Naringin inhibits vascular endothelial cell apoptosis via endoplasmic reticulum stress‑ and mitochondrial‑mediated pathways and promotes intraosseous angiogenesis in ovariectomized rats

Abstract

In this study, to investigate the effects of naringin on vascular endothelial cell (VEC) function, proliferation, apoptosis, and angiogenesis, rat VECs were cultured in vitro and randomly divided into four groups: control, serum-starved, low-concentration naringin treatment, and high-concentration naringin treatment. MTT assay was used to detect cell proliferation while Hoechst 33258 staining and flow cytometry were used to detect apoptosis. Changes in the expression of apoptosis-associated proteins [GRP78, CHOP, caspase-12, and cytochrome c (Cyt.c)] were detected using western blotting. JC-1 staining was employed to detect changes in mitochondrial membrane potential. Intracellular caspase-3, -8, and -9 activity was determined by spectrophotometry. ELISA was used to detect endothelin (ET), and a Griess assay was used to detect changes in the expression of nitric oxide (NO) in culture medium. The study further divided an ovariectomized (OVX) rat model of osteoporosis randomly into four groups: OVX, sham-operated, low-concentration naringin treatment (100 mg/kg), and high-concentration naringin treatment (200 mg/kg). After 3 months of treatment, changes in serum ET and NO expression, bone mineral density (BMD), and microvessel density of the distal femur (using CD34 labeling of VECs) were determined. At each concentration, naringin promoted VEC proliferation in a time- and dose-dependent manner. Naringin also significantly reduced serum starvation-induced apoptosis in endothelial cells, inhibited the expression of GRP78, CHOP, caspase-12, and Cyt.c proteins, and reduced mitochondrial membrane potential as well as reduced the activities of caspase-3 and -9. Furthermore, naringin suppressed ET in vitro and in vivo while enhancing NO synthesis. Distal femoral microvascular density assessment showed that the naringin treatment groups had a significantly higher number of microvessels than the OVX group, and that microvascular density was positively correlated with BMD. In summary, naringin inhibits apoptosis in VECs by blocking the endoplasmic reticulum (ER) stress- and mitochondrial-mediated pathways. Naringin also regulates endothelial cell function and promotes angiogenesis to exert its anti-osteoporotic effect.

miR‑21/PTEN pathway mediates the cardioprotection of geniposide against oxidized low‑density�lipoprotein‑induced endothelial injury via suppressing oxidative stress and inflammatory response

“…Geniposide, a major compound extracted from the gardenia fruit, is a type of traditional chinese medicine for the treatment of inflammation, brain disorders and hepatic disease (11). Geniposide exhibits a broad spectrum of pharmacological actions involving anti-apoptosis (12), anti-inflammatory injury (13), anti-oxidative stress (14), anti-cancer (15) and anti-angiogenesis effects (16).…”

Effects of Bergamot Polyphenols on Mitochondrial Dysfunction and Sarcoplasmic Reticulum Stress in Diabetic Cardiomyopathy

“…These results showed that the protective action of naringin on SR occurs regardless of the type of damage that generated it [ 168 ]. Many cellular alterations present in the myocardium of patients suffering from diabetic cardiomyopathy, including cardiac-cell apoptosis, oxidative stress, mitochondrial damage, SR damage, proinflammatory cytokine production, myocardial hypertrophy, myocardial remodeling, and cardiac fibrosis are related to the activation of the nuclear factor kappa B (NF-κB) pathway both in vitro and in vivo: in fact, transcription factor NF-κB controls most of the molecular processes within cardiomyocytes, and its dysregulation is involved in many cardiovascular diseases [ 169 ]. Normally, NF-kB remains in the cell cytoplasm, bound to the IkB factor that keeps it inactive.…”

Bioinspired bone therapies using naringin: applications and advances

“…(c) Naringin markedly inhibited (100 mg/kg) the OVX-induced reduction in bone marrow microvessels (black arrows). Adapted, with permission, from [37] and [38] and [39].…”

“…Moreover, ovariectomized mice achieved equally increased cell proliferation when treated with naringin or conventional parathyroid hormone, but naringin-treated mice were characterized with the highest enhancement in ALP activity(Figure 4biii). Adding to this evident potential, a recent study found that naringin (100 and 200 mg/kg) significantly inhibited the ovariectomized-induced reduction in bone marrow microvessels, regulating the function of endothelial cells while promoting angiogenesis in bone(Figure 4c)[39]. In parallel, oral administration of naringin (300 mg/kg) has recently been shown to augment the vascularization of the callus in osteoporotic fractures in ovariectomized rats, by significantly improving the expression of vascular endothelial factor (VEGF) and VEGFR-2[40].…”