Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via coopted ubiquitin ligases have enormous potential to transform the field of medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) in the chemical literature, enable the controlled degradation of specific proteins via their direction to the cellular proteasome. In this report, we describe the second phase of our research focused on exploring antibody−drug conjugates (ADCs), which incorporate BRD4-targeting chimeric degrader entities. We employ a new BRD4-binding fragment in the construction of the chimeric ADC payloads that is significantly more potent than the corresponding entity utilized in our initial studies. The resulting BRD4-degrader antibody conjugates exhibit potent and antigen-dependent BRD4 degradation and antiproliferation activities in cell-based experiments. Multiple ADCs bearing chimeric BRD4-degrader payloads also exhibit strong, antigen-dependent antitumor efficacy in mouse xenograft assessments that employ several different tumor models.

No abstract

No abstract

No abstract

BackgroundNotch signaling is known to be activated following myocardial ischemia, but its role in cardioprotection provided by ischemic preconditioning (IPC) and ischemic postconditioning (IPost) remains unclear.MethodsLentiviral vectors were constructed to overexpress or knockdown N1ICD in H9c2 cardiomyocyte and rat heart exposed to ischemia reperfusion injury (IRI), IPC or IPost.ResultsNotch1 signaling was activated during myocardial IPC and IPost, and could enhance cell viability and inhibit apoptosis. Furthermore, activated Notch1 signaling stabilized mitochondrial membrane potential and reduced reactive oxygen species induced by IRI. The cardioprotection provided by activated Notch1 signaling resembled that of IPC and IPost, which was related to Stat3 activation and regulation of apoptosis related proteins. Furthermore, in langendorff heart perfusion model, activated Notch1 signaling restored cardiac function, decreased lactate dehydrogenase release and limited infarct size after myocardial ischemia. Conclusions: Notch1 signaling is activated and mediates cardioprotection provided by IPC and Ipost. Notch1 signaling may represent a potential new pharmacologic mimic for cardioprotection of ischemic heart disease.

Mycotoxins which mainly consist of Aflatoxin (AF), Zearalenone (ZEN) and Deoxynivalenol (DON) are commonly found in many food commodities. Although each component has been shown to cause liver toxicity and oxidative stress in several species, there is no evidence regarding the effect of naturally contained multiple mycotoxins on tissue toxicity and oxidative stress in vivo. In the present study, mycotoxins-contaminated maize (AF 597 µg/kg, ZEN 729 µg/kg, DON 3.1 mg/kg maize) was incorporated into the diet at three different doses (0, 5 and 20%) to feed the mice, and blood and tissue samples were collected to examine the oxidative stress related indexes. The results showed that the indexes of liver, kidney and spleen were all increased and the liver and kidney morphologies changed in the mycotoxin-treated mice. Also, the treatment resulted in the elevated glutathione peroxidase (GPx) activity and malondialdehyde (MDA) level in the serum and liver, indicating the presence of the oxidative stress. Moreover, the decrease of catalase (CAT) activity in the serum, liver and kidney as well as superoxide dismutase (SOD) activity in the liver and kidney tissue further confirmed the occurrence of oxidative stress. In conclusion, our data indicate that the naturally contained mycotoxins are toxic in vivo and able to induce the oxidant stress in the mouse.

No abstract

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are known to increase the risk of developing Alzheimer disease and Parkinson's disease (PD). However, the potential role of TREM2 effect on synucleinopathy has not been characterized. In this study, we investigated whether loss of TREM2 function affects α‐synucleinopathy both in vitro and in vivo. In vitro, BV2 microglial cells were exposed to α‐synuclein (α‐syn) in the presence or absence of TREM2 small interference RNA. For in vivo studies, wild‐type controls and TREM2 gene knockout mice were intracranially injected in the substantia nigra with adeno‐associated viral vectors expressing human α‐syn (AAV‐SYN) to induce PD. Our results revealed that knockdown of TREM2 aggravated α‐syn‐induced inflammatory responses in BV2 cells and caused greater apoptosis in SH‐SY5Y cells treated with BV2‐conditioned medium. In mice, TREM2 knockout exacerbated dopaminergic neuron loss in response to AAV‐SYN. Moreover, both in vitro and in vivo TREM2 deficiency induced a shift from an anti‐inflammatory toward a proinflammatory activation status of microglia. These data suggest that impairing microglial TREM2 signaling aggravates proinflammatory responses to α‐syn and exacerbates α‐syn‐induced neurodegeneration by modulating microglial activation state.—Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., Lou, H. TREM2 deficiency aggravates α‐synuclein‐induced neurodegeneration and neuroinflammation in Parkinson's disease models. FASEB J. 33, 12164–12174 (2019). http://www.fasebj.org