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Identification of primary neurons. DAPI staining labeled all nuclei (A, E); NEUN staining labeled primary neuron nuclei (B, F); MAP-2 staining labeled primary neuron dendrites (C, G); merged Figure (D, H). Scale = 100 μM (A–D); scale = 50 μM (E–H).
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Neuroinflammation and neuro-oxidative damage are now considered to be key factors in the neurological diseases. Therefore, it is important to study anti-inflammatory and neuroprotective agents. The present study investigated the anti-inflammatory and neuroprotective effects of catalpol (CAT), and the potential molecular mechanisms involved. The fin...
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Citations
... Another research suggests that catalpol of processed Dihuang exhibits significant anti-diabetic bioactivity, and thus it has attracted increasing research attention for its potential use in treating diabetic nephropathy . Treatment with catalpol significantly improved renal function in diabetic nephropathy animal models by restoring serum creatinine and blood urea nitrogen levels, reducing proteinuria and fasting blood glucose, improving kidney indices, and alleviating renal pathological changes in the animal models (Yang C et al. 2020;Wang et al. 2021). Zhishouwu can improve liver mitochondrial function and alleviate glucolipid metabolic disorders by regulating mitochondrial metabolic pathways. ...
Context
Nine steaming and nine drying is a traditional Chinese medicine (TCM) processing method and it is widely used for processing tonifying herbs. Modern research reveals that the repeated steaming and drying process varies the composition and clinical efficacy of TCM.
Objective
This paper analyzes and explores the historical evolution, research progress, development strategies, and problems encountered in the nine steaming and nine drying process so as to provide a reasonable explanation for this method.
Methods
English and Chinese literature from 1986 to 2023 was collected from databases including Web of Science, PubMed, Elsevier, Chinese Pharmacopoeia 2020 (CP), and CNKI (Chinese). Nine steaming and nine drying, processing, TCM and pharmacological activity were used as the key words.
Results
Nine steaming and nine drying has undergone thousands of years of clinical practice. Under specific processing conditions of nine steaming and nine drying, the ingredients of the TCM have significant changes, which in turn altered clinical applications.
Conclusions
This review provides sufficient evidence to prove the rationality and scientific value of nine steaming and nine drying and puts forward a development direction for future research.
... Related pharmacokinetic studies (Lu et al., 2009;Li-nan et al., 2012) showed that catalpol could pass the blood-brain barrier and has a potential to be orally administrated, could be absorbed quickly, and exhibits a higher absolute bioavailability and a relatively longer half-life. It has been extensively studied in many disease states and has been shown to exhibit several biological effects, including neuroprotective (Yang et al., 2020), cardiovascular protective (He et al., 2021), anticancer (Wang and Zhan-Sheng, 2018), hepatoprotective, anti-inflammatory, antioxidant, and anti-diabetic effects (Xu et al., 2020;2015;Bhattamisra et al., 2019). ...
Aim of the Study: Rehmannia glutinosa is a core Chinese herbal medicine for the treatment of diabetes and diabetic nephropathy (DN). It has been used for the treatment of diabetes for over 1,000 years. Catalpol is the main active compound in Rehmannia roots. Current evidence suggests that catalpol exhibits significant anti-diabetic bioactivity, and thus it has attracted increasing research attention for its potential use in treating DN. However, no studies have systematically evaluated these effects, and its mechanism of action remains unclear. This study aimed to evaluate the effects of catalpol on DN, as well as to summarize its possible mechanisms of action, in DN animal models.
Materials and Methods: We included all DN-related animal studies with catalpol intervention. These studies were retrieved by searching eight databases from their dates of inception to July 2022. In addition, we evaluated the methodological quality of the included studies using the Systematic Review Center for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool. Furthermore, we calculated the weighted standard mean difference (SMD) with 95% confidence interval (CI) using the Review Manager 5.3 software and evaluated publication bias using the Stata (12.0) software. A total of 100 studies were retrieved, of which 12 that included 231 animals were finally included in this review.
Results: As compared to the control treatment, treatment with catalpol significantly improved renal function in DN animal models by restoring serum creatinine (Scr) ( p = 0.0009) and blood urea nitrogen (BUN) ( p < 0.00001) levels, reducing proteinuria ( p < 0.00001) and fasting blood glucose (FBG) ( p < 0.0001), improving kidney indices ( p < 0.0001), and alleviating renal pathological changes in the animal models. In addition, it may elicit its effects by reducing inflammation and oxidative stress, improving podocyte apoptosis, regulating lipid metabolism, delaying renal fibrosis, and enhancing autophagy.
Conclusion: The preliminary findings of this preclinical systematic review suggest that catalpol elicits significant protective effects against hyperglycemia-induced kidney injury. However, more high-quality studies need to be carried out in the future to overcome the methodological shortcomings identified in this review.
... The primary cortical neurons were cultured in a 24-well plate and treated with the PBS vehicle, 100 ng/mL of lipopolysaccharide, 100 mM or 200 mM of apocynin, and nanoparticle conjugate for 4, 24, or 48 h and then examined for their nitric oxide (NO) production. The NO measurements were conducted in real time with a World Precision Instruments Free Radical Analyzer TBR4100/1025 as previously described [35,37]. Briefly, after polarizing the ISO-NOP NO probe until the current reached a steady baseline value, the probe was calibrated via the decomposition of the photoactivatable nitric oxide donor S-nitroso-N-acetylpenicillamine, N7892, N7927 (SNAP). ...
Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide, affecting over 10 million people annually, with an estimated cost of $76.5 billion. Although apocynin freely transverses the blood–brain barrier (BBB), its application is limited due to its rapid elimination, low terminal half-life (t1/2 = 6.7 min), narrow dose–response relationship, and cytotoxicity, thereby requiring repeated dosages. With this study, we aimed to develop transferrin-functionalized nanoparticles encapsulating apocynin to treat neuroinflammation for targeted drug delivery to sites of brain injury. As a preliminary approach, we endeavored to optimize the formulation parameters of apocynin-loaded albumin nanoparticles prepared through the desolvation method. The nanoparticles were characterized for their size, polydispersity, surface charge, drug loading and in vitro drug release. In this study, we also investigated the anti-inflammatory and neuroprotective effects of free apocynin and nanoparticle-loaded apocynin in neuronal cells. We show that the developed formulation displayed monodispersed, nanosized particles with higher entrapment efficiency, loading, stability, and sustained release profiles. The permeability of the nanoparticles across HBMECs reached the maximum at 67%. The in vivo evaluation revealed the enhanced uptake of transferrin-anchored nanoparticles in the brain tissues when compared with unmodified nanoparticles after I.V. administration. In vivo nanoparticle localization studies using a blast TBI (bTBI) model and confocal fluorescence microscopy have shown that tf-apoANPs are successful in delivering relatively high amounts of nanoparticles to the brain parenchyma and glial cells compared to non-targeted nanoparticles. We also establish that targeted nanoparticles accumulate in the brain. In conclusion, tf-apoANPs are efficacious carriers for targeted delivery across the blood–brain barrier to potentially treat neuroinflammation in brain injury and other diseases.
... The NF-κB then migrates to the nucleus, where it is phosphorylated at the p65 subunit [26,64,65]. The latter event subsequently activates the transcription of inflammatory cytokines [65,66]. Therefore, we evaluated the expression of NF-κB in the kidney to elucidate its role in the anti-inflammatory mechanism of CAT. ...
Chronic kidney disease (CKD) is a stealthy disease, and its development is linked to mechanisms including inflammation and oxidative stress. Catalpol (CAT), an iridoid glucoside from the root of Rehmannia glutinosa, is reported to manifest anti-inflammatory, antioxidant, antiapoptotic and antifibrotic properties. Hence, we studied the possible nephroprotective effects of CAT and its mechanisms in an adenine-induced (0.2% w/w in feed for 4 weeks) murine model of CKD by administering 5 mg/kg CAT to BALB/c mice for the duration of 4 weeks except during weekends. Upon sacrifice, the kidney, plasma and urine were collected and various physiological, biochemical and histological endpoints were assessed. CAT significantly ameliorated the adenine-induced altered body and kidney weight, water intake, urine volume, and concentrations of urea and creatinine in plasma, as well as the creatinine clearance and the albumin and creatinine ratio. Moreover, CAT significantly ameliorated the effect of adenine-induced kidney injury by reducing the kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, cystatin C and adiponectin. Similarly, the augmented concentrations of markers of inflammation and oxidative stress in the adenine-treated group were markedly reduced with CAT pretreatment. Furthermore, CAT prevented adenine-induced deoxyribonucleic acid damage and apoptotic activity in the kidneys. Histologically, CAT significantly reduced the formation of tubular necrosis and dilation, as well as interstitial fibrosis in the kidney. In addition to that, CAT significantly decreased the adenine-induced increase in the phosphorylated NF-κB and reversed the reduced expression of sirtuin-1 in the kidney. In conclusion, CAT exhibits salutary effects against adenine-induced CKD in mice by mitigating inflammation, oxidative stress and fibrosis via mechanisms involving sirtuin-1 activation and NF-κB inhibition. Confirmatory studies are warranted in order to consider CAT as a potent nephroprotective agent against CKD.
... Thus, neuroprotectants targeting multiple pathological mechanisms are attractive as potential candidates for the treatment of TBI [26]. Catalpol, an iridoid glucoside, has been shown to reduce damage arising both from oxidative stress and the inflammatory response, two major mechanisms in the progression of TBI pathology [12,27,28]. Accordingly, in this study, we explored the neuroprotective effect of catalpol against brain damage in a rat model of TBI and investigated its underlying mechanisms of action. ...
... Genetic elimination of Nrf2 exacerbates TBI-induced secondary injury, while Nrf2 signalling activation can protect against neurological dysfunction after TBI [36]. Intriguingly, catalpol has been shown to upregulate Nrf2 and HO-1 protein expression and enhance the antioxidant activity of oxidative stress-injured primary cortical neurons [27]. In accordance with the results from the in vitro study, we found that catalpol treatment significantly induced the nuclear translocation of Nrf2 in neurons and increased the cytoplasmic expression of HO-1 in the rat brain after TBI, suggesting that activation of Nrf2 signalling may be involved in the antioxidative effect of catalpol in TBI. ...
Oxidative stress and neuroinflammation are deemed the prime causes of neurological damage after traumatic brain injury (TBI). Catalpol, an active ingredient of Rehmannia glutinosa, has been suggested to possess antioxidant and anti-inflammatory properties. This study was designed to investigate the protective effects of catalpol against TBI and the underlying mechanisms of action of catalpol. A rat model of TBI was induced by controlled cortical impact. Catalpol (10 mg/kg) or vehicle was administered via intravenous injection 1 h post trauma and then once daily for 3 consecutive days. Following behavioural tests performed 72 h after TBI, the animals were sacrificed and pericontusional areas of the brain were collected for neuropathological experiments and analysis. Treatment with catalpol significantly ameliorated neurological impairment, blood–brain barrier disruption, cerebral oedema, and neuronal apoptosis after TBI (P < 0.05). Catalpol also attenuated TBI-induced oxidative insults, as evidenced by reduced reactive oxygen species generation; decreased malondialdehyde levels; and enhanced superoxide dismutase, catalase and glutathione peroxidase activity (P < 0.05). Catalpol promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 and the expression of its downstream antioxidant enzyme HO-1 following TBI (P < 0.05). Moreover, catalpol treatment markedly inhibited posttraumatic microglial activation and neutrophil infiltration, suppressed NLRP3 inflammasome activation and reduced the production of the proinflammatory cytokine IL-1β (P < 0.05). Taken together, these findings reveal that catalpol provides neuroprotection against oxidative stress and neuroinflammation after TBI in rats. Therefore, catalpol may be a novel treatment strategy for TBI patients.
... Regarding the biological activities [18][19][20][21][22][23], the alcoholic extracts of Plantaginaceae have been proven to exhibit antimicrobial [18][19][20], antiviral [21], antioxidant [23,24], and antitumor activities [24][25][26][27]. Antimicrobial behavior was manifested against: bacteria (such as Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Salmonella typhimuium); fungi (such as Candida albicans, Candida galabrata, Candida krusei [28]); as well as micromycetes (such as Alternaria alternata, Pyrenophora teres, Pyrenophora tritici-repentis [29], Fusarium solani [30], and Ustilago scitaminea [31]). ...
... Regarding the biological activities [18][19][20][21][22][23], the alcoholic extracts of Plantaginaceae have been proven to exhibit antimicrobial [18][19][20], antiviral [21], antioxidant [23,24], and antitumor activities [24][25][26][27]. Antimicrobial behavior was manifested against: bacteria (such as Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Salmonella typhimuium); fungi (such as Candida albicans, Candida galabrata, Candida krusei [28]); as well as micromycetes (such as Alternaria alternata, Pyrenophora teres, Pyrenophora tritici-repentis [29], Fusarium solani [30], and Ustilago scitaminea [31]). ...
... Antimicrobial behavior was manifested against: bacteria (such as Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Salmonella typhimuium); fungi (such as Candida albicans, Candida galabrata, Candida krusei [28]); as well as micromycetes (such as Alternaria alternata, Pyrenophora teres, Pyrenophora tritici-repentis [29], Fusarium solani [30], and Ustilago scitaminea [31]). Antioxidant activity [3,7,23] was attributed to contained secondary metabolites, mainly polyphenolics content as well as antitumor potency, proved on numerous human cancer cell lines (e.g., human gastric cancer cells, human solid tumor cell lines, human non-small-cell lung cancer, human colorectal cancer, and human renal cell carcinoma) [24][25][26][27]. Research performed on Plantain from Isparta, Turkey, by Bahadori et al. [7] reveals the existence of compounds such as verbascoside, phenylethanoid glycosides, phenolic acids (chlorogenic acid, rosmarinic acid), as well flavonoid glycosides (i.e., hesperidin, hyperoside) in the alcoholic extract, analyzed by LC-ESI-MS/MS [7]. ...
In this study, three types of extracts isolated from leaves of Plantain (Plantago lanceolata) were tested for their chemical content and biological activities. The three bioproducts are combinations of polysaccharides and polyphenols (flavonoids and iridoidic compounds), and they were tested for antioxidant, antifungal, antitumor, and prebiotic activity (particularly for polysaccharides fraction). Briefly, the iridoid-enriched fraction has revealed a pro-oxidant activity, while the flavonoid-enriched fraction had a high antioxidant potency; the polysaccharide fraction also indicated a pro-oxidant activity, explained by the co-presence of iridoid glycosides. All three bioproducts demonstrated moderate antifungal effects against Aspergillus sp., Penicillium sp., and dermatophytes, too. Studies in vitro proved inhibitory activity of the three fractions on the leukemic tumor cell line THP-1, the main mechanism being apoptosis stimulation, while the polysaccharide fraction indicated a clear prebiotic activity, in the concentration range between 1 and 1000 µg/mL, evaluated as higher than that of the reference products used, inulin and dextrose, respectively.
... Yang C. et al. suggested that catalpol could significantly downregulate the levels of proinflammatory mediators nitric oxide and cytokines (interleukin and tumor necrosis factor α) in LPS-treated BV2 microglia. In addition, catalpol significantly reduced the levels of reactive oxygen species and malondialdehyde (MDA) in primary cortical neurons stimulated by hydrogen peroxide, increased the activity of superoxide dismutase (SOD) and glutathione (GSH), reversed cell apoptosis, and restored mitochondrial membrane potential (MMP) [15]. Transcriptional data also showed that catalpol significantly reduced the expression of inflammation-related genes, such as inducible nitric oxide synthase (iNOS), cyctoxase-2 (COX-2), and Toll-like receptor 4 (TLR4). ...
... (1) Downregulation of proinflammatory mediators NO and cytokines [15] (2) Reduce the expression of genes associated with inflammation [16] (3) Inhibit the production and expression of proinflammatory cytokines induced by LPS [17] (4) Protects neuron cells from damage caused by various toxic stimuli [18] Antioxidant stress ...
... Catalpol may play a neuroprotective role by inhibiting the NF-kB signaling pathway to attenuate the microgliamediated neuroinflammatory response. It blocks oxidative damage of cortical neurons by inhibiting the p53-mediated Bcl-2/Bax/caspase-3 apoptosis pathway and regulating the Keap1/Nrf2 pathway [15]. Catalpol significantly reduced the production of NO and ROS and the activity of iNOS. ...
Alzheimer’s disease (AD) is a degenerative disease of the central nervous system characterized by memory loss and cognitive dysfunction. With the increasing aging of the population, the incidence of AD and the number of patients are also increasing year by year, causing more and more heavy burdens to the family and society. Catalpol, an iridoid glycoside compound, is one of the main active components of Rehmannia glutinosa. At present, a large number of experimental studies in vivo and in vitro have confirmed that catalpol has antioxidant, anti-inflammatory, antiapoptotic, and other neuroprotective effects, and it plays a significant role in the prevention and treatment of AD, with very small side effects and high safety. Therefore, it may be an ideal drug for the treatment of AD. Based on this, the role and mechanism of catalpol in AD will be comprehensively reviewed in the following.
... Catalpol, an iridoid glucoside, is primarily isolated from Radix rehmannia and is commonly used as a traditional Chinese medicine [203]. Previous studies have been reported that catalpol exhibits a wide range of pharmacological effects, including exhibiting anti-diabetic, anti-tumor, anti-inflammatory, and antioxidant activities. ...
... Previous studies have been reported that catalpol exhibits a wide range of pharmacological effects, including exhibiting anti-diabetic, anti-tumor, anti-inflammatory, and antioxidant activities. Growing evidence indicates that catalpol has a robust antidepressant effect that acts through its antiinflammatory and anti-oxidative properties in vitro and in vivo [203,204]. Catalpol (5, 10, or 20 mg/kg/day, i.g.) administration for 5 weeks ameliorated CMS-induced depressive-like behavior in the SPT, and its underlying mechanisms might be at least partially ascribed to reducing HPA axis dysfunction, upregulating BDNF and its specific binding receptor tyrosine kinase B (TrkB), downregulating COX-2 expression, thus reducing prostaglandin E2 level in the brain [204]. It was also confirmed that catalpol at 20 mg/kg decreased the expression of NLRP3 inflammasome-associated proteins and inhibited proinflammatory microglial polarization in the HIP (IL-1β, TNF-α, and iNOS) [205]. ...
Major depressive disorder is a highly debilitating psychiatric disorder involving the dysfunction of different cell types in the brain. Microglia are the predominant resident immune cells in the brain and exhibit a critical role in depression. Recent studies have suggested that depression can be regarded as a microglial disease. Microglia regulate inflammation, synaptic plasticity, and the formation of neural networks, all of which affect depression. In this review, we highlighted the role of microglia in the pathology of depression. First, we described microglial activation in animal models and clinically depressed patients. Second, we emphasized the possible mechanisms by which microglia recognize depression-associated stress and regulate conditions. Third, we described how antidepressants (clinical medicines and natural products) affect microglial activation. Thus, this review aimed to objectively analyze the role of microglia in depression and focus on potential antidepressants. These data suggested that regulation of microglial actions might be a novel therapeutic strategy to counteract the adverse effects of devastating mental disorders.
... In order to reveal the scientific connotation of the antidepressant effects of Rehmanniae Radix, researchers including us [12][13][14] have confirmed that the coarse powder, water extract, steamed roots, and 80% ethanol extract of Rehmanniae Radix have antidepressant-like effects, and catalpol could be served as its key anti-depressant chemical component [15]. Catalpol is one of the major iridoid glycoside compound richly contained in Rehmanniae Radix, and it has multiple nutrients and biological activities including neuroprotection [16], anti-cerebral ischemia [17], anti-Parkinson's disease [18], anti-Alzheimer's disease [19], anti-oxidation [17], anti-inflammation [20], anti-diabetes [21], anti-diabetic complications [21], anti-cardiovascular disease [22], anti-cancer [23], liver protection [24], and ovarian protection [25]. In particular, our recent studies [26][27][28] have shown that the antidepressant-like mechanism of catalpol on chronic unpredictable mild stress (CUMS)induced, streptozotocin (STZ)-induced, and corticosterone (CORT)-induced animal models may all involve heme oxygenase (HO)-1, but the exact antidepressant targets of catalpol are still unclear. ...
Catalpol is an iridoid glycoside with rich content, rich nutrition, and numerous biological activities in Rehmanniae Radix contained in classic antidepressant prescriptions in Chinese clinical medicine. Catalpol has been confirmed previously its exact antidepressant-like effect involved heme oxygenase (HO)-1, but its antidepressant molecular targets and mechanism are still unclear. Here, catalpol's antidepressant-like molecular target was diagnosed and confirmed by ZnPP intervention [the antagonist of HO-1, (10 μg/rat), intracerebroventricular] for the first time, and its molecule mechanism network was determined through HO-1 related pathway and molecules in the hippocampus. Results showed that ZnPP significantly abolished catalpol’s (10 mg/kg) reversal on depressive-like behaviors of chronic unpredictable mild stress rats, abolished catalpol’s up-regulation on the phosphorylation level of extracellular regulated protein kinases (ERK)1/2 and brain-derived neurotrophic factor (BDNF)’s receptor tropomyosin-related kinase B (TrkB), the nuclear expression level of nuclear factor E 2-related factor 2 (Nrf2), the levels of anti-oxidant factors (such as HO-1, SOD, GPX, GST, GSH) and BDNF, and abolished catalpol’s down-regulation on the levels of peroxide and neuroinflammation factors [cyclooxygenase-2 (COX-2), induced nitrogen monoxide synthase (iNOS), nitric oxide (NO)]. Thus, HO-1 could serve as an important potential molecular target for catalpol's antidepressant-like process, and the antidepressant-like mechanism of catalpol could at least involve the activation of HO-1 triggering the up-regulation of the ERK1/2/Nrf2/HO-1 pathway-related factors to enhance the anti-oxidant defense, triggering the down-regulation of the COX-2/iNOS/NO pathway-related factors to inhibit neuroinflammation, and triggering the up-regulation of the BDNF/TrkB pathway to enhance neurotrophy.
... P53 signaling pathway is known for its mediation of anti-oxidative, anti-inf lammatory, and anti-apoptotic effects. 9,10 Under normal conditions, P53 keeps in a low level, while it is activated after receiving injury signal. 11 MDM2 is a P53-binding protein, negatively regulating P53 activity. ...
Nonylphenol (NP) is an endocrine disrupting chemical, which widely exists in environment and can result in multiple system dysfunction. Pancreas as one of the most important organs is sensitive to NP, while the detail toxic effect is still less studied. Previously, we unveiled nonylphenol causes pancreatic damage in rats, herein, we further explore the potential mechanism and seek protection strategy in vitro. Insulinoma (INS-1) cells exposed to NP were observed to suffer oxidative stress and mitochondrial dysfunction, as reflected by the abnormal levels of reactive oxygen species, malonic dialdehyde, superoxide dismutase, Ca2+, and mitochondrial membrane potential. Melatonin (MT) was found to alleviate NP-induced mitochondrial dysfunction and oxidative stress, further inhibit apoptosis and restore pancreas function. Mechanically, MT induced the MDM2-P53-P21 signaling, which upregulated the Nrf2 signaling pathway. In summary, our study clarified NP-induced INS-1 cells mitochondrial dysfunction and oxidative stress, which could be ameliorated by MT through MDM2-P53-P21 axis.
