Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis.

The incidence of rheumatoid arthritis (RA) is increasing with age. DNA fragments is known to accumulate in certain autoimmune diseases, but the mechanistic relationship among ageing, DNA fragments and RA pathogenesis remain unexplored. Here we show that the accumulation of DNA fragments, increasing with age and regulated by the exonuclease TREX1, promotes abnormal activation of the immune system in an adjuvant-induced arthritis (AIA) rat model. Local overexpression of TREX1 suppresses synovial inflammation in rats, while conditional genomic deletion of TREX1 in AIA rats result in higher levels of circulating free (cf) DNA and hence abnormal immune activation, leading to more severe symptoms. The dysregulation of the heterodimeric transcription factor AP-1, formed by c-Jun and c-Fos, appear to regulate both TREX1 expression and SASP induction. Thus, our results confirm that DNA fragments are inflammatory mediators, and TREX1, downstream of AP-1, may serve as regulator of cellular immunity in health and in RA.

Hyperoside alleviates toxicity of ß-amyloid via endoplasmic reticulum-mitochondrial calcium signal transduction cascade in APP/PS1 double transgenic Alzheimer's disease mice.

Alzheimer's disease is a neurodegenerative disorder characterized by a decline in cognitive function. The ß-amyloid (Aß) hypothesis suggests that Aß peptides can spontaneously aggregate into ß-fragment-containing oligomers and protofibrils, and this activation of the amyloid pathway alters Ca2+ signaling in neurons, leading to neurotoxicity and thus apoptosis of neuronal cells. In our study, a blood-brain barrier crossing flavonol glycoside hyperoside was identified with anti-Aß aggregation, BACE inhibitory, and neuroprotective effect in cellular or APP/PSEN1 double transgenic Alzheimer's disease mice model. While our pharmacokinetic data confirmed that intranasal administration of hyperoside resulted in a higher bio-availability in mice brain, further in vivo studies revealed that it improved motor deficit, spatial memory and learning ability of APP/PSEN1 mice with reducing level of Aß plaques and GFAP in the cortex and hippocampus. Bioinformatics, computational docking and in vitro assay results suggested that hyperoside bind to Aß and interacted with ryanodine receptors, then regulated cellular apoptosis via endoplasmic reticulum-mitochondrial calcium (Ca2+) signaling pathway. Consistently, it was confirmed that hyperoside increased Bcl2, decreased Bax and cyto-c protein levels, and ameliorated neuronal cell death in both in vitro and in vivo model. By regulating Aß-induced cell death via regulation on Ca2+ signaling cascade and mitochondrial membrane potential, our study suggested that hyperoside may work as a potential therapeutic agent or preventive remedy for Alzheimer's disease.

Antimalarial and Anticancer Activity Evaluation of Bridged Ozonides, Aminoperoxides, and Tetraoxanes.

Bridged aminoperoxides, for the first time, were investigated for the in vitro antimalarial activity against the chloroquine-resistant Plasmodium falciparum strain K1 and for their cytotoxic activities against immortalized human normal liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Aminoperoxides exhibit good cytotoxicity against lung A549 cancer cell line. Synthetic ozonides were shown to have high activity against the chloroquine-resistant P. falciparum. A cyclic voltammetry study of peroxides was performed, and most of the compounds did not show a direct correlation in oxidative capacity-activity. Peroxides were analyzed for ROS production to understand their mechanism of action. However, none of the compounds has an impact on ROS generation, suggesting that ozonides induce apoptosis in HepG2 cells through ROS-independent dysfunction pathway.

Biological Evaluation in Resistant Cancer Cells and Study of Mechanism of Action of Arylvinyl-1,2,4-Trioxanes.

1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only 7 and 8 showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds 7 and 8 exhibited docking scores of -7.089 and -8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential.

Saponins isolated from Radix polygalae extent lifespan by modulating complement C3 and gut microbiota.

With the increase in human lifespan, population aging is one of the major problems worldwide. Aging is an irreversible progressive process that affects humans via multiple factors including genetic, immunity, cellular oxidation and inflammation. Progressive neuroinflammation contributes to aging, cognitive malfunction, and neurodegenerative diseases. However, precise mechanisms or drugs targeting age-related neuroinflammation and cognitive impairment remain un-elucidated. Traditional herbal plants have been prescribed in many Asian countries for anti-aging and the modulation of aging-related symptoms. In general, herbal plants' efficacy is attributed to their safety and polypharmacological potency via the systemic manipulation of the body system. Radix polygalae (RP) is a herbal plant prescribed for anti-aging and the relief of age-related symptoms; however, its active components and biological functions remained un-elucidated. In this study, an active methanol fraction of RP containing 17 RP saponins (RPS), was identified. RPS attenuates the elevated C3 complement protein in aged mice to a level comparable to the young control mice. The active RPS also restates the aging gut microbiota by enhancing beneficial bacteria and suppressing harmful bacteria. In addition, RPS treatment improve spatial reference memory in aged mice, with the attenuation of multiple molecular markers related to neuroinflammation and aging. Finally, the RPS improves the behavior and extends the lifespan of C. elegans, confirming the herbal plant's anti-aging ability. In conclusion, through the mouse and C. elegas models, we have identified the beneficial RPS that can modulate the aging process, gut microbiota diversity and rectify several aging-related phenotypes.

Current pharmacological intervention and development of targeting IVIG resistance in Kawasaki disease.

Kawasaki disease is an acute childhood self-limited vasculitis, causing the swelling or inflammation of medium-sized arteries, eventually leading to cardiovascular problems such as coronary artery aneurysms. Acetylsalicylic acid combined with intravenous immunoglobulin (IVIG) is the standard treatment of Kawasaki disease (KD). However, a rising number of IVIG resistant cases were reported with severe disease complications such as the KD Shock Syndrome or KD-Macrophage activation syndrome. Recent reports have depicted the overlapped number of children with SARS-CoV-2 and KD, which was called multisystem inflammatory syndrome. Simultaneously, the incidence rate of KD-like diseases are increased after the outbreak of COVID-19, suggesting the virus may be associated with KD. New intervention is important to overcome the problem of IVIG treatment resistance. This review aims to introduce the current pharmacological intervention and possible resistance genes for the discovery of new drug for IVIG resistant KD.

2,2'-[(1E,1'E)-2,2'-(2,5-Dibut-oxy-1,4-phenyl-ene)bis-(ethene-2,1-di-yl)]dipyridine.

The centrosymmetric title mol-ecule, C(28)H(32)N(2)O(2), has a central benzene ring subsituted in the 1- and 4-positions by (ethene-2,1-di-yl)pyridine groups, and in the 2- and 5-positions by but-oxy groups. The whole mol-ecule is X-shaped and relatively flat, the dihedral angle between the pyridine and the central benzene ring being 11.29 (10)°. In the crystal, neighboring mol-ecules are linked by weak C-H⋯N inter-actions, forming a two-dimensional undulating network.