Microglial forkhead box O3a deficiency attenuates LPS-induced neuro-inflammation and depressive-like behaviour through regulating the expression of peroxisome proliferator-activated receptor-γ.

Background And Purpose: Depression is closely linked with microglial activation and neuro-inflammation. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in M2 activation of microglia. Forkhead box (FOX) O3a has been implicated in the regulation of mood-relevant behaviour.

Microglial FoxO3a deficiency ameliorates ferroptosis-induced brain injury of intracerebral haemorrhage via regulating autophagy and heme oxygenase-1.

Microglial HO-1 regulates iron metabolism in the brain. Intracerebral haemorrhage (ICH) shares features of ferroptosis and necroptosis; hemin is an oxidized product of haemoglobin from lysed red blood cells, leading to secondary injury. However, little is known about the underlying molecular mechanisms attributable to secondary injury by hemin or ICH.

Role of omentin-1 in susceptibility to anxiety and depression like behaviors.

Neuro-inflammation and blood-brain barrier (BBB) dysfunction are associated with depression. Evidence shows that adipokines enter the brain from the circulation, which regulates depressive behaviors. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about its role in neuro-inflammation and mood-relevant behavior.

Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis.

Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays an important role in cell metabolism, mitochondrial dysfunction and oxidative stress response. Although the AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway plays a pivotal role in maintaining energy homeostasis under conditions of energy stress, the role of AMPK/FoxO3a signaling in mitochondria-associated ferroptosis has not yet been fully elucidated.

Design, Synthesis and Anti-Tumor Activity Evaluation of Novel 3,4-(Methylenedioxy)cinnamic Acid Amide-Dithiocarbamate Derivatives.

The fragments, 3,4-(methylenedioxy)cinnamic acid amide and dithiocarbamates, have received increasing attention because of their multiple pharmacological activities in recent years, especially in anti-tumor. We synthesized 17 novel 3,4-(methylenedioxy)cinnamic acid amide-dithiocarbamate derivatives based on the principle of pharmacophore assembly and discovered that compound 4a displayed the most potent antiproliferative activity against HeLa cells with IC value of 1.01 μM.

Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Background: Alzheimer's disease (AD) belongs to neurodegenerative disease, and the increasing number of AD patients has placed a heavy burden on society, which needs to be addressed urgently. ChEs/MAOs dual-target inhibitor has potential to treat AD according to reports.

Purpose: To obtain effective multi-targeted agents for the treatment of AD, a novel series of hybrid compounds were designed and synthesized by fusing the pharmacophoric features of 3,4-dihydro-2 (1)-quinolinone and dithiocarbamate.

Intermediate monocytes induced by IFN-γ inhibit cancer metastasis by promoting NK cell activation through FOXO1 and interleukin-27.

Background: Circulating monocytes are functionally heterogeneous and can be divided into classical (CMo), intermediate (IMo), and non-CMo/patrolling monocyte (PMo) subsets. CMo can differentiate into PMo through IMo. PMos have been shown to inhibit cancer metastasis but the role of IMo is unclear.

FoxO3a cooperates with RUNX1 to promote chondrogenesis and terminal hypertrophic of the chondrogenic progenitor cells.

FoxO transcription factors (FoxOs) have recently been shown to protect against chondrocyte dysfunction and modulate cartilage homeostasis in osteoarthritis. The mechanism underlying of FoxOs regulate chondrocyte differentiation remains unknown. Runt related transcription factor 1 (RUNX1) mediated both chondrocyte and osteoblast differentiation.

Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer's disease.

In this study, a series of multifunctional hybrids against Alzheimer's disease were designed and obtained by conjugating the pharmacophores of xanthone and alkylbenzylamine through the alkyl linker. Biological activity results demonstrated that compound 4j was the most potent and balanced dual ChEs inhibitor with IC values 0.85 μM and 0.

Val-Val-Tyr-Pro protects against non-alcoholic steatohepatitis in mice by modulating the gut microbiota and gut-liver axis activation.

Val-Val-Tyr-Pro (VVYP) peptide is one of the main active components of Globin digest (GD). Our previous studies indicated that VVYP could protect against acetaminophen and carbon tetrachloride-induced acute liver failure in mice and decrease blood lipid level. However, the effects and underlying mechanisms of VVYP in the treatment of non-alcoholic steatohepatitis (NASH) have not been discovered.

Hemolysis inhibits humoral B-cell responses and modulates alloimmunization risk in patients with sickle cell disease.

Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely unknown. Intravascular hemolysis, a hallmark of SCD, results in the release of heme with potent immunomodulatory activity, although its effect on SCD humoral response, specifically alloimmunization, remains unclear. Here, we found that cell-free heme suppresses human B-cell plasmablast and plasma cell differentiation by inhibiting the DOCK8/STAT3 signaling pathway, which is critical for B-cell activation, as well as by upregulating heme oxygenase 1 (HO-1) through its enzymatic byproducts, carbon monoxide and biliverdin.

FoxO3a suppresses neuropeptide W expression in neuronal cells and in rat hypothalamus and its implication in hypothalamic-pituitary-adrenal (HPA) axis.

FoxO3a, a forkhead family member of transcription factors, is involved in the regulation of cell metabolism, proliferation, differentiation and apoptosis. However, whether FoxO3a participates in the regulation of glucocorticoids induced-hypothalamic-pituitary-adrenal (HPA) dysfunction is still unknown. Our present results indicate that dexamethasone(DEX) increased FoxO3a expression in PC12 and hypothalamic neuronal cultures in correlation to reduced expression of NPW, a process that could be blocked by GR2 antagonist.

Design, synthesis and biological evaluation of coumarin-based N-hydroxycinnamamide derivatives as novel histone deacetylase inhibitors with anticancer activities.

A series of novel coumarin-based N-hydroxycinnamamide derivatives were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds showed potent HDAC inhibitory activity and significant antiproliferative activity against human cancer cell lines MCF-7, HepG2, HeLa and HCT-116. Among them, compound 14f displayed the most potent HDAC inhibition, especially against HDAC1 with IC value of 0.

MeCP2 inhibits proliferation and migration of breast cancer via suppression of epithelial-mesenchymal transition.

Methyl-CpG-binding protein 2 (MeCP2) is an important epigenetic regulator for normal neuronal maturation and brain glial cell function. Additionally, MeCP2 is also involved in a variety of cancers, such as breast, prostate, lung, liver and colorectal. However, whether MeCP2 contributes to the progression of breast cancer remains unknown.

Intra-articular delivery of extracellular vesicles secreted by chondrogenic progenitor cells from MRL/MpJ superhealer mice enhances articular cartilage repair in a mouse injury model.

Background: Chondrogenic progenitor cells (CPCs) have high self-renewal capacity and chondrogenic potential. Intra-articular delivery of purified mesenchymal stem cells (MSCs) from MRL/MpJ "superhealer" mice increased bone volume during repair and prevents post-traumatic arthritis. Recently, although extracellular vesicles released from MSCs have been used widely for treating OA, the application of extracellular vesicles secreted by CPCs from MRL/MpJ mice in OA therapy has never been reported.

Pristimerin attenuates cell proliferation of uveal melanoma cells by inhibiting insulin-like growth factor-1 receptor and its downstream pathways.

Uveal melanoma (UM) has a high mortality rate due to liver metastasis. The insulin-like growth factor-1 receptor (IGF-1R) is highly expressed in UM and has been shown to be associated with hepatic metastases. Targeting IGF signalling may be considered as a promising approach to inhibit the process of metastatic UM cells.

N2L, a novel lipoic acid-niacin dimer protects HT22 cells against β-amyloid peptide-induced damage through attenuating apoptosis.

β-amyloid protein (Aβ) is thought to be the primary cause of the pathogenesis of Alzheimer's disease (AD). Niacin has been reported to have beneficial effects on AD. Previously, we synthesized a novel compound lipoicacid-niacin dimer (N2L) and revealed that it had potent blood-lipid regulation and antioxidative properties without aflushing effect.

Core regulatory RNA molecules identified in articular cartilage stem/progenitor cells during osteoarthritis progression.

To assess cartilage-derived stem/progenitor cells (CSPCs) in osteoarthritis (OA) by employing mRNA-miRNA-circRNA-lncRNA network biology approach. Differentially expressed (DE) RNAs in CSPCs from 2-/4-/8-month-old STR/Ort and CBA mice were identified to construct networks via RNA sequencing. Compared with age-matched CBA mice, 4-/8-month-old STR/Ort mice had cartilage lesions and their CSPCs exhibited lower proliferative and differentiation capacity (decreased CD44 and CD90), and identified 7082 DE RNAs in STR/Ort mice were associated with strain differences or OA progression.

Neuropeptide W regulates proliferation and differentiation of ATDC5: Possible involvement of GPR7 activation, PKA and PKC-dependent signalling cascades.

Various neuropeptides related to the energy equilibrium affect bone growth in humans and animals. Neuropeptides W (NPW) are identical in the internal ligands of the two G-protein receptors (GPRs) included in subtypes 7 and 8. Neuropeptides W inhibits proliferation in the cultivated rat calvarial osteoblast-like (ROB) cells.

Role of Forkhead Box O Transcription Factors in Oxidative Stress-Induced Chondrocyte Dysfunction: Possible Therapeutic Target for Osteoarthritis?

Chondrocyte dysfunction occurs during the development of osteoarthritis (OA), typically resulting from a deleterious increase in oxidative stress. Accordingly, strategies for arresting oxidative stress-induced chondrocyte dysfunction may lead to new potential therapeutic targets for OA treatment. Forkhead box O (FoxO) transcription factors have recently been shown to play a protective role in chondrocyte dysfunction through the regulation of inflammation, autophagy, aging, and oxidative stress.

Introduction of Z-GP scaffold into procarbazine reduces spermatoxicity and myelosuppression.

Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or β position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The overall yield was 32.7%.

Crocin, a natural product attenuates lipopolysaccharide-induced anxiety and depressive-like behaviors through suppressing NF-kB and NLRP3 signaling pathway.

Depression is one of the foremost psychological illness which is closely leagued with inflammation. Crocin is a natural product that exhibits both anti-inflammatory and anti-oxidant activities. However, little is known about anti-inflammatory mechanisms of crocin on LPS-induced anxiety and depressive-like behaviors.

Design and synthesis of novel senkyunolide analogues as neuroprotective agents.

A class of senkyunolide analogues bearing benzofuranone fragment were designed, synthesized and evaluated for their neuroprotective effect in models of oxygen glucose deprivation (OGD) and oxidative stress. All tested compounds showed neuroprotection profile based on the cell viability assay. In particular, derivatives 1f-1i possessing furoxan-based nitric oxide releasing functionality exhibited significant biological activities in OGD models.

Role of brain-derived neurotrophic factor and nerve growth factor in the regulation of Neuropeptide W in vitro and in vivo.

Nerve growth factor (NGF) and Brain-derived neurotrophic factor (BDNF) are neurotrophic factors involved in the growth, survival and functioning of neurons. In addition, a possible role of neurotrophins, particularly BDNF, in HPA axis hyperactivation has recently been proposed. Neuropeptide W (NPW) is an endogenous peptide ligand for the GPR7 and GPR8 and a stress mediator in the hypothalamus.

L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice.

Amounting evidences demonstrated that Rho/Rho-associated kinase (ROCK) might be a novel target for the therapy of Parkinson's disease (PD). Recently, we synthesized L-F001 and revealed it was a potent ROCK inhibitor with multifunctional effects. Here we investigated the effects of L-F001 in PD models.