Figure - available from: BioMed Research International
This content is subject to copyright. Terms and conditions apply.
Source publication
Growing evidences indicate that immune-mediated mechanisms contribute to the development of cerebral ischemia/reperfusion (I/R) injury. Daphnetin (DAP) is a coumarin derivative extracted from Daphne odora var., which displays anti-inflammatory properties. However, the effect of DAP on cerebral I/R injury is not yet clear. Recent studies have demons...
Similar publications
Rupture of abdominal aortic aneurysm (AAA) is a devastating event that can be prevented by inhibiting the growth of small aneurysms. Therapeutic strategies targeting certain events that promote the development of AAA must be developed, in order to alter the course of AAA. Chronic inflammation of the aortic mural is a major characteristic of AAA and...
Citations
... In addition, in another study, MCAO/R rats were treated with various concentrations (5, 10, and 20 mg/kg) of Daphnetin. It was found that Daphnetin at 20 mg/kg concentration could significantly reduce the overexpression of TNF-α, IL-1β and IL-6 through the TLR4/NF-κB signaling pathway, and alleviate apoptosis of nerve cells, thus exerting neuroprotective and anti-inflammatory effects (Liu et al., 2016a) (Figure 2.).In addition to the TCM monomers, casticin (Huang et al., 2021a), saikosaponin A (Wang and Yang, 2020), salvianolic acid D (Zhang et al., 2020b), schisandrin B (Fan et al., 2020) and Z-Guggulsterone have all played neuroprotective and anti-inflammatory roles in CIRI by inhibiting TLR4/NF-κB (Table 2). ...
Ischemia/reperfusion (I/R) injury is a pathological process wherein reperfusion of an ischemic organ or tissue exacerbates the injury, posing a significant health threat and economic burden to patients and their families. I/R triggers a multitude of physiological and pathological events, such as inflammatory responses, oxidative stress, neuronal cell death, and disruption of the blood-brain barrier (BBB). Hence, the development of effective therapeutic strategies targeting the pathological processes resulting from I/R is crucial for the rehabilitation and long-term enhancement of the quality of life in patients with cerebral ischemia/reperfusion injury (CIRI). Traditional Chinese medicine (TCM) monomers refer to bioactive compounds extracted from Chinese herbal medicine, possessing anti-inflammatory and antioxidative effects, and the ability to modulate programmed cell death (PCD). TCM monomers have emerged as promising candidates for the treatment of CIRI and its subsequent complications. Preclinical studies have demonstrated that TCM monomers can enhance the recovery of neurological function following CIRI by mitigating oxidative stress, suppressing inflammatory responses, reducing neuronal cell death and functional impairment, as well as minimizing cerebral infarction volume. The neuroprotective effects of TCM monomers on CIRI have been extensively investigated, and a comprehensive understanding of their mechanisms can pave the way for novel approaches to I/R treatment. This review aims to update and summarize evidence of the protective effects of TCMs in CIRI, with a focus on their role in modulating oxidative stress, inflammation, PCD, glutamate excitotoxicity, Ca ²⁺ overload, as well as promoting blood-brain barrier repairment and angiogenesis. The main objective is to underscore the significant contribution of TCM monomers in alleviating CIRI.
... Studies have shown that inflammation accompanies the entire course of CIR injury, and neuroinflammation leads to neuronal damage (Petrovic-Djergovic et al., 2016). TNF-α, IL-1β, and IL-6 are important inflammatory cytokines involved in the progression of CIR injury (Liu et al., 2016); however, IL-10 is an anti-inflammatory factor that increases at the time of injury to counteract external stimuli. ...
Cerebral ischemia-reperfusion (CIR) seriously affects human health and life as it is accompanied by inflammation and apoptosis in brain tissues. Tubeimoside I (TBMS-1) can inhibit neuroinflammation and has neuroprotective effects; however, its effects on ischemia-reperfusion (IR) injury of the brain requires clarity. A mouse cerebral artery occlusion/reperfusion model was used to simulate CIR injury. The neurological function and the area of cerebral infarction were assessed by 2,3,5-triphenyltetrazolium chloride staining. Tumor necrosis factor-α, Interleukin (IL)-1β, IL-6, and IL-10 levels were measured by enzyme-linked-immunosorbent serologic assay kits. Protein blot analysis was performed to assess the expression of apoptosis-related factors. In addition, PC12 (pheo-chromocytoma) cells were treated with oxygen–glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model of CIR injury. The cell viability was measured by cell counting kit-8 assay, and apoptosis levels were detected by flow cytometry. In vivo results indicated that Tubeimoside I reduced cerebral infarct size, decreased inflammatory factor content, inhibited the expression of apoptosis-related factors, including Bax and cleaved-caspase-3 (Asp175), and promoted the expression of survival factor, such as B-cell lymphoma protein 2. In vitro, Tubeimoside I was able to increase cell viability and inhibit apoptosis. Mechanistically, Tubeimoside I was able to enhance both in vivo and in vitro expressions of NAD-dependent deacetylase sirtuin-3 (SIRT3). SIRT3 inhibitor abolished the protective effect of Tubeimoside I on OGD/R-treated cells. Tubeimoside I lessened CIR injury by activating SIRT3. Hence, it could be a potential drug candidate for treating IR injury of the brain.
... Daphnetin (DAP) is a coumarin derivative extracted from Daphne odora var. DAP inhibits TLR4/NF-κ B expression and reduces neuronal apoptosis [260]. Protosappanin A selectively induces the degradation of the pro-apoptotic protein Bax without affecting other Bcl-2 family members, and in addition maintains mitochondrial function in neuronal cells through Bax/LC3B binding, which in turn promotes the autophagic degradation of Bax [261]. ...
Cerebral ischemia, one of the leading causes of neurological dysfunction of brain cells, muscle dysfunction, and death, brings great harm and challenges to individual health, families, and society. Blood flow disruption causes decreased glucose and oxygen, insufficient to maintain normal brain tissue metabolism, resulting in intracellular calcium overload, oxidative stress, neurotoxicity of excitatory amino acids, and inflammation, ultimately leading to neuronal cell necrosis, apoptosis, or neurological abnormalities. This paper summarizes the specific mechanism of cell injury that apoptosis triggered by reperfusion after cerebral ischemia, the related proteins involved in apoptosis, and the experimental progress of herbal medicine treatment through searching, analyzing, and summarizing the PubMed and Web Of Science databases, which includes active ingredients of herbal medicine, prescriptions, Chinese patent medicines, and herbal extracts, providing a new target or new strategy for drug treatment, and providing a reference for future experimental directions and using them to develop suitable small molecule drugs for clinical application. With the research of anti-apoptosis as the core, it is important to find highly effective, low toxicity, safe and cheap compounds from natural plants and animals with abundant resources to prevent and treat Cerebral ischemia/reperfusion (I/R) injury (CIR) and solve human suffering. In addition, understanding and summarizing the apoptotic mechanism of cerebral ischemia–reperfusion injury, the microscopic mechanism of CIR treatment, and the cellular pathways involved will help to develop new drugs.
... The activation of innate immune receptors such as Tlrs serves an important role in induction of inflammatory responses; Tlr4 was the first mammalian Tlr recognized (26). Previous studies have reported that Tlr4 expression is upregulated following cerebral i/r and that this is alleviated in TLR4-deficient mice (27,28). A case of previous study has also reported that oSr exerts antioxidant and anti-inflammatory effects in Alzheimer's disease by targeting the Tlr4/nF-κB signaling pathway and TLR4-specific inhibitor TaK-242 effectively enhances the effects of oSr (23). ...
Oxysophoridine (OSR) is an alkaloid extracted from Sophora alopecuroides L. and exerts beneficial effects in cerebral ischemia/reperfusion (I/R) injury. However, the molecular mechanism underlying the regulatory effects of OSR in cerebral I/R injury remains unclear. In the present study, a cerebral I/R injury rat model was established by occlusion of the right middle cerebral artery. Hematoxylin and eosin and triphenyltetrazolium chloride staining were performed to assess histopathological changes and the extent of cerebral injury to the brain. A Cell Counting Kit‑8 and TUNEL assay and western blotting were performed to assess cell viability and apoptosis. Ferroptosis and oxidative stress were evaluated based on ATP and Fe2+ levels and DCFH‑DA staining. The protein expression levels of inflammatory factors were assessed using ELISA. The protein expression levels of members of the toll‑like receptor (TLR)4/p38MAPK signaling pathway were evaluated using immunofluorescence staining and western blotting. The results demonstrated that OSR decreased brain injury and neuronal apoptosis in the hippocampus in I/R‑induced rats. OSR inhibited reactive oxygen species (ROS) production, decreased levels of ATP, Fe2+ and acyl‑CoA synthetase long‑chain family member 4 (ACSL4) and transferrin 1 protein and increased the protein expression levels of ferritin 1 and glutathione peroxidase 4. Furthermore, OSR blocked TLR4/p38MAPK signaling in brain tissue in the I/R‑induced rat. In vitro experiments demonstrated that TLR4 overexpression induced generation of ROS, ATP and Fe2+, which promoted the expression of ferroptosis‑associated proteins in hippocampal HT22 neuronal cells. The ferroptosis inducer erastin decreased the effects of OSR on oxygen‑glucose deprivation/reoxygenation (OGD/R)‑induced cell viability, oxidative stress and inflammatory response. Together, the results demonstrated that OSR alleviated cerebral I/R injury via inhibition of TLR4/p38MAPK‑mediated ferroptosis.
... In an earlier study, DAP was used for treating cerebral ischemia/reperfusion injury and it was found to exhibit neuroprotective and antiinflammatory effect by inhibiting TLR4/NF-kβ pathway, Frontiers in Pharmacology frontiersin.org 07 alleviating the production of inflammatory cytokines and neural cell apoptosis (Liu et al., 2016a). DAP (at 5, 10, 25, 50, 75, and 100 μM/L) displayed dose-dependent neuroprotective action in glutamate-induced toxicity in hippocampal HT22 cells and ischemic brain injury by restoring reduced glutathione (GSH) and superoxide dismutase (SOD) (Du et al., 2014). ...
... In numerous preclinical researches, DAP's neuroprotective effects have been thoroughly documented. Studies have demonstrated the protective effect of DAP against ischemic/ reperfusion injury, and spatial memory impairment caused by CUS, NMDA-induced excitotoxicity, glutamate-excited HT-22 cells, as well as cerebral ischemia (Liao et al., 2013;Du et al., 2014;Yang et al., 2014;Liu et al., 2016a;Berman and Bayati, 2018). The neuroprotective effect can be significantly achieved by the modification of the TLR-4/NF-κB, HSP70, JAK/STAT, and Nrf-2/HO −1 downstream pathways (Figure 4). ...
Daphnetin (DAP), a coumarin derivative extracted from Daphne species, is biologically active phytochemical with copious bioactivities including anti-inflammatory, anti-oxidant, neuroprotective, analgesic, antipyretic, antimalarial, anti-bacterial, anti-arthritic, neuroprotective, hepatoprotective, nephroprotective and, anti-cancer activities. It is reported to interact with multiple cellular mediators and signaling pathways to provide protection against neurodegeneration and arthritis. This review focuses on sources, synthesis, structure activity relationship, and various bioactivities of DAP. Neuroprotective and anti-inflammatory action of DAP is additionally aided by its modulation of the JNK-MAPK, JAK-STAT, and TLR-4/NF-κB signaling pathways. Although, the part of its anti-arthritic effect is mediated through immunoregulation, antioxidant and anti-inflammatory actions via regulation of NF-κB, MAPK and MMP signaling pathways, the anticancer action of DAP is mediated due to inhibition of Akt/ NF-Kb, MAPK signaling pathways, and the activation of Keap1-Nrf2 pathway. It is devoid of any organ toxicity and mortality as well as mutagenicity, mucosal irritation and sensitization reactions. Based on a review of the literature, DAP has a promising pharmacological and safety profiles and can be employed as a pharmaceutical moiety to treat a variety of illnesses. The current review intends to provide an in-depth focus on pharmacological activity and phytoanalytical approaches of DAP.
... Daphnetin treatment significantly attenuated the clinical and pathological manifestation of arthritis through contraction of arthritis scores, repressing the infiltration of inflammatory cells and modulating the balance of Treg and Th17 (Yao et al., 2011). These immunosuppressive effects were tightly associated with decreasing the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 (Liu et al., 2016), increasing expression of Foxp3 and IL-10 (Yao et al., 2011), and suppressing Th1 and Th17 cell responses (Wang et al., 2016). ...
Multiple sclerosis (MS) is the most typical chronic inflammatory, autoimmune demyelinating disease of the central nervous system
(CNS) which leads to physical dysfunction and paralysis in patients. A commonly used animal model for this disease is experimental
autoimmune encephalomyelitis (EAE). Daphnetin (7,8‑dihydroxycoumarin) has been reported to exert various pharmacological
activities, such as being neuroprotective and anti‑inflammatory, together with having antioxidant, anticancer, and antiviral properties.
Eight‑week‑old C57BL/6 female mice were segregated into 3 groups, namely 1) a control group receiving PBS, 2) a low‑dose treatment
group receiving 2 mg/kg of daphnetin, and, 3) a high‑dose treatment group receiving 8 mg/kg of daphnetin. EAE was induced with
a subcutaneous injection of a combination of myelin oligodendrocyte glycoprotein (MOG) and complete Freund’s adjuvant. On the
day of induction, and again two days later, mice were injected intraperitoneally with pertussis toxin. Histological studies showed low
lymphocyte infiltration and demyelination in the high and low dose treated groups. The ratio of spleen Treg cells and the levels of
IL‑4, IL‑10, TGF‑β, and IL‑33 enhanced significantly in the treatment group related to the control group. Furthermore, both IL‑27 and
IL‑35 were also enhanced significantly in the treatment group compared to the control group. Moreover, the levels of IFN‑γ, TNF‑α,
and IL‑17 displayed a noticeable reduction in the daphnetin treated group. Daphnetin appears to improve the disease by increasing
the expression of anti‑inflammatory cytokines and transcription factors (IL‑4, IL‑10, IL‑33, GATA3, TGF‑β, FoxP3), and reducing the
production of pro‑inflammatory cytokines and transcription factors (IFN‑γ, STAT4, T‑bet, IL‑17, STAT3, ROR‑γt, TNF‑α).
... Besides, xanthotoxol, IMM-H004, and osthole have been shown to reduce IL-1β, IL-6, TNFα, and nitric oxide (NO) in vivo [53][54][55]. The ability of coumarins to relieve neuroinflammation may involve interference with the binding of Aβ and microglia receptors [56] that induced an inhibitory effect on the nuclear translocation of NF-κB, the phosphorylation of Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) pathways, leading to suppression of the synthesis and release of pro-inflammatory cytokines [45,57]. In addition, coumarins exhibit acetylcholinesterase (AChE) inhibitory activity, which in turn increases acetylcholine (ACh) levels in the brain [58][59][60], ultimately leading to decreases in cognitive impairment caused by Aβ 1-42 injection. ...
Background
Alzheimer’s disease (AD) pathogenesis is associated with amyloid-β (Aβ)-induced neuroinflammation. In AD, the activation of microglia caused by Aβ accumulation is followed by the synthesis and release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα), and ultimately leads to cognitive impairments. Clausena harmandiana (CH) is a medicinal plant in the Rutaceae family and has been used in folk medicine to relieve illnesses such as stomachache and headache, and as a health tonic. Interestingly, CH root extract (CHRE) has several anti-inflammatory and other pharmacological activities, but there are no studies in AD-like animal models.
Objectives
This study aims to evaluate the effects of CHRE on cognitive impairments, increased Aβ 1–42 protein levels, and neuroinflammation in Aβ 1–42 -induced rats.
Methods
Forty-eight adult male Sprague-Dawley rats (250–300 g) were randomly divided into 6 groups ( n = 8) of the sham control, V + Aβ, CB + Aβ CHRE125 + Aβ, CHRE250 + Aβ, and CHRE500 + Aβ. Sodium carboxymethylcellulose, Celebrex (10 mg/kg BW) and CHRE (125, 250, and 500 mg/kg BW) were given orally or without any treatment for 35 days. On day 21, aggregated Aβ 1–42 at a concentration of 1 μg/μl were injected into both lateral ventricles (1 μl/side) of all treated rats, while sterilized normal saline were injected to untreated rats. Ten days later, the novel object recognition test was performed to assess their recognition memory. At the end of the test period, an overdose of thiopental sodium (120 mg/kg BW) and transcardial perfusion with 0.9% normal saline solution were used to euthanize all rats. Then Aβ 1–42 protein levels and the expression of inflammatory markers (CD11b-positive microglia, IL-1β, and TNFα) were investigated in the cerebral cortex and hippocampus.
Results
Pretreatment with CHRE at all doses could attenuate short- and long-term impairments in recognition memory. Additionally, CHRE also inhibited the increase of Aβ 1–42 protein levels and the expression of inflammatory markers in both brain regions as well as receiving Celebrex.
Conclusions
This suggests that preventive treatment of CHRE might be a potential therapy against cognitive impairments via reducing Aβ 1–42 protein levels and neuroinflammation caused by Aβ 1–42 .
... GroupII: Mice received ACR (40mg/kg b.w. in physiological saline) i.p for 15 days according to Kopanska et al., [18] . Group III: Mice received DAPH via intraperitoneal injection (20mg/kg) for 15 days diluted in 0.9% saline according to Liu et al., [19] . Group IV: Mice received DAPH via intraperitoneal injection (20mg/kg) along with ACR as in group II for 15 days. ...
... Many studies have shown that DAP exhibits broad pharmacological effects, including anti-inflammatory, antioxidative, and antithrombotic activities [9][10][11][12]. Additionally, a recent study revealed that DAP protects against cerebral I/R injury in mice via inhibiting inflammation and apoptosis [13]. However, there have been few studies on the cardioprotective effect of DAP. ...
Background/aims:
Daphnetin (7,8-dihydroxycoumarin, DAP) exhibits various bioactivities, such as anti-inflammatory and antioxidant activities. However, the role of DAP in myocardial ischaemia/reperfusion (I/R) injury and I/R-related arrhythmia is still uncertain. This study aimed to investigate the mechanisms underlying the effects of DAP on myocardial I/R injury and electrophysiological properties in vivo and in vitro.
Methods:
Myocardial infarct size was measured by triphenyltetrazolium chloride staining. Cardiac function was assessed by echocardiographic and haemodynamic analyses. The levels of creatine kinase-MB, lactate dehydrogenase, malondialdehyde, superoxide dismutase, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) were detected using commercial kits. Apoptosis was measured by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labelling staining and flow cytometry. The viability of H9c2 cells was determined by the Cell Counting Kit-8 assay. In vitro, the levels of IL-6 and TNF-α were measured by quantitative PCR. The expression levels of proteins associated with apoptosis, inflammation, and the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signalling pathway were detected by Western blot analysis. The RR, PR, QRS, and QTc intervals were assessed by surface ECG. The 90% action potential duration (APD90), threshold of APD alternans, and ventricular tachycardia inducibility were measured by the Langendorff perfusion technique.
Results:
DAP preconditioning decreased myocardial I/R injury and hypoxia/reoxygenation (H/R) injury in cells. DAP preconditioning improved cardiac function after myocardial I/R injury. DAP preconditioning also suppressed apoptosis, attenuated oxidative stress, and inhibited inflammatory responses in vivo and in vitro. Furthermore, DAP preconditioning decreased the susceptibility to ventricular arrhythmia after myocardial I/R. Finally, DAP preconditioning inhibited the expression of TLR4, MyD88, and phosphorylated NF-κB (p-NF-κB)/P65 in mice subjected to I/R and cells subjected to H/R.
Conclusions:
DAP preconditioning protected against myocardial I/R injury and decreased susceptibility to ventricular arrhythmia by inhibiting the TLR4/MyD88/NF-κB signalling pathway.
... Daphnetin displays analgesic, anti-inflammatory, antimalarial, antimicrobial, and antioxidant properties [160,[162][163][164][165]. A study by Du et al. [57] showed that intraperitoneal injection of 10 mg/kg of daphnetin 1 h prior to the HI insult to P7 rat pups resulted in a reduction of brain infarct volume, whereas daphnetin administered post-treatment 4 or 6 h after HI caused partial or no reduction in infarct volume, respectively. The same study showed that daphnetin reduced brain infarct volume and improved neurological deficits after ischemic injury using a middle cerebral artery occlusion mouse model [57], as shown by others [166]. Daphnetin also protected hippocampal neurons against glutamate-induced cell death by reducing oxidative stress in vitro [57], in agreement with another report showing that daphnetin attenuated oxidative stress and neuronal apoptosis after oxygen-glucose deprivation/reoxygenation injury in hippocampal cells through the activation of the Nrf2/HO-1 signaling pathway [167]. ...
Neonatal hypoxia–ischemia (HI) is a brain injury caused by oxygen deprivation to the brain due to birth asphyxia or reduced cerebral blood perfusion, and it often leads to lifelong limiting sequelae such as cerebral palsy, seizures, or mental retardation. HI remains one of the leading causes of neonatal mortality and morbidity worldwide, and current therapies are limited. Hypothermia has been successful in reducing mortality and some disabilities, but it is only applied to a subset of newborns that meet strict inclusion criteria. Given the unpredictable nature of the obstetric complications that contribute to neonatal HI, prophylactic treatments that prevent, rather than rescue, HI brain injury are emerging as a therapeutic alternative. Nutraceuticals are natural compounds present in the diet or used as dietary supplements that have antioxidant, anti-inflammatory, or antiapoptotic properties. This review summarizes the preclinical in vivo studies, mostly conducted on rodent models, that have investigated the neuroprotective properties of nutraceuticals in preventing and reducing HI-induced brain damage and cognitive impairments. The natural products reviewed include polyphenols, omega-3 fatty acids, vitamins, plant-derived compounds (tanshinones, sulforaphane, and capsaicin), and endogenous compounds (melatonin, carnitine, creatine, and lactate). These nutraceuticals were administered before the damage occurred, either to the mothers as a dietary supplement during pregnancy and/or lactation or to the pups prior to HI induction. To date, very few of these nutritional interventions have been investigated in humans, but we refer to those that have been successful in reducing ischemic stroke in adults. Overall, there is a robust body of preclinical evidence that supports the neuroprotective properties of nutraceuticals, and these may represent a safe and inexpensive nutritional strategy for the prevention of neonatal HI encephalopathy.
