Dexmedetomidine Inhibits NF-κB-Transcriptional Activity in Neurons Undergoing Ischemia-Reperfusion by Regulating O-GlcNAcylation of SNW1.

Dexmedetomidine (Dex) is neuroprotective in ischemia-reperfusion (I/R) by suppressing inflammation but the underlying molecular mechanisms are not known. SNW domain-containing protein 1 (SNW1) is a coactivator of the pro-inflammatory transcription factor NF-κB p65. Because SNW1 is regulated by O-GlcNAcylation, we aimed to determine whether this modification influences NF-κB transcriptional activity in neurons undergoing I/R and how Dex may affect the O-GlcNAcylation of SNW1. SH-SY5Y and PC12 cells under hypoxia/reoxygenation (H/R) conditions were treated with Dex and with inhibitors of O-GlcNAc transferase (OGT). O-GlcNAc levels in SNW1 and effects of SNW1 on NF-κB p65 were determined by immunoprecipitation. H/R increased SNW1 protein levels but inhibited O-GlcNAcylation of SNW1. A Luciferase reporter assay demonstrated that increased SNW1 levels led to increased NF-κB p65 activity and increased secretion of neuron-derived inflammatory factors demonstrated by ELISA. Dex reversed the H/R-induced increase of SNW1 protein by upregulating OGT and enhancing O-GlcNAcylation of SNW1. Dex suppression of the SNW1/NF-κB complex resulted in neuroprotection in vitro and in a middle cerebral artery occlusion model in vivo. PKA and ERK1/2 inhibitors abolished the effect of Dex on OGT protein. Taken together, these data indicate that Dex inhibits NF-κB-transcriptional activity in neurons undergoing I/R by regulating O-GlcNAcylation of SNW1.

Association Between Wisdom and Psychotic-Like Experiences in the General Population: A Cross-Sectional Study.

Introduction: Wisdom has been empirically researched as a complex psychological characteristic that is associated with many mental health outcomes. However, its association with psychotic-like experiences (PLEs) remains unclear. This is the first work to assess wisdom, explore its association with PLEs, and test its moderating effect on the relation between the frequency of PLEs and their associated distress in the general population. Methods: From January 29th to February 5th, 2021, our online self-administered survey recruited 927 participants (ages 14 to 65) from thirteen Chinese provinces. Convenience sampling was employed. We measured wisdom with the 12-item three-dimensional wisdom scale (3D-WS-12) and PLEs with the 15-item positive subscale of the Community Assessment of Psychic Experiences (CAPE-P15). Results: Using the cut-off value of 1.47 in the mean frequency score, we divided our participants into high-PLEs group (188, 22.1%) and low-PLEs group (663, 77.9%). Three-dimensional wisdom score was decreased in the high-PLEs group compared to the low-PLEs group (Kruskal-Wallis t = 59.9, p < 0.001). Wisdom was associated with less frequent PLEs (Spearman's rho = -0.21, p < 0.01) and lower distress related to PLEs (Spearman's rho = -0.28) in the high-PLEs group (all above p < 0.001), which were replicated in the low-PLEs group. Notably, wisdom significantly attenuated the distress associated with PLEs [coefficient = -0.018, Bootstrap 95% CI (-0.029, -0.008)], but only in the low-PLEs group. Conclusion: Our results implicated that wisdom could protect individuals from distressful subclinical psychotic symptoms and wiser individuals have better general mental health.

Environmental enrichment ameliorates high-fat diet induced olfactory deficit and decrease of parvalbumin neurons in the olfactory bulb in mice.

Overweight induced by high-fat diet (HFD) represents one of the major health concerns in modern societies, which can cause lasting peripheral and central metabolic disorders in all age groups. Specifically, childhood obesity could lead to life-long impact on brain development and functioning. On the other hand, environmental enrichment (EE) has been demonstrated to be beneficial for learning and memory. Here, we explored the impact of high-fat diet on olfaction and organization of olfactory bulb cells in adolescent mice, and the effect of EE intervention thereon. Puberty mice (3-week-old) fed with HFD for 10 weeks exhibited poorer odor sensitivity and olfactory memory relative to controls consuming standard chows. The behavioral deficits were rescued in the HFD group with EE intervention. Neuroanatomically, parvalbumin (PV) interneurons in the olfactory bulb (OB) were reduced in the HFD-fed animals relative to control, while EE intervention also normalized this alteration. In contrast, cells expressing calbindin (CB), doublecortin (DCX) in the OB were not altered. Our findings suggest that PV interneurons may play a crucial role in mediating the HFD-induced olfactory deficit in adolescent mice, and can also serve a protective effect of EE against the functional deficit.

Overprotection and overcontrol in childhood: An evaluation on reliability and validity of 33-item expanded Childhood Trauma Questionnaire (CTQ-33), Chinese version.

Overprotection and overcontrol from parents or other family members, which are not rare in the Chinese culture, have been suggested to be traumatic experiences for some children. However, research on overprotection/overcontrol is much rarer in China compared with other childhood trauma subtypes. One of the possible reasons for this is the lack of easy and feasible screening tools. In this study, we therefore translated and validated a Chinese version of the 33-item Childhood Trauma Questionnaire (CTQ-33), which was expanded from the widely-used 28-item CTQ with an additional overprotection/overcontrol subscale. A total of 248 young healthy participants were recruited and completed the Chinese version of CTQ-33, and 50 of them were retested after an interval of two weeks. At baseline, all participants also completed the 9-item Patient Health Questionnaire and the 7-item Generalized Anxiety Disorder Scale to assess their depression and anxiety, respectively. Our main findings include that: (1) the Chinese version of CTQ-33 showed a good internal consistency (Cronbach's α coefficient = 0.733) and an excellent test-retest reliability over a two-week period (ICC = 0.861); (2) the previously reported significant associations between the overprotection/overcontrol and other subtypes of childhood trauma (abuse and neglect), as well as psychopathological conditions such as depression can all be replicated using the Chinese version of CTQ-33. These results suggest that the Chinese version of CTQ-33 would be a promising tool for assessing various subtypes of childhood adversities, especially the overprotection/overcontrol experiences in Chinese populations.

ER stress modulates apoptosis in A431 cell subjected to EtNBSe-PDT via the PERK pathway.

Photodynamic therapy (PDT) is a promising modality against various cancers including squamous cell carcinoma (SCC) with which the induction of apoptosis is an effective mechanism. Here, we initially describe the preclinical activity of 5-ethylamino-9-diethylaminobenzo [a] phenoselenazinium(EtNBSe)-mediated PDT treatment in SCC. Results of our studies suggest that EtNBSe-PDT provokes a cellular state of endoplasmic reticulum (ER) stress triggering the PERK/ eIF2α signaling pathway and induces the appearance of apoptosis in A431 cells at the meantime. With ER stress inhibitor 4-PBA or eIF2α inhibitor ISRIB, suppressing the EtNBSe-PDT induced ER stress substantially promotes apoptosis of A431 cells. Furthermore, we demonstrate that ATF4, whose expression is ER-stress-inducible and elevated in response to the PERK/eIF2α signaling pathway activation, contributes to cytoprotection against EtNBSe-PDT induced apoptosis. In a mouse model bearing A431 cells, EtNBSe shows intense phototoxicity and when associated with decreased ER stress, EtNBSe-PDT ameliorates tumor growth. Taken together, our study reveals an antagonistic activity of ER stress against EtNBSe-PDT treatment via inhibiting apoptosis in A431 cells. With further development, these results provide a proof-of-concept that downregulation of ER stress response has a therapeutic potential to improve EtNBSe-PDT sensitivity in SCC patients via the promotion of induced apoptosis.

Emerging Roles of Long Non-Coding RNAs in Renal Fibrosis.

Renal fibrosis is an unavoidable consequence that occurs in nearly all of the nephropathies. It is characterized by a superabundant deposition and accumulation of extracellular matrix (ECM). All compartments in the kidney can be affected, including interstitium, glomeruli, vasculature, and other connective tissue, during the pathogenesis of renal fibrosis. The development of this process eventually causes destruction of renal parenchyma and end-stage renal failure, which is a devastating disease that requires renal replacement therapies. Recently, long non-coding RNAs (lncRNAs) have been emerging as key regulators governing gene expression and affecting various biological processes. These versatile roles include transcriptional regulation, organization of nuclear domains, and the regulation of RNA molecules or proteins. Current evidence proposes the involvement of lncRNAs in the pathologic process of kidney fibrosis. In this review, the biological relevance of lncRNAs in renal fibrosis will be clarified as important novel regulators and potential therapeutic targets. The biology, and subsequently the current understanding, of lncRNAs in renal fibrosis are demonstrated-highlighting the involvement of lncRNAs in kidney cell function, phenotype transition, and vascular damage and rarefaction. Finally, we discuss challenges and future prospects of lncRNAs in diagnostic markers and potential therapeutic targets, hoping to further inspire the management of renal fibrosis.

Acidic pH and short-chain fatty acids activate Na+ transport but differentially modulate expression of Na+/H+ exchanger isoforms 1, 2, and 3 in omasal epithelium.

Low sodium content in feed and large amounts of salivary sodium secretion are essential requirements to efficient sodium reabsorption in the dairy cow. It is already known that Na(+)/H(+) exchange (NHE) of the ruminal epithelium plays a key role in Na(+) absorption, and its function is influenced by the presence of short-chain fatty acids (SCFA) and mucosal pH. By contrast, the functional role and regulation of NHE in omasal epithelium have not been completely understood. In the present study, we used model studies in small ruminants (sheep and goats) to investigate NHE-mediated Na(+) transport and the effects of pH and SCFA on NHE activity in omasal epithelium and on the expression of NHE isoform in omasal epithelial cells. Conventional Ussing chamber technique, primary cell culture, quantitative PCR, and Western blot were used. In native omasal epithelium of sheep, the Na(+) transport was electroneutral, and it was inhibited by the specific NHE3 inhibitor 3-[2-(3-guanidino-2-methyl-3-oxo-propenyl)-5-methyl-phenyl]-N-isopropylidene-2-methyl-acrylamide dihydrochloride, which decreased mucosal-to-serosal, serosal-to-mucosal, and net flux rates of Na(+) by 80% each. The application of low mucosal pH (6.4 or 5.8) in the presence of SCFA activated the Na(+) transport across omasal epithelium of sheep compared with that at pH 7.4. In cultured omasal epithelial cells of goats, mRNA and protein of NHE1, NHE2, and NHE3 were detected. The application of SCFA increased NHE1 mRNA and protein expression, which was most prominent when the culture medium pH decreased from 7.4 to 6.8. At variance, the mRNA and protein expression of NHE2 and NHE3 were decreased with low pH and SCFA, which was contrary to the published data from ruminal epithelial studies. In conclusion, this paper shows that (1) NHE1, NHE2, and NHE3 are expressed in omasal epithelium; (2) NHE3 mediates the major portion of transepithelial Na(+) transport in omasal epithelium; and (3) SCFA and acidic pH acutely activate Na(+) transport but suppress the expression of NHE2 and NHE3 in the longer term. By contrast, the expression of NHE1 is increased by SCFA and acidic pH, indicating a prominent role for NHE1 in the regulation of intracellular pH of omasal epithelium. Our results suggest a regulatable Na(+) absorption in ruminal and omasal epithelium. It is of benefit for intracellular pH homeostasis and highly relevant to dairy cows fed on high-concentrate diets.