Neuroprotective effect of acetoxypachydiol against oxidative stress through activation of the Keap1-Nrf2/HO-1 pathway.

BACKGROUND: Excessive oxidative stress in the brain is an important pathological factor in neurological diseases. Acetoxypachydiol (APHD) is a lipophilic germacrane-type diterpene extracted as a major component from different species of brown algae within the genus Dictyota. There have been no previous reports on the pharmacological activity of APHD. The present research aims to explore the potential neuroprotective properties of APHD and its underlying mechanisms. METHODS: The possible mechanism of APHD was predicted using a combination of molecular docking and network pharmacological analysis. PC12 cells were induced by H2O2 and oxygen-glucose deprivation/reoxygenation (OGD/R), respectively. Western blot, flow cytometry, immunofluorescence staining, and qRT-PCR were used to investigate the antioxidant activity of APHD. The HO-1 inhibitor ZnPP and Nrf2 gene silencing were employed to confirm the influence of APHD on the signaling cascade involving HO-1, Nrf2, and Keap1 in vitro. RESULTS: APHD exhibited antioxidant activity in both PC12 cells subjected to H2O2 and OGD/R conditions by downregulating the release of LDH, the concentrations of MDA, and ROS, and upregulating SOD, GSH-Px, and GSH concentrations. APHD could potentially initiate the Keap1-Nrf2/HO-1 signaling cascade, according to the findings from network pharmacology evaluation and molecular docking. Furthermore, APHD was observed to increase Nrf2 and HO-1 expression at both mRNA and protein levels, while downregulating the protein concentrations of Keap1. Both Nrf2 silencing and treatment with ZnPP reversed the neuroprotective effects of APHD. CONCLUSIONS: APHD activated antioxidant enzymes and downregulated the levels of LDH, MDA, and ROS in two cell models. The neuroprotective effect is presumably reliant on upregulation of the Keap1-Nrf2/HO-1 pathway. Taken together, APHD from brown algae of the genus Dictyota shows potential as a candidate for novel neuroprotective agents.

Anti-Neuroinflammatory Meroterpenoids from a Chinese Collection of the Brown Alga Sargassum siliquastrum.

Nine new chromane-type meroterpenoids, including the rare nor-meroterpenoid sargasilol A (1) and the eight meroditerpenoids sargasilols B-I (2-9), were isolated from a China Sea collection of the brown alga Sargassum siliquastrum, together with six known analogues (10-15). The structures of the new chromanes were identified by extensive spectroscopic analysis and by comparison with previously reported data. Compounds 1-3 and 6-15 exhibited inhibition against LPS-induced NO production in BV-2 microglial cells, and 1, with a shorter carbon chain, was the most active one. Compound 1 was established as an anti-neuroinflammatory agent through targeting the IKK/IκB/NF-κB signaling pathway. As such, the chromanes from brown algae could provide promising anti-neuroinflammatory lead compounds for further structural modification.

Antioxidant and Neuroprotective Xenicane Diterpenes from the Brown Alga Dictyota coriacea.

Five new xenicane diterpenes, including three rare nitrogen-containing derivatives, dictyolactams A (1) and B (2) and 9-demethoxy-9-ethoxyjoalin (3), a rare diterpene with a cyclobutanone moiety, named 4-hydroxyisoacetylcoriacenone (4), and 19-O-acetyldictyodiol (5), were isolated from an East China Sea collection of the brown alga Dictyota coriacea, along with 15 known analogues (6-20). The structures of the new diterpenes were elucidated by spectroscopic analyses and theoretical ECD calculations. All compounds had cytoprotective effects against oxidative stress in neuron-like PC12 cells. The antioxidant mechanism of 18-acetoxy-6,7-epoxy-4-hydroxydictyo-19-al (6) was related to the activation of Nrf2/ARE signaling pathway; it also showed significant neuroprotective effects against cerebral ischemia-reperfusion injury (CIRI) in vivo. This study provided xenicane diterpene as a promising lead scaffold for the development of potent neuroprotective agents against CIRI.

Gene coexpression networks allow the discovery of two strictosidine synthases underlying monoterpene indole alkaloid biosynthesis in Uncaria rhynchophylla.

Plant-derived monoterpene indole alkaloids (MIAs) from Uncaria rhynchophylla (UR) have huge medicinal properties in treating Alzheimer's disease, Parkinson's disease, and depression. Although many bioactive UR-MIA products have been isolated as drugs, their biosynthetic pathway remains largely unexplored. In this study, untargeted metabolome identified 79 MIA features in UR tissues (leaf, branch stem, hook stem, and stem), of which 30 MIAs were differentially accumulated among different tissues. Short time series expression analysis captured 58 pathway genes and 12 hub regulators responsible for UR-MIA biosynthesis and regulation, which were strong links with main UR-MIA features. Coexpression networks further pointed to two strictosidine synthases (UrSTR1/5) that were coregulated with multiple MIA-related genes and highly correlated with UR-MIA features (r > 0.7, P < 0.005). Both UrSTR1/5 catalyzed the formation of strictosidine with tryptamine and secologanin as substrates, highlighting the importance of key residues (UrSTR1: Glu309, Tyr155; UrSTR5: Glu295, Tyr141). Further, overexpression of UrSTR1/5 in UR hairy roots constitutively increased the biosynthesis of bioactive UR-MIAs (rhynchophylline, isorhynchophylline, corynoxeine, etc), whereas RNAi of UrSTR1/5 significantly decreased UR-MIA biosynthesis. Collectively, our work not only provides candidates for reconstituting the biosynthesis of bioactive UR-MIAs in heterologous hosts but also highlights a powerful strategy for mining natural product biosynthesis in medicinal plants.

Engineering aluminum hydroxyphosphate nanoparticles with well-controlled surface property to enhance humoral immune responses as vaccine adjuvants.

Aluminum phosphate adjuvants play a critical role in human inactivated and subunit prophylactic vaccines. However, a major challenge is that the underlying mechanism of immune stimulation remains poorly understood, which impedes the further optimal design and application of more effective adjuvants in vaccine formulations. To address this, a library of amorphous aluminum hydroxyphosphate nanoparticles (AAHPs) is engineered with defined surface properties to explore the specific mechanism of adjuvanticity at the nano-bio interface. The results demonstrate that AAHPs could induce cell membrane perturbation and downstream inflammatory responses, with positively-charged particles showing the most significantly enhanced immunostimulation potentials compared to the neutral or negatively-charged particles. In a vaccine using Staphylococcus aureus (S. aureus) recombinant protein as antigens, the positively-charged particles elicit long-lasting and enhanced humoral immunity, and provide protection in S. aureus sepsis mice models. In addition, when formulated with human papillomavirus type 18 virus-like particles, it is demonstrated that particles with positive charges outperform in promoting serum antigen-specific antibody productions. This study shows that engineering AAHPs with well-controlled physicochemical properties enable the establishment of a structure-activity relationship that is critical to instruct the design of suitable engineered nanomaterial-based adjuvants within vaccine formulations for the benefits of human health.

Adjuvants for Coronavirus Vaccines.

Vaccine development utilizing various platforms is one of the strategies that has been proposed to address the coronavirus disease 2019 (COVID-19) pandemic. Adjuvants are critical components of both subunit and certain inactivated vaccines because they induce specific immune responses that are more robust and long-lasting. A review of the history of coronavirus vaccine development demonstrates that only a few adjuvants, including aluminum salts, emulsions, and TLR agonists, have been formulated for the severe acute respiratory syndrome-associated coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and currently the SARS-CoV-2 vaccines in experimental and pre-clinical studies. However, there is still a lack of evidence regarding the effects of the adjuvants tested in coronavirus vaccines. This paper presents an overview of adjuvants that have been formulated in reported coronavirus vaccine studies, which should assist with the design and selection of adjuvants with optimal efficacy and safety profiles for COVID-19 vaccines.

Microgravity versus Microgravity and Irradiation: Investigating the Change of Neuroendocrine-Immune System and the Antagonistic Effect of Traditional Chinese Medicine Formula.

During spaceflight, the homeostasis of the living body is threatened with cosmic environment including microgravity and irradiation. Traditional Chinese medicine could ameliorate the internal imbalance during spaceflight, but its mechanism is still unclear. In this article, we compared the difference of neuroendocrine-immune balance between simulated microgravity (S) and simulated microgravity and irradiation (SAI) environment. We also observed the antagonistic effect of SAI using a traditional Chinese medicine formula (TCMF). Wistar rats were, respectively, exposed under S using tail suspending and SAI using tail suspending and 60Co-gama irradiation exposure. The SAI rats were intervened with TCMF. The changes of hypothalamic-pituitary-adrenal (HPA) axis, splenic T-cell, celiac macrophages, and related cytokines were observed after 21 days. Compared with the normal group, the hyperfunction of HPA axis and celiac macrophages, as well as the hypofunction of splenic T-cells, was observed in both the S and SAI group. Compared with the S group, the levels of plasmatic corticotropin-releasing hormone (CRH), macrophage activity, and serous interleukin-6 (IL-6) in the SAI group were significantly reduced. The dysfunctional targets were mostly reversed in the TCMF group. Both S and SAI could lead to NEI imbalance. Irradiation could aggravate the negative feedback inhibition of HPA axis and macrophages caused by S. TCMF could ameliorate the NEI dysfunction caused by SAI.

A Comparison Study of Chaihu Shugan San and Fluoxetine on Antidepression and Regulating Blood Rheology Effects with Chronic Restrained Stress Rats.

Chaihu Shugan San (CHSGS) is a traditional Chinese herbal formula that is often used in clinical practice to treat live Qi stagnation syndrome and depression. Fluoxetine is one of the commonly used drugs for the clinical treatment of depression. This study involved a comparison of CHSGS and fluoxetine on antidepression and regulating blood rheology effects with chronic restraint stress- (CRS-) induced depression rat models. Rats were induced depression models by CRS for 4 weeks. Upon successful induction of depression in the rats, the animal was administered CHSGS at 0.6 g/kg/d, 1.2 g/kg/d, or fluoxetine 1.8 mg/kg/d to corresponding groups by gavage for 2 weeks. The changes of CRS rats were determined by behavior observations and sucrose preference test and hypothalamic-pituitary-adrenal cortex (HPA) axis functional status. The changes in monoamine neurotransmitters and related indicators of blood status were detected by enzyme-linked immunosorbent assay (ELISA), blood rheometer, and other methods. The outcome shows that CHSGS is superior to fluoxetine in regulating the appearance and HPA axis function of model rats. In addition, CHSGS and fluoxetine have similar effects in improving blood rheology, and both can alleviate the hypercoagulable state of blood via the platelet 5-hydroxytryptamine receptor 2A (5-HT2A) pathway in rats of depression. It was also observed that CHSGS can improve the blood state of depressed rats by restoring liver coagulation-anticoagulation balance and endothelium-related functions.

Vaccine adjuvants: Understanding the structure and mechanism of adjuvanticity.

In conjugate, inactivated, recombinant, and toxoid vaccines, adjuvants are extensively and essentially used for enhanced and long-lasting protective immune responses. Depending on the type of diseases and immune responses required, adjuvants with different design strategies are developed. With aluminum salt-based adjuvants as the most used ones in commercial vaccines, other limited adjuvants, e.g., AS01, AS03, AS04, CpG ODN, and MF59, are used in FDA-approved vaccines for human use. In this paper, we review the uses of different adjuvants in vaccines including the ones used in FDA-approved vaccines and vaccines under clinical investigations. We discuss how adjuvants with different formulations could affect the magnitude and quality of adaptive immune response for optimized protection against specific pathogens. We emphasize the molecular mechanisms of various adjuvants, with the aim to establish structure-activity relationships (SARs) for designing more effective and safer adjuvants for both preventative and therapeutic vaccines.