Berberine exerts antidepressant-like effects via regulating miR-34a-synaptotagmin1/Bcl-2 axis.

Objective: Berberine, a cationic alkaloid first isolated in 1917, has been approved by the China Drug Administration for decades. Accumulating evidence demonstrated its antidepressant-like activities in vivo. Our previous study has shown that chronic stress leads to the upregulation of miR-34a in the hippocampus of mice. This study aims to evaluate the underlying miR-34a mediated mechanism of berberine in chronic stress-induced depression in mice. Methods: In the present study, mice were administered with berberine during chronic stress. Levels of miR-34a, dendritic density, mitochondrial morphology, and neurogenesis were assessed in the hippocampus. Subsequently, miR-34a agomir was used as a pharmacological intervention for the investigation of berberine. Results: The results showed that berberine reversed the decrease in sucrose preference and the increase in latency to feed without altering total food consumption. Furthermore, chronic stress-induced overexpression of miR-34a decreased synaptotagmin-1 and Bcl-2 levels, thereby impairing spinal morphology, mitochondria and neurogenesis. Berberine inhibited miR-34a expression, in turn restored synaptotagmin-1 and Bcl-2 levels, and thus improved spinal morphology, mitochondria and neurogenesis in the hippocampus. However, the improvements induced by berberine were totally blocked by the pretreatment of miR-34a agomir, which caused the elevation of miR-34a levels in the hippocampus. Conclusion: This finding demonstrated that miR-34a downregulation was involved in the antidepressant-like effects of berberine in mice exposed to chronic stress.

miR-34a induces spine damages via inhibiting synaptotagmin-1 in depression.

MicroRNAs (miRNAs) are noncoding RNAs that participate in the pathophysiology of depression by targeting many functional genes. As shown in our previous study, chronic stress up-regulates miR-34a in the hippocampus. However, little is known about the mechanism by which miR-34a regulates the process of depression or its functions as an antidepressant by regulating its targets. In the present study, the dynamic alterations in miR-34a expression and the mechanism underlying miR-34a regulation were assessed after the administration of the antidepressant fluoxetine to mice exposed to chronic stress. In addition, the effects of miR-34a inhibition on mice were directly evaluated. Both lipopolysaccharide (LPS) and corticosterone treatment caused depression-like symptoms and increased miR-34a expression. Additionally, the expression of miR-34a, which was regulated by tropomyosin receptor kinase B (TrkB)/MEK1/ERK signaling, was consistent with the onset of action of fluoxetine. A luciferase reporter assay identified synaptotagmin-1 and Bcl-2 as the targets of miR-34a. Moreover, a miR-34a antagomir exerted antidepressant-like effects, activated TrkB/MEK1/ERK signaling and improved spine morphology in the hippocampus. In conclusion, hippocampal miR-34a overexpression was a typical feature in depression-like animals, and miR-34a downregulation exerts antidepressant-like effects by restoring the spine morphology through its target synaptotagmin-1.

[Safety evaluation of allelochemical derivative pyrone on different millet varieties]. / åŒ–æ„Ÿç‰©è´¨è¡ç”Ÿç‰©å¡å–ƒé ®å¯¹ä¸åŒè°·å­å“ç§çš„å®‰å ¨æ€§è¯„ä»·.

The development of new herbicides based on allelochemicals is a potential strategy of weed control in arable field. Pyrone, a novel derivative of tricin, has significant inhibitory effects on weeds. Its safety for crops, especially for millet that are sensitive to commercial herbicides, is still poorly understood. In this study, germination test and pot experiments were conducted to evaluate the safety of pyrone on 20 millet varieties, compared with 2,4-D. The results showed that, except that Jinfen109 was sensitive to high concentration 2,4-D, both pyrone and 2,4-D had no effect on the germination rates of other varieties. Results of the pot experiment showed that pyrone treatment significantly increased the chlorophyll content of millet by 9.0%-67.9%, which was the greatest for Jigu 42. Pyrone treatment did not affect maximal photochemical efficiency, potential photochemical activity, actual photochemical efficiency, and non-photochemical quenching coefficient. On the contrary, 2,4-D significantly inhibited the fluorescence parameters of millet varieties. Pyrone treatment increased the activities of superoxide dismutase, peroxidase and catalase in leaves of Dunza16, Jigu 39, Jigu 41 and Jingu 28, with the magnitude of enhancement being higher than 2,4-D. The results indicated that the allelochemical derivative pyrone is highly safe to the growth of millet seedlings and has the potential to be a new herbicide to millet field.

[Allelopathic effects of water extracts from different parts of foxtail millet straw on three kinds of weeds]. / 谷子秸秆不同部位水浸液对3种杂草的化感作用.

We examined the allelopathic effect of extracts from different parts of foxtail millet straw with different concentrations (undiluted water extracts, 10-fold, 50-fold, and 100-fold dilution) on three different kinds of malignant weeds (Amaranthus retroflexus, Chenopodium album, and Setaria viridis) by water extract. In this experiment, we measured biological indicators for seed germination period and potted seedling physiological parameters. The results showed that water extract of foxtail millet leaves and stems had significant allelopathic effects on the three species of weeds, with the effects of different concentrations being different. Undiluted water extract inhibited the growth, while dilution (10-fold, 50-fold, 100-fold dilution) promoted the growth. Under the treatment of undiluted water extract of leaf and stem, the germination rate of three weeds decreased 63.9%, 37.3% and 41.7%, respectively, while root length was only 27.8%, 37.8% and 18.4% of the control. The bud length was only 34.5%, 27.7% and 17.6% of the control. The net photosynthetic rate accounted for 66.6%, 89.9% and 88.2% of the control. The transpiration rate accounted for 69.0%, 87.5% and 56.1% of the control, while the synthesis allelopathic index of the three weeds were -0.699, -0.716 and -0.795 by undiluted water extract, respectively. Results implied strong allelopathic inhibition. The allelopathy promoting effect of dilution increased first and then decreased with the increases of dilution folds. Among which, 50-fold dilution had the strongest promoting effect with the germination rate, root length and bud length of the three weeds being significantly different from those of the control, with the synthesis allelopathic index being 0.261, 0.217, and 0.165, respectively. A large number of associated weeds grow in foxtail millet field which is related to the leaching of allelopathic substances in straw.

Humic acid improves the physiological and photosynthetic characteristics of millet seedlings under drought stress.

We aimed to determine whether humic acid (HA) can alleviate the injury of millet caused by drought and its potential mechanism. Millet seeds (Jingu 21 and Zhangza 10) were soaked in different concentrations of HA (0, 50, 10, 200, and 300 mg L-1) for 12 h. The physiological and photosynthetic characteristics of millet seedlings, including growth parameters, osmotic regulators, antioxidase activity, photosynthesis, chlorophyll fluorescence, and P700 parameters, were determined before and after drought stress. HA significantly promoted the growth of millet seedlings under drought stress. Pretreatment with 100 mg L-1 or 200 mg L-1 HA significantly increased free proline, soluble protein, and activity of the antioxidant enzyme system (superoxide dismutase, peroxidase, and catalase) in both Zhangza 10 and Jingu 21. The accumulation of reactive oxygen species ([Formula: see text] and H2O2) was reduced in HA treatments compared with that of the control (P < .05). Moreover, HA (100 mg L-1) significantly increased net photosynthetic rate, stomatal conductance, effective quantum yield of photosystem II, relative photosynthetic electron transfer rate of photosystem II, and photochemical quenching. HA also reduced intercellular CO2 concentration and non-photochemical quenching. Furthermore, 200 mg L-1 HA significantly increased the maximum P700, effective quantum yield of photosystem I, and relative photosynthetic electron transfer rate of photosystem I in Zhangza 10 and decreased non-photochemical energy dissipation in Jingu 21 and Zhangza 10 under drought stress. HA promoted the growth of millet seedlings under drought stress by promoting the osmotic adjustment ability and antioxidant capacity of seedlings and increased photosynthesis.

Curcumin attenuates cognitive impairment by enhancing autophagy in chemotherapy.

Cisplatin, a commonly used chemotherapy drug, can increase the survival rate of cancer patients. However, it often causes various side effects, including neuronal deficit-induced cognitive impairment. Considering that curcumin is effective in neuronal protection, the action of curcumin on cognitive improvement was evaluated in cisplatin-treated C57BL/6 mice in the present study. Our results first showed that curcumin restored impaired cognitive behaviors. Consistent with this, neurogenesis and synaptogenesis were improved by curcumin. In addition, cisplatin-induced dysfunction of apoptosis-related proteins was partly reversed by curcumin. Moreover, cisplatin-induced autophagy was enhanced by curcumin. Our results also indicated that cisplatin induced autophagy through the endoplasmic reticulum (ER) stress-mediated ATF4-Akt-mTOR signaling pathway. Curcumin activated AMPK-JNK signaling, which mediated both mTOR inhibition and Bcl-2 upregulation and in turn enhanced autophagy and suppressed apoptosis, respectively. In contrast, pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) completely abolished the effects of curcumin on cognitive improvement and improved neurogenesis, synaptogenesis and autophagy. Our results show that cognitive improvement induced by curcumin during chemotherapy is mediated by the enhancement of hippocampal autophagy.

Oleanolic acid decreases SGK1 in the hippocampus in corticosterone-induced mice.

Our previous study has demonstrated that oleanolic acid produced an antidepressant-like effect in mice exposed to chronic stress. Considering that serine/threonine-protein kinase 1 (SGK1) is involved in stress response, the present study aimed to evaluate the involvement of SGK1 in the antidepressant-like effects of oleanolic acid in depression-like mice induced by long term corticosterone (CORT) injection. Behaviors, SGK1, brain-derived neurotrophic factor (BDNF) and its downstream targets were assessed after administration with oleanolic for three weeks. The results indicated that oleanolic acid increased the sucrose preference and decreased the immobility time. In addition, oleanolic acid decreased SGK1 and activated BDNF-AKT/mTOR signaling in the hippocampus of CORT-induced animals. However, we found that GSK650394, an inhibitor of SGK1 did not exert any effects on the behaviors, GR levels and BDNF signaling. The number of spines in hippocampal neurons was not changed by GSK650394 as well. Taken together, this study demonstrated that oleanolic acid produced the antidepressant-like effects, which might be related to the down-regulation of SGK1. However, inhibition of SGK1 directly lacks the effects in the treatment of depression.

Hippocampal BDNF signaling is required for the antidepressant effects of perillaldehyde.

BACKGROUND: Perillaldehyde is one of the main components in perilla. Previous studies have shown that perillaldehyde exerted an antidepressant effect in mice, some of which is mediated through regulation of the anti-inflammatory system and the monoamine system. The primary objective of this study was to investigate the possible effects of perillaldehyde on the neurotrophic system and to elucidate whether its antidepressant effect requires brain-derived neurotrophic factor (BDNF) signaling. METHODS: Mice were exposed to chronic unpredictable mild stress (CUMS) and orally administrated with perillaldehyde for 4 weeks for behavioral testing. RESULTS: Perillaldehyde not only reversed the decrease in sucrose preference but also attenuated the increase in feeding latency. In addition, perillaldehyde can attenuate the reduction of CUMS-induced hippocampal BDNF levels. Our further study found that the BDNF receptor tropomyosin receptor kinase B (TrkB) antagonist K252a completely blocked the antidepressant effect of perillaldehyde in mice. Biochemical analysis showed that K252a pretreatment completely prevented the improvement of BDNF, extracellular signal-regulated kinase (ERK) phosphorylation and synaptic protein. CONCLUSIONS: These results indicated that activation of BDNF-ERK signaling in the hippocampus was required, at least in part for the antidepressant effects of perillaldehyde.

Gypenosides reverses depressive behavior via inhibiting hippocampal neuroinflammation.

Gypenosides, a saponins extract isolated from the Gynostemma pentaphyllum plant, produces neuroprotective effects in the brain. Our previous studies have shown that hippocampal glucocorticoid receptor (GR)-brain-derived neurotrophic factor (BDNF)-TrkB signaling was involved in the antidepressant-like effects of gypenosides. It remains unknown whether gypenosides could alleviate neuroinflammation in depressive-like animals. The aim of the present study was to address this issue in chronic unpredictable mild stress (CUMS). Gypenosides was administrated for four weeks, followed by sucrose preference test and tail suspension test, which were performed to evaluate the effects of gypenosides. The results showed that gypenosides reversed both the decreased sucrose preference and increased immobility time in CUMS mice. In addition, gypenosides also attenuated the increase of pro-inflammatory cytokine levels in the hippocampus of CUMS animals. Furthermore, the activation of NF-κB, as well as its upstream mediators IKKα and IKKß were inhibited by gypenosides. Last but not the least, CUMS promoted the activation of microglia, while gypenosides suppressed it according to the reduced number of iba1 positive cells. In conclusion, this study demonstrates that gypenosides exhibits the antidepressant-like effects in mice, which may be mediated by the inhibition of microglia and NF-κB signaling in the hippocampus.

The antidepressant-like effects of Chaihu Shugan San: Dependent on the hippocampal BDNF-TrkB-ERK/Akt signaling activation in perimenopausal depression-like rats.

Chaihu Shugan San (CSS), a traditional Chinese medicine formula, has been used to treat depression for hundreds of years. Recently, the antidepressant-like mechanism of CSS has been increasingly evaluated and demonstrated. However, there are few studies focused on the involvement of the neurotrophic system in mediating the antidepressant-like effects of CSS. Considering the high prevalence of perimenopausal depression around the world, the goal of the present study was to determine whether brain-derived neurotrophic factor (BDNF) signaling is required for the antidepressant-like effects of CSS in perimenopausal depressive-like rats. The results indicate that CSS reverses depressive-like behaviors and attenuates the downregulation of BDNF in the hippocampus of perimenopausal rats exposed to chronic unpredictable mild stress (CUMS). We found that the TrkB antagonist K252 not only blocks the effects of CSS on behavioral improvement but also abolishes the activation of CSS in BDNF-TrkB signaling. As a result, the downstream targets of BDNF signaling, such as the ERK and Akt pathways, are significantly inhibited by K252a. Furthermore, CSS increases hippocampal neurogenesis, while K252a fully prevents this action. In conclusion, the present results demonstrate that the activation of the hippocampal BDNF-TrkB-ERK/Akt signaling pathway is required for the antidepressant-like effects of CSS on the depressive-like state during perimenopause. Additionally, this study also demonstrates that neurogenesis is required for the effects of antidepressants in aging perimenopausal animals and provides fundamental evidence for the clinical application of CSS.

miR-124 antagonizes the antidepressant-like effects of standardized gypenosides in mice.

Our previous study demonstrated that gypenosides produced antidepressant-like effects in mice exposed to chronic mild stress in a brain-derived neurotrophic factor-dependent manner. However, whether other mechanisms are involved in the antidepressant-like effects of gypenosides is not clear. miR-124 is one of the most abundant microRNAs in the hippocampus, and its dysregulation is related to the pathophysiology of depression. The glucocorticoid receptor is dysfunctional in depression, and it is a direct target of miR-124. Therefore, the present study used corticosterone-induced mice as a model to evaluate the role of miR-124 on the antidepressant-like effects of gypenosides. miR-124 agomir was intracerebrally injected prior to administration of gypenosides and corticosterone injection. Sucrose preference and forced swimming tests were performed 21 days later. Proteins related to glucocorticoid receptors and brain-derived neurotrophic factor-tyrosine receptor kinase B signaling in the hippocampus were evaluated. Our results demonstrated that gypenosides reversed the chronic corticosterone injection-induced decreased sucrose preference and increased immobility time. In contrast, this effect was antagonized by miR-124 injection. In addition, gypenosides increased glucocorticoid receptor and tyrosine receptor kinase B expression in the hippocampus, which activated brain-derived neurotrophic factor signaling. miR-124 also blocked these effects. In conclusion, this study demonstrated that a reduction in miR-124 was required for the antidepressant-like effects of gypenosides induced by chronic corticosterone injection in mice.

Saikosaponin A attenuates perimenopausal depression-like symptoms by chronic unpredictable mild stress.

Accumulating studies have shown that a traditional Chinese decoction Chaihu-Shugan-San produced the antidepressant-like effects in rodents including in perimenopausal. Previous studies and our preliminary study indicated that saikosaponin A, one of the main constituents of Chaihu-Shugan-San, enhanced brain-derived neurotrophic factor (BDNF) expression in rats. Herein, this study aimed to evaluate the antidepressant-like effects of saikosaponin A in perimenopausal rats exposed to chronic unpredictable mild stress (CUMS). The sucrose preference test, novelty-suppressed feeding test and forced swimming test were performed after administration of saikosaponin A for 4 weeks. Serum corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone levels, as well as hypothalamus CRH and hippocampal glucocorticoid receptor were measured. In addition, pro-inflammatory cytokines such as interleukin-1beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the hippocampus were detected for evaluation of the neuroinflammation. Further, BDNF levels and its receptor TrkB were also determined. Our results indicated that four-week treatment with saikosaponin A increased sucrose preference, decreased latency to feed in the novelty-suppressed feeding test and reduced the immobility time in the forced swimming test. In addition, saikosaponin A restored the dsyregulation of HPA axis and neuroinflammation in rats exposed to CUMS. Moreover, saikosaponin A promoted BDNF-TrkB signaling in the hippocampus. This study demonstrates that saikosaponin A produced the antidepressant-like effects in rats, which may be mediated by restoration of neuroendocrine, neuroinflammation and neurotrophic systems in the hippocampus during perimenopausal.

Spraying Brassinolide improves Sigma Broad tolerance in foxtail millet (Setaria italica L.) through modulation of antioxidant activity and photosynthetic capacity.

To explore the role of Brassinolide (BR) in improving the tolerance of Sigma Broad in foxtail millet (Setaria italica L.), effects of 0.1 mg/L of BR foliar application 24 h before 3.37 g/ha of Sigma Broad treatment at five-leaf stage of foxtail millet on growth parameters, antioxidant enzymes, malondialdehyde (MDA), chlorophyll, net photosynthetic rate (P N), chlorophyll fluorescence and P700 parameters were studied 7 and 15 d after herbicide treatment, respectively. Results showed that Sigma Broad significantly decreased plant height, activities of superoxide dismutase (SOD), chlorophyll content, P N, PS II effective quantum yield (Y (II)), PS II electron transport rate (ETR (II)), photochemical quantum yield of PSI(Y (I)) and PS I electron transport rate ETR (I), but significantly increased MDA. Compared to herbicide treatment, BR dramatically increased plant height, activities of SOD, Y (II), ETR (II), Y (I) and ETR (I). This study showed BR pretreatment could improve the tolerance of Sigma Broad in foxtail millet through improving the activity of antioxidant enzymes, keeping electron transport smooth, and enhancing actual photochemical efficiency of PS II and PSI.

microRNA-124 targets glucocorticoid receptor and is involved in depression-like behaviors.

Dysregulation of microRNA (miRNA) has been shown to be involved in early observations of depression. MicroRNA-124-3p (miR-124) is the most abundant microRNA in the brain. Previous studies have shown that miR-124 plays a major role in depression. Here we showed that miR-124 directly targeted glucocorticoid receptor (GR) in HEK 293 cells. In addition, inhibition of miR-124 by its antagomir (2nmol/every two days) could reverse the decrease of sucrose preference and the increase of immobility time in mice exposed to chronic corticosterone (CORT, 40mg/kg) injection. Moreover, these effects on behavioral improvement were coupled to the activation of brain-derived neurotrophic factor (BDNF), TrkB, ERK, and CREB, as well as the induction of synaptogenesis and neuronal proliferation. Altogether, our study suggests that miR-124 can be served as a biomarker for depression and a novel target for drug development, and demonstrates that inhibition of miR-124 may be a strategy for treating depression by activating BDNF-TrkB signaling pathway in the hippocampus.

Increasing Selenium and Yellow Pigment Concentrations in Foxtail Millet (Setaria italica L.) Grain with Foliar Application of Selenite.

Although addition of selenium (Se) is known to increase Se in crops, it is unclear whether exogenous Se is linked to nutritional and functional components in foxtail millet (Setaria italica L.). In this study, we examined the potential of increasing Se and yellow pigment (YP) in foxtail millet grain by foliar application of Se. Field experiments were conducted during the growing season of foxtail millet in 2013 and 2014 to assess the effects of foliar spray of sodium selenite (10-210 g Se ha(-1)) on the yield, Se uptake and accumulation, total YP, and microminerals in the grain. Average grain yields with Se application were 5.60 and 4.53 t ha(-1) in the 2 years, showing no significant differences from the unfertilized control. However, grain Se concentration increased linearly with Se application rate, by 8.92 and 6.09 µg kg(-1) in the 2 years with application of 1 g Se ha(-1) (maximum grain recovery rates of Se fertilizer, 52 and 28 %). Likewise, total grain YP concentration markedly increased by 0.038 and 0.031 mg kg(-1) in the 2 years with application of 1 g Se ha(-1). Grain Mn, Cu, Fe, and Zn concentrations were not significantly affected by Se application. This study indicated that foliar application of Se effectively and reliably increased the concentrations of Se and YP in foxtail millet grain without affecting the yield or mineral micronutrient concentrations. Thus, foliar-applied selenite has a significant potential to increase the concentrations of selenium and YP (putative lutein (Shen, J Cereal Sci 61:86-93, 2015; Abdel-Aal, Cereal Chem 79:455-457, 2002; Abdel-Aal, J Agric Food Chem 55:787-794, 2007)) of foxtail millet and, thus, the health benefits of this crop.