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.

Cerebral ischemia-reperfusion is a complicated pathological process. The injury and cascade reactions caused by cerebral ischemia and reperfusion are characterized by high mortality, high recurrence, and high disability. However, only a limited number of antithrombotic drugs, such as recombinant tissue plasminogen activator (r-TPA), aspirin, and heparin, are currently available for ischemic stroke, and its safety concerns is inevitable which associated with reperfusion injury and hemorrhage. Therefore, it is necessary to further explore and examine some potential neuroprotective agents with treatment for cerebral ischemia and reperfusion injury to reduce safety concerns caused by antithrombotic drugs in ischemic stroke. Ginseng Rg1 (G-Rg1) is a saponin composed of natural active ingredients and derived from the roots or stems of Panax notoginseng and ginseng in traditional Chinese medicine. Its pharmacological effects exert remarkable neurotrophic and neuroprotective effects in the central nervous system. To explore and summarize the protective effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury, we conducted this review, in which we searched the PubMed database to obtain and organize studies concerning the pharmacological effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury. This study provides a valuable reference and clues for the development of new agents to combat ischemic stroke. Our summarized review and analysis show that the pharmacological effects of and mechanisms underlying ginsenoside Rg1 activity against cerebral ischemia and reperfusion injury mainly involve 4 sets of mechanisms: anti-oxidant activity and associated apoptosis via the Akt, Nrf2/HO-1, PPARγ/HO-1, extracellular regulated protein kinases (ERK), p38, and c-Jun N-terminal kinase (JNK) pathways (or mitochondrial apoptosis pathway) and the caspase-3/ROCK1/MLC pathway; anti-inflammatory and immune stimulatory-related activities that involve apoptosis or necrosis via MAPK pathways (the JNK1/2 + ERK1/2 and PPARγ/HO-1 pathways), endoplasmic reticulum stress (ERS), high mobility group protein1 (HMGB1)-induced TLR2/4/9 and receptor for advanced glycation end products (RAGE) pathways, and the activation of NF-κB; neurological cell cycle, proliferation, differentiation, and regeneration via the MAPK pathways (JNK1/2 + ERK1/2, PI3K-Akt/mTOR, PKB/Akt and HIF-1α/VEGF pathways); and energy metabolism and the regulation of cellular ATP levels, the blood-brain barrier and other effects via N-methyl-D-aspartic acid (NMDA) receptors, ERS, and AMP/AMPK-GLUT pathways. Collectively, these mechanisms result in significant neuroprotective effects against cerebral ischemic injury. These findings will be valuable in that they should further promote the development of candidate drugs and provide more information to support the application of previous findings in stroke clinical trials.

It is currently believed that inflammation plays a central role in the pathophysiology of atherosclerosis (AS). 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-1β, 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.

Ischemic stroke is a clinically common cerebrovascular disease whose main risks include necrosis, apoptosis and cerebral infarction, all caused by cerebral ischemia and reperfusion (I/R). Ischemia and reperfusion-induced injury or apoptosis inhibition in human brain tissue may exert an irreplaceable protective effect on ischemic nerves. This process has particular significance for the treatment of stroke patients. However, the development of neuroprotective drugs remains challenging. Radix Scrophulariae, traditionally considered a valuable medicine, has been discovered to have neuroprotective effects. To explore the neuroprotective effects of an aqueous extract of Radix Scrophulariae (RSAE) on cerebral ischemia/reperfusion and their underlying mechanisms, oxygen-glucose deprivation and reperfusion (OGD/R)-induced PC12 cells were used, and a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was established. In vitro results showed that 12.5 μg/mL RSAE markedly improved cell viability; inhibited LDH leakage; increased SOD, GSH-Px and CAT enzyme activity; stabilized the mitochondrial membrane potential; and reduced OGD-induced cell injury and apoptosis. Additionally, in vivo results preliminarily suggested that in MCAO/R model mice, RSAE treatments attenuated infarct volume; reduced brain water content and nitric oxide (NO) and malondialdehyde (MDA) concentrations; inhibited I/R-induced neurological deficits; reduced the levels of lactate dehydrogenase (LDH) leakage release; improved antioxidant capacity by upregulating SOD, GSH-Px and CAT enzyme activity; and reduced neuronal apoptosis, necrosis and loss of neurons. Moreover, it was found that RSAE upregulated the expression of Bcl-2 and downregulated the expression of Bax. In addition, the phosphorylation levels of MAPK signal pathways were elucidated via western blot analysis and immunohistochemical evaluation. In summary, this study investigated the neuroprotective effects and potential mechanisms of RSAE on focal cerebral I/R injury in mice. Radix Scrophulariae has been previously identified as a potential neuroprotective natural plant. Hence, our results may offer insight into discovering new active compounds or drugs for the treatment of ischemic stroke. Many new natural active chemicals in this extract may be discovered by chemical separation and identification and may provide new insights into therapeutic targets in stroke patients.

Notoginseng Leaf Triterpenes Ameliorates OGD/R-Induced Neuronal Injury via SIRT1/2/3-Foxo3a-MnSOD/PGC-1α Signaling Pathways Mediated by the NAMPT-NAD Pathway: Background. Cerebral ischemic stroke (CIS) is a common cerebrovascular disease whose main risks include necrosis, apoptosis, and cerebral infarction. But few therapeutic advances and prominent drugs seem to be of value for ischemic stroke in the clinic yet. In the previous study, notoginseng leaf triterpenes (PNGL) from Panax notoginseng stem and leaf have been confirmed to have neuroprotective effects against mitochondrial damages caused by cerebral ischemia in vivo. However, the potential mechanisms of mitochondrial protection have not been fully elaborated yet. Methods. The oxygen and glucose deprivation and reperfusion (OGD/R)-induced SH-SY5Y cells were adopted to explore the neuroprotective effects and the potential mechanisms of PNGL in vitro. Cellular cytotoxicity was measured by MTT, viable mitochondrial staining, and antioxidant marker detection in vitro.Mitochondrial functions were analyzed by ATP content measurement, MMP determination, ROS, NAD, and NADH kit in vitro. And the inhibitor FK866 was adopted to verify the regulation of PNGL on the target NAMPT and its key downstream. Results. In OGD/R models, treatment with PNGL strikingly alleviated ischemia injury, obviously preserved redox balance and excessive oxidative stress, inhibited mitochondrial damage, markedly alleviated energy metabolism dysfunction, improved neuronal mitochondrial functions, obviously reduced neuronal loss and apoptosis in vitro, and thus notedly raised neuronal survival under ischemia and hypoxia. Meanwhile, PNGL markedly increased the expression of nicotinamide phosphoribosyltransferase (NAMPT) in the ischemic regions and OGD/R-induced SH-SY5Y cells and regulated the downstream SIRT1/2-Foxo3a and SIRT1/3-MnSOD/PGC-1α pathways. And FK866 further verified that the protective effects of PNGL might be mediated by the NAMPT in vitro. Conclusions. The mitochondrial protective effects of PNGL are, at least partly, mediated via the NAMPT-NAD+ and its downstream SIRT1/2/3-Foxo3a-MnSOD/PGC-1α signaling pathways. PNGL, as a new drug candidate, has a pivotal role in mitochondrial homeostasis and energy metabolism therapy via NAMPT against OGD-induced SH-SY5Y cell injury.

Atherosclerosis is an arterial disease associated with inflammation. Hence, the discovery of novel therapeutic agents for suppressing inflammatory responses is urgent and vital for the treatment of atherosclerosis in cardiovascular diseases. The total saponins of Aralia elata (Miq.) Seem. (TAS) are the main components extracted from the Chinese traditional herb Longya Aralia chinensis L., a folk medicine used in Asian countries for treating numerous diseases, enhancing energy and boosting immunity. However, the protective effects of TAS against inflammation-triggered vascular endothelial dysfunction, a critical early event during the course of atherosclerosis, and the potential mechanisms of this protection have been not demonstrated. Accordingly, the aim of this study was to investigate the anti-inflammatory and anti-apoptotic effects and the protective mechanisms of TAS, and show how TAS ameliorates human umbilical vein endothelial cell (HUVEC) damage caused by tumour necrosis factor-α (TNF-α). The results indicated that TAS exerted cytoprotective effects by inhibiting TNF-α-triggered HUVEC apoptosis, mitochondrial membrane potential depolarisation, and the regulation of inflammatory factors (IL-6, MCP-1, and VCAM-1) while suppressing NF-κB transcription. Furthermore, this phenomenon was related to activation of the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway. Blocking the Akt pathway with LY294002, a PI3K inhibitor, reversed the cytoprotective effect of TAS against TNF-α-induced endothelial cell death. Moreover, LY294002 partially abolished the effects of TAS on the upregulation of the Bcl-2 family of proteins and the downregulation of Bax protein expression. In conclusion, the results of our study suggest that TAS suppresses the inflammation and apoptosis of HUVECs induced by TNF-α and that PI3K/Akt signalling plays a key role in promoting cell survival and anti-inflammatory reactions during this process.