Stress-related alterations in brain-derived neurotrophic factor (BDNF) expression, a neurotrophin that plays a key role in synaptic plasticity, are believed to contribute to the pathophysiology of depression. Here, we show that in a chronic mild stress (CMS) model of depression the Gαi1 and Gαi3 subunits of heterotrimeric G proteins are down-regulated in the hippocampus, a key limbic structure associated with major depressive disorder. We provide evidence that Gαi1 and Gαi3 (Gαi1/3) are required for the activation of TrkB downstream signaling pathways. In mouse embryonic fibroblasts (MEFs) and CNS neurons, Gαi1/3 knockdown inhibited BDNF-induced tropomyosin-related kinase B (TrkB) endocytosis, adaptor protein activation, and Akt-mTORC1 and Erk-MAPK signaling. Functional studies show that Gαi1 and Gαi3 knockdown decreases the number of dendrites and dendritic spines in hippocampal neurons. In vivo, hippocampal Gαi1/3 knockdown after bilateral microinjection of lentiviral constructs containing Gαi1 and Gαi3 shRNA elicited depressive behaviors. Critically, exogenous expression of Gαi3 in the hippocampus reversed depressive behaviors in CMS mice. Similar results were observed in Gαi1/Gαi3 double-knockout mice, which exhibited severe depressive behaviors. These results demonstrate that heterotrimeric Gαi1 and Gαi3 proteins are essential for TrkB signaling and that disruption of Gαi1 or Gαi3 function could contribute to depressive behaviors.

Platelet-derived extracellular vesicles were engineered for targeted delivery of anti-inflammation therapeutics to treat pneumonia. This delivery strategy improved therapeutic efficacy, inhibited the pulmonary inflammatory cell infiltration, and calmed local cytokine storm syndromes compared with the free drug-treated group.

Prolonged or overdose glucocorticoids (GCs) usage is the common cause of osteoporosis. In the present study, we studied the cellular mechanism of dexamethasone (Dex)-induce osteoblast cell death by focusing on the role of mitochondrial permeability transition pore (mPTP). In cultured osteoblastic MC3T3-E1 cells, Dex-induced mPTP opening, which was demonstrated by mitochondrial membrane potential (MPP) decrease, cyclophilin-D (CyPD)-adenine nucleotide translocator 1 (ANT-1) mitochondrial complexation and cytochrome C (cyto-C) release. The mPTP inhibitor sanglifehrin A (SfA) dramatically inhibited Dex-induced MPP loss, cyto-C release and MC3T3-E1 cell death. Dex-induced cell death requires mPTP composing protein CyPD, as CyPD inhibitor cyclosporin A (CsA) and CyPD siRNA knockdown inhibited Dex-induced MC3T3-E1 cell death, while CyPD overexpression aggravated Dex's cytotoxic effect. We found that Dex induced P53 phosphorylation and translocation to mitochondria, where it formed a complex with CyPD. Glucocorticoid receptor (GR) siRNA knockdown, or P53 inhibition (by its inhibitor pifithrin-α or shRNA silencing) suppressed Dex-induced CyPD-P53 mitochondrial association and subsequent MC3T3-E1 cell death. Finally, in primary cultured osteoblasts, Dex-induced cell death was inhibited by CsA, SfA or pifithrin-α. Together, our data suggest that Dex-induced osteoblast cell death is associated with GR-P53-regulated mPTP opening.

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