Potential Plausible Role of Stem Cell for Treating Depressive Disorder: a Retrospective Review.

Depression poses a significant threat to global physical and mental health, impacting around 3.8% of the population with a rising incidence. Current treatment options primarily involve medication and psychological support, yet their effectiveness remains limited, contributing to high relapse rates. There is an urgent need for innovative and more efficacious treatment modalities. Stem cell therapy, a promising avenue in regenerative medicine for a spectrum of neurodegenerative conditions, has recently garnered attention for its potential application in depression. While much of this work remains preclinical, it has demonstrated considerable promise. Identified mechanisms underlying the antidepressant effects of stem cell therapy encompass the stimulation of neurotrophic factors, immune function modulation, and augmented monoamine levels. Nonetheless, these pathways and other undiscovered mechanisms necessitate further investigation. Depression fundamentally manifests as a neurodegenerative disorder. Given stem cell therapy's success in addressing a range of neurodegenerative pathologies, it opens the door to explore its application in depression treatment. This exploration may include repairing damaged nerves directly or indirectly and inhibiting neurotoxicity. Nevertheless, significant challenges must be overcome before stem cell therapies can be applied clinically. Successful resolution of these issues will ultimately determine the feasibility of incorporating stem cell therapies into the clinical landscape. This narrative review provides insights into the progress of research, potential avenues for exploration, and the prevailing challenges in the implementation of stem cell therapy for treatment of depression.

Saikosaponin D exerts antidepressant effect by regulating Homer1-mGluR5 and mTOR signaling in a rat model of chronic unpredictable mild stress.

BACKGROUND: Many studies about depression have focused on the dysfunctional synaptic signaling in the hippocampus that drives the pathophysiology of depression. Radix Bupleuri has been used in China for over 2000 years to regulate liver-qi. Extracted from Radix Bupleuri, Saikosaponin D (SSD) is a pharmacologically active substance that has antidepressant effects. However, its underlying mechanism remains unknown. MATERIALS AND METHODS: A chronic unpredictable mild stress (CUMS) paradigm was used as a rat model of depression. SD rats were randomly assigned to a normal control (NC) group or one exposed to a CUMS paradigm. Of the latter group, rats were assigned to four subgroups: no treatment (CUMS), fluoxetine-treated (FLU), high-dose and low-dose SSD-treated (SSDH and SSDL). SSD was orally administrated of 1.50 mg/kg and 0.75 mg/kg/days for three weeks in the SSDH and SSDL groups, respectively. Fluoxetine was administrated at a dose of 2.0 mg/kg/days. SSD's antidepressant effects were assessed using the open field test, forced swim test, and sucrose preference test. Glutamate levels were quantified by ELISA. Western blot and immunochemical analyses were conducted to quantify proteins in the Homer protein homolog 1 (Homer1)-metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) pathways in the hippocampal CA1 region. To measure related gene expression, RT-qPCR was employed. RESULTS: CUMS-exposed rats treated with SSD exhibited increases in food intake, body weight, and improvements in the time spent in the central are and total distance traveled in the OFT, and less pronounced pleasure-deprivation behaviors. SSD also decreased glutamate levels in CA1. In CA1 region of CUMS-exposed rats, SSD treatment increased mGluR5 expression while decreasing Homer1 expression. SSD also increased expressions of postsynaptic density protein 95 (PSD95) and synapsin I (SYP), and the ratios of p-mTOR/mTOR, p-p70S6k/p70S6k, and p-4E-BP1/4E-BP1 in the CA1 region in CUMS-exposed rats. CONCLUSIONS: SSD treatment reduces glutamate levels in the CA1 region and promotes the expression of the synaptic proteins PSD-95 and SYP via the regulation of the Homer1-mGluR5 and downstream mTOR signaling pathways. These findings suggest that SSD could act as a natural neuroprotective agent in the prevention of depression.

Effects of Histone Modification in Major Depressive Disorder.

Major depressive disorder (MDD) is a disease associated with many factors; specifically, environmental, genetic, psychological, and biological factors play critical roles. Recent studies have demonstrated that histone modification may occur in the human brain in response to severely stressful events, resulting in transcriptional changes and the development of MDD. In this review, we discuss five different histone modifications, histone methylation, histone acetylation, histone phosphorylation, histone crotonylation and histone ß-hydroxybutyrylation, and their relationships with MDD. The utility of histone deacetylase (HDAC) inhibitors (HDACis) for MDD treatment is also discussed. As a large number of MDD patients in China have been treated with traditional Chineses medicine (TCM), we also discuss some TCM therapies, such as Xiaoyaosan (XYS), and their effects on histone modification. In summary, targeting histone modification may be a new strategy for elucidating the mechanism of MDD and a new direction for MDD treatment.

Xiaoyaosan Alleviates Hippocampal Glutamate-Induced Toxicity in the CUMS Rats via NR2B and PI3K/Akt Signaling Pathway.

Purpose: It is revealed that Xiaoyaosan could reduce glutamate level in the hippocampus of depressed rats, whose metabolism leads to the pathophysiology of depression. However, the underlying mechanism remains unclear. This study aims to explore the effect of Xiaoyaosan on glutamate metabolism, and how to regulate the excitatory injury caused by glutamate. Methods: Rats were induced by chronic unpredictable mild stress, then divided into control, vehicle (distilled water), Xiaoyaosan, fluoxetine, vehicle (DMSO), Xiaoyaosan + Ly294002 and Ly294002 groups. Ly294002 was microinjected into the lateral ventricular catheterization at 5 mM. Xiaoyaosan (2.224 g/kg) and fluoxetine (2.0 mg/kg) were orally administered for three weeks. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to assess depressive behavior. The glutamate and corticosterone (CORT) levels were detected by ELISA. Western blot, immunochemistry or immunofluorescence were used to detect the expressions of NR2B, MAP2, PI3K and P-AKT/Akt in the hippocampal CA1 region. The mRNA level of MAP2, NR2B and PI3K were detected by RT-qPCR. Results: Compared to the rats in control group, body weight and food intake of CUMS rats was decreased. CUMS rats also showed depression-like behavior as well as down regulate the NR2B and PI3K/Akt signaling pathway. Xiaoyaosan treatments could increase food intake and body weight as well as improved time spent in the central area, total distance traveled in the OFT. Xiaoyaosan could also decrease the immobility time as well as increase the sucrose preference in SPT. Moreover, xiaoyaosan decreased the level of glutamate in the hippocampal CA1 region and serum CORT in CUMS rats. Furthermore, xiaoyaosan improved the expression of MAP2 as well as increased the expression of NR2B, PI3K and the P-AKT/AKT ratio in the hippocampal CA1 region in the CUMS rats. Conclusion: Xiaoyaosan treatment can exert the antidepressant effect by rescuing hippocampal neurons loss induced by the glutamate-mediated excitotoxicity in CUMS rats. The underlying pathway maybe through NR2B and PI3K/Akt signaling pathways. These results may suggest the potential of Xiaoyaosan in preventing the development of depression.

Anti-tumor and Phenotypic Regulation Effect of Matrine on Dendritic Cells through Regulating TLRs Pathway.

OBJECTIVE: To investigate the effects of matrine on antigen presentation of dendritic cells (DCs), and to explore the pharmacological mechanism of matrine on anti-tumor effect. METHODS: Different concentrations (0, 1, 2, 4, 8 and 16 µ g/mL) of matrine were co-cultured with DCs, the harvested DCs were co-cultured with antigens of Lewis lung cancer (LLC) cells, and then DCs and T cells were co-cultured to produce DCs-activated killer (DAK) cells, which have significant tumor-killing activity. The expression of cytokines, mRNA and protein of toll-like receptors (TLRs) in DCs were detected by enzyme linked immunosobent assay, polymerase chain reaction and Western blot, respectively. And the killing effect of DAK were measured by MTT assay. RESULTS: Matrine significantly increased the mRNA expression of TLR7, TLR8, myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF-6) and I κ B kinase (IKK), as well as the protein expression of TLR7 and TLR8, and up-regulated the levels of interleukin-12 (IL-12), IL-6 and tumor necrosis factor-α (TNF-α), meanwhile, it also increased the expressions of MHC-II, CD54, CD80 and CD86 in DCs. DCs-activated effector T cells had significant tumor-killing activity. When the concentration of matrine was more than 4 µg/mL, all indices had significant difference (P<0.01 or P<0.05). CONCLUSION: Matrine plays an anti-tumor role by regulating TLRs signal transduction pathway, promoting the secretion of inflammatory cytokines and enhancing immune function.

Panax Notoginseng Saponins Inhibits Ventricular Remodeling after Myocardial Infarction in Rats Through Regulating ATF3/MAP2K3/p38 MAPK and NF κ B Pathway.

OBJECTIVE: To explore whether Panax notoginseng saponins (PNS) exhibits heart protective effect in myocardial infarction (MI) rats and to identify the potential signaling pathways involved. METHODS: MI rats induced by ligating the left anterior descending (LAD) coronary artery were assigned to sham coronary artery ligation or coronary artery ligation. Totally 36 Sprague-Dawley rats were randomly divided into sham group (distilled water, n=9), MI group (distilled water, n=9), PNS group (PNS, 40 mg/kg daily, n=9) and fosinopril group (FIP, 1.2 mg/kg daily, n=9) according to a random number table. The left ventricular morphology and function were conducted by echocardiography. Histological alterations were evaluated by the stainings of HE and Masson. The serum levels of C reactive protein (CRP), tumor necrosis factor α (TNF-α), growth differentiation factor-15 (GDF-15) and the ratio of metalloproteinase-9 (MMP-9) and tissue inhibitor of MMP-9 (TIMP-1) were determined by ELISA. The levels of activating transcription factor 3 (ATF3), mitogen-activated protein kinase kinase 3 (MAP2K3), p38 mitogen-activated protein kinase (p38 MAPK), phosphorylation of p38 MAPK (p-p38 MAPK), transforming growth factor-ß (TGF-ß1), collagen I, nuclear factor kappa B p65 (NFκB p65), phosphorylation of NFκB p65 (p-NFκB p65), and phosphorylation of inhibitory kappa Bα (p-Iκ Bα) in hearts were measured by Western blot and immunohistochemical staining, respectively. RESULTS: PNS improved cardiac function and fibrosis in MI rats (P<0.05). The serum levels of CRP, TNF-α, GDF-15 and the ratio of MMP9/TIMP1 were reversed by PNS in MI rats. The expressions of TGF-ß1, collagen I, MAP2K3, p38 MAPK, p-p38 MAPK, NFκB p65, p-NFκB p65, and p-IκBα were down-regulated, while ATF3 increased with the treatment of PNS (P<0.05). CONCLUSIONS: PNS may improve cardiac function and fibrosis in MI rats via regulating ATF3/MAP2K3/p38 MAPK and NFκB signaling pathways. These results suggest the potential of PNS in preventing the development of ventricular remodeling in MI rats.