Therapeutic targets for endothelial dysfunction in vascular diseases Abstract Vascular endothelial cells are located on the surface of the blood vessels. It has been recognized as an important barrier to the regulation of vascular homeostasis by regulating the blood flow of micro- or macrovascular vessels. Indeed, endothelial dysfunction is an initial stage of vascular diseases and is an important prognostic indicator of cardiovascular and metabolic diseases such as atherosclerosis, hypertension, heart failure, or diabetes. Therefore, in order to develop therapeutic targets for vascular diseases, it is important to understand the key factors involved in maintaining endothelial function and the signaling pathways affecting endothelial dysfunction. The purpose of this review is to describe the function and underlying signaling pathway of oxidative stress, inflammatory factors, shear stress, and epigenetic factors in endothelial dysfunction, and introduce recent therapeutic targets for the treatment of cardiovascular diseases.

Attenuation of hyperoxic acute lung injury by Lycium barbarum polysaccharide via inhibiting NLRP3 inflammasome Abstract Lycium barbarum polysaccharide (LBP), an active component from Goji berry which is a traditional Chinese medicine, has anti-inflammatory and antioxidant features. The aim of our study was to investigate whether LBP has any role in hyperoxia-induced acute lung injury (ALI). Using a murine model of hyperoxia-induced ALI, we investigate the effect of LBP on pulmonary pathological changes as well as Sirtuin 1 (SIRT1) and the nucleotide binding domain and leucine-rich repeat pyrin domain containing 3 (NLRP3) inflammasome. Exposure to 100% oxygen for 72 h in male C57BL/6 mice resulted in increased protein levels of tumor necrosis factor-α and interleukin-1β in lung tissues, and aggravated lung histological alterations. These hyperoxia-induced changes and mortality were improved by LBP. LBP markedly suppressed the activation of NLRP3 inflammasome both in vivo and in vitro. Moreover, LBP upregulated SIRT1 expression compared with vehicle-treated group. Importantly, knockdown of SIRT1 reversed the inhibitory effect of LBP on NLRP3 inflammasome activation in vitro. LBP meliorated hyperoxia-induced ALI in mice by SIRT1-dependent inhibition of NLRP3 inflammasome activation.

Correction to: Pharmacology of natural radioprotectors We apologize that there are some errors in the references for three sentences and Table 2.

Astragalin reduces lipopolysaccharide-induced acute lung injury in rats via induction of heme oxygenase-1 Abstract Astragalin, a bioactive component of medicinal plants such as Rosa agrestis, has anti-inflammatory and antioxidant features. Induction of heme oxygenase (HO)-1 is an effective strategy to reduce excessive generated oxidants during the pathogenesis of acute lung injury (ALI). The aim of the present study is to investigate that whether the anti-inflammatory and antioxidant features of astragalin is HO-1 dependent in lipopolysaccharide (LPS)-induced ALI. Sprague–Dawley rats were used in animal study. Intratracheal LPS was performed to induce experimental ALI model. Astragalin was administrated 1 h after LPS challenge. Human lung epithelial cells were used in cell study. Samples from rats were harvested at 24 h post LPS challenge. Astragalin treatment inhibited LPS-induced inflammatory cells infiltration in the lung and pulmonary edema. Astragalin treatment markedly enhanced the activity of HO-1 compared with vehicle-treated group at 24 h post LPS challenge. Levels of lipid hydroperoxide, a marker for oxidative stress, were decreased in astragalin-treated animals compared with vehicle-treated group. However, the protective effect of astragalin on LPS-induced ALI was abolished in an inhibitor of HO-1-treated animals. Moreover, the astragalin-induced the upregulation of HO-1 in human lung epithelial cells was inhibited when nuclear factor erythroid-2-related factor 2 (Nrf2) was silenced by small interfering RNA. Astragalin reduces LPS-induced ALI via activation of Nrf2/HO-1 pathway.

Camptothecin activates SIRT1 to promote lipid catabolism through AMPK/FoxO1/ATGL pathway in C 2 C 12 myogenic cells Abstract Caloric restriction activates sirtuin 1 (SIRT1) and induces a variety of metabolic effects that are beneficial for preventing age-related disease. The present study screened a commercially available used drug library to develop small molecule activators of SIRT1 as therapeutics for treatment of metabolic disorders. Using an in vitro fluorescence assay, the cancer therapeutic camptothecin increased SIRT1 enzymatic activity by 5.5-fold, indicating it to be a potent SIRT1 activator. Camptothecin also elevated the nicotinamide adenine dinucleotide (NAD)+/NADH ratio and increased SIRT1 protein levels in differentiated C2C12 myogenic cells. Treatment of C2C12 myotubes with camptothecin increased phosphorylation of AMP-dependent kinase (AMPK) and acetyl-coenzyme A carboxylase, caused nuclear translocation and deacetylation of forkhead box O1 (FoxO1), increased transcription and protein expression of adipose triglyceride lipase (ATGL), decreased the amount of intracellular oil droplets, and significantly increased β-oxidation of fatty acids. These in vitro data were confirmed in vivo as camptothecin treatment of C57BL/6J mice reduced fat and plasma triglyceride levels. All of the above camptothecin-induced alterations were attenuated by the SIRT1-specific inhibitor nicotinamide and/or 6-[4-(2-piperidin-1-ylethoxy) phenyl]-3-pyridin-4-ylpyrazolo [1,5-a]pyrimidin (compound C). Thus, camptothecin activation of SIRT1 promotes lipid catabolism through AMPK/FoxO1/ATGL signaling.

Hesperetin inhibits neuroinflammation on microglia by suppressing inflammatory cytokines and MAPK pathways Abstract Neuroinflammation is a specific or nonspecific immunological reaction in the central nervous system that is induced by microglia activation. Appropriate regulation of activated microglial cells is therefore important for inhibiting neuroinflammation. Hesperetin is a natural flavanone and an aglycone of hesperidin that is found in citrus fruits. Hesperetin reportedly possesses anti-inflammatory, anti-cancer, and antioxidant effects. However, the anti-neuroinflammatory effects of hesperetin on microglia are still unknown. Here, we investigated the anti-neuroinflammatory effects of hesperetin on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. We found that hesperetin strongly inhibited nitric oxide production and expression of inducible nitric oxide synthase in LPS-stimulated BV-2 microglial cells. Hesperetin also significantly reduced secretion of inflammatory cytokines including interleukin (IL)-1β and IL-6. Furthermore, hesperetin down-regulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase, exerting anti-inflammatory effects. Hesperetin suppressed astrocyte and microglia activation in the LPS-challenged mouse brain. Collectively, our findings indicate that hesperetin inhibits microglia-mediated neuroinflammation and could be a prophylactic treatment for neurodegenerative diseases.

Filtering through the role of NRF2 in kidney disease Abstract Kidney disease affects ~ 10% of the population worldwide, resulting in millions of deaths each year. Mechanistically, oxidative stress is a major driver of various kidney diseases, and promotes the progression from acute to chronic injury, as well as renal cancer development. NRF2, the master regulator of redox balance, has been shown to protect against kidney disease through its negation of reactive oxygen species (ROS). However, many kidney diseases exhibit high levels of ROS as a result of decreased NRF2 protein levels and transcriptional activity. Many studies have tested the strategy of using NRF2 inducing compounds to alleviate ROS to prevent or slow down the progression of kidney diseases. Oppositely, in specific subsets of renal cancer, NRF2 is constitutively activated and contributes to tumor burden and overall poor prognosis; therefore, there has been a recent interest in studies investigating the benefits of NRF2 inhibition. In this review, we summarize recent literature investigating the role of NRF2 and oxidative stress in various kidney diseases, and how pharmacological modification of NRF2 signaling could play a protective role.

Isoorientin improves scopolamine-induced cognitive impairments by restoring the cholinergic system, antioxidant defense, and p-CREB/BDNF signaling in the hippocampus and frontal cortex Abstract Isoorientin (ISO) is considered one of the most important flavonoids with various pharmacological effects such as antioxidant, anti-inflammatory, and anti-cancer activities. Despite these beneficial activities, the effects of ISO on learning and memory have not been investigated so far. The current study evaluated the memory-enhancing effects of ISO in a scopolamine-treated mouse model by using the Y-maze and passive avoidance tests. The results showed that ISO (5 and 10 mg/kg, p.o.) treatment significantly improved the cognitive impairments caused by scopolamine. Additionally, ISO significantly decreased scopolamine-induced acetylcholinesterase and thiobarbituric acid reactive substance activities in both the hippocampus and frontal cortex of mice. In addition, ISO significantly increased the levels of total superoxide dismutase induced by scopolamine in the hippocampus and frontal cortex. Moreover, Western blot results indicated that ISO reversed the decreases in expression of phosphorylated cAMP response element binding (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus and frontal cortex of scopolamine-treated mice. Thus, our results provide initial evidence that ISO ameliorates scopolamine-induced memory and cognitive impairments partly by restoring the cholinergic system, antioxidant defense, and p-CREB/BDNF signaling pathway, thereby exhibiting memory-enhancing activities.

Preventive approach for overcoming dementia Abstract Dementia is used as a general term to describe chronic disorders of mental processes caused by the deterioration of cognitive functions to the extent that one’s ability to perform daily activities is impaired. Currently, age is known to be the main risk factor for dementia, suggesting that the risk of being diagnosed with dementia significantly increases later in one’s life. Therefore, there are two approaches one can take when confronting dementia: to cure it when it occurs in late adulthood or to prevent the onset of symptoms beforehand. Recently, the latter strategy of delaying and preventing Alzheimer’s disease, the most prevalent form and most studied type of dementia, through both pharmaceutical and nonpharmaceutical interventions is becoming increasingly recognized. In this review, we discuss studies conducted in various fields that addresses nonpharmaceutical lifestyle interventions, including diet, physical activity, cognitive stimulation, and social engagement, and their effects in preventing and inhibiting dementia.

Idelalisib inhibits osteoclast differentiation and pre-osteoclast migration by blocking the PI3Kδ-Akt-c-Fos/NFATc1 signaling cascade Abstract Since increased number of osteoclasts could lead to impaired bone structure and low bone mass, which are common characteristics of bone disorders including osteoporosis, the pharmacological inhibition of osteoclast differentiation is one of therapeutic strategies for preventing and/or treating bone disorders and related facture. However, little data are available regarding the functional relevance of phosphoinositide 3-kinase (PI3K) isoforms in the osteoclast differentiation process. To elucidate the functional involvement of PI3Kδ in osteoclastogenesis, here we investigated how osteoclast differentiation was influenced by idelalisib (also called CAL-101), which is p110δ-selective inhibitor approved for the treatment of specific human B cell malignancies. Here, we found that receptor activator of nuclear factor kappa B ligand (RANKL) induced PI3Kδ protein expression, and idelalisib inhibited RANKL-induced osteoclast differentiation. Next, the inhibitory effect of idelalisib on RANKL-induced activation of the Akt-c-Fos/NFATc1 signaling cascade was confirmed by western blot analysis and real-time PCR. Finally, idelalisib inhibited pre-osteoclast migration in the last stage of osteoclast differentiation through down-regulation of the Akt-c-Fos/NFATc1 signaling cascade. It may be possible to expand the clinical use of idelalisib for controlling osteoclast differentiation. Together, the present results contribute to our understanding of the clinical value of PI3Kδ as a druggable target and the efficacy of related therapeutics including osteoclastogenesis.