Indocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial.

Indocyanine green (ICG) fluorescence imaging-guided lymphadenectomy has been demonstrated to be effective in increasing the number of lymph nodes (LNs) retrieved in laparoscopic gastrectomy for gastric cancer (GC). Previously, we reported the primary outcomes and short-term secondary outcomes of a phase 3, open-label, randomized clinical trial (NCT03050879) investigating the use of ICG for image-guided lymphadenectomy in patients with potentially resectable GC. Patients were randomly (1:1 ratio) assigned to either the ICG or non-ICG group. The primary outcome was the number of LNs retrieved and has been reported. Here, we report the primary outcome and long-term secondary outcomes including three-year overall survival (OS), three-year disease-free survival (DFS), and recurrence patterns. The per-protocol analysis set population is used for all analyses (258 patients, ICG [n = 129] vs. non-ICG group [n = 129]). The mean total LNs retrieved in the ICG group significantly exceeds that in the non-ICG group (50.5 ± 15.9 vs 42.0 ± 10.3, P < 0.001). Both OS and DFS in the ICG group are significantly better than that in the non-ICG group (log-rank P = 0.015; log-rank P = 0.012, respectively). There is a difference in the overall recurrence rates between the ICG and non-ICG groups (17.8% vs 31.0%). Compared with conventional lymphadenectomy, ICG guided laparoscopic lymphadenectomy is safe and effective in prolonging survival among patients with resectable GC.

Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1.

Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26Tdtomato and Tff1-CreERT2; Apcfl/fl ; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.

HnRNPK is involved in stress-induced depression-like behavior via ERK-BDNF pathway in mice.

As a ubiquitous RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) interacts with numerous nucleic acids and proteins and is involved in various cellular functions. Available literature indicates that it can regulate dendritic spine density through the extracellular signal-regulating kinase (ERK) - brain-derived neurotrophic factor (BDNF) pathway, which is crucial to retain the synaptic plasticity in patients with major depressive disorder (MDD) and mouse depression models. However, ERK upstream regulatory kinase has not been fully elucidated. Furthermore, it remains unexplored whether hnRNPK may impact the depressive condition via the ERK pathway. The present study addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing. We found that hnRNPK in the brain was mainly distributed in the hippocampal neurons; that it was significantly downregulated in mice that displayed stress-induced depression-like behaviors; and that the level of hnRNPK markedly decreased in MDD patients from the GEO database. Further in vivo and in vitro analyses revealed that the changes in the expressions of BDNF and PSD95 and in the phosphorylation of ERK (Thr202/Tyr204) paralleled the variation of hnRNPK levels in the ventral hippocampal neurons in mice with depression-like behaviors. Finally, esketamine treatment significantly increased the level of hnRNPK in mice. These findings evidence that hnRNPK involved in the pathogenesis of depression via the ERK-BDNF pathway, pinpointing hnRNPK as a potential therapeutic target in treating MDD patients.

Combination of Shengmai San and Radix puerariae ameliorates depression-like symptoms in diabetic rats at the nexus of PI3K/BDNF/SYN protein expression.

BACKGROUND: Hyperglycemia is a characteristic feature of diabetes that often results in neuropsychological complications such as depression. Diabetic individuals are more vulnerable to experience depression compared to the normal population. Thus, novel treatment approaches are required to reduce depressive symptoms among diabetic individuals. Traditional Chinese medicines (TCMs) such as Shengmai San (SMS) and Radix puerariae (R) are usually widely used to treat ailments such as neurological complications since ancient time. METHODS: In this study, SMS was combined with R to prepare an R-SMS formulation and screened for their antidepressant activity in diabetic rats. The antidepressant potential of the prepared combination was evaluated behaviorally using open field test, novelty-induced hypophagia, and forced swim test in diabetic rats with biochemical and protein expression (PI3K, BDNF [brain-derived neurotrophic factor], and SYN [presynaptic vesicle protein]) analysis. RESULTS: Diabetic rats (streptozotocin, 45 mg/kg) showed elevated fasting blood glucose (FBG) >12 mM with depressive symptoms throughout the study. Treatment with R-SMS (0.5, 1.5, and 4.5 g/kg) significantly reverted depressive symptoms in diabetic rats as evinced by significantly (p < 0.05) reduced immobility time with an increased tendency to eat food in a novel environment. Treatment with R-SMS also significantly increased the protein expression of PI3K, BDNF, and SYN protein, which play a crucial role in depression. CONCLUSION: This study showed that R-SMS formulation antagonized depressive symptoms in diabetic rats; thus, this formulation might be studied further to develop as an antidepressant.

Comparison of the efficacy between immunochemotherapy and chemotherapy in gastric cancer accompanied with synchronous liver metastases: A real-world retrospective study.

BACKGROUND: Few studies have investigated the efficacy of comprehensive therapies, including immunotherapy, for gastric cancer with synchronous liver metastases (GCLM). We retrospectively compared the effect of immunochemotherapy and chemotherapy alone as conversion therapies on the oncological outcomes of patients with GCLM. METHODS: The clinicopathological data of 100 patients with GCLM from February 2017 to October 2021 at our institution were retrospectively analyzed. Patients were divided into immunochemotherapy (n = 33) and chemotherapy-alone (n = 67) groups. RESULTS: Baseline clinicopathological data did not differ significantly between the two groups. The immunochemotherapy group had a higher overall response rate (59.4% vs. 44.0%, p = 0.029) and disease control rate (71.9% vs. 49.2%, p = 0.036) than the chemotherapy group. The immunochemotherapy group showed better tumor regression in the gastric mass, metastatic lymph nodes, and liver lesions than the chemotherapy group. Ten (30.3%) patients in the immunochemotherapy group and 13 (19.4%) patients in the chemotherapy group underwent surgery after conversion therapy. However, the difference was not statistically significant. The overall survival (OS) and progression-free survival (PFS) rates were better in the immunochemotherapy group than in the chemotherapy group. Treatment-related adverse events occurred in 24 (72.7%) and 47 (70.1%) patients in the immunochemotherapy and chemotherapy groups, respectively. CONCLUSIONS: As a conversion therapy for GCLM, immunotherapy yielded better primary and metastatic tumor regression and survival benefits, with no increase in adverse events compared to chemotherapy.

Circuit-wide proteomics profiling reveals brain region-specific protein signatures in the male WKY rats with endogenous depression.

BACKGROUND: Although the Wistar Kyoto (WKY) rat has been consistently recognized as an animal model with endogenous depression, the exact molecular mechanisms underlying its genetic susceptibility to depression remain undetermined. METHODS: Compared with the Wistar rats, the depression-like behaviors of the male WKY ones were evaluated by both the sucrose preference test and forced swimming test. Golgi staining analysis was conducted to access the dendritic morphology. TMT-labelled quantitative proteomics analyses were respectively performed in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and hippocampus (Hip), followed by KEGG enrichment-based clustering analysis, Venn diagram analysis, and Pearson correlation analysis. RESULTS: The WKY strain showed significant differences in both the depression-like behaviors and synaptic plasticity. Moreover, the WKY model displayed markedly distinct differentially-expressed protein (DEP) profiles, with minor differences between the WKY subgroups. A cerebral regional commonality and specificity were evident in the signaling pathways enriched in the WKY model, and a total of 15 brain region-specific DEPs were identified to closely correlate with the depression-like phenotypes (in the mPFC: Lrrc8d, Dcun1d2, and Mtnd5; in the NAc: Ccdc154, Sec14l2, Kif2a, LOC680322, Me1, Mknk1, and Ret7; in the Hip: Sec14l2, Serpinf2, LOC103694855, Fam13c, and Loxl1). Data were available via ProteomeXchange with identifier PXD029079. LIMITATIONS: Female WKY rats are not included, and the roles of these candidate DEPs in depression remain further elucidation. CONCLUSION: The present study further evidences the brain region-specific protein signatures in the male WKY model with endogenous depression, providing novel insights into the pathogenesis of depression in males.

Ganoderma Lucidum Triterpenoids Improve Maternal Separation-Induced Anxiety- and Depression-like Behaviors in Mice by Mitigating Inflammation in the Periphery and Brain.

Although early life stress (ELS) can increase susceptibility to adulthood psychiatric disorders and produce a greater inflammatory response in a stressful event, targeted preventive and therapeutic drugs still remain scarce. Ganoderma lucidum triterpenoids (GLTs) can exert anti-inflammatory effects in the periphery and central nervous systems. This study employed a combined model of "childhood maternal separation + adulthood sub-stress" to explore whether GLTs may alleviate anxiety- and depression-like behaviors in male and female mice by mitigating inflammation. Male and female pups were separated from their mothers for four hours per day from postnatal day 1 (PND 1) to PND 21; starting from PND 56, GLTs were administered intraperitoneally once daily for three weeks and followed by three days of sub-stress. Results showed that maternal separation increased the anxiety- and depression-like behaviors in both male and female mice, which disappeared after the preemptive GLTs treatment (40 mg/kg) before adulthood sub-stress. Maternal separation up-regulated the pro-inflammatory markers in the periphery and brain, and activated microglia in the prefrontal cortex and hippocampus. All the abnormalities were reversed by GLTs administration, with no adverse effects on immune organ indices, liver, and renal function. Our findings suggest that GLTs can be a promising candidate in treating ELS-induced psychiatric disorders.

Effect of Qingyangshen glycosides on social defeat mice model.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingyangshen (Cynanchum otophyllum C.K.Schneid.PI.Wilson.) is the folk medicine of Yunnan which is renowned for its use in the management of neuropsychiatric diseases. The isolated glycosides from Qingyangshen have demonstrated relief in the social defeat stress, however, mechanism of action has not yet been elucidated. AIM OF THE STUDY: This study is aimed to elucidate the effect of Qingyangshen glycosides (QYS) on chronic social defeat stress (CSDS)-induced depression-like symptoms and the related mechanism. MATERIALS AND METHODS: In mice, CSDS model was developed, and the effect of QYS was evaluated by observing the behavioral performance of these mice exposed to tasks related to depression-like activities. Moreover, microscopic pathological examinutesation was also done. Furthermore, the protein expressions related to social defeat stress were also determined to elucidate the possible underlying mechanism. RESULTS: Our results indicated that QYS treatment reversed the CSDS-induced depressive-like behaviors as measured by the increased sucrose preference, open field activity, and social interactions among mice. The reversal of the morphological changes in the hippocampus of the CSDS mice was also noted. Additionally, QYS treatment also upregulated the silent mating type information regulation 2 homolog 1 (SIRT1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), fibronectin III domain containing protein 5 (FNDC5), brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), and mitogen-activated protein kinase (MAPK) proteins. CONCLUSIONS: Our study indicated that QYS had a good anti-social defeat stress effect on CSDS-induced depression in mice, mainly through SIRT1/PGC-1α/FNDC5/BDNF-TrkB signaling pathway activation.

Effect of Xiongmatang Extract on Behavioral and TRPV1-CGRP/CGRP-R Pathway in Rats With Migraine.

Migraine is a complex neurovascular disease, which seriously affects the quality of life in patients. This study aimed to evaluate the effect of Xiongmatang (XMT) extract on rats with migraine induced by inflammatory soup and the underlying mechanisms. First, 1 week after dural catheterization, inflammatory soup was injected through a microsyringe to stimulate the dura of rats for 6 times (12 days), once every 2 days, 10 µL each time, to establish a migraine model. According to pain threshold analysis, behavioral change detection, and pathological analysis, the effects of XMT extract on rats with migraine were evaluated. The positive, mRNA and protein expression of related factors were detected by immunohistochemistry, RT-QPCR, and Western blot analysis to elucidate the underlying mechanism. XMT extract improved the behavioral performance of rats, and improve the pathological changes in the trigeminal nerve in rats. Further experimental results show that XMT extract regulated the expression of migraine-related factors in the trigeminal nerve, manifested as transient receptor potential vanilloid 1 (TRPV1), calcitonin-gene-related peptide (CGRP), calcitonin receptor-like receptor (CRLR), and receptor activity-modifying protein 1 (RAMP1) positive expression, mRNA expression, and protein expression reduction. XMT extract can significantly improved the behavioral performance of rats with migraine, and its mechanism of action might involve regulating the activity of TRPV1-CGRP/CGRP-R pathway.

APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline.

Population-based studies reveal that apolipoprotein E (APOE) ε4 gene allele is closely associated with late-life depression (LLD). However, its exact role and underlying mechanism remain obscure. The current study found that aged apoE4-targeted replacement (TR) mice displayed obvious depression-like behavior when compared with age-matched apoE3-TR mice. Furthermore, apoE4 increased stress-induced depression-like behaviors, accompanied by declines in the hippocampal 5-HT (1A) radioligand [18F] MPPF uptake evidenced by positron emission tomography (PET). In [18F]-fluorodeoxyglucose PET ([18F]-FDG PET) analyses, the FDG uptake in the prefrontal cortex, temporal cortex and hippocampus of apoE4-TR mice significantly declined when compared with that of apoE3-TR mice after acute stress. Further biochemical analysis revealed that ATP levels in the prefrontal cortex of apoE4-TR mice decreased during aging or stress process and ATP supplementation effectively rescued the depression-like behaviors of elderly apoE4-TR mice. In primary cultured astrocytes from the cortex of apoE-TR mice, apoE4, when compared with apoE3, obviously decreased the mitochondrial membrane potential, mitochondrial respiration, and glycolysis in a culture time-dependent manner. Our findings highlight that apoE4 is a potential risk factor of depression in elderly population by impairing the glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes, which indicates that in clinical settings ATP supplementation may be effective for elderly depression patients with apoE4 carrier.

The miR-193a-5p/NCX2/AKT axis promotes invasion and metastasis of osteosarcoma.

MiR-193a-5p has been observed to have oncogenic or tumor suppressive functions in different kinds of cancers, but its role and molecular mechanism in osteosarcoma are elusive. Na+/Ca2+ exchangers (NCX1, NCX2 and NCX3) normally extrude Ca2+ from the cell, and deregulation of the intracellular Ca2+ homeostasis is related to several kinds of diseases, including cancer. The present study demonstrated that miR-193a-5p was upregulated in osteosarcoma tissues compared with the corresponding adjacent noncancerous tissues, and promoted colony formation, migration, invasion and epithelial-mesenchymal transition (EMT) in osteosarcoma cells (SaOS-2 and U-2OS), as well as metastasis in a murine xenograft model. Tandem mass tag-based quantitative proteomics analysis identified NCX2 as a potential target of miR-193a-5p. Luciferase activity assays and Western blotting further confirmed that miR-193a-5p recognized the 3'-untranslated region of NCX2 mRNA, and negatively regulated NCX2 expression. NCX2 was downregulated in osteosarcoma tissues, and its expression was negatively correlated with miR-193a-5p levels. Ectopic expression of NCX2 in osteosarcoma cells could reverse the oncogenicity of miR-193a-5p, indicating that miR-193a-5p exerted its effects by targeting NCX2. Further study demonstrated that NCX2 suppresses Ca2+-dependent Akt phosphorylation by decreasing intracellular Ca2+ concentration, and then inhibited EMT process. Treatment with the antagomir against miR-193a-5p sensitized osteosarcoma to the Akt inhibitor afuresertib in a murine xenograft model. In conclusion, a miR-193a-5p/NCX2/AKT signaling axis contributes to the progression of osteosarcoma, which may provide a new therapeutic target for osteosarcoma treatment.

Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia cells by inactivating AKT.

Curcumin, a phytochemical from rhizomes of the plant Curcuma longa, has been reported to exert potential anticancer properties in various cancer types, including acute myeloid leukemia (AML). However, the underlying mechanism remains poorly understood. The present study demonstrated that curcumin had a stronger cytotoxic activity against AML cells compared with three other types of phytochemicals (epigallocatechin gallate, genistein and resveratrol). Protein phosphorylation profiling using an antibody array identified that curcumin treatment increased the phosphorylation levels of 14 proteins and decreased those of four proteins. A protein­protein interaction network was constructed using the STRING database, in which AKT was identified as a hub protein with the highest connectivity (PRAS40, 4E­BP1, P70S6K, RAF­1 and p27). Western blotting results indicated that curcumin dose­dependently suppressed the phosphorylation of AKT, PRAS40, 4E­BP1, P70S6K, RAF­1 and p27 in AML cell lines (ML­2 and OCI­AML5). It was also demonstrated that curcumin regulated the cell cycle­ and apoptosis­related proteins (cyclin D1, p21, Bcl2, cleaved­caspase­3 and cleaved­PARP), leading to cell cycle arrest and apoptosis in both ML­2 and OCI­AML5 cells. These effects of curcumin were enhanced by the AKT inhibitor afuresertib but were suppressed by the AKT activator SC­79, indicating that curcumin functions via AKT. In the AML xenograft mouse model, curcumin and afuresertib synergistically suppressed the engraftment, proliferation and survival of AML cells. Collectively, the present study demonstrated that curcumin exerted anti­AML roles by inactivating AKT and these findings may aid in the treatment of AML.

The Antidepressant-Like Effects of Shen Yuan in a Chronic Unpredictable Mild Stress Rat Model.

Depression is a common yet severe neuropsychiatric condition that causes imposes considerable personal, economic, and social burdens worldwide. Medicinal plant species (e.g., Panax ginseng and Polygala tenuifolia) demonstrate potent antidepressant-like effects with less toxicity and other side effects. Shen yuan prescription (SY), composed of Panax ginseng (GT) and Polygala tenuifolia (YT). The present study aimed to elucidate the effects of SY treatment on chronic unpredictable mild stress (CUMS) rats and study the underlying mechanism. Our results indicated that SY (67.5, 135, or 270 mg/kg) significantly reverses the depressive-like behaviors in rats with a 5-week CUMS exposure, as demonstrated by increased sucrose consumption in the sucrose preference test, and decreased immobility time in the tail suspension and forced swim test. Moreover, SY altered serum corticosterone levels, pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α), and oxidative markers (SOD, CAT, and MDA), and increased the levels of hippocampal neurotransmitters (5-HT, DA, and NE) in rats exposed to CUMS. Furthermore, rats treated with SY showed a reduction in the protein expression of BDNF, p-TrkB, p-Akt, and p-mTOR proteins induced by CUMS exposure in the hippocampus. In conclusion, SY prevented depressive-like behaviors in CUMS-exposed rats by preventing hypothalamus-pituitary-adrenal axis dysfunction, decreasing the levels of the neurotransmitters, minimizing oxidative stress, suppressing neuroinflammation, and activating the PI3K/Akt/mTOR-mediated BDNF/TrkB pathway, all of which are the key players in the pathological basis of depression.

The antidepressant-like effects of Shen Yuan: Dependence on hippocampal BDNF-TrkB signaling activation in chronic social defeat depression-like mice.

The Shen Yuan prescription (SY) comprises Panax ginseng (GT) and Polygala tenuifolia (YT), elicited superior antidepressant activity compared with that of GT or YT alone. The aim of this paper is to elucidate the effects of SY treatment on chronic social defeat stress (CSDS)-induced depression-like symptoms and the related mechanism. Our results indicated that SY treatment reverses the depressive-like behaviors induced by CSDS as measured by the social interaction test, sucrose preference test, forced swim test, and tail suspension test. SY decreased the serum levels of CORT and increased hippocampal neurotransmitters (5-HT, DA, and NE) in CSDS mice. Meanwhile, SY upregulated the brain-derived neurotrophic factor (BDNF) signaling pathway and reversed the decreased hippocampal neurogenesis caused by CSDS. In addition, we found that the TrkB antagonist K252a fully blocked the SY effects on behavioral improvement and eliminated the promoting effects of SY on hippocampal neurogenesis and BDNF-TrkB signaling (including the downstream ERK and Akt pathways) activation, thus further demonstrating that BDNF-TrkB signaling was necessary for the SY effects. In conclusion, our study showed that SY acted as an antidepressant in mice exhibiting CSDS-induced depression-like symptoms, and its effect was facilitated by promoting hippocampal neurogenesis and BDNF signaling pathway activation.

Increased Notch2/NF-κB Signaling May Mediate the Depression Susceptibility: Evidence from Chronic Social Defeat Stress Mice and WKY Rats.

The susceptibility to depression has been attributed to the chronic stress and genetic factors but still fails to identify definite biomarkers. The present study aimed to investigate the role of disrupted Notch signaling in the medial prefrontal cortex of the chronic social defeat stress (CSDS) mice and Wistar Kyoto (WKY) rats. RNA-sequencing and quantitative real-time PCR analyses evidenced the involvement of Notch signaling pathway in depression. Western blotting reported an increased level of Notch2 and NF-κB and a decreased level of Hes1 and Bcl2/Bax ratio both in the susceptible mice when compared with the control or resilient ones and in the depression WKY rats when compared with the Wistar or non-depression WKY groups. Further analysis showed that the above-mentioned changes were significantly correlated with the depression-like behaviors and that the elicited Notch2 strongly correlated with the upregulated NF-κB, not with the downregulated Hes1 or Bcl2/Bax ratio. In conclusion, the increased Notch2/NF-κB signaling in the medial prefrontal cortex may mediate depression susceptibility, providing a potential diagnostic biomarker or therapeutic target for treating major depressive disorder.

Carnosic acid ameliorates depressive-like symptoms along with the modulation of FGF9 in the hippocampus of middle carotid artery occlusion-induced Sprague Dawley rats.

The increased survival rate of stroke patients has led to the higher incidences of post-stroke depression. Carnosic acid has the ability to cross blood brain barrier with good neuro-modulatory actions. Recently, inclined level of fibroblast growth factor 9 (FGF9) in the postmortem brain of the depressed patients was noted. Therefore, in the present study, the effect of carnosic acid on post-stroke depression-like behavior, and the expression of FGF9 were evaluated. After 3 weeks of middle carotid artery occlusion in Sprague Dawley rats, carnosic acid (20 and 40 mg/kg) was administered for 2 weeks. Sucrose preference test, forced swimming test, and open field test were performed and hippocampi were analyzed for FGF9 and FGFR-3. In comparison to post-stroke depressed rats, carnosic acid increased the sucrose preference, and reduced the immobility time of the rats by ~2×. The speed and distance-covered were also increased. At 40 mg/kg, FGF9 was reduced by ~3× while FGFR-3/Actin was increased by ~1.5×. Altogether results suggest anti-depressant-like activity of carnosic acid in post-stroke depressed rats with decreased expression of hippocampal FGF9.

The antidepressant-like effects of the water extract of Panax ginseng and Polygala tenuifolia are mediated via the BDNF-TrkB signaling pathway and neurogenesis in the hippocampus.

ETHNOPHARMACOLOGY RELEVANCE: The water extract of Panax ginseng (GT) and Polygala tenuifolia (YT), the main constituents of the commonly used kai-xin-san formula of traditional Chinese medicine, represents SY. It possesses strong neuroprotective effects. Using behavioural tests, we have previously established that the SY formulation exerts superior antidepressant activity than that of GT or YT. AIM: To elucidate the impact of SY treatment on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviours and the prospective mechanism related to hippocampal neurogenesis and the BDNF signaling pathway. METHODS: We exposed Sprague-Dawley rats (male; 180-200 g) to CUMS for 35 days. The rats in the experimental treatment groups were daily treated with either fluoxetine (10 mg kg-1d-1) or SY (67.5, 135, or 270 mg kg-1d-1) orally until the behavioural tests (tail suspension test [TST], novelty-suppressed feeding test [NSFT], sucrose preference test [SPT], and forced swim test [FST]) were completed. We assessed the modifications in the hippocampal neurogenesis and the BDNF signaling pathway post-treatment with CUMS and SY. Additionally, K252a, a tyrosine protein kinase inhibitor, was utilized to evaluate the antidepressant mechanisms of SY. RESULT: s: The results of SPT, NSFT, FST, and TST in CUMS-exposed rats confirmed the antidepressant actions of SY. Additionally, SY treatment induced the BDNF signaling pathway and reversed the hippocampal neurogenesis caused by CUMS. Moreover, we found that the TrkB antagonist K252a blocked SY effects on behavioural improvement, inhibited the incremental effects of SY on hippocampal neurogenesis, and eliminated the impact of SY on BDNF-TrkB signaling activation. Thus, the impact of SY treatment on BDNF signaling molecules (pAkt, pERK1/2, and pCREB) were significantly inhibited by K252a. CONCLUSIONS: This study showed that SY acted as an antidepressant in rats exhibiting CUMS-induced depressive-like behaviours, and was facilitated by promoting hippocampal neurogenesis and the BDNF signaling pathway activation. Thus, SY could act as a potential novel supplement or adjuvant to prevent or treat clinical depressive disorders.

Acetate supplementation produces antidepressant-like effect via enhanced histone acetylation.

BACKGROUND: Abnormal energy metabolism is often documented in the brain of patients and rodents with depression. In metabolic stress, acetate serves as an important source of acetyl coenzyme A (Ac-CoA). However, its exact role and underlying mechanism remain to be investigated. METHOD: We used chronic social failure stress (CSDS) to induce depression-like phenotype of C57BL/6J mice. The drugs were administered by gavage. We evaluated the depressive symptoms by sucrose preference test, social interaction, tail suspension test and forced swimming test. The dendritic branches and spine density were detected by Golgi staining, mRNA level was analyzed by real-time quantitative RT-PCR, protein expression level was detected by western blot, and the content of Ac-CoA was detected by ELISA kit. RESULT: The present study found that acetate supplementation significantly improved the depression-like behaviors of mice either in acute forced swimming test (FST) or in CSDS model and that acetate administration enhanced the dendritic branches and spine density of the CA1 pyramidal neurons. Moreover, the down-regulated levels of BDNF and TrkB were rescued in the acetate-treated mice. Of note, chronic acetate treatment obviously lowered the transcription level of HDAC2, HDAC5, HDAC7, HDAC8, increased the transcription level of HAT and P300, and boosted the content of Ac-CoA in the nucleus, which facilitated the acetylation levels of histone H3 and H4. LIMITATIONS: The effect of acetate supplementation on other brain regions is not further elucidated. CONCLUSION: These findings indicate that acetate supplementation can produce antidepressant-like effects by increasing histone acetylation and improving synaptic plasticity in hippocampus.