFR protein expression, which was reversed by a lysosome inhibitor. Furthermore, GPS2 reduced EGFR protein stability by enhancing the binding of EGFR and an E3 ligase, c‐Cbl, which promoted the ubiquitination of EGFR, ultimately leading to its degradation through the lysosomal pathway. Further analysis indicated that GPS2 activated autophagy and promoted the autophagic flux by destabilizing EGFR. Taken together, these results suggest that low GPS2 expression is associated with GC progression and provide insights into the applicability of the GPS2‐EGFR axis as a potential therapeutic target in GC. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a disabling neurodegenerative disease mainly caused by degeneration of mesencephalic dopaminergic neurons in the substantia nigra pars compacta (SNpc). The neuroprotective role of Na+/H+ exchangers isoform‐1 (NHE1) inactivation in cerebral ischemic damage has been elucidated. The current study aimed to investigate the impacts of NHE1 in PD. In this study, 6‐hydroxydopamine (6‐OHDA)‐induced PD rat models were established to attempt to illuminate the role and underlying mechanisms of NHE1 in SNpc neurons of PD. Meanwhile, nerve growth factor‐stimulated PC12 cells followed by 6‐OHDA treatment was used to mimic PD in vitro. Results showed that the protein levels of NHE1 were significantly increased in the SNpc neurons of rats and differentiated PC12 cells after 6‐OHDA treatment. Inactivation of NHE1 with chemical inhibitor HOE642 suppressed SNpc neuronal loss and NHE1 expression in PD rats. The overlays of tyrosine hydroxylase and NHE1 displayed that NHE1 expression was not colocalized but closely associated with TH. Besides, treatment with HOE642 relieved the dyskinesia, mitochondrial dysfunction, and neuronal apoptosis. Further in vitro evidence confirmed that inhibition of NHE1 by genetic‐knockdown prevented mitochondrial dysfunction and apoptosis. Our study represents the first experimental evidence of a potential role for NHE1 in the pathogenesis of PD. [ABSTRACT FROM AUTHOR]

Summary: Sulfurimonas species (class Campylobacteria, phylum Campylobacterota) were globally distributed and especially predominant in deep‐sea hydrothermal environments. They were previously identified as chemolithoautotrophic sulfur‐oxidizing bacteria (SOB), whereas little is known about their potential in sulfur reduction. In this report, we found that the elemental sulfur reduction is quite common in different species of genus Sulfurimonas. To gain insights into the sulfur reduction mechanism, growth tests, morphology observation, as well as genomic and transcriptomic analyses were performed on a deep‐sea hydrothermal vent bacterium Sulfurimonas sp. NW10. Scanning electron micrographs and dialysis tubing tests confirmed that elemental sulfur reduction occurred without direct contact of cells with sulfur particles while direct access strongly promoted bacterial growth. Furthermore, we demonstrated that most species of Sulfurimonas probably employ both periplasmic and cytoplasmic polysulfide reductases, encoded by genes psrA1B1CDE and psrA2B2, respectively, to accomplish cyclooctasulfur reduction. This is the first report showing two different sulfur reduction pathways coupled to different energy conservations could coexist in one sulfur‐reducing microorganism, and demonstrates that most bacteria of Sulfurimonas could employ both periplasmic and cytoplasmic polysulfide reductases to perform cyclooctasulfur reduction. The capability of sulfur reduction coupling with hydrogen oxidation may partially explain the prevalenceof Sulfurimonas in deep‐sea hydrothermal vent environments. [ABSTRACT FROM AUTHOR]

We model the interaction of financial market transparency and different accounting regimes. This paper provides a theoretical rationale for the recently proposed shift in accounting standards from historic cost accounting to marking to market. The paper shows that marking to market can provide investors with an early warning mechanism while historical cost gives management a “veil” under which they can potentially mask a firm's true economic performance. The model provides new explanations for several empirical findings and has some novel implications. We show that greater opacity in financial markets leads to more frequent and more severe crashes in asset prices (under a historic-cost-accounting regime). Moreover, our model indicates that historic cost accounting can make the financial market more rather than less volatile, which runs counter to conventional wisdom. The mechanism shown in the model also sheds light on the cause of many financial scandals in recent years. [ABSTRACT FROM AUTHOR]

A new polypyridyl ligand containing a nitro group and two new ruthenium complexes of it were synthesized. The two complexes exhibited non‐dppz DNA ‘light switch’ effects after interaction with calf thymus DNA. Introducing both electron‐withdrawing group (─ NO2) and electron‐donating group (─ CH3) may be the reason that the two complexes display DNA ‘light switch’ behaviors. Furthermore, one of the complexes showed higher photocleavage activity, topoisomerase I inhibition activity and DNA affinity than the other. The present work shows that the more active complex can be employed as a non‐dppz DNA ‘light switch’, DNA photocleaver and topoisomerase I inhibitor. In addition, the two complexes have no or weak cytotoxic activities against Eca‐109 and A549 cells. [ABSTRACT FROM AUTHOR]