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Biomedicine & pharmacotherapy
Masson Pub. USA, Inc.
Biomedicine & pharmacotherapy

Masson Pub. USA, Inc.

0753-3322

Biomedicine & pharmacotherapy/Journal Biomedicine & pharmacotherapySCIISTP
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    NOD1 splenic activation confers ferroptosis protection and reduces macrophage recruitment under pro-atherogenic conditions

    Victoria Fernez-GarciaSilvia Gonzalez-RamosJose Avendano-OrtizPaloma Martín-Sanz...
    1页
    查看更多>>摘要：The bioavailability and regulation of iron is essential for central biological functions in mammals. The role of this element in ferroptosis and the dysregulation of its metabolism contribute to diseases, ranging from anemia to infections, alterations in the immune system, inflammation and atherosclerosis. In this sense, monocytes and macrophages modulate iron metabolism and splenic function, while at the same time they can worsen the atherosclerotic process in pathological conditions. Since the nucleotide-binding oligomerization domain 1 (NOD1) has been linked to numerous disorders, including inflammatory and cardiovascular diseases, we investigated its role in iron homeostasis. The iron content was measured in various tissues of Apoe~-/- and Apoe~-/-Nod1~-/- mice fed a high-fat diet (HFD) for 4 weeks, under normal or reduced splenic function after ligation of the splenic artery. In the absence of NOD1 the iron levels decreased in spleen, heart and liver regardless the splenic function. This iron decrease was accompanied by an increase in the recruitment of F4/80~+-macrophages in the spleen through a CXCR2-dependent signaling, as deduced by the reduced recruitment after administration of a CXCR2 inhibitor. CXCR2 mediates monocyte/macrophage chemotaxis to areas of inflammation and accumulation of leukocytes in the atherosclerotic plaque. Moreover, in the absence of NOD1, inhibition of CXCR2 enhanced atheroma progression. NOD1 activation increased the levels of GPX4 and other iron and ferroptosis regulatory proteins in macrophages. Our findings highlight the preeminent role of NOD1 in iron homeostasis and ferroptosis. These results suggest promising avenues of investigation for the diagnosis and treatment of iron-related diseases directed by NOD1.
      原文链接:
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    Identification of difluorinated curcumin molecular targets linked to traumatic brain injury pathophysiology

    Amirhossein SahebkarThozhukat SathyapalanPaul C. GuestGeorge E. Barreto...
    1页
    查看更多>>摘要：Traumatic brain injury (TBI) affects approximately 50% of the world population at some point in their lifetime. To date, there are no effective treatments as most of the damage occurs due to secondary effects through a variety of pathophysiological pathways. The phytoceutical curcumin has been traditionally used as a natural remedy for numerous conditions including diabetes, inflammatory diseases, and neurological and neurodegenerative disorders. We have carried out a system pharmacology study to identify potential targets of a difluorinated curcumin analogue (CDF) that overlap with those involved in the pathophysiological mechanisms of TBI. This resulted in identification of 312 targets which are mostly involved in G protein-coupled receptor activity and cellular signalling. These include adrenergic, serotonergic, opioid and cannabinoid receptor families, which have been implicated in regulation of pain, inflammation, mood, learning and cognition pathways. We conclude that further studies should be performed to validate curcumin as a potential novel treatment to ameliorate the effects of TBI.
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    • NSTL

    Recent update on application of dihydromyricetin in metabolic related diseases

    Yirong WangJunmin WangHongjiao XiangPeilun Ding...
    1页
    查看更多>>摘要：As a new type of natural flavonoids, dihydromyricetin (DMY) has attracted more and more attention. It has a series of pharmacological effects, such as anti-inflammatory, anti-tumor, anti-oxidation, antibacterial and so on, and it is almost no toxicity and with excellent safety. Therefore, even if the bioavailability is poor, it is often added to daily food, beverages and even medicines. In recent years, some researchers have found that DMY can treat some diseases by anti-oxidation, anti-inflammation, promoting cell death and regulate the activity of lipid and glucose metabolism. In addition, the mechanism of DMY on these diseases was also related to the signal pathway of AMPK, PI3K/Akt, PPAR and the participation of microRNAs. This review describes the mechanism of DMY in metabolic related diseases from three aspects: metabolic diseases, liver diseases, and cancers, hoping to provide some new ideas for clinical researches.
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    Acute coronary syndromes in diabetic patients, outcome, revascularization, and antithrombotic therapy

    Elena Emilia BabesCristiana BusteaTapan BehlMohamed M. Abdel-Daim...
    1页
    查看更多>>摘要：Diabetes exacerbates the progression of atherosclerosis and is associated with increased risk of developing acute coronary syndrome (ACS). Approximatively 25-30% of patients admitted for ACS have diabetes. ACS occurs earlier in diabetics and is associated with increased mortality and a higher risk of recurrent ischemic events. An increased proinflammatory and prothrombotic state is involved in the poorer outcomes of diabetic patients. In the past decade advancement in both percutaneous coronary intervention (PCI) and coronary artery by-pass graft (CABG) techniques and more potent antiplatelet drugs like prasugrel and ticagrelor improved outcomes of diabetic patients with ACS, but this population still experiences worse outcomes compared to non-diabetic patients. While in ST elevation myocardial infarction urgent PCI is the method of choice for revascularization, in patients with non-ST elevation ACS an early invasive approach is suggested by the guidelines, but in the setting of multivessel (MV) or complex coronary artery disease (CAD) the revascularization strategy is less clear. This review describes the accumulating evidence regarding factors involved in promoting increased incidence and poor prognosis of ACS in patients with diabetes, the evolution over time of prognosis and outcomes, revascularization strategies and antithrombotic therapy studied until now.
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    Exploring the potential role of rab5 protein in endo-lysosomal impairment in Alzheimer's disease

    Tapan BehlDapinder KaurAayush SehgalSukhbir Singh...
    1页
    查看更多>>摘要：Growing evidence suggests that neuronal dysfunction in the endo-lysosomal and autophagic processes contributes to the onset and progression of neurodegenerative diseases such as Alzheimer's disease (AD). Since they are the primary cellular systems involved in the production and clearance of aggregated amyloid plaques, endo-lysosomal or autophagic equilibrium must be maintained throughout life. As a result, variations in the autophagic and endo-lysosomal torrent, as a measure of degenerative function in these sections or pathways, may have a direct impact on disease-related processes, such as A? clearance from the brain and interneuronal deposition of A? and tau aggregates, thus disrupting synaptic plasticity. The discovery of several chromosomal factors for Alzheimer's disease that are clinically linked to regulation of the endocytic pathway, including protein aggregation and removal, supports the theory that the endo-lysosomal/autophagic torrent is more susceptible to impairment, especially as people age, thus catalysing the onset of disease. Although the role of endo-lysosomal/ autophagic dysfunction in neurodegeneration has progressed in recent years, the field remains underdeveloped. Because of its possible therapeutic implications in Alzheimer's disease, further study is needed to explain the possibilities for effective autophagy regulation.
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    Rutin hydrate and extract from Castanopsis tribuloides reduces pyrexia via inhibiting microsomal prostaglandin E synthase-1

    Tarek HasanEsrat JahanKhondoker Shahin AhmedHemayet Hossain...
    1页
    查看更多>>摘要：Castanopsis tribuloides belongs to the oak species (Fagaceae) and it is commonly distributed in evergreen forests of Bangladesh, India, Myanmar, Nepal, China, and Thailand. Our present study aimed at uncovering the antipyretic potential of methanol extract of C. tribuloides bark (CTB) in the mice models. Baker's yeast pyrexia model was employed to determine the antipyretic potentials of the extract. Besides, molecular docking and dynamics simulation of CTB phenolic compounds were explored to validate the experimental results and gain insight into the possible antipyretic mechanism of action that can lead to the design and discovery of novel drugs against mPGES-1. The results revealed that CTB (400 mg/kg) significantly inhibited (P < 0.001) the elevated body temperature of mice since 0.5 h, which is more prominent than the standard. At dose 200 mg/kg, the bark extract also produced significant (P < 0.05) antipyretic activity since 2 h. HPLC-DAD analysis identified and quantified nine polyphenolic compounds from the extract, including rutin hydrate, (-) epicatechin, caffeic acid, catechin hydrate, catechol, trans-ferulic acid, p-coumaric acid, vanillic acid, and rosmarinic acid. Molecular docking study suggested probable competition of these phenolic compounds with glutathione, an essential cofactor for microsomal prostaglandin E synthase-1 (mPGES-1) activity. Additionally, RMSF, RMSD, Rg, and hydrogen bonds performed during MD simulations revealed that rutin hydrate (rich in CTB) bound to the mPGES-1 active site in a stable manner and thus inactivating mPGES-1. Therefore, it can be concluded that rutin hydrate reduces pyrexia in mice via downregulating PGE2 synthesis by inhibiting mPGES-1 activity.
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    Attenuation of isoprenaline-induced myocardial infarction by Rheum turkestanicum

    Azar HosseiniArezoo RajabianMohammad-Ali SobhanifarMohaddeseh Sadat Alavi...
    1页
    查看更多>>摘要：Background: Oxidative stress plays a major role in the pathogenesis of myocardial infarction. This study evaluated the cardioprotective effects of the hydroalcoholic extract of Rheum turkestanicum on isoprenaline-induced myocardial infarction (MI) in Wistar rats. Methods: In this study, we used liquid chromatography-mass spectrometry to determine the active compounds present in the extract. Thirty rats were divided to 5 groups (6 rats in each group). The extract was administered orally at the doses of 100 and 300 mg/kg body weight and then a subcutaneous injection of isoprenaline (85 mg/ kg) was administered on the 8th and 9th days. Serum levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and creatinine kinase (CPK) were measured using standard commercial kits. Serum activities of su-peroxide dismutase, catalase, and cardiac levels of thiol and lipid peroxidation were also determined. Hema-toxylin and eosin were used for histopathological staining. Results: Phytochemical analysis revealed the presence of 24 compounds in the hydro-ethanolic extract of R. turkestanicum. Isoprenaline increased malondialdehyde (4.002 ± 0178, P < 0.001) while decreased thiol content (101.7 ± 6.186, P < 0.001). Moreover, reduced activities of superoxide dismutase (139 ± 10.88, P < 0.001) and catalase (2.812 ± 0.215, P < 0.001), and elevated levels of LDH (1245 ± 62.28, P < 0.001), CPK (898 ± 23.06, P < 0.001) and CK-MB (697 ± 50.22, P < 0.001) were observed. Pretreatment with the R. turkestanicum extract significantly reduced cardiac markers and increased thiol content as well as the activity of antioxidant enzymes. The extract attenuated the histopathological changes induced by isoprenaline. Conclusion: According to the obtained results, R. turkestanicum may be an appropriate candidate to reduce isoprenaline-induced MI through modulation of oxidative stress. Administration of the extract attenuated cardiac enzymes following isoprenaline administration. The cardioprotective action of the extract can be attributed to the bioactive antioxidant ingredients of R. turkestanicum. To identify the precise mechanisms, further investigations are required.
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    The α7 nAChR allosteric modulator PNU-120596 amends neuroinflammatory and motor consequences of parkinsonism in rats: Role of JAK2/NF-κB/GSk3β/ TNF-α pathway

    Mennatallah A. GowayedNorhan S. El-SayedNoura A. MatarElham A. Afify...
    1页
    查看更多>>摘要：Parkinson's disease (PD) is the second most common neurodegenerative disorder and a leading cause of disability. The current gold standard for PD treatment, L-Dopa, has limited clinical efficacy and multiple side effects. Evidence suggests that activation of α7 nicotinic acetylcholine receptors (α7nAChRs) abrogates neuronal and inflammatory insults. Here we tested whether PNU-120596 (PNU), a type II positive allosteric modulator of α7 nAChR, has a critical role in regulating motor dysfunction and neuroinflammation correlated with the associated PD dysfunction. Neuroprotective mechanisms were investigated through neurobehavioral, molecular, histopathological, and immunohistochemical studies. PNU reversed motor incoordination and hypokinesia induced via the intrastriatal injection of 6-hydroxydopamine and manifested by lower falling latency in the rotarod test, short ambulation time and low rearing incidence in open field test. Tyrosine hydroxylase immu-nostaining showed a significant restoration of dopaminergic neurons following PNU treatment, in addition to histopathological restoration in nigrostriatal tissues. PNU halted striatal neuroinflammation manifested as a suppressed expression of JAK2/NF-κB/GSk3β accompanied by a parallel decline in the protein expression of TNF-oc in nigrostriatal tissue denoting the modulator anti-inflammatory capacity. Moreover, the protective effects of PNU were partially reversed by the α7 nAChR antagonist, methyllycaconitine, indicating the role of α7 nAChR modulation in the mechanism of action of PNU. This is the first study to reveal the positive effects of PNU-120596 on motor derangements of PD via JAK2/NF-κB/GSk3β/ TNF-α neuroinflammatory pathways, which could offer a potential therapeutic strategy for PD.
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    Astaxanthin, a carotenoid antioxidant, pretreatment alleviates cognitive deficits in aircraft noised mice by attenuating inflammatory and oxidative damage to the gut, heart and hippocampus

    Xiaojing LinHongjian BoJia GuXueqing Yi...
    1页
    查看更多>>摘要：Background: We first explore whether aircraft noise (AN) induces cognitive deficit via inducing oxidative damage in multiple vital organs including intestines, hearts and hippocampus tissues. Second, we explore whether the AN-induced cognitive deficits and inflammatory and oxidative damage to multiple organs can be alleviated by Astaxanthin (AX) pretreatment. Methods: Cognitive deficits were induced by subjecting the mice to AN 2 h daily for 7 consecutive days. An intragastrical dose of AX emulsifier (at the dose of daily feed intake [6 g] of a mouse three times weekly) was given to mice for consecutive 8 weeks prior to the start of AN. Cognitive functions were evaluated by using passive avoidance apparatus, Y-maze, Morris water maze and novel recognition test. Intestinal permeability was determined by measuring the intestinal clearance of fluorescein-isothiocyante. Evans Blue extravasation assay was used to measure the permeability of blood-brain-barrier. Inflammatory and oxidative damage to multiple organs were determined by measuring several pro-inflammatory cytokines and oxidative stress indicators in intestines; hearts and hippocampus. Results: Mice treated with AN displayed exacerbated stress reactions, cognitive deficits, gut barrier hyper-permeability, increased upload of lipopolysaccharide translocation, systemic pro-inflammatory cytokines overproduction, blood-brain-barrier hyperpermeability, hippocampal neuroinflammation and increased levels of oxidative stress indicators in intestine, heart and hippocampus. All of the above-mentioned disorders caused by AN were significantly (P < 0.05) reversed by AX. Conclusions: Our data indicate that AX pretreatment alleviates cognitive deficits in aircraft noised mice by attenuating inflammatory and oxidative damage to intestines, hearts and hippocampal tissues.
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    The dual gastro- and neuroprotective effects of curcumin loaded chitosan nanoparticles against cold restraint stress in rats

    Kholoud A. AliMona M. El-NaaAlaa F. BakrMohamed Y. Mahmoud...
    1页
    查看更多>>摘要：Stress is a condition affecting different body systems. Curcumin (CUR) is a natural compound that has various pharmacological benefits. However, its poor oral bioavailability limits its therapeutic value. This study aimed to formulating curcumin loaded chitosan nanoparticles (CS.CUR.NPs) and investigate its gastroprotective and neuroprotective effects in rats subjected to cold restraint stress (CRS), in reference to conventional oral CUR preparation, and explore its underlying mechanism. Treated groups received either CUR or CS.CUR.NPs (100 mg/kg) orally for 14 days before exposure to CRS. CRS elicited marked behavioral changes and gastric ulcer accompanied by histopathological abnormalities of the brain and stomach along with elevation of pain score. CUR and CS.CUR.NPs improved stress-induced gastric ulcer, cognitive performance, and pain sensation. Mechanistically, CRS disrupts oxidative and inflammatory status of the brain as manifested by high malondialdehyde and IL-6 and low total antioxidant capacity and IL-10, along with high C-reactive protein level. CRS decreased nuclear factor erythroid 2-related factor2 (Nrf2) and increased nuclear factor-kappa B (NF-κB) expressions. Furthermore, brain levels of unphosphorylated signal transducer and activator of transcription3 (U-STAT3) and glial fibrillary acidic protein (GFAP) were upregulated with stress. CUR and CS.CUR.NPs provided beneficial effects against harmful consequences resulting from stress with superior beneficial effects reported with CS.CUR. NPs. In conclusion, these findings shed light on the neuroprotective effect of CUR and CS.CUR.NPs against stress-induced neurobehavioral and neurochemical deficits and protection against stress-associated gastric ulcer. Moreover, we explored a potential crosslink between neuroinflammation, U-STAT3, NF-κB, and GFAP in brain dysfunction resulted from CRS.
      原文链接:
    • NSTL