PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness.

Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.

Alisol B 23-acetate broadly inhibits coronavirus through blocking virus entry and suppresses proinflammatory T cells responses for the treatment of COVID-19.

INTRODUCTION: Emerging severe acute respiratory syndrome (SARS) coronavirus (CoV)-2 causes a global health disaster and pandemic. Seeking effective anti-pan-CoVs drugs benefit critical illness patients of coronavirus disease 2019 (COVID-19) but also may play a role in emerging CoVs of the future. OBJECTIVES: This study tested the hypothesis that alisol B 23-acetate could be a viral entry inhibitor and would have proinflammatory inhibition for COVID-19 treatment. METHODS: SARS-CoV-2 and its variants infected several cell lines were applied to evaluate the anti-CoVs activities of alisol B 23-aceate in vitro. The effects of alisol B 23-acetate on in vivo models were assessed by using SARS-CoV-2 and its variants challenged hamster and human angiotensin-converting enzyme 2 (ACE2) transgenic mice. The target of alisol B 23-acetate to ACE2 was analyzed using hydrogen/deuterium exchange (HDX) mass spectrometry (MS). RESULTS: Alisol B 23-acetate had inhibitory effects on different species of coronavirus. By using HDX-MS, we found that alisol B 23-acetate had inhibition potency toward ACE2. In vivo experiments showed that alisol B 23-acetate treatment remarkably decreased viral copy, reduced CD4+ T lymphocytes and CD11b+ macrophages infiltration and ameliorated lung damages in the hamster model. In Omicron variant infected human ACE2 transgenic mice, alisol B 23-acetate effectively alleviated viral load in nasal turbinate and reduced proinflammatory cytokines interleukin 17 (IL17) and interferon γ (IFNγ) in peripheral blood. The prophylactic treatment of alisol B 23-acetate by intranasal administration significantly attenuated Omicron viral load in the hamster lung tissues. Moreover, alisol B 23-acetate treatment remarkably inhibited proinflammatory responses through mitigating the secretions of IFNγ and IL17 in the cultured human and mice lymphocytes in vitro. CONCLUSION: Alisol B 23-acetate could be a promising therapeutic agent for COVID-19 treatment and its underlying mechanisms might be attributed to viral entry inhibition and anti-inflammatory activities.

Niuhuang Qingxin Wan ameliorates depressive-like behaviors and improves hippocampal neurogenesis through modulating TrkB/ERK/CREB signaling pathway in chronic restraint stress or corticosterone challenge mice.

Introduction: Chronic stress-associated hormonal imbalance impairs hippocampal neurogenesis, contributing to depressive and anxiety behaviors. Targeting neurogenesis is thus a promising antidepressant therapeutic strategy. Niuhuang Qingxin Wan (NHQXW) is an herbal formula for mental disorders in Traditional Chinese Medicine (TCM) practice, but its anti-depressant efficacies and mechanisms remain unverified. Methods: In the present study, we tested the hypothesis that NHQXW could ameliorate depressive-like behaviors and improve hippocampal neurogenesis by modulating the TrkB/ERK/CREB signaling pathway by utilizing two depression mouse models including a chronic restraint stress (CRS) mouse model and a chronic corticosterone (CORT) stress (CCS) induced mouse model. The depression-like mouse models were orally treated with NHQXW whereas fluoxetine was used as the positive control group. We evaluated the effects of NHQXW on depressive- and anxiety-like behaviors and determined the effects of NHQXW on inducing hippocampal neurogenesis. Results: NHQXW treatment significantly ameliorated depressive-like behaviors in those chronic stress mouse models. NHQXW significantly improved hippocampal neurogenesis in the CRS mice and CCS mice. The potential neurogenic mechanism of NHQXW was identified by regulating the expression levels of BDNF, TrkB, p-ERK (T202/T204), p-MEK1/2 (S217/221), and p-CREB (S133) in the hippocampus area of the CCS mice. NHQXW revealed its antidepressant and neurogenic effects that were similar to fluoxetine. Moreover, NHQXW treatment revealed long-term effects on preventing withdrawal-associated rebound symptoms in the CCS mice. Furthermore, in a bioactivity-guided quality control study, liquiritin was identified as one of the bioactive compounds of NHQXW with the bioactivities of neurogenesis-promoting effects. Discussion: Taken together, NHQXW could be a promising TCM formula to attenuate depressive- and anxiety-like behaviors against chronic stress and depression. The underlying anti-depressant mechanisms could be correlated with its neurogenic activities by stimulating the TrkB/ERK/CREB signaling pathway.

Naringin Mediates Adult Hippocampal Neurogenesis for Antidepression via Activating CREB Signaling.

The brain-derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element-binding protein (BDNF/TrkB/CREB) signaling pathway is a critical therapeutic target for inducing adult hippocampal neurogenesis and antidepressant therapy. In this study, we tested the hypothesis that naringin, a natural medicinal compound, could promote adult hippocampal neurogenesis and improve depression-like behaviors via regulating the BDNF/TrkB/CREB signaling pathway. We first investigated the effects of naringin on promoting adult hippocampal neurogenesis in both normal and chronic corticosterone (CORT)-induced depressive mice. Under physiological condition, naringin treatment enhanced the proliferation of neural stem/progenitor cells (NSPCs) and accelerated neuronal differentiation. In CORT-induced depression mouse model, naringin treatment promoted neuronal differentiation and maturation of NSPCs for hippocampal neurogenesis. Forced swim test, tail suspension test, and open field test confirmed the antidepressant and anxiolytic effects of naringin. Co-treatment of temozolomide (TMZ), a neurogenic inhibitor, abolished these antidepressant and anxiolytic effects. Meanwhile, naringin treatment increased phosphorylation of cAMP response element binding protein (CREB) but had no effect on the expression of brain-derived neurotrophic factor and phosphorylation of TrkB in the hippocampus of CORT-induced depressive mice. Co-treatment of CREB inhibitor 666-15, rather than TrkB inhibitor Cyc-B, abolished the neurogenesis-promoting and antidepressant effects of naringin. Taken together, naringin has antidepressant and anxiolytic effects, and the underlying mechanisms could be attributed to enhance hippocampal neurogenesis via activating CREB signaling.

Baoyuan Capsule promotes neurogenesis and neurological functional recovery through improving mitochondrial function and modulating PI3K/Akt signaling pathway.

BACKGROUND: Bao Yuan Capsule (BYC) is a patented Chinese medicinal formula for health promotion but its application for ischemic stroke remains unknown. In this study, we proposed the hypothesis that BYC could promote neurogenesis and neurological functional recovery through promoting mitochondrial function and activating PI3K/Akt signaling pathway. METHODS: We firstly performed chemical identification studies by using QIT-TOF-MS technology. Then, we investigated the effects of BYC (1 g/kg, 2 g/kg, 4 g/kg per day) on improving the recovery of the neurological functions in transient middle cerebral artery occlusion (MCAO) ischemic mice. RESULTS: We tentatively characterized 36 compounds from the BYC extractions. At dosage of 4 g/kg, BYC effectively improved locomotor ability, attenuated anxiety-like behaviors, and enhanced the exploring behaviors, learning and memory capability in the transient MCAO ischemic mice. BYC treatment promoted neural stem cell differentiations in the subventricular zone (SVZ) and subgranular zone (SGZ) of the MCAO mice. BYC also up-regulated the expression of Aconitase 2 (ACO2), Succinate dehydrogenase complex, subunit A (SDHA), phosphorylation of AMP-activated protein kinase (p-AMPK), protein kinase B (p-Akt) and glycogen synthase kinase 3ß (p-GSK3ß) in the hippocampus of the MCAO mice. BYC (200 µg/ml) significantly improved the mitochondrial functions in cultured mouse multipotent neural stem like C17.2 cells. BYC treatment also promoted neuronal differentiations in the C17.2 cells under oxygen-glucose deprivation (OGD) condition. The neurogenetic effects were abolished by co-treatments of ATP synthesis inhibitor oligomycin and PI3K/Akt inhibitor wortmannin. Moreover, Akt phosphorylation was dramatically reduced by oligomycin. CONCLUSION: BYC could promote neurogenesis and neurological functional recovery in post ischemic brains by regulating the mitochondrial functions and Akt signaling pathway.

Combination of matrix solid phase dispersion and response surface evaluation for simultaneous detections of multiple bioactive constituents of traditional Chinese medicine formula: Using Baoyuan Capsule as an example.

Traditional Chinese Medicine (TCM) formulae contain abundant chemical ingredients, leading to the development of high quality TCM productions be difficult. With different pharmacokinetic and pharmacodynamic parameters of the chemical ingredients in a TCM formula, it is desirable to simultaneously identify multiple ingredients for accurate quality control. In the present study, we introduce a novel strategy for TCM formula quality assessment by using the combined methods of the extraction condition optimization, quantitative analyzation, and response surface evaluation. We used Bao-Yuan Capsule (BYC), a patented TCM production, as a model system for quality assessment. We applied matrix solid phase dispersion (MSPD) as a rapid and efficient method to prepare sample extraction. Q-Trap-MS related accurate methods were applied to simultaneously analyze 13 bioactive constituents as bioactive markers in the BYC. Those methods revealed a high sensitivity to detect the target compounds at the concentrations ranging from 0.12 to 0.95 ng/mL for flavonoids and ginsenosides whose recoveries were ranged from 91.93%-105.84%. We employed the response surface methodology to optimize the extraction conditions including dispersant/sample ratio, solvent concentration, and elution volume based on the content of ginsenosides as the test samples. The results showed the high extraction efficiency of ginsenosides with dispersant/sample ratio at 3/4, methanol concentration at 85 %, and elution volume at 15 mL. Taken together, we conclude that the combination strategy of MSPD and response surface evaluation for simultaneous detections of multiple bioactive constituents could be a powerful and efficient method for performing accurately quality control of complex TCM production preparations.

Targeting Myeloperoxidase (MPO) Mediated Oxidative Stress and Inflammation for Reducing Brain Ischemia Injury: Potential Application of Natural Compounds.

Oxidative stress and inflammation are two critical pathological processes of cerebral ischemia-reperfusion injury. Myeloperoxidase (MPO) is a critical inflammatory enzyme and therapeutic target triggering both oxidative stress and neuroinflammation in the pathological process of cerebral ischemia-reperfusion injury. MPO is presented in infiltrated neutrophils, activated microglial cells, neurons, and astrocytes in the ischemic brain. Activation of MPO can catalyze the reaction of chloride and H2O2 to produce HOCl. MPO also mediates oxidative stress by promoting the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), modulating the polarization and inflammation-related signaling pathways in microglia and neutrophils. MPO can be a therapeutic target for attenuating oxidative damage and neuroinflammation in ischemic stroke. Targeting MPO with inhibitors or gene deficiency significantly reduced brain infarction and improved neurological outcomes. This article discusses the important roles of MPO in mediating oxidative stress and neuroinflammation during cerebral ischemia-reperfusion injury and reviews the current understanding of the underlying mechanisms. Furthermore, we summarize the active compounds from medicinal herbs with potential as MPO inhibitors for anti-oxidative stress and anti-inflammation to attenuate cerebral ischemia-reperfusion injury, and as adjunct therapeutic agents for extending the window of thrombolytic treatment. We highlight that targeting MPO could be a promising strategy for alleviating ischemic brain injury, which merits further translational study.

Nitration of Drp1 provokes mitophagy activation mediating neuronal injury in experimental autoimmune encephalomyelitis.

Active autophagy/mitophagy could mediate neurodegeneration and motor disabilities in multiple sclerosis (MS). Mitochondrial recruitment of dynamin-related protein 1 (Drp1) is a crucial step to initiate mitophagy. Peroxynitrite (ONOO-) could be a player in MS pathology but the mechanisms remain unknown. We used animal model of experimental autoimmune encephalomyelitis (EAE) and tested whether ONOO- mediates Drp1 assembly in mitochondria for mitophagy and aggravates MS pathology. We found that autophagy/mitophagy activation was coincidently increased with axonal damage, apoptosis and disease progression in active EAE mice, which were remarkably attenuated by mitochondrial division/mitophagy inhibitor Mdivi-1. Importantly, increased ONOO- production was companied with Drp1 mitochondrial recruitment, PINK1/Parkin-mediated mitophagy, axonal degeneration and neuronal cell death, which were reversed by peroxynitrite decomposition catalyst (PDC). Furthermore, ONOO- production induced Drp1 nitration, promoted Drp1 assembly and mitochondrial recruitment for mitophagy activation, contributing to the EAE pathology. Together, we conclude that ONOO- serves as a key mediator in Drp1 nitration modification and assembly for facilitating mitophagy activation. Targeting ONOO--mediated Drp1 assembly and mitochondrial recruitment could be an important therapeutic strategy for multiple sclerosis treatment.

Baicalin Modulates APPL2/Glucocorticoid Receptor Signaling Cascade, Promotes Neurogenesis, and Attenuates Emotional and Olfactory Dysfunctions in Chronic Corticosterone-Induced Depression.

Olfactory dysfunction is often accompanied with anxiety- and depressive-like behaviors in depressive patients. Impaired neurogenesis in hippocampus and subventricular zone (SVZ)-olfactory bulb (OB) contribute to anxiety- and depressive-like behaviors and olfactory dysfunctions. However, the underlying mechanisms of olfactory dysfunction remain unclear. Our previous study indicates that adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2 (APPL2), could affect the activity and sensitivity of glucocorticoid receptor (GR) and mediate impaired hippocampal neurogenesis, which contribute the development of depression. In the present study, we further identified the roles of APPL2 in olfactory functions. APPL2 Tg mice displayed higher GR activity and less capacity of neurogenesis at olfactory system with less olfactory sensitivity than WT mice, indicating that APPL2 could be a potential therapeutic target for depression and olfactory deficits. We then studied the effects of baicalin, a medicinal herbal compound, on modulating APPL2/GR signaling pathway for promoting neurogenesis and antidepressant as well as improving olfactory functions. Baicalin treatment inhibited APPL2/GR signaling pathway and improved neurogenesis at SVZ, OB, and hippocampus in APPL2 Tg mice and chronic corticosterone-induced depression mouse model. Behavioral tests revealed that baicalin attenuated depressive- and anxiety-like behaviors and improve olfactory functions in the chronic depression mouse model and APPL2 Tg mice. Taken together, APPL2 could be a novel therapeutic target for improving depressant-related olfactory dysfunctions and baicalin could inhibit APPL2-mediated GR hyperactivity and promote adult neurogenesis, subsequently releasing depressive and anxiety symptoms and improving olfactory functions for antidepressant therapy.

Dynamic changes of flavonoids in Actinidia valvata leaves at different growing stages measured by HPLC-MS/MS.

Flavonoids are a large group of phenolic secondary metabolites havinga wide range of biochemical and pharmacological effects. Quantitative analysis of flavonoid profiles in the genus Actinidia, which has not been intensively conducted, is useful to a better understanding of the pattern and distribution of flavonoids. In the present work, a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method was developed to profile the flavonoids, which was then used to determine the dynamic change of 17 biologically active flavonoids in the leaves of Actinidia valvata at the main growing stages, including glucuronides and acylated di- and triglycosides of flavonoids. The contents of flavonoid triglycosides were significantly higher than other flavonoids. The highest concentrations of kaemperol glycosides were observed in June, while other flavonoids showed highest concentrations in October. On the other hand, the contents of four isorhamnetin glycosides were increased sharply in September to October. The flavonoid profiles seem to be related to temperature, UV-B, and water deficit. Further studies are required to examine the functions of flavonoids in the Actinidia valvata and the underlying molecular mechanisms of actions.

A Review: The Pharmacology of Isoliquiritigenin.

Isoliquiritigenin (ISL) is one of the bioactive ingredients isolated from the roots of plants belonging to licorice, including Glycyrrhiza uralensis, Mongolian glycyrrhiza, Glycyrrhiza glabra, and so forth. Liquiritigenin is available in common foods and alternative medicine, and its derivative-ISL is applied into food additives and disease treatment like cancer therapy, antibiotic therapy, and so on. This review aims at providing a comprehensive summary of the pharmacological activities of ISL. The information published between 1972 and 2014 from a number of reliable sources including PubMed, ScienceDirect, Springer, and Wiley-Blackwell. The practical application of ISL on the various disease prevention and treatments may stem from its numerous pharmacological properties such as antiinflammatory, anti-microbial, anti-oxidative, anticancer activities, immunoregulatory, hepatoprotective, and cardioprotective effects. However, further studies are needed to verify the target-organ toxicity or side effects investigation.

Pharmacology and phytochemistry of the Nitraria genus (Review).

Plants from the Nitraria genus, members of the Zygophyllaceae family, grow naturally in Europe, Africa, Australia and the central Asian desert. Previous pharmacological research has provided evidence that members of the Nitraria genus have numerous beneficial effects. In the present review, the pharmacological and phytochemical studies of Nitraria were presented and assessed. The review was written using information published between 1968 and 2013 from a number of reliable sources, including ScienceDirect, Springer, PubMed, EMBASE and CNKI. Numerous compounds, such as alkaloids and flavonoids have been isolated from the plants of this genus in the past, and multiple members of these constituents have been demonstrated to exert antitumor or anti-oxidative activities. The extracts of plants of the Nitraria genus possess antitumor, antiproliferative, anti-oxidative, antifatigue, anti-mutagenic, antimicrobial, hypotensive, hepatoprotective, lipid-lowering and hypoglycemic effects. However, the possible active components in the fraction and the molecular mechanisms require further investigation prior to their use in clinical practice.

Polydatin: a review of pharmacology and pharmacokinetics.

CONTEXT: Polydatin, also named piceid (3,4',5-trihydroxystilbene-3-ß-d-glucoside, PD), is a monocrystalline compound isolated from Polygonum cuspidatum Sieb. et Zucc. (Polygonaceae), but is also detected in grape, peanut, hop cones, red wines, hop pellets, cocoa-containing products, chocolate products and many daily diets. There are numerous investigations reported of PD in the past 22 years, but they are usually scattered across various publications, which may block further research and clinical use of PD. OBJECTIVE: The article summarizes and evaluates the published scientific information of PD pharmacological effects and pharmacokinetics since 1990. MATERIALS AND METHODS: The information from 98 cases included in this review was compiled using major databases such as MEDLINE, Elsevier, Springer, PubMed, Scholar and CNKI. RESULTS: Numerous pharmacological investigations of PD mainly focus on cardiovascular effects, neuroprotection, anti-inflammatory and immunoregulatory effects, anti-oxidation, anti-tumor, liver and lung protection, etc. CONCLUSION: A great number of pharmacological and pharmacokinetic investigations in the past 22 years have demonstrated that PD has favorable therapeutic properties, indicating its potential as an effective material. However, further research is needed to explore its molecular mechanisms of action and definitive target proteins.