Activation of angiotensin converting enzyme 2 promotes hippocampal neurogenesis via activation of Wnt/ß-catenin signaling in hypertension.

Hypertension-induced brain renin-angiotensin system (RAS) activation and neuroinflammation are hallmark neuropathological features of neurodegenerative diseases. Previous studies from our lab have shown that inhibition of ACE/Ang II/AT1R axis (by AT1R blockers or ACE inhibitors) reduced neuroinflammation and accompanied neurodegeneration via up-regulating adult hippocampal neurogenesis. Apart from this conventional axis, another axis of RAS also exists i.e., ACE2/Ang (1-7)/MasR axis, reported as an anti-hypertensive and anti-inflammatory. However, the role of this axis has not been explored in hypertension-induced glial activation and hippocampal neurogenesis in rat models of hypertension. Hence, in the present study, we examined the effect of ACE2 activator, Diminazene aceturate (DIZE) at 2 different doses of 10 mg/kg (non-antihypertensive) and 15 mg/kg (antihypertensive dose) in renovascular hypertensive rats to explore whether their effect on glial activation, neuroinflammation, and neurogenesis is either influenced by blood-pressure. The results of our study revealed that hypertension induced significant glial activation (astrocyte and microglial), neuroinflammation, and impaired hippocampal neurogenesis. However, ACE2 activation by DIZE, even at the low dose prevented these hypertension-induced changes in the brain. Mechanistically, ACE2 activation inhibited Ang II levels, TRAF6-NFκB mediated inflammatory signaling, NOX4-mediated ROS generation, and mitochondrial dysfunction by upregulating ACE2/Ang (1-7)/MasR signaling. Moreover, DIZE-induced activation of the ACE2/Ang (1-7)/MasR axis upregulated Wnt/ß-catenin signaling, promoting hippocampal neurogenesis during the hypertensive state. Therefore, our study demonstrates that ACE2 activation can effectively prevent glial activation and enhance hippocampal neurogenesis in hypertensive conditions, regardless of its blood pressure-lowering effects.

Ormeloxifene, a selective estrogen receptor modulator, protects against pulmonary hypertension.

PURPOSE: Protective effect of 17ß-estradiol is well-known in pulmonary hypertension. However, estrogen-based therapy may potentially increase the risk of breast cancer, necessitating a search for novel drugs. This study, therefore, investigated the ameliorative effects of a selective estrogen receptor modulator, ormeloxifene, in pulmonary hypertension. METHODS: Cardiomyocytes (H9C2) and human pulmonary arterial smooth muscle cells (HPASMCs) were exposed to hypoxia (1% O2) for 42 and 96 h, respectively, with or without ormeloxifene pre-treatment (1 µM). Also, female (ovary-intact or ovariectomized) and male Sprague-Dawley rats received monocrotaline (60 mg/kg, once, subcutaneously), with or without ormeloxifene treatment (2.5 mg/kg, orally) for four weeks. RESULTS: Hypoxia dysregulated 17ß-hydroxysteroid dehydrogenase (17ßHSD) 1 & 2 expressions, reducing 17ß-estradiol production and estrogen receptors α and ß in HPASMC but increasing estrone, proliferation, inflammation, oxidative stress, and mitochondrial dysfunction. Similarly, monocrotaline decreased plasma 17ß-estradiol and uterine weight in ovary-intact rats. Further, monocrotaline altered 17ßHSD1 & 2 expressions and reduced estrogen receptors α and ß, increasing right ventricular pressure, proliferation, inflammation, oxidative stress, endothelial dysfunction, mitochondrial dysfunction, and vascular remodeling in female and male rats, with worsened conditions in ovariectomized rats. Ormeloxifene was less uterotrophic; however, it attenuated both hypoxia and monocrotaline effects by improving pulmonary 17ß-estradiol synthesis. Furthermore, ormeloxifene decreased cardiac hypertrophy and right ventricular remodeling induced by hypoxia and monocrotaline. CONCLUSION: This study demonstrates that ormeloxifene promoted pulmonary 17ß-estradiol synthesis, alleviated inflammation, improved the NOX4/HO1/Nrf/PPARγ/PGC-1α axis, and attenuated pulmonary hypertension. It is evidently safe at tested concentrations and may be effectively repurposed for pulmonary hypertension treatment.

Inhibition of poly (ADP-ribose) Polymerase-1 (PARP-1) improves endothelial function in pulmonary hypertension.

Endothelial dysfunction is critical in the pulmonary vasculature during pulmonary hypertension (PH). Moreover, in PH, increased inflammation and oxidative/nitrosative stress cause DNA damage, activating poly (ADP-ribose) polymerase-1 (PARP-1). Meloche et al. (2014) and our previous research have shown that inhibiting PARP-1 is protective in PH and associated RV hypertrophy. However, the role of PARP-1 in pulmonary arterial endothelial dysfunction has not been explored completely. Therefore, the current study aims to investigate the involvement of PARP-1 in endothelial dysfunction associated with PH. Hypoxia (1% O2) was used to induce a PH-like phenotype in human pulmonary artery endothelial cells (HPAECs), and PARP-1 inhibition was achieved via siRNA (60 nM). For the in vivo study, male Sprague Dawley rats were administered monocrotaline (MCT; 60 mg/kg, SC, once) to induce PH, and 1, 5-isoquinolinediol (ISO; 3 mg/kg) was administered daily intraperitoneally to inhibit PARP-1. PARP-1 inhibition decreased proliferation and inflammation, as well as improved mitochondrial dysfunction in hypoxic HPAECs. Furthermore, PARP-1 inhibition also promoted apoptosis by increasing DNA damage in hypoxic HPAECs. In addition, inhibition of PARP-1 reduced cell migration, VEGF expression, and tubule formation in hypoxic HPAECs. In in vivo studies, PARP-1 inhibition by ISO significantly decreased the RVP and RVH as well as improved endothelial function by increasing the pulmonary vascular reactivity and expression of p-eNOS in MCT-treated rats.

Evaluation of cytogenotoxic potential of Morinda lucida leaf extract on Swiss albino male mice using two bioassays.

BACKGROUND: Utilization of Morinda lucida for the treatment of ailments such as malaria, diarrhea, infertility in women, and dysentery in many countries including Nigeria is on increase due to its efficiency, availability, and affordability. However, its cytogenotoxicity has not been elucidated. This study investigated the phytochemical constituents and possible genotoxic and cytotoxic effects of M. lucida leaf extract in Swiss albino male mice using bone marrow micronucleus and sperm morphology assays. METHODS: Plant materials was collected, thoroughly washed, and air-dried at room temperature prior to maceration. The extract was assessed for the presence of the phytochemical compounds. Swiss albino male mice (Mus musculus) (n=4) were treated with different concentrations of this extract (400 mg/kg, 800 mg/kg, and 1200 mg/kg) while distilled water was used as negative control. RESULTS: Phytochemical analysis revealed that the extract contains saponins, terpenoids, flavonoids, glycosides, and tannins. We observed micronucleated polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) of 3.20%, 1.10%, and 1.95% at different concentrations of 400 mg/kg, 800 mg/kg, and 1200 mg/kg respectively in the treated animals. The result showed no significant increase in the frequency of abnormalities (p < 0.05) when compared to the negative control; however, in separate analysis of mono-micronucleated PCE and mono-micronucleated NCE per group, a significant increase at 400 mg/kg and 1200 mg/kg concentrations was observed. The sperm anomalies decreased with increase in concentration. CONCLUSIONS: This study recommends 800 mg/kg concentration of the plant extract; however, it should be further and properly investigated as it contains some pharmaceutical components that can be used for pharmacological purposes.