INVOLVEMENT OF THE RENIN ANGIOTENSIN SYSTEM IN MARFAN SYNDROME ASSOCIATED THORACIC AORTIC ANEURYSMS

Thoracic aortic aneurysms (TAAs) are clinically-silent dilations of the aorta which greatly increase the risk of aortic rupture, a condition with 50-90% mortality. Marfan syndrome (MFS) is caused by mutations in fibrillin-1 (FBN1) and is associated with TAAs. Due to an absence of validated and effective pharmacologic therapies to prevent or reverse TAA, most MFS patients require surgical aortic repair. Understanding MFS associated TAA pathogenesis would direct development of new pharmacologic therapies. Previous research has implicated the renin angiotensin system in TAA. In both males and females, angiotensinogen (AGT) is cleaved serially to generate the main effector peptide angiotensin II (AngII). AngII is the main ligand of AngII receptor type 1a (AT1aR). However, the role of angiotensin II (AngII) receptor type 1a (AT1aR) in MFS associated TAA formation is unclear. Here, we test the hypothesis that AngII-dependent AT1aR stimulation is responsible for Marfan syndrome associated TAA. To study the contribution of the renin angiotensin system on MFS associated TAA, we used the fibrillin-1 haploinsufficient (Fbn1C1041G/+) and fibrillin-1 hypomorphic (Fbn1mgR/mgR) mouse models. TAA in MFS mice demonstrated sexual dimorphism. Compared to male Fbn1C1041G/+ mice, female Fbn1C1041G/+ mice exhibited less ascending aortic dilation. To study AT1aR in MFS associated TAA, we bred male and female AT1aR deficient (AT1aR‑/‑) x Fbn1C1041G/+ mice. We measured the ascending aorta up to 12 months of age by high frequency ultrasound sequentially. We evaluated aortic medial structure at study termination. Compared to male AT1aR+/+ x Fbn1C1041G/+ mice, male AT1aR‑/‑ x Fbn1C1041G/+ mice exhibited less ascending aortic dilation and reduced elastin fragmentation. Ascending aortic dilation was not significant between female AT1aR‑/‑ x Fbn1C1041G/+ mice and female AT1aR+/+ x Fbn1C1041G/+ mice. To study the contribution of angiotensin peptides, we administered angiotensinogen antisense oligonucleotides (AGT ASO) to male Fbn1C1041G/+ mice. Compared to male Fbn1C1041G/+ mice administered control ASO, mice administered AGT ASO exhibited less ascending aortic dilation and reduced elastin fragmentation. TAA in the mouse models of MFS is sexually dimorphic. Inhibition of the renin angiotensin system via either AT1aR deletion or AGT ASO is sufficient to attenuate ascending aortic dilation in male Fbn1C1041G/+ mice. However, the effect of AT1aR deletion was not detectable in female Fbn1C1041G/+ mice. Depletion of angiotensin ligands was efficacious in attenuating MFS associated TAA in male Fbn1C1041G/+ mice. However, factors that impact TAA of other etiologies have minimal impact on MFS associated TAA. These studies indicate that modulating the renin angiotensin system is highly effective to attenuate MFS associated TAA in males

Combined therapy with GABA and proinsulin/alum acts synergistically to restore long-term normoglycemia by modulating T-cell autoimmunity and promoting β-cell replication in newly diabetic NOD mice.

Antigen-based therapies (ABTs) fail to restore normoglycemia in newly diabetic NOD mice, perhaps because too few β-cells remain by the time that ABT-induced regulatory responses arise and spread. We hypothesized that combining a fast-acting anti-inflammatory agent with an ABT could limit pathogenic responses while ABT-induced regulatory responses arose and spread. γ-Aminobutyric acid (GABA) administration can inhibit inflammation, enhance regulatory T-cell (Treg) responses, and promote β-cell replication in mice. We examined the effect of combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly diabetic NOD mice. Proinsulin/alum monotherapy failed to correct hyperglycemia, while GABA monotherapy restored normoglycemia for a short period. Combined treatment restored normoglycemia in the long term with apparent permanent remission in some mice. Proinsulin/alum monotherapy induced interleukin (IL)-4- and IL-10-secreting T-cell responses that spread to other β-cell autoantigens. GABA monotherapy induced moderate IL-10 (but not IL-4) responses to β-cell autoantigens. Combined treatment synergistically reduced spontaneous type 1 T-helper cell responses to autoantigens, ABT-induced IL-4 and humoral responses, and insulitis, but enhanced IL-10 and Treg responses and promoted β-cell replication in the islets. Thus, combining ABT with GABA can inhibit pathogenic T-cell responses, induce Treg responses, promote β-cell replication, and effectively restore normoglycemia in newly diabetic NOD mice. Since these treatments appear safe for humans, they hold promise for type 1 diabetes intervention

Novel hybrids of natural β-elemene bearing isopropanolamine moieties: synthesis, enhanced anticancer profile, and improved aqueous solubility

A series of novel β-elemene isopropanolamine derivatives were synthesized and evaluated for their antitumor activity. The results indicated that all of the compounds showed stronger antiproliferative activities than β-elemene as well as improved aqueous solubility. In particular dimer 6q showed the strongest cytotoxicity against four tumor cell lines (SGC-7901, HeLa, U87 and A549) with IC50 values ranging from 4.37 to 10.20 μM. Moreover, combination of 6q with cisplatin exhibited a synergistic effect on these cell lines with IC50 values ranging from 1.21 to 2.94 μM, and reversed the resistance of A549/DPP cells with an IC50 value of 2.52 μM. The mechanism study revealed that 6q caused cell cycle arrest at the G2 phase and induced apoptosis of SGC-7901 cells through a mitochondrial-dependent apoptotic pathway. Further in vivo study in H22 liver cancer xenograft mouse model validated the antitumor activity of 6q with a tumor inhibitory ratio (TIR) of 60.3%, which was higher than that of β-elemene (TIR, 49.1%) at a dose of 60 mg/kg. Altogether, the potent antitumor activity of 6qin vitro and in vivo warranted further preclinical investigation for potential anticancer chemotherapy

Discovery of novel antitumor nitric oxide-donating b-elemene hybrids through inhibiting the PI3K/Akt pathway

A series of novel furoxan-based NO-donating b-elemene hybrids were designed and synthesized to improve the anticancer efficacy of natural b-elemene. The bioassay results indicated that all of the target compounds exhibited significantly improved antiproliferative activities against three cancer cell lines (SGC-7901, HeLa and U87) compared to parent compound b-elemene. Interestingly, these compounds displayed excellent sensitivity to U87 cells with IC50 values ranging from 173 to 2 nM. Moreover, most compounds produced high levels of NO in vitro, and the antitumor activity of 11a in U87 cells was markedly attenuated by an NO scavenger (hemoglobin or carboxy-PTIO). Further mechanism studies revealed that 11a caused the G2 phase arrest of the cell cycle and induced apoptosis of U87 cells by preventing the activation of the PI3K/Akt pathway. Moreover, 11a significantly suppressed the tumor growth in H22 liver cancer xenograft mouse model with a tumor inhibitory ratio (TIR) of 64.8%, which was superior to that of b-elemene (TIR, 49.6%) at the same dose of 60 mg/kg. Together, the remarkable biological profiles of these novel NO-donating b-elemene derivatives may make them promising candidates for the intervention of human cancers

6,7-seco-ent-kauranoids derived from oridonin as potential anticancer agents

Structurally unique 6,7-seco-ent-kaurenes, which are widely distributed in the genus Isodon, have attracted considerable attention because of their antitumor activities. Previously, a convenient conversion of commercially available oridonin (1) to 6,7-seco-ent-kaurenes was developed. Herein, several novel spiro-lactone-type ent-kaurene derivatives bearing various substituents at the C-1 and C-14 positions were further designed and synthesized from the natural product oridonin. Moreover, a number of seven-membered C-ring-expanded 6,7-seco-ent-kaurenes were also identified for the first time. It was observed that most of the spiro-lactone-type ent-kaurenes tested markedly inhibited the proliferation of cancer cells, with an IC50 value as low as 0.55 μM. An investigation on its mechanism of action showed that the representative compound 7b affected the cell cycle and induced apoptosis at a low micromolar level in MCF-7 human breast cancer cells. Furthermore, compound 7b inhibited liver tumor growth in an in vivo mouse model and exhibited no observable toxic effects. Collectively, the results warrant further preclinical investigations of these spiro-lactone-type ent-kaurenes as potential novel anticancer agents

Hydrocortisone Mitigates Alzheimer’s-Related Cognitive Decline through Modulating Oxidative Stress and Neuroinflammation

Alzheimer’s disease (AD), an age-related degenerative disorder, is characterized by β-amyloid deposition, abnormal phosphorylation of tau proteins, synaptic dysfunction, neuroinflammation, and oxidative stress. Despite extensive research, there are no medications or therapeutic interventions to completely treat and reverse AD. Herein, we explore the potential of hydrocortisone (HC), a natural and endogenous glucocorticoid known to have potent anti-inflammatory properties, in an Aβ1–42-induced AD mouse model. Our investigation highlights the beneficial effects of HC administration on cognitive impairment, synaptic function enhancement, and neuronal protection in Aβ1–42-induced AD mice. Notably, HC treatment effectively suppresses the hyperactivation of microglia and astrocytes, leading to a reduction in proinflammatory factors and alleviation of neuroinflammation. Furthermore, HC intervention demonstrates the capacity to mitigate the generation of ROS and oxidative stress. These compelling findings underscore the potential therapeutic application of HC in AD and present promising opportunities for its utilization in AD prevention and treatment. The implications drawn from our findings indicate that hydrocortisone holds promise as a viable candidate for adjunctive use with other anti-AD drugs for the clinical management of patients presenting with moderate to severe AD

Asiaticoside Mitigates Alzheimer’s Disease Pathology by Attenuating Inflammation and Enhancing Synaptic Function

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder, hallmarked by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Due to the uncertainty of the pathogenesis of AD, strategies aimed at suppressing neuroinflammation and fostering synaptic repair are eagerly sought. Asiaticoside (AS), a natural triterpenoid derivative derived from Centella asiatica, is known for its anti-inflammatory, antioxidant, and wound-healing properties; however, its neuroprotective function in AD remains unclear. Our current study reveals that AS, when administered (40 mg/kg) in vivo, can mitigate cognitive dysfunction and attenuate neuroinflammation by inhibiting the activation of microglia and proinflammatory factors in Aβ1-42-induced AD mice. Further mechanistic investigation suggests that AS may ameliorate cognitive impairment by inhibiting the activation of the p38 MAPK pathway and promoting synaptic repair. Our findings propose that AS could be a promising candidate for AD treatment, offering neuroinflammation inhibition and enhancement of synaptic function