Electroacupuncture Promotes Proliferation of Amplifying Neural Progenitors and Preserves Quiescent Neural Progenitors from Apoptosis to Alleviate Depressive-Like and Anxiety-Like Behaviours

The present study was designed to investigate the effects of electroacupuncture (EA) on depressive-like and anxiety-like behaviours and neural progenitors in the hippocampal dentate gyrus (DG) in a chronic unpredictable stress (CUS) rat model of depression. After being exposed to a CUS procedure for 2 weeks, rats were subjected to EA treatment, which was performed on acupoints Du-20 (Bai-Hui) and GB-34 (Yang-Ling-Quan), once every other day for 15 consecutive days (including 8 treatments), with each treatment lasting for 30 min. The behavioural tests (i.e., forced swimming test, elevated plus-maze test, and open-field entries test) revealed that EA alleviated the depressive-like and anxiety-like behaviours of the stressed rats. Immunohistochemical results showed that proliferative cells (BrdU-positive) in the EA group were significantly larger in number compared with the Model group. Further, the results showed that EA significantly promoted the proliferation of amplifying neural progenitors (ANPs) and simultaneously inhibited the apoptosis of quiescent neural progenitors (QNPs). In a word, the mechanism underlying the antidepressant-like effects of EA is associated with enhancement of ANPs proliferation and preserving QNPs from apoptosis

A tailored series of engineered yeasts for the cell-dependent treatment of inflammatory bowel disease by rational butyrate supplementation

ABSTRACTIntestinal microbiota dysbiosis and metabolic disruption are considered essential characteristics in inflammatory bowel disorders (IBD). Reasonable butyrate supplementation can help patients regulate intestinal flora structure and promote mucosal repair. Here, to restore microbiota homeostasis and butyrate levels in the patient’s intestines, we modified the genome of Saccharomyces cerevisiae to produce butyrate. We precisely regulated the relevant metabolic pathways to enable the yeast to produce sufficient butyrate in the intestine with uneven oxygen distribution. A series of engineered strains with different butyrate synthesis abilities was constructed to meet the needs of different patients, and the strongest can reach 1.8 g/L title of butyrate. Next, this series of strains was used to co-cultivate with gut microbiota collected from patients with mild-to-moderate ulcerative colitis. After receiving treatment with engineered strains, the gut microbiota and the butyrate content have been regulated to varying degrees depending on the synthetic ability of the strain. The abundance of probiotics such as Bifidobacterium and Lactobacillus increased, while the abundance of harmful bacteria like Candidatus Bacilloplasma decreased. Meanwhile, the series of butyrate-producing yeast significantly improved trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice by restoring butyrate content. Among the series of engineered yeasts, the strain with the second-highest butyrate synthesis ability showed the most significant regulatory and the best therapeutic effect on the gut microbiota from IBD patients and the colitis mouse model. This study confirmed the existence of a therapeutic window for IBD treatment by supplementing butyrate, and it is necessary to restore butyrate levels according to the actual situation of patients to restore intestinal flora

Additional file 2: Figure S2. of Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors

There was no significant sexual difference in the mice model of depression induced by chronic unpredictable stress. (A) Experimental paradigm. Wild-type C57BL6/J (WT) male and female mice were exposed to CUS for 35 days. Behavioral indicators were then assessed, including (B) immobility time in forced swimming test (FST) (interaction: F1,34 = 0.0003, p = 0.9857; stress: F1,34 = 26.51, p < 0.0001; sex: F1,34 = 0.4940, p = 0.4869), (C) the number of rearing in open-field test (OFT) (interaction: F1,34 = 0.01154, p = 0.9151; stress: F1,34 = 20.44, p < 0.0001; sex: F1,34 = 0.1414, p = 0.7092), (D) total distance in open-field test (OFT) (interaction: F1,34 = 0.03584, p = 0.8510; stress: F1,34 = 4.501, p = 0.0412; sex: F1,34 = 0.1341, p = 0.7165), (E) open-arm entrance percent in elevated plus maze test (EPM) (interaction: F1,34 = 0.1817, p = 0.6728; stress: F1,34 = 16.47, p = 0.0003; sex: F1,34 = 7.879, p = 0.0084), (F) open-arm time percent in elevated plus maze test (EPM) (interaction: F1,34 = 0.7491, p = 0.3932; stress: F1,34 = 5.100, p = 0.0309; sex: F1,34 = 0.2789, p = 0.6011) n = 8–12 per group, all data are expressed as the mean ± SEM. # p < 0.05, ## p < 0.01, ### p < 0.001, compared to male before CUS. *p < 0.05 and **p < 0.01, compared to female before CUS. (G) Experimental paradigm. Wild-type C57BL6/J (WT) and P2X7-null female mice were exposed to CUS for 35 days. Behavioral indicators were then assessed, including (H) immobility time in forced swimming test (FST) (interaction: F1,23 = 1.038, p = 0.3188; stress: F1,23 = 8.155, p = 0.0089; genotype: F1,23 = 1.610, p = 0.2171), (I) the number of rearing in open-field test (OFT) (interaction: F1,23 = 3.690, p = 0.0672; stress: F1,23 = 3.929, p = 0.0595; genotype: F1,23 = 1.221, p = 0.2805), (J) total distance in open-field test (OFT) (interaction: F1,23 = 4.348, p = 0.0483; stress: F1,23 = 0.2596, p = 0.6153; genotype: F1,23 = 2.684, p = 0.1150), (K) open-arm entrance percent in elevated plus maze test (EPM) (interaction: F1,23 = 5.294, p = 0.0308; stress: F1,23 = 2.595, p = 0.1208; genotype: F1,23 = 1.976, p = 0.1732), and (L) open-arm time percent in elevated plus maze test (EPM) (interaction: F1,23 = 5.914, p = 0.0232; stress: F1,23 = 3.100, p = 0.0916; genotype: F1,23 = 3.463, p = 0.0756). n = 5–8 per group, all data are expressed as the mean ± SEM. # p < 0.05, ## p < 0.01, ### p < 0.001, compared to wild-type before CUS. p < 0.05, comparing genotypes. (TIF 9760 kb

Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries

status: publishe

GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)

Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool <b>1</b> (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of <b>1</b> into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure–activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant <b>19</b> (GNE-781, TR-FRET IC₅₀ = 0.94 nM, BRET IC₅₀ = 6.2 nM; BRD4(1) IC₅₀ = 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound <b>19</b> displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner

Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300

The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure–activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded <b>59</b> (GNE-272, TR-FRET IC₅₀ = 0.02 μM, BRET IC₅₀ = 0.41 μM, BRD4(1) IC₅₀ = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound <b>59</b> showed a marked antiproliferative effect in hematologic cancer cell lines and modulates <i>MYC</i> expression in vivo that corresponds with antitumor activity in an AML tumor model