scholarly journals Cimicifuga racemosa Extract Ze 450 Re-Balances Energy Metabolism and Promotes Longevity

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1432
Author(s):  
Malena Rabenau ◽  
Benjamin Dillberger ◽  
Madeline Günther ◽  
Sylvia Krippner ◽  
Veronika Butterweck ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Damage ◽  
Neuronal Cells ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Metabolic Shift ◽  
Protective Effects ◽  
Cimicifuga Racemosa ◽  
Complex Activity

Recently, we reported that the Cimicifuga racemosa extract Ze 450 mediated protection from oxidative cell damage through a metabolic shift from oxidative phosphorylation to glycolysis. Here, we investigated the molecular mechanisms underlying the effects of Ze 450 against ferroptosis in neuronal cells, with a particular focus on mitochondria. The effects of Ze 450 on respiratory complex activity and hallmarks of ferroptosis were studied in isolated mitochondria and in cultured neuronal cells, respectively. In addition, Caenorhabditis elegans served as a model organism to study mitochondrial damage and longevity in vivo. We found that Ze 450 directly inhibited complex I activity in mitochondria and enhanced the metabolic shift towards glycolysis via cMyc and HIF1α regulation. The protective effects against ferroptosis were mediated independently of estrogen receptor activation and were distinct from effects exerted by metformin. In vivo, Ze 450 protected C. elegans from the mitochondrial toxin paraquat and promoted longevity in a dose-dependent manner. In conclusion, Ze 450 mediated a metabolic shift to glycolysis via direct effects on mitochondria and altered cell signaling, thereby promoting sustained cellular resilience to oxidative stress in vitro and in vivo.

scholarly journals The Protective Effects of α-Mangostin Attenuate Sodium Iodate-Induced Cytotoxicity and Oxidative Injury via Mediating SIRT-3 Inactivation via the PI3K/AKT/PGC-1α Pathway

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1870
Author(s):  
Chen-Ju Chuang ◽  
Meilin Wang ◽  
Jui-Hsuan Yeh ◽  
Tzu-Chun Chen ◽  
Shang-Chun Tsou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caspase 3 ◽  
Cell Damage ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Dependent Manner ◽  
Protective Effects ◽  
Age Related

It is well known that age-related macular degeneration (AMD) is an irreversible neurodegenerative disease that can cause blindness in the elderly. Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is a part of the pathogenesis of AMD. In this study, we evaluated the protective effect and mechanisms of alpha-mangostin (α-mangostin, α-MG) against NaIO3-induced reactive oxygen species (ROS)-dependent toxicity, which activates apoptosis in vivo and in vitro. MTT assay and flow cytometry demonstrated that the pretreatment of ARPE-19 cells with α-MG (0, 3.75, 7.5, and 15 μM) significantly increased cell viability and reduced apoptosis from NaIO3-induced oxidative stress in a concentration-dependent manner, which was achieved by the inhibition of Bax, cleaved PARP-1, cleaved caspase-3 protein expression, and enhancement of Bcl-2 protein. Furthermore, pre-incubation of ARPE-19 cells with α-MG markedly inhibited the intracellular ROS and extracellular H2O2 generation via blocking of the abnormal enzyme activities of superoxide dismutase (SOD), the downregulated levels of catalase (CAT), and the endogenous antioxidant, glutathione (GSH), which were regulated by decreasing PI3K-AKT-PGC-1α-STRT-3 signaling in ARPE-19 cells. In addition, our in vivo results indicated that α-MG improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer by inhibiting the expression of cleaved caspase-3 protein. Taken together, our results suggest that α-MG effectively protects human ARPE-19 cells from NaIO3-induced oxidative damage via antiapoptotic and antioxidant effects.

scholarly journals Protective Effect of Pyrus ussuriensis Maxim. Extract against Ethanol-Induced Gastritis in Rats

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 439
Author(s):  
Naila Boby ◽  
Muhammad Aleem Abbas ◽  
Eon-Bee Lee ◽  
Zi-Eum Im ◽  
Walter H. Hsu ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Adenosine Monophosphate ◽  
Ethanol Ingestion ◽  
Dependent Manner ◽  
Protective Effects ◽  
Gastric Mucosal Lesions ◽  
Cellular Degeneration ◽  
Mucosal Lesions ◽  
Pyrus Ussuriensis Maxim

Pyrus ussuriensis Maxim (Korean pear) has been used for hundreds of years as a traditional herbal medicine for asthma, cough, and atopic dermatitis in Korea and China. Although it was originally shown to possess anti-inflammatory, antioxidant, and antiatopic properties, its gastroprotective effects have not been investigated. In the present study, we evaluated the protective effects of Pyrus ussuriensis Maxim extract (PUE) against ethanol-induced gastritis in rats. The bioactive compound profile of PUE was determined by gas chromatography mass spectroscopy (GC-MS) and high-performance liquid chromatography (HPLC). The gastroprotection of PUE at different doses (250 and 500 mg/kg body weight) prior to ethanol ingestion was evaluated using an in vivo gastritis rat model. Several endpoints were evaluated, including gastric mucosal lesions, cellular degeneration, intracellular damage, and immunohistochemical localization of leucocyte common antigen. The gastric mucosal injury and ulcer score were determined by evaluating the inflamed gastric mucosa and by histological examination. To identify the mechanisms of gastroprotection by PUE, antisecretory action and plasma prostaglandin E2 (PGE2), gastric mucosal cyclic adenosine monophosphate (cAMP), and histamine levels were measured. PUE exhibited significant antioxidant effects with IC50 values of 56.18 and 22.49 µg/mL for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′- azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) inhibition (%), respectively. In addition, GC/MS and HPLC analyses revealed several bioactive compounds of PUE. Pretreatment with PUE significantly (P < 0.05) decreased the ulcer index by preventing gastric mucosal lesions, erosion, and cellular degeneration. An immunohistochemical analysis revealed that PUE markedly attenuated leucocyte infiltration in a dose-dependent manner. The enhancement of PGE2 levels and attenuation of cAMP levels along with the inhibition of histamine release following PUE pretreatment was associated with the cytoprotective and healing effects of PUE. In contrast, the downregulation of the H+/K+ ATPase pathway as well as muscarinic receptor (M3R) and histamine receptor (H2R) inhibition was also involved in the gastroprotective effects of PUE; however, the expression of cholecystokinin-2 receptors (CCK2R) was unchanged. Finally, no signs of toxicity were observed following PUE treatment. Based on our results, we conclude that PUE represents an effective therapeutic option to reduce the risk of gastritis and warrants further study.

scholarly journals Norepinephrine Protects against Methamphetamine Toxicity through β2-Adrenergic Receptors Promoting LC3 Compartmentalization

2021 ◽  
Vol 22 (13) ◽  
pp. 7232
Author(s):  
Gloria Lazzeri ◽  
Carla L. Busceti ◽  
Francesca Biagioni ◽  
Cinzia Fabrizi ◽  
Gabriele Morucci ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Light Chain ◽  
Adrenergic Receptors ◽  
Cell Damage ◽  
Protective Effects ◽  
Autophagy Flux ◽  
Brain Areas ◽  
Indirect Consequence

Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane β2-adrenergic receptors (ARs). Evidence indicates that β2-ARs activation restores autophagy, which is impaired by Meth administration. This occurs via restoration of the autophagy flux and, as assessed by ultrastructural morphometry, by preventing the dissipation of microtubule-associated protein 1 light chain 3 (LC3) from autophagy vacuoles to the cytosol, which is produced instead during Meth toxicity. These findings may have an impact in a variety of degenerative conditions characterized by NE deficiency along with autophagy impairment.

scholarly journals Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

2021 ◽  
Author(s):  
Young-Min Han ◽  
Min Sun Kim ◽  
Juyeong Jo ◽  
Daiha Shin ◽  
Seung-Hae Kwon ◽  
...  
Keyword(s):  
Inhibitory Action ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Middle Phase ◽  
Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

scholarly journals The impact of indole-3-lactic acid on immature intestinal innate immunity and development: a transcriptomic analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wuyang Huang ◽  
Ky Young Cho ◽  
Di Meng ◽  
W. Allan Walker
Keyword(s):  
Lactic Acid ◽  
Mechanistic Model ◽  
Transcriptomic Analysis ◽  
Dependent Manner ◽  
Protective Effects ◽  
Very Preterm Infants ◽  
Anti Inflammatory ◽  
The Impact

AbstractAn excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants. Indole-3-lactic acid (ILA) of breastmilk tryptophan was identified as the anti-inflammatory metabolite involved in probiotic conditioned media from Bifidobacteria longum subsp infantis. This study aimed to explore the molecular endocytic pathways involved in the protective ILA effect against inflammation. H4 cells, Caco-2 cells, C57BL/6 pup and adult mice were used to compare the anti-inflammatory mechanisms between immature and mature enterocytes in vitro and in vivo. The results show that ILA has pleiotropic protective effects on immature enterocytes including anti-inflammatory, anti-viral, and developmental regulatory potentials in a region-dependent and an age-dependent manner. Quantitative transcriptomic analysis revealed a new mechanistic model in which STAT1 pathways play an important role in IL-1β-induced inflammation and ILA has a regulatory effect on STAT1 pathways. These studies were validated by real-time RT-qPCR and STAT1 inhibitor experiments. Different protective reactions of ILA between immature and mature enterocytes indicated that ILA’s effects are developmentally regulated. These findings may be helpful in preventing NEC for premature infants.

scholarly journals ADP-ribosylation factor–like 4A interacts with Robo1 to promote cell migration by regulating Cdc42 activation

2019 ◽  
Vol 30 (1) ◽  
pp. 69-81 ◽  
Author(s):  
Tsai-Shin Chiang ◽  
Ming-Chieh Lin ◽  
Meng-Chen Tsai ◽  
Chieh-Hsin Chen ◽  
Li-Ting Jang ◽  
...  
Keyword(s):  
Cell Migration ◽  
Molecular Mechanisms ◽  
Small Gtpase ◽  
Dependent Manner ◽  
Amino Acid Residues ◽  
Adp Ribosylation ◽  
Promote Cell Migration ◽  
Cytoskeleton Remodeling ◽  
Adp Ribosylation Factor

Cell migration is a highly regulated event that is initiated by cell membrane protrusion and actin reorganization. Robo1, a single-pass transmembrane receptor, is crucial for neuronal guidance and cell migration. ADP-ribosylation factor (Arf)–like 4A (Arl4A), an Arf small GTPase, functions in cell morphology, cell migration, and actin cytoskeleton remodeling; however, the molecular mechanisms of Arl4A in cell migration are unclear. Here, we report that the binding of Arl4A to Robo1 modulates cell migration by promoting Cdc42 activation. We found that Arl4A interacts with Robo1 in a GTP-dependent manner and that the Robo1 amino acid residues 1394–1398 are required for this interaction. The Arl4A-Robo1 interaction is essential for Arl4A-induced cell migration and Cdc42 activation but not for the plasma membrane localization of Robo1. In addition, we show that the binding of Arl4A to Robo1 decreases the association of Robo1 with the Cdc42 GTPase-activating protein srGAP1. Furthermore, Slit2/Robo1 binding down-regulates the Arl4A-Robo1 interaction in vivo, thus attenuating Cdc42-mediated cell migration. Therefore, our study reveals a novel mechanism by which Arl4A participates in Slit2/Robo1 signaling to modulate cell motility by regulating Cdc42 activity.

In vitro and in vivo GABAA Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid

Pharmacology ◽  
2018 ◽  
Vol 103 (1-2) ◽  
pp. 10-16 ◽  
Author(s):  
Alessia Cenani ◽  
Robert J. Brosnan ◽  
Heather K. Knych
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Water Solubility ◽  
Plasma Concentrations ◽  
Receptor Activation ◽  
Receptor Interaction ◽  
Dependent Manner ◽  
Benzeneacetic Acid

Background: Propanidid is a γ-aminobutyric acid type A (GABAA) receptor agonist general anesthetic and its primary metabolite is 4-(2-[diethylamino]-2-oxoethoxy)-3-methoxy-benzeneacetic acid (DOMBA). Despite having a high water solubility at physiologic pH that might predict low-affinity GABAA receptor interactions, DOMBA is reported to have no effect on GABAA receptor currents, possibly because the DOMBA concentrations studied were simply insufficient to modulate GABAA receptors. Our objectives were to measure the propanidid and DOMBA concentration responses on ­GABAA receptors and to measure the behavioral responses of DOMBA in mice at concentrations that affect GABAA receptor currents in vitro. Methods: GABAA receptors were expressed in oocytes using clones for the human GABAA α1, β2 and γ2s subunits. The effects of DOMBA (0.2–10 mmol/L) and propanidid (0.001–1 mmol/L) on oocyte GABAA currents were studied using standard 2-electrode voltage clamp techniques. Based on in vitro results, 6 mice received ­DOMBA 32 mg intraperitoneal and were observed for occurrence of neurologic effects and DOMBA plasma concentration was measured by liquid chromatography tandem mass spectrometry. Results: DOMBA both directly activates GABAA receptors and antagonizes its GABA-mediated opening in a concentration-dependent manner at concentrations between 5–10 and 0.5–10 mmol/L respectively. In vivo, DOMBA produced rapid onset sedation at plasma concentrations that correlate with direct GABAA receptor activation. Conclusion: DOMBA modulation of GABAA receptors is associated with sedation in mice. Metabolites of propanidid analogues currently in development may similarly modulate GABAA, and impaired elimination of these metabolites could produce clinically relevant neurophysiologic effects.

scholarly journals Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Hiroshi Yamaguchi ◽  
Toshihiko Maruyama ◽  
Yoshihiro Urade ◽  
Shigekazu Nagata
Keyword(s):  
Adenosine Receptor ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Adenosine Monophosphate ◽  
Receptor Activation ◽  
Death Process ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
A2a Adenosine Receptor ◽  
Anti Inflammatory

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal.

scholarly journals Coagulation Factor XII protects neurons from apoptosis by triggering a crosstalk between HGFR/c-Met and EGFR/ErbB1 signaling pathways

2020 ◽  
Author(s):  
Eugénie Garnier ◽  
Damien Levard ◽  
Carine Ali ◽  
Yannick Hommet ◽  
Tiziana Crepaldi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Neuronal Cell ◽  
Coagulation Factor ◽  
Receptor Activation ◽  
Target Cells ◽  
Cultured Neurons ◽  
Factor Xii ◽  
Protective Effects

Abstract Background Factor XII (FXII) is a serine protease that participates in the intrinsic coagulation pathway. Several studies have shown that plasmatic FXII exert a deleterious role in cerebral ischemia and traumatic brain injury by promoting thrombo-inflammation. Nevertheless, the direct impact of FXII on neuronal cell fate remains unknown.Methods We investigated whether FXII influenced neuronal death induced in vivo by stereotaxic injection of N-methyl-D-Aspartate (NMDA) and in vitro by serum deprivation of cultured neurons.Results We found that FXII reduced brain lesions induced in vivo and protected cultured neurons from apoptosis through a growth factor-like effect. This mechanism was triggered by direct interaction with epidermal growth factor (EGF) receptor, activation of this receptor and engagement of anti-apoptotic intracellular pathways. Interestingly, the “proteolytically” active and two-chain form of FXII, αFXIIa, exerted additional protective effects by converting the pro-form of hepatocyte growth factor (HGF) into its mature form, which in turn activated HGF receptor (HGFR/c-Met) pathway. Lastly, the use of non-proteolytic FXII (αFXIIa-PPACK) unveiled an alternative EGFR and HGFR co-activation pathway, through co-receptor transphosphorylation. Conclusion This study describes novel mechanisms of action of FXII and discloses neurons as target cells for the protective effects of single and double-chain forms of FXII.

scholarly journals Triptolide Attenuates Vascular Calcification by Upregulating Expression of miRNA-204

2021 ◽  
Vol 11 ◽  
Author(s):  
Yu-qiang Pei ◽  
Yong-qiu Zheng ◽  
Yao-dong Ding ◽  
Qi-xiang Xu ◽  
Di Cao ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Calcium Content ◽  
Rat Aorta ◽  
Protective Role ◽  
Bone Morphogenetic Protein 2 ◽  
Dependent Manner ◽  
Protective Effects ◽  
Alp Activity

Background: Triptolide (TP), a naturally derived compound from Tripterygium wilfordii, has been proven effective in protecting against cardiovascular system, but the molecular mechanisms underlying its protective effects are poorly understood. In the current study, we sought to test the potential protective role of TP in the regulation of vascular calcification in a rat model and explore whether TP attenuates medial vascular calcification by upregulating miRNA-204.Methods: Vitamin D3 plus nicotine (VDN) was used to induce a vascular calcification (VC) model of rat aorta. Von Kossa and Hematoxylin-Eosin staining were applied to assess the degree of calcification of rat aortas. Calcium content and alkaline phosphatase activity were measured. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was applied to quantify miRNA-204 expression. The localization of runt-related transcription factor-2 (RUNX2) and bone morphogenetic protein-2 (BMP2) expressions were detected by immunohistochemistry and western blotting.Results: Administration of TP greatly reduced vascular calcification in a dose-dependent manner compared with VC controls. The increase in ALP activity and calcium content was ameliorated by TP. Moreover, protein expression levels of BMP2 and RUNX2 were significantly reduced in calcified aortas. MiRNA-204 expression was increased in the TP-treated groups compared with VC controls and the effects of TP were reversed by the intravenous injection of miRNA-204-interfering lentivirus. However, the miRNA-204-overexpressing lentivirus had no additional effects on ALP activity, calcium content, BMP2 and RUNX2 expressions compared with those from TP group.Conclusion: TP inhibited BMP2 and RUNX2 expression and attenuated vascular calcification via upregulating the level of miRNA-204. TP appears to be a potential new therapeutic option for treating vascular calcification.

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