Terpenes and terpenoids are the largest groups of plant secondary metabolites. However, unlike polyphenols, they are rarely associated with geroprotective properties. Here we evaluated the conformity of the biological effects of terpenoids with the criteria of geroprotectors, including primary criteria (lifespan-extending effects in model organisms, improvement of aging biomarkers, low toxicity, minimal adverse effects, improvement of the quality of life) and secondary criteria (evolutionarily conserved mechanisms of action, reproducibility of the effects on different models, prevention of age-associated diseases, increasing of stress-resistance). The number of substances that demonstrate the greatest compliance with both primary and secondary criteria of geroprotectors were found among different classes of terpenoids. Thus, terpenoids are an underestimated source of potential geroprotectors that can effectively influence the mechanisms of aging and age-related diseases.

Terpenoids as Potential Geroprotectors.

Protective effects of AS-IV on diabetic cardiomyopathy by improving myocardial lipid metabolism in rat models of T2DM

Iron overload has been found very common in diseases such as hereditary hemochromatosis, thalassemia, and sickle cell disease and in healthy postmenopausal women. Recent studies have shown that iron overload is considered an independent risk factor for osteoporosis. Studies have demonstrated that iron overload could induce apoptosis and inhibit viability in osteoblasts. However, the underlying mechanism still remains poorly understood. The purpose of the present study is to investigate possible mechanism of iron overload–induced apoptosis, and the roles autophagy and reactive oxygen species (ROS) played under iron overload conditions. Ferric ammonium citrate (FAC) (100–1600 μM) was utilized as iron donor to induce iron overload conditions. Intracellular iron concentration was measured using Iron Assay Kit. The viability was assessed by CCK-8 assay. Cell apoptosis was examined using Annexin V-FITC/PI staining with a flow cytometry, and levels of Bax, Bcl-2, cleaved caspase-3, and cleaved PARP were evaluated with Western blot. Cell autophagy was detected by evaluating LC3 with immunofluorescence and Western blot. The expressions of Beclin-1 and P62 were also assessed with Western blot. The intracellular ROS level was evaluated using a DCFH-DA probe with a flow cytometry, and NADPH oxidase 4 (Nox4) expressions were assessed with Western blot. Our results showed that FAC increased intracellular iron concentration and significantly inhibited cell viability. Furthermore, iron overload induced apoptosis and autophagy in osteoblast cells. What’s more, pretreatment with autophagy inhibitor chloroquine (CQ) enhanced iron overload–induced osteoblast apoptosis via the activation of caspases. Moreover, iron overload increased ROS production and Nox4 expression. Inhibition of autophagy increased ROS production, and scavenging of ROS by antioxidant N-Acetyl-L-cysteine (NAC) inhibited caspases activity and rescued iron overload–induced apoptosis. These results suggested that autophagy exerted cytoprotective effect, and scavenging excessive intracellular ROS could be a novel approach for the treatment of iron overload–induced osteoporosis.

Iron Overload Induces Apoptosis and Cytoprotective Autophagy Regulated by ROS Generation in Mc3t3-E1 Cells

Adriamycin (ADR) has been utilized to treat cancer for several decades. However, ADR-induced renal injury is one of the most common side effects accompanying ADR therapy. In the present study, we revealed that astragaloside IV (ASIV) was beneficial for renal injury caused by Adriamycin. We demonstrated that ASIV significantly ameliorated kidney injury, improved renal dysfunction, reduced oxidative stress, alleviated iron accumulation, and inhibited the induction of ferroptosis by ADR. ASIV also rescued the intracellular levels of nuclear factor-erythroid-2-related factor 2 (Nrf2) and promoted nuclear translocation of Nrf2. These protective effects of ASIV on renal injury might be attained through the ASIV-induced activation of the Pi3K/Akt signaling pathway. In vitro, the treatment of the HK-2 cells with fer-1 or deferoxamine mesylate obviously improved cell viability during Adriamycin administration. On the other hand, the protective role of ASIV can be abrogated by RSL3 to some extent. Moreover, ASIV lowered the expression of transferrin receptor 1 and divalent metal transporter 1 while enhancing the expression of ferropotin 1 and glutathione peroxidase 4 in ADR administrated cells, the effects of which were akin to those of deferoxamine mesylate. Furthermore, ASIV increased the phosphorylation of Pi3K, Akt, and the expression of Nrf2 and glutathione peroxidase 4 compared to HK-2 cells stimulated by ADR. However, Pi3K inhibitor LY294002 abrogated these activations. In conclusion, ferroptosis may involve in ADR-induced nephrotoxicity, and ASIV might protect nephrocytes against ADR-induced ferroptosis, perhaps via activations of the Pi3K/Akt and Nrf2 signaling pathways.

/pdf/therapeutic-potential-of-astragaloside-iv-against-adriamycin-12udnjti.pdf

Therapeutic Potential of Astragaloside IV Against Adriamycin-Induced Renal Damage in Rats via Ferroptosis

Astragaloside IV protects against retinal iron overload toxicity through iron regulation and the inhibition of MAPKs and NF-κB activation.

Background: Cerebral ischemia-reperfusion injury (CIRI) inevitably occurs after vascular recanalization treatment for ischemic stroke. The accompanying inflammatory cascades have a major impact on outcome and regeneration after ischemic stroke. Evidences have demonstrated that TLR/MyD88/NF-κB signaling contributes to CIRI. This study aimed to investigate the druggability of MyD88 in the central nervous system (CNS) and the neuroprotective and anti-neuroinflammatory effects of the MyD88 inhibitor TJ-M2010-5 on CIRI. Methods: A middle cerebral artery occlusion (MCAO) model was used to simulate CIRI in mice. BV-2 cells were stimulated with oxygen glucose deprivation/reoxygenation (OGD/R) or lipopolysaccharide, and SH-SY5Y cells were induced by OGD/R in vitro. Neurological deficit scores and cerebral infarction volumes were evaluated. Immunofluorescence staining was performed to measure neuronal damage and apoptosis in the brain. The anti-neuroinflammatory effect of TJ-M2010-5 was evaluated by analyzing the expression of inflammatory cytokines, activation of microglia, and infiltration of peripheral myeloid cells. The expression of proteins of the MyD88/NF-κB and ERK pathway was detected by Simple Western. The concentrations of TJ-M2010-5 in the blood and brain were analyzed by liquid chromatography-mass spectrometry. Results: The cerebral infarction volume decreased in mice treated with TJ-M2010-5, with the most prominent decrease being approximately 80% of the original infarction volume. Neuronal loss and apoptosis were reduced following TJ-M2010-5 treatment. TJ-M2010-5 inhibited the infiltration of peripheral myeloid cells and the activation of microglia. TJ-M2010-5 also downregulated the expression of inflammatory cytokines and inhibited the MyD88/NF-κB and ERK pathway. Furthermore, TJ-M2010-5 showed good blood-brain barrier permeability and no neurotoxicity. Conclusion: TJ-M2010-5 has an excellent therapeutic effect on CIRI as a novel CNS drug candidate by inhibiting excessive neuroinflammatory responses.

/pdf/tj-m2010-5-a-novel-cns-drug-candidate-attenuates-acute-2g7tlw8i.pdf

TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway

Weifuchun alters tongue flora and decreases serum trefoil factor I levels in gastric intestinal metaplasia: A CONSORT-compliant article

Suitable content of iron is essential for human body, but iron overload is associated with many kinds of diseases including chronic liver damage. Recently, researchers find that iron overload promotes hepatocyte autophagy and apoptosis. However, the mechanism of iron overload in liver damage remains unclear. In this study, Lo2 cells were selected as the research object, iron dextran was a model drug, and astragaloside IV was a therapeutic drug to explore the role of iron overload. MTT assay and Annexin/PI double staining were used to measure cell viability and apoptosis. Ultrastructure was observed by transmission electron microscopy. The expression levels of apoptosis and autophagy-related proteins were determined by real-time PCR and Western Blot. The results showed that iron dextran could significantly inhibit Lo2 cell viability and increase the apoptosis rate, while astragaloside IV could reverse the inhibition of Lo2 cell viability and decrease the apoptosis rate. Transmission electron microscopy showed a significant increase in the number of autophagosomes after administration of iron dextran, and the application of astragaloside IV reduced the production of autophagosomes. LC3II/I was significantly upregulated in the model group but decreased in the astragaloside IV treatment group, and P62 showed the opposite trend. Iron dextran significantly upregulated the expression of Bax and downregulated Bcl2, while astragaloside IV reversed this trend. Finally, the inhibition of hepcidin caused by iron dextran was counteracted by astragaloside IV. In conclusion, the experimental results show that the iron overload model mainly induces excessive autophagy and apoptosis of hepatocytes, thus causing damage to hepatocytes, but astragaloside IV plays a certain therapeutic role in reversing this damage.

/pdf/protective-effect-of-astragaloside-iv-on-hepatic-injury-1jhkpfs4n2.pdf

Protective Effect of Astragaloside IV on Hepatic Injury Induced by Iron Overload.

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TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway

Weifuchun alters tongue flora and decreases serum trefoil factor I levels in gastric intestinal metaplasia: A CONSORT-compliant article

Protective Effect of Astragaloside IV on Hepatic Injury Induced by Iron Overload.