Parkin deficiency promotes liver cancer metastasis by TMEFF1 transcription activation via TGF-ß/Smad2/3 pathway.

Parkin (PARK2) deficiency is frequently observed in various cancers and potentially promotes tumor progression. Here, we showed that Parkin expression is downregulated in liver cancer tissues, which correlates with poor patient survival. Parkin deficiency in liver cancer cells promotes migration and metastasis as well as changes in EMT and metastasis markers. A negative correlation exists between TMEFF1 and Parkin expression in liver cancer cells and tumor tissues. Parkin deficiency leads to upregulation of TMEFF1 which promotes migration and metastasis. TMEFF1 transcription is activated by Parkin-induced endogenous TGF-ß production and subsequent phosphorylation of Smad2/3 and its binding to TMEFF1 promotor. TGF-ß inhibitor and TMEFF1 knockdown can reverse shParkin-induced cell migration and changes of EMT markers. Parkin interacts with and promotes the ubiquitin-dependent degradation of HIF-1α/HIF-1ß and p53, which accounts for the suppression of TGF-ß production. Our data have revealed that Parkin deficiency in cancer leads to the activation of the TGF-ß/Smad2/3 pathway, resulting in the expression of TMEFF1 which promotes cell migration, EMT, and metastasis in liver cancer cells.

Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Hypothalamic CRF neurons facilitate brain reward function.

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.

The Molecular Gut-Brain Axis in Early Brain Development.

Millions of nerves, immune factors, and hormones in the circulatory system connect the gut and the brain. In bidirectional communication, the gut microbiota play a crucial role in the gut-brain axis (GBA), wherein microbial metabolites of the gut microbiota regulate intestinal homeostasis, thereby influencing brain activity. Dynamic changes are observed in gut microbiota as well as during brain development. Altering the gut microbiota could serve as a therapeutic target for treating abnormalities associated with brain development. Neurophysiological development and immune regulatory disorders are affected by changes that occur in gut microbiota composition and function. The molecular aspects relevant to the GBA could help develop targeted therapies for neurodevelopmental diseases. Herein, we review the findings of recent studies on the role of the GBA in its underlying molecular mechanisms in the early stages of brain development. Furthermore, we discuss the bidirectional regulation of gut microbiota from mother to infant and the potential signaling pathways and roles of posttranscriptional modifications in brain functions. Our review summarizes the role of molecular GBA in early brain development and related disorders, providing cues for novel therapeutic targets.

Stepwise clustering future meteorological drought projection and multi-level factorial analysis under climate change: A case study of the Pearl River Basin, China.

Climate change has significant impacts on the Pearl River Basin, and the regional ecological environment and human production may face severe challenges in the future due to changes in temperature and precipitation, as well as their derivative disasters (e.g., drought). Therefore, a full understanding of the possible impacts of climate change on Pearl River Basin is desired. In this study, the potential changes in temperature, precipitation, and drought conditions were projected through a stepwise clustering projection (SCP) model driven by multiple GCMs under two different RCPs. The developed model could facilitate specifying the inherently complex relationship between predictors and predictands, and its performance was proven to be great by comparing the observations and model simulations. A multi-level factorial analysis was employed to explore the major contributing factors to the variations in projecting drought conditions. The results suggested that the Pearl River Basin would suffer significant increasing trends in Tmean (i.e., 0.25-0.34 °C per decade under RCP4.5 and 0.42-0.60 °C per decade under RCP8.5), and the annual mean precipitation would increase under both RCPs. The drought events lasting for 1-2 months would be decreased by 7.7%, lasting for 3-4 months would be increased by 4.3%, and lasting for more than five months would be increased by 3.4% under RCP4.5, respectively. While they changed to 6.1%, 1.4%, and 4.7% under RCP8.5, respectively. More medium and long-term drought events with higher drought severity would occur. GCM has dominant influences on four different responses of drought duration, accounting for 50.20%, 52.61%, 56.71%, and 56.24% of total variabilities, respectively. Meanwhile, the effects explained by GCM*RCP interactions cannot be neglected, with an average contribution rate of 44.37%, 37.86%, 37.66%, and 35.83%, respectively.

Physiological functions of urea transporter B.

Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in endothelial cell membrane of the renal medulla and in other tissues, including the brain, heart, pancreas, colon, bladder, bone marrow, and cochlea. UT-B is responsible for the maintenance of urea concentration, male reproductive function, blood pressure, bone metabolism, and brain astrocyte and cardiac functions. Its deficiency and dysfunction contribute to the pathogenesis of many diseases. Actually, UT-B deficiency increases the sensitivity of bladder epithelial cells to apoptosis triggers in mice and UT-B-null mice develop II-III atrioventricular block and depression. The expression of UT-B in the rumen of cow and sheep may participate in digestive function. However, there is no systemic review to discuss the UT-B functions. Here, we update research approaches to understanding the functions of UT-B.

Arabidopsis SIMILAR TO RCD-ONE genes are ubiquitous and respond to multiple abiotic stresses through diverse signaling pathways.

The SIMILAR TO RCD-ONE (SROs) have been characterized as a group of plant-specific proteins which play important functions in stress responses and development. Here, we analyze the expression profiles of six SRO genes under different stress treatments in Arabidopsis. Our results revealed that RCD1 play an essential role in plant responses to various environmental stresses. SRO1 has partially overlapping functions with RCD1 in plant response to HgCl2 and H2O2 stress. Analysis of the transcriptional expression of SROs indicated that both of the RCD1 and SRO1 transcripts were up-regulated by HgCl2 and light, not by other stresses, and that of SRO5 was induced by salt. Expression of SRO3 and SRO4 were not influenced by stresses. The different effects of these stresses on the expression of the SRO genes indicate that the SRO family is regulated by multiple signaling pathways. Sequence analyses of the SRO proteins implicate a highly preserved protein structure and are specific to plants, which might have implications for functional conservation. The ubiquitous expression and nuclear localization of SRO family suggested that their function might be related to transcription factor regulation and complex formation. Taken together, SRO family is critical for proper plant development and multiple stress responses.

Fructus Psoraleae contains natural compounds with potent inhibitory effects towards human carboxylesterase 2.

Fructus Psoraleae (FP) is an edible Chinese herbal which is widely used in Asia for the treatment of various diseases including asthma, diarrhea, and osteoporosis. This study aimed to investigate the inhibitory effects of the crude ethanol extract from FP on human carboxylesterase 2 (hCE2), as well as to identity and characterize the naturally occurring inhibitors of hCE2 in FP. Our results demonstrated that the ethanol extract of FP displayed potent inhibitory effects towards hCE2, while five major bioactive constitutes in FP were efficiently identified by LC-DAD-ESI-MS/MS, with the aid of LC-based activity profiling. The identified bioactive compounds including neobavaisoflavone, isobavachalcone, bavachinin, corylifol A and bakuchiol were found to be naturally occurring potent inhibitors of hCE2, with low Ki values ranging from 0.62µM to 3.89µM. This is the first report of the chemical constitutes in FP as potent inhibitors of hCE2.