Correction: Zhou, P., et al. Notoginsenoside R1 Ameliorates Diabetic Retinopathy through PINK1-Dependent Activation of Mitophagy. Cells, 2019, 8, 213.

The authors wish to make the following corrections to this paper [...].

Antidepressant-like effects of the Guanxin Danshen formula via mediation of the CaMK II-CREB-BDNF signalling pathway in chronic unpredictable mild stress-induced depressive rats.

BACKGROUND: Depression is a chronic and recurrent syndrome of mood disorder causing immense social and economic burden; thus, treatment should be improved. Guanxin Danshen formula (GXDSF), a natural botanical drug composition prescription, has significant cardiovascular protective effects and is widely used in the clinical treatment of myocardial ischaemic diseases. However, it is still unclear and seldom studied whether GXDSF has neuroprotective effects against depressive disorders. This study explored whether GXDSF has antidepressant-like effects in rats exposed to chronic unpredictable mild stress (CUMS) and analysed the possible underlying neurotrophic expression and psychotropic mechanisms. METHODS: The present study was designed to investigate the antidepressant effects of GXDSF treatment in a CUMS-induced rat model. Based on the clinical doses, the drug-treated group was intragastrically administered GXDSF for 30 days, and rats were simultaneously exposed to CUMS stimulation for 30 days. After induction and drug administration, the depression-like behaviours were determined via the sucrose preference test (SPT), the open field test (OFT), the tail suspension test (TST), and the forced swim test (FST). ELISA kits were used to examine the monoaminergic neurotransmitters, monoamine oxidase (MAO) and Ca2+ levels in the hippocampus. Moreover, we measured and analysed the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels and the upstream regulation and signal pathways of BDNF and NGF to explore their related mechanisms in this animal model of depression, including calcium-calmodulin dependent protein kinase-II (CaMKII) and cAMP response element-binding (CREB). RESULTS: The results revealed that GXDSF may possess significant antidepressant-like effects via improving body weight, raising the sucrose preference in the SPT, increasing the total distance, the number of upright stands, and the residence time of the central zone in the open field test (OPF) and reducing the immobility time in the TST and FST. In addition, GXDSF significantly upregulated the relative levels of neurotransmitters, including dopamine (DA), norepinephrine (NE), and serotonin (5-HT), in a dose-dependent manner and inhibited MAO activities in the hippocampus. Moreover, GXDSF reversed the decline in intracellular CREB and p-CREB expression induced by CUMS, downregulated the phosphorylation levels of intracellular CaMKII and its two subunits CaMKIIα and CaMKIIß in the hippocampus, and thus, clearly upregulated the downstream effector protein expression levels of BDNF, NGF, and synitaxine-1 in the hippocampus. These data suggest that the antidepressant effects of GXDSF have a potential relationship with regulating changes in the CaMKII-CREB-BDNF pathway. CONCLUSIONS: Despite several limitations of this study, the results have suggested that GXDSF administration possesses antidepressant-like effects in CUMS-treated rats and provide the first in vivo demonstration of a possible mechanism of GXDSF via regulating changes in the CaMKII-CREB-BDNF signalling pathway. These findings provide a novel potential substrate by which herbal antidepressants may exert therapeutic effects in the treatment of depression.

Notoginsenoside R1 Ameliorates Diabetic Retinopathy through PINK1-Dependent Activation of Mitophagy.

: Accumulating evidence has indicated that inflammation, oxidative stress, apoptosis, and autophagy in retinal Müller cells are involved in diabetic retinopathy (DR). Notoginsenoside R1 (NGR1), a novel saponin extracted from Panax notoginseng, posesses pharmacological properties, including treating diabetic encephalopathy and improving microcirculatory disorders. Nevertheless, its beneficial effects on DR and the potential mechanism remain to be elucidated. In this study, we found retinal vascular degeneration, reduced retinal thickness, and impaired retinal function in db/db mice were all dramatically attenuated by oral treatment with NGR1 (30 mg/kg) for 12 weeks. NGR1 pretreatment also significantly inhibited apoptosis, markedly suppressed the VEGF expression, markedly increased PEDF expression and markedly inhibited oxidative stress and inflammation in rat retinal Müller cells (rMC-1) subjected to high glucose (HG) and in the retinas of db/db mice. Furthermore, NGR1 pre-treatment upregulated the level of PINK1 and Parkin, increased the LC3-II/LC3-I ratio, and downregulated the level of p62/SQSTM1 in rMC-1 cells induced by HG and in the retinas of db/db mice. Moreover, NGR1 administration enhanced the co-localization of GFP-LC3 puncta and MitoTracker in rMC-1 cells. Importantly, knockdown of PINK1 abolished the protective effects of NGR1. In conclusion, these phenomena suggested that NGR1 prevented DR via PINK1-dependent enhancement of mitophagy.

Gastrodin Ameliorates Cognitive Dysfunction in Diabetes Rat Model via the Suppression of Endoplasmic Reticulum Stress and NLRP3 Inflammasome Activation.

Patients with diabetes mellitus (DM) are at high risk for cognitive dysfunction. Endoplasmic reticulum stress (ERS) and inflammation play crucial roles in DM. Gastrodin (Gas), the main component of Gastrodia elata, possesses anti-oxidative stress, anti-inflammatory, and neuroprotective effects. This present study aims to investigate whether Gas could ameliorate cognitive dysfunction in DM and to explore its underlying mechanisms. Rats with streptozotocin-induced type 2 DM were used in this study. After administration of Gas for 5 weeks, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) in serum, TNF-α, IL-1ß, MDA and SOD in the hippocampus were measured. Morris water maze, hematoxylin and eosin (HE) and Nissl staining were performed to assess the effects of Gas on cognitive function and hippocampal neuronal apoptosis. Protein levels of GLUT3, brain derived neurotrophic factor (BDNF), GRP78, PERK, P-PERK, TXNIP, ASC, NLRP3, CHOP, Bcl-2 and Bax were measured by using Western blot. The results showed that Gas could improve hyperglycemia and dyslipidemia in DM rats, as the levels of TC, TG LDL-C in serum were decreased. TNF-α, IL-1ß, MDA contents in the hippocampus were decreased, and SOD contents was increased in the hippocampus of DM rats. Inflammation, oxidative stress, ERS, and apoptosis were observed in the hippocampus of DM rats, accompanied with decreased expression of BDNF and GLUT3. Gas improved the cognitive deficits caused by diabetes and inhibited inflammation, oxidative stress, ERS, and apoptosis in the hippocampus. Furthermore, Gas substantially increased the expression of GLUT3, and inhibited hippocampal ERS and ERS-mediated apoptosis. Additionally, Gas increased the expression of BDNF and decreased the activation of NLRP3 inflammasome. These results suggested that by inhibiting ERS and NLRP3 inflammasome activation and increasing the expression of BDNF and GLUT3, Gas exhibits neuroprotective effects against cognitive dysfunction in DM.

D-dencichine Regulates Thrombopoiesis by Promoting Megakaryocyte Adhesion, Migration and Proplatelet Formation.

Life-threatening chemotherapy-induced thrombocytopenia can increase the risk of bleeding due to a dramatic low platelet count, which may limit or delay treatment schedules in cancer patients. The pressing need for the rapid alleviation of the symptoms of thrombocytopenia has prompted us to search for novel highly effective and safe thrombopoietic agents. Pharmacological investigations have indicated that dencichine can prevent and treat blood loss and increase the number of platelets. On the basis of the neurotoxicity of dencichine, D-dencichine is artificially synthesized in the laboratory. Our initial results showed that D-dencichine had potential to elevate peripheral platelet levels in mice with carboplatin-induced thrombocytopenia. However, the mechanisms of D-dencichine on thrombopoiesis have been poorly understood. In this study, we found that sequential administration of D-dencichine had a distinct ability to elevate numbers of reticulated platelets, and did not alter their clearance. Moreover, we demonstrated that D-dencichine was able to modulate the return of hematopoietic factors to normal levels, including thrombopoietin and IL-6. However, subsequent analysis revealed that D-dencichine treatment had no direct effects on megakaryocytes proliferation, differentiation, and polyploidization. Further in vitro studies, we demonstrated for the first time that D-dencichine significantly stimulated megakaryocyte adhesion, migration, and proplatelet formation in a dose-dependent manner through extracellular regulated protein kinases1/2 (ERK1/2) and v-akt murine thymoma viral oncogene homolog (AKT) signaling pathways. This study sufficiently characterized the role of the effects of D-dencichine treatment on the regulation of thrombopoiesis and provided a promising avenue for CIT treating.

Panax Notoginseng Saponins: A Review of Its Mechanisms of Antidepressant or Anxiolytic Effects and Network Analysis on Phytochemistry and Pharmacology.

Panax notoginseng (Burk) F. H. Chen, as traditional Chinese medicine, has a long history of high clinical value, such as anti-inflammatory, anti-oxidation, inhibition of platelet aggregation, regulation of blood glucose and blood pressure, inhibition of neuronal apoptosis, and neuronal protection, and its main ingredients are Panax notoginseng saponins (PNS). Currently, Panax notoginseng (Burk) F. H. Chen may improve mental function, have anti-insomnia and anti-depression effects, alleviate anxiety, and decrease neural network excitation. However, the underlying effects and the mechanisms of Panax notoginseng (Burk) F. H. Chen and its containing chemical constituents (PNS) on these depression-related or anxiety-related diseases has not been completely established. This review summarized the antidepressant or anxiolytic effects and mechanisms of PNS and analyzed network targets of antidepressant or anxiolytic actions with network pharmacology tools to provide directions and references for further pharmacological studies and new ideas for clinical treatment of nervous system diseases and drug studies and development. The review showed PNS and its components may exert these effects through regulating neurotransmitter mechanism (5-HT, DA, NE), modulation of the gamma-amino butyric acid (GABA) neurotransmission, glutamatergic system, hypo-thalamus-pituitary-adrenal (HPA) axis, brain-derived neurotrophic factor (BDNF), and its intracellular signaling pathways in the central nervous system; and produce neuronal protection by anti-inflammatory, anti-oxidation, or inhibition of neuronal apoptosis, or platelet aggregation and its intracellular signaling pathways. Network target analysis indicated PNS and its components also may have anti-inflammatory and anti-apoptotic effects, which leads to the preservation of brain nerves, and regulate the activity and secretion of nerve cells, exerting anti-depression and anxiolytic effects, which may provide new directions for further in-depth researches of related mechanisms.

Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice.

Diabetes is associated with a high risk of developing cognitive dysfunction and neuropsychiatric disabilities, and these disease symptomsare termed diabetic encephalopathy (DEP). Inflammation is involved in the development of DEP. The cleavage and maturation of the proinflammatory cytokine interleukin (IL)-1ß is regulated by the NLRP3 inflammasome. Obese and type 2 diabetic db/db mice show anxiety- and depression-like behaviors and cognitive disorders associated with hippocampal inflammation. The purpose of this study was to explore the role of NLRP3 inflammasome in DEP. Results showed that expression levels of inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1, as well as IL-1ß in the hippocampus of diabetic db/db mice were higher than those of non-diabetic db/m mice. Treatment of db/db mice with NLRP3 inflammasome inhibitor MCC950 ameliorated anxiety- and depression-like behaviors as well as cognitive dysfunction, and reversed increased NLRP3, ASC, and IL-1ßexpression levels and caspase-1 activity in hippocampus. Moreover, MCC950 treatment significantly improved insulin sensitivity in db/db mice. These results demonstrate that inhibition of NLRP3 inflammasome activation may prove to be a potential therapeutic approach for DEP treatment.

Notoginsenoside R1 ameliorates diabetic encephalopathy by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation.

Numerous researches supported that oxidative stress and inflammation play important roles in the development of diabetic encephalopathy (DEP). Notoginsenoside R1 (NGR1), one major component of Panax notoginseng, is believed to have anti-oxidative, anti-inflammatory and neuroprotective properties. However, its neuroprotective effects against DEP and underlying mechanisms are still unknown. In this study, db/db mice as well as high-glucose (HG)-treated HT22 hippocampal neurons were used as in vivo and in vitro models to estimate NGR1 neuroprotection. NGR1 administration for 10 weeks could ameliorate cognitive dysfunction, depression-like behaviors, insulin resistance, hyperinsulinemia, dyslipidemia, and inflammation in db/db mice. NGR1 markedly decreased the oxidative stress induced by hyperglycemia in hippocampal neurons. NGR1 significantly activated the protein kinase B (Akt)/nuclear factor-erythroid 2-related factor2 (Nrf2) pathway, and inhibited NLRP3 inflammasome activation in hippocampal neurons, which might be essential for the neuroprotective effects of NGR1. Further supporting these results, we observed that pretreatment with the phosphatidylinositol 3-kinase inhibitor LY294002 abolished NGR1-mediated neuroprotective effects against oxidative stress and NLRP3 inflammasome activation in HG-treated HT22 hippocampal neurons. In conclusion, the present study demonstrates the neuroprotective effects of NGR1 on DEP by activating the Akt/Nrf2 pathway and inhibiting NLRP3 inflammasome activation. This study also provides a novel strategy for the application of NGR1 as a therapeutic agent for patients with DEP.

Dai-Zong-Fang, A Traditional Chinese Herbal Formula, Ameliorates Insulin Resistance in db/db Mice.

Intricate health problems, such as insulin resistance (IR) and its associated diseases, call for multi-targeted therapies with few side effects. Based on traditional Chinese medicine (TCM), Dai-Zong-Fang (DZF) is an herbal formula mainly composed of Rhizoma Coptidis (Huanglian) and Fructus Aurantii Immaturus (Zhishi), of which berberine and naringin are the main constituents. Though DZF has been clinically used for treatment of IR and metabolic syndrome for decades, its mechanism in vivo remains unknown. In the present study, we observed that both DZF and metformin, the first-line drug for type 2 diabetes, ameliorated insulin resistance with significant improvement of oral glucose tolerance test (OGTT) and homeostasis model assessment of IR (HOMA-IR) level in diabetic C57BL/Ksj-Lepr db-/- (db/db) mice. Low-density lipoprotein cholesterol (LDL-C) and fatty acids (FAs) also decreased in the blood. Higher dose of DZF (1 g·kg-1), but not metformin (0.25 g·kg-1), alleviated hepatic steatosis with reduced liver weight and hepatic lipid accumulation and provided protection from hepatic injury with lower alanine aminotransferase and aspartate aminotransferase and increased hepatic superoxide dismutase activity in db/db mice. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed a decrease in FA synthase gene (Fasn) and an increase in FA oxidation gene Ppara expression. Western blot demonstrated that both DZF and metformin activated 5' AMP-activated protein kinase (AMPK) but inhibited Notch intracellular domain (NICD) and Hairy/enhancer-of-split 1 (Hes1) of Notch signaling pathway in the liver. DZF also dramatically improved the ultrastructure of skeletal muscles, AMPK phosphorylation, and GLUT4 translocation. DZF also promoted FA transport and oxidation with Cd36 and Cpt1b up-regulation in the skeletal muscle. In conclusion, DZF improves insulin sensitivity by reducing hepatic lipids through AMPK activation and Notch signal pathway inhibition and enhancing energy metabolism in the skeletal muscle via AMPK. This study provides insights into the treatment of complex conditions, such as IR, where TCM herbal formulas exert multipronged effects through correlating pathways.

Performance enhancement of high-field asymmetric waveform ion mobility spectrometry by applying differential-RF-driven operation mode.

The traditional operation mode of high-field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) uses a one-way radio frequency (RF) voltage input as the dispersion voltage. This requires a high voltage input and limits power consumption reduction and miniaturization of instruments. With higher dispersion voltages or larger compensation voltages, there also exist problems such as low signal intensity or the fact that the dispersion voltage is no longer much larger than the compensation voltage. In this paper, a differential-RF-driven operation mode of FAIMS is proposed. The two-way RF is used to generate the dispersion field, and a phase difference is added between the two RFs to generate a single step waveform field. Theoretical analysis, and experimental results from an ethanol sample, showed that the peak positions of the ion spectra changed linearly (R2 = 0.9992) with the phase difference of the two RFs in the differential-RF-driven mode and that the peak intensity of the ion spectrum could be enhanced by more than eight times for ethanol ions. In this way, it is possible to convert the ion spectrum peaks outside the separation or compensation voltage range into a detectable range, by changing the phase difference. To produce the same separation electric field, the high-voltage direct current input voltage can be maximally reduced to half of that in the traditional operation mode. Without changing the drift region size or drift condition, the differential-RF-driven operation mode can reduce power consumption, increase signal-to-noise ratio, extend the application range of the dispersion voltage and compensation voltage, and improve FAIMS detection performance.

Attenuation of TNF-α-Induced Inflammatory Injury in Endothelial Cells by Ginsenoside Rb1 via Inhibiting NF-κB, JNK and p38 Signaling Pathways.

It is currently believed that inflammation plays a central role in the pathophysiology of atherosclerosis. Oxidative stress and redox-sensitive transcription factors are implicated in the process. Ginsenoside Rb1, a major active ingredient in processed Radix notoginseng, has attracted widespread attention because of its potential to improve cardiovascular function. However, the effects of ginsenoside Rb1 on tumor necrosis factor-α (TNF-α)-induced vascular endothelial cell injury and the underlying molecular mechanisms have never been studied. This study showed that TNF-α-induced oxidative stress, inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) could be attenuated by ginsenoside Rb1 pretreatment. Using JC-1, Annexin V/PI and TUNEL staining, and a caspase-3 activity assay, we found that Rb1 provided significant protection against TNF-α-induced cell death. Furthermore, Rb1 pretreatment could inhibit TNF-α-induced ROS and MDA production; increase the activities of SOD, CAT, and GSH-Px; and decrease the levels of IL-1ß, IL-6, VCAM-1, ICAM-1, VEGF, MMP-2 and MMP-9. Importantly, the cytoprotective effects of Rb1 were correlated with NF-κB signaling pathway inhibition. Additionally, we found that Rb1 may suppress the NF-κB pathway through p-38 and JNK pathway activation, findings supported by the results of our experiments involving anisomycin (AM), a JNK and p38 activator. In conclusion, this study showed that ginsenoside Rb1 protects HUVECs from TNF-α-induced oxidative stress and inflammation by inhibiting JNK and p38. This inhibition suppressed NF-κB signaling and down-regulated the expression of inflammatory factors and apoptosis-related proteins.

Cardioprotective effect of the xanthones from Gentianella acuta against myocardial ischemia/reperfusion injury in isolated rat heart.

Gentianella acuta (Michx.) Hulten is widely used for the treatment of arrhythmia and coronary heart disease in Ewenki Folk Medicinal Plants and Mongolian Medicine, popularly known as "Wenxincao" in China. To investigate the potential protective role of the xanthones from G. acuta against myocardial I/R injury in isolated rat heart and its possible related mechanism. The protective role of xanthones on myocardial I/R injury was studied on Langendorff apparatus. The hemodynamic parameters including the left ventricular developed pressure (LVDP), the maximum rate of up/down left intraventricular pressure (±dp/dtmax), coronary flow (CF) and heart rate (HR) were recorded during the perfusion. The results demonstrated that the xanthones from G. acuta treatment significantly improved myocardial function (LVDP, ±dp/dtmax and CF), increased the levels of superoxide dismutase (SOD) and catalase (CAT), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), ATP and the ratio of glutathione and glutathione disulfide (GSH/GSSG), whereas suppressed the levels of Lactate dehydrogenase (LDH), creatine kinase (CK) and malondialdehyde (MDA). Furthermore, the xanthones upregulate the level of Bcl-2 protein and downregulate the level of Bax protein. These results indicated that xanthones from G. acuta exhibited cardioprotective effects on myocardial I/R injury through its activities of anti-oxidative effect and anti-apoptosis effect.

Merging visible-light photoredox and copper catalysis in catalytic aerobic oxidation of amines to nitriles.

Visible-light-initiated homogeneous oxidative synthesis of nitriles from amines was accomplished through a combined use of photoredox and copper catalysis. This transformation was performed at room temperature with O2 as the oxidant.

Triterpenoids and Flavonoids from the Leaves of Astragalus membranaceus and Their Inhibitory Effects on Nitric Oxide Production.

Four new cycloartane triterpenes, named huangqiyegenins V and VI and huangqiyenins K and L (1-4, resp.), together with nine known triterpenoids, 5-13, and eight flavonoids, 14-21, were isolated from a 70%-EtOH extract of Astragalus membranaceus leaves. The structures of the new compounds were elucidated by detailed spectroscopic analyses, and the compounds were identified as (9ß,11α,16ß,20R,24S)-11,16,25-trihydroxy-20,24-epoxy-9,19-cyclolanostane-3,6-dione (1), (9ß,16ß,24S)-16,24,25-trihydroxy-9,19-cyclolanostane-3,6-dione (2), (3ß,6α,9ß,16ß,20R,24R)-16,25-dihydroxy-3-(ß-D-xylopyranosyloxy)-20,24-epoxy-9,19-cyclolanostan-6-yl acetate (3), and (3ß,6α,9ß,16ß,24E)-26-(ß-D-glucopyranosyloxy)-16-hydroxy-3-(ß-D-xylopyranosyloxy)-9,19-cyclolanost-24-en-6-yl acetate (4). All isolated compounds were evaluated for their inhibitory activities against LPS-induced NO production in RAW264.7 macrophage cells. Compounds 1-3, 14, 15, and 18 exhibited strong inhibition on LPS-induced NO release by macrophages with IC50 values of 14.4-27.1 µM.

[Study on lignans of Gentianella acuta].

OBJECTIVE: To study the lignans from the whole plant of Gentianella acuta. METHODS: The compounds were isolated by various chromatographic techniques and indentified by spectroscopic methods. RESULTS: Nine compounds were isolated and identified as (7R,8S) -dehydrodiconiferyl alcohol-4,9'-O-beta-D-glucopyranoside (1), alaschanisoside A (2), citrusin A (3), olivil-4'-O-beta-D-glucopyranoside (4), leptolepisol D (5), acanthoside D (6), (+) pinoresinol-4-O-beta-D-glucopyranoside (7), (+) 8-hydroxypinoresinol-4-O-beta-D-glucopyranoside (8), and (+) pinoresinol-8-O-beta-D-glucopyranoside (9). CONCLUSION: Compounds 1 - 9 are isolated from this plant for the first time, compounds 1 and 9 are isolated from Gentianella genus for the first time,and compounds 2, 3 and 5 - 8 are isolated from Gentianaceae family for the first time.