7, 8-Dihydroxy-4-methylcoumarin reverses depression model-induced depression-like behaviors and alteration of dendritic spines in the mood circuits.

Major depressive disorder (MDD) is a common mental disorder characterized by a persistent feeling of sadness, slow thought, impaired focus and loss of interest but the underlying mechanisms are largely unknown. Dendritic spines play an important role in the formation and maintenance of emotional circuits in the brain. Abnormalities in this process can lead to psychiatric diseases. 7,8-Dihydroxy-4-methylcoumarin (Dhmc), a precursor in the synthesis of derivatives of 4-methyl coumarin, plays an important role in protecting the nervous system from developing diseases and its most distinctive feature is safety. The aim of this study was to investigate whether Dhmc alleviates chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and reverses CUMS-induced alterations in dendritic spines of principal neurons in brain areas of the emotional circuits including the hippocampus, medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and basolateral amygdala (BLA) in male rats. Our results showed that CUMS-induced depression-like behaviors were accompanied by a decrease in spine density in pyramidal neurons of both the hippocampal CA3 area and the mPFC, and an increase in spine density in both the neurons of BLA and the medium spiny neurons (MSNs) of the NAc, as well as a decrease in the levels of the AMPA receptor subunit GluA1 and Kalirin-7 in the hippocampus compared with the control group. Intraperitoneal injection (i.p.) of Dhmc to the CUMS-exposed rats ameliorated CUMS-induced depression-like behaviors and reversed CUMS-mediated alterations in spine density and the levels of both GluA1 and Kalirin-7. Our results show an important role of Dhmc in reversing CUMS-induced depression-like behaviors and CUMS-mediated alterations in spine density.

Systematic analysis of SmWD40s, and responding of SmWD40-170 to drought stress by regulation of ABA- and H2O2-induced stomal movement in Salvia miltiorrhiza bunge.

WD40 proteins play crucial roles in response to abiotic stress. By screening the genome sequences of Salvia miltiorrhiza Bunge, 225 SmWD40 genes were identified and divided into 9 subfamilies (I-IX). Physiological, biochemical, gene structure, conserved protein motif and GO annotation analyses were performed on SmWD40 family members. The SmWD40-170 was found in 110 SmWD40 genes that contain drought response elements, SmWD40-170 was one of these genes whose response in terms of expression under drought was significant. The expression of SmWD40-170 was also up-regulated by ABA and H2O2. Through observed the stomatal phenotype of SmWD40-170 transgenic lines, the stomatal closure was abolished under dehydration, ABA and H2O2 treatment in SmWD40-170 knockdown lines. Abscisic acid (ABA), as the key phytohormone, elevates reactive oxygen species (ROS) levels under drought stress. The ABA-ROS interaction mediated the generation of H2O2 and the activation of anion channel in guard cells. The osmolality alteration of guard cells further accelerated the stomatal closure. As a second messenger, nitric oxide (NO) regulated ABA signaling, the NO stimulated protein kinase activity inhibited the K+ influx which result in stomatal closure. These NO-relevant events were essential for ABA-induced stomatal closure. The reduction of NO production was also observed in the guard cells of SmWD40-170 knockdown lines. The abolished of stomatal closure attributed to the SmWD40-170 deficiency induced the reduction of NO content. In general, the SmWD40-170 is a critical drought response gene in SmWD40 gene family and regulates ABA- and H2O2-induced stomatal movement by affecting the synthesis of NO.

Tanshinone IIA alleviates brain damage in a mouse model of neuromyelitis optica spectrum disorder by inducing neutrophil apoptosis.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune astrocytopathic disease associated with the anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions primarily located on the optic nerves and spinal cord. Tanshinone IIA (TSA), an active natural compound extracted from Salvia miltiorrhiza Bunge, has profound immunosuppressive effects on neutrophils. OBJECTIVE: The present study aimed to evaluate the effect of TSA on NMOSD mice and explore the underlying mechanisms. Mice were initially administered TSA (pre-TSA group, n = 20) or vehicle (vehicle group, n = 20) every 8 h for 3 days, and then NMOSD model was induced by intracerebral injection of NMOSD-immunoglobulin G (NMO-IgG) and human complement (hC). In addition, post-TSA mice (n = 10) were administered equal dose of TSA at 8 h and 16 h after model induction. At 24 h after intracerebral injection, histological analysis was performed to assess the inhibitory effects of TSA on astrocyte damage, demyelination, and neuroinflammation in NMOSD mice, and western blotting was conducted to clarify the effect of TSA on the NF-κB and MAPK signaling pathways. Furthermore, flow cytometry and western blotting were conducted to verify the proapoptotic effects of TSA on neutrophils in vitro. RESULTS: There was a profound reduction in astrocyte damage and demyelination in the pre-TSA group and post-TSA group. However, prophylactic administration of TSA induced a better effect than therapeutic treatment. The number of infiltrated neutrophils was also decreased in the lesions of NMOSD mice that were pretreated with TSA. We confirmed that prophylactic administration of TSA significantly promoted neutrophil apoptosis in NMOSD lesions in vivo, and this proapoptotic effect was mediated by modulating the caspase pathway in the presence of inflammatory stimuli in vitro. In addition, TSA restricted activation of the NF-κB signaling pathway in vivo. CONCLUSION: Our data provide evidence that TSA can act as a prophylactic agent that reduces NMO-IgG-induced damage in the mouse brain by enhancing the resolution of inflammation by inducing neutrophil apoptosis, and TSA may serve as a promising therapeutic agent for neutrophil-associated inflammatory disorders, such as NMOSD.

Tanshinone IIA Ameliorates CNS Autoimmunity by Promoting the Differentiation of Regulatory T Cells.

Tanshinone IIA (TSA), an important natural lipophilic diterpene compound from the traditional Chinese herb Salvia miltiorrhiza Bunge, has long been widely used for the prevention and treatment of various diseases because of its anti-inflammatory activities; however, the anti-inflammatory mechanism remains unknown. In the present work, we examined the effects of TSA on experimental autoimmune encephalomyelitis (EAE), a model of autoreactive T/B cell-mediated central nervous system (CNS) autoimmunity. The data showed that TSA significantly attenuates the severity of EAE when administered at the pre-onset and peak of clinical disease. In vivo, the protective effects of TSA on EAE mice are correlated with diminished inflammatory infiltration, demyelination, and GM-CSF-producing CD4+ T cells in the spinal cord and selectively increased regulatory T (Treg) cell frequencies in both the spinal cord and spleen. We further confirm that TSA can promote the polarization of naïve CD4+ T cells into Treg cells both by targeting dendritic cells (DCs) to drive transforming growth factor ß1 (TGF-ß1) upregulation and by directly targeting naïve CD4+ T cells in vitro. Most importantly, we showed that TSA-induced Treg cells display an effective suppressive activity at a level comparable to TGF-ß1-polarized Treg Cells in vitro and in vivo. Taken together, our data provide evidence that TSA can promote Treg cell differentiation, and TSA may have a promising application as a therapeutic agent for the treatment of neuroinflammatory diseases.