OBJECTIVE:To compare the anti-inflammatory effects of three decoctions for coronavirus disease 2019(COVID-19)[Qingfei Paidu Tang(清肺排毒汤),QF;Huashi Baidu Fang(化湿败毒方),HS;Xuanfei Baidu Fang(宣肺败毒方),XF]in par...OBJECTIVE:To compare the anti-inflammatory effects of three decoctions for coronavirus disease 2019(COVID-19)[Qingfei Paidu Tang(清肺排毒汤),QF;Huashi Baidu Fang(化湿败毒方),HS;Xuanfei Baidu Fang(宣肺败毒方),XF]in parallelly experimental models by using severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-related toll-like receptors(TLRs)ligands and its spike(S)protein as stimulators.METHODS:RAW264.7 macrophages were used to investigate the effects of three decoctions on the inflammations induced by R848,poly(I:C),lipopolysaccharide(LPS),as well as SARS-CoV-2 S protein,in vitro.Mouse endotoxemia model was used for evaluating their anti-inflammatory actions in vivo.The levels of monocyte chemoattractant protein-1(MCP-1),interleukin-6(IL-6),tumor necrosis factorα(TNF-α),and interferon-β(IFN-β)were determined by enzyme-linked immunosorbent assay.RESULTS:Three decoctions could decrease supernatant IL-6,MCP-1,nitric oxide(NO)and TNF-αto varying degrees in activated macrophages.Meanwhile,they did not increase the level of antiviral cytokine IFN-βinduced by TLR3 and TLR4 ligands,but rather suppressed it,suggesting that externally administrated type I interferons(IFN-Is)may be needed for the severe COVID-19 cases characterized by deficient IFN-Is.In mouse endotoxemia model,all three decoctions could suppress serum pro-inflammatory cytokines,but only QF could relieve hypothermia and antagonize diarrhea.CONCLUSIONS:Collectively,our study compared,for the first time,the effects of three decoctions on SARSCoV-2-related TLRs-mediated inflammations.In vitro,three decoctions exert similar suppressive effects on inflammatory cytokines induced by SARS-CoV-2-related TLRs ligands,as well as S protein.In vivo,QF possesses the strongest effects compared with HS and XF.These findings may provide not only experimental basis for the clinical use of three decoctions,but also a rationale for the combination therapy with IFN-Is.展开更多
<b><span style="font-family:Verdana;">Background</span></b><span style="font-family:""><span style="font-family:Verdana;">: The recognition of hum...<b><span style="font-family:Verdana;">Background</span></b><span style="font-family:""><span style="font-family:Verdana;">: The recognition of human blood microbiota, consisting of cell wall-deficient microbes (L-forms), is a major challenge today in the field of microbiology. There are accumulating data confirming the concept of “internal” blood L-form microbiota and its significance for health and diseases. Finding out whether the blood microbiota can be of diagnostic and prognostic importance for detection and evaluation of chronic infections anywhere in </span><span style="font-family:Verdana;">the body is a major objective. In the context of chronically infected upper</span> <span style="font-family:Verdana;">respiratory tract (URT), the aim of the current study was to understand</span><span style="font-family:Verdana;"> wheth</span><span style="font-family:Verdana;">er a local infection can be a source for entry of bacteria and fungi in th</span><span style="font-family:Verdana;">e blood. </span><b><span style="font-family:Verdana;">Methods: </span></b><span style="font-family:Verdana;">Blood samples from six persons with chronic inflammations</span><span style="font-family:Verdana;"> in URT diagnosed with hypertrophied adenoids, chronic sinusitis, nasal polyps, chronic naso-pharyngitis and one control healthy person were studied. Blood microbiota assessment methodology that be used, included three phases: </span></span><span style="font-family:Verdana;">1</span><span style="font-family:""><span style="font-family:Verdana;">) </span><span style="font-family:Verdana;">isolation of L-form cultures from blood-development and propagation;</span></span><span style="font-family:Verdana;">2</span><span style="font-family:""><span style="font-family:Verdana;">) cultivation directed to conversion of L-forms into bacterial and fungal cul</span><span style="font-family:Verdana;">tures;</span></span><span style="font-family:Verdana;">3</span><span style="font-family:Verdana;">) isolation of pure classical bacterial and fungal cultures and their</span><span style="font-family:""> <span><span style="font-family:Verdana;">identification by MALDI-TOF method. </span><b><span style="font-family:Verdana;">Results:</span></b><span style="font-family:Verdana;"> From the patients were isolated </span></span><span style="font-family:Verdana;">L-forms of opportunistic bacteria (</span><i><span style="font-family:Verdana;">Streptococcus mitis</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Roseomonas mucosa</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Dermacoccus nishinomiyaensis</span></i><span><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Enterococcus faecalis</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Acinetobacter johnsonii</span></i><span style="font-family:Verdana;">, </span></span><i><span style="font-family:Verdana;">Pseudomonas putida</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Staphylococcus aureus</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Pseudomonas luteola</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Enterobacter cloacae</span></i><span style="font-family:Verdana;">) and fungi such as </span><i><span style="font-family:Verdana;">Rhodotorula mucilaginosa</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Aspergillus niger</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Aspergillus fumigatus and Mucorales.</span></i> <b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> The novel innovative methodology for assessment of blood L-form microbiota was successfully applied for detection of microbes responsible for chronic infections at URT.展开更多
Compared to fluorescence imaging,chemiluminescence imaging does not need external excitation light,and hence presents high imaging depth and signal-to-noise ratio without autofluorescence and phototoxicity,making it a...Compared to fluorescence imaging,chemiluminescence imaging does not need external excitation light,and hence presents high imaging depth and signal-to-noise ratio without autofluorescence and phototoxicity,making it a promising tool for biological detection and analysis.However,the target-specific activatable near-infrared emission chemiluminescent probes still need to be developed for the precise diagnosis of diseases.In this paper,we synthesized four direct near-infrared emission Schaap’s chemiluminophores(AINCL,AIFCL,ABTCL,and APYCL)by incorporating different electronic acceptors,respectively,and studied the effect of the acceptors on the optical properties of the chemiluminophores.To achieve the specific detection of hydrogen sulfide(H_(2)S)-related diseases,we used H_(2)S-cleavable 2,4-dinitrophenylsulfonate to cage the phenol groups in the chemiluminophores.It was demonstrated that the endogenous H_(2)S in inflammations and tumors could activate effectively the chemiluminescence with high specificity,which provided the precise location of nidus in chemiluminescence imaging and allowed us to perform surgical resection.展开更多
Erratum to:Nano Research,2024,17(7):6332-6341.https://doi.org/10.1007/s12274-024-6547-z.One of the authors’affiliations,Sino-Danish College,Sino-Danish Center for Education and Research,University of Chinese Academy ...Erratum to:Nano Research,2024,17(7):6332-6341.https://doi.org/10.1007/s12274-024-6547-z.One of the authors’affiliations,Sino-Danish College,Sino-Danish Center for Education and Research,University of Chinese Academy of Sciences,Beijing 100049,China,was unfortunately omitted.And the online version of this paper is corrected.展开更多
Microcystin-LR(MC-LR)is a highly toxic category of biotoxins that can damage eye development and retinal structure in zebrafish,while probiotics can largely benefit the function of the retina.Although they both act on...Microcystin-LR(MC-LR)is a highly toxic category of biotoxins that can damage eye development and retinal structure in zebrafish,while probiotics can largely benefit the function of the retina.Although they both act on the visual system,whether probiotics can alleviate the visual damage caused by MC-LR in fish and the underlying mechanisms remains unclear.In this study,we exposed adult zebrafish for 28 days at MC-LR concentrations of 0,2.20,and 22.00μg/L with or without the probiotic Lactobacillus rhamnosus in the diet.MC-LR exposure alone resulted in structural damage to the retina and abnormal phototropic behavior,whereas L.rhamnosus could alleviate these damages.Biochemical analyses showed thatMCLR-induced abnormalities in apoptosis of ocular cells,retinal inflammatory responses,neurotransmission,and phototransduction were restored in the L.rhamnosus treatment group,indicating L.rhamnosus alleviated MC-LR-induced defects in the visual system and dysfunctions.This study underlines the defensive role of probiotics in protecting the host from environmental pollutants,which may provide guidance for the application of probiotics in aquaculture.展开更多
The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke,which promotes neuronal death and inhibits nerve tissue regeneration.As the first i...The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke,which promotes neuronal death and inhibits nerve tissue regeneration.As the first immune cells to be activated after an ischemic stroke,microglia play an important immunomodulatory role in the progression of the condition.After an ischemic stroke,peripheral blood immune cells(mainly T cells)are recruited to the central nervous system by chemokines secreted by immune cells in the brain,where they interact with central nervous system cells(mainly microglia)to trigger a secondary neuroimmune response.This review summarizes the interactions between T cells and microglia in the immune-inflammatory processes of ischemic stroke.We found that,during ischemic stroke,T cells and microglia demonstrate a more pronounced synergistic effect.Th1,Th17,and M1 microglia can co-secrete proinflammatory factors,such as interferon-γ,tumor necrosis factor-α,and interleukin-1β,to promote neuroinflammation and exacerbate brain injury.Th2,Treg,and M2 microglia jointly secrete anti-inflammatory factors,such as interleukin-4,interleukin-10,and transforming growth factor-β,to inhibit the progression of neuroinflammation,as well as growth factors such as brain-derived neurotrophic factor to promote nerve regeneration and repair brain injury.Immune interactions between microglia and T cells influence the direction of the subsequent neuroinflammation,which in turn determines the prognosis of ischemic stroke patients.Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke.However,such studies have been relatively infrequent,and clinical experience is still insufficient.In summary,in ischemic stroke,T cell subsets and activated microglia act synergistically to regulate inflammatory progression,mainly by secreting inflammatory factors.In the future,a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells,along with the activation of M2-type microglia.These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.展开更多
Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modu...Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as ‘cell polarization.’ There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations(microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.展开更多
It has been reported that the PI3K/AKT signaling pathway plays a key role in the pathogenesis of ischemic stroke.As a result,the development of drugs targeting the PI3K/AKT signaling pathway has attracted increasing a...It has been reported that the PI3K/AKT signaling pathway plays a key role in the pathogenesis of ischemic stroke.As a result,the development of drugs targeting the PI3K/AKT signaling pathway has attracted increasing attention from researchers.This article reviews the pathological mechanisms and advancements in research related to the signaling pathways in ischemic stroke,with a focus on the PI3K/AKT signaling pathway.The key findings include the following:(1)The complex pathological mechanisms of ischemic stroke can be categorized into five major types:excitatory amino acid toxicity,Ca^(2+)overload,inflammatory response,oxidative stress,and apoptosis.(2)The PI3K/AKT-mediated signaling pathway is closely associated with the occurrence and progression of ischemic stroke,which primarily involves the NF-κB,NRF2,BCL-2,mTOR,and endothelial NOS signaling pathways.(3)Natural products,including flavonoids,quinones,alkaloids,phenylpropanoids,phenols,terpenoids,and iridoids,show great potential as candidate substances for the development of innovative anti-stroke medications.(4)Recently,novel therapeutic techniques,such as electroacupuncture and mesenchymal stem cell therapy,have demonstrated the potential to improve stroke outcomes by activating the PI3K/AKT signaling pathway,providing new possibilities for the treatment and rehabilitation of patients with ischemic stroke.Future investigations should focus on the direct regulatory mechanisms of drugs targeting the PI3K/AKT signaling pathway and their clinical translation to develop innovative treatment strategies for ischemic stroke.展开更多
Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are ne...Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.展开更多
Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxid...Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.展开更多
Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has...Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3(NLRP3). However, whether sirtuin 2-mediated pathways induce a pro-or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.展开更多
Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic ...Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.展开更多
Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition;this phenomenon is known as cerebral ischemia-reperfusion injury.Curre...Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition;this phenomenon is known as cerebral ischemia-reperfusion injury.Current studies have elucidated the neuroprotective role of the sirtuin protein family(Sirtuins)in modulating cerebral ischemia-reperfusion injury.However,the potential of utilizing it as a novel intervention target to influence the prognosis of cerebral ischemia-reperfusion injury requires additional exploration.In this review,the origin and research progress of Sirtuins are summarized,suggesting the involvement of Sirtuins in diverse mechanisms that affect cerebral ischemia-reperfusion injury,including inflammation,oxidative stress,blood-brain barrier damage,apoptosis,pyroptosis,and autophagy.The therapeutic avenues related to Sirtuins that may improve the prognosis of cerebral ischemia-reperfusion injury were also investigated by modulating Sirtuins expression and affecting representative pathways,such as nuclear factor-kappa B signaling,oxidative stress mediated by adenosine monophosphate-activated protein kinase,and the forkhead box O.This review also summarizes the potential of endogenous substances,such as RNA and hormones,drugs,dietary supplements,and emerging therapies that regulate Sirtuins expression.This review also reveals that regulating Sirtuins mitigates cerebral ischemia-reperfusion injury when combined with other risk factors.While Sirtuins show promise as a potential target for the treatment of cerebral ischemiareperfusion injury,most recent studies are based on rodent models with circadian rhythms that are distinct from those of humans,potentially influencing the efficacy of Sirtuinstargeting drug therapies.Overall,this review provides new insights into the role of Sirtuins in the pathology and treatment of cerebral ischemia-reperfusion injury.展开更多
Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand...Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.展开更多
The mechanism of cell damage during acute pancreatitis (AP) has not been fully elucidated, and there is still a lack of specific or effective treatments. Increasing evidence has implicated mitochondrial dysfunction as...The mechanism of cell damage during acute pancreatitis (AP) has not been fully elucidated, and there is still a lack of specific or effective treatments. Increasing evidence has implicated mitochondrial dysfunction as a key event in the pathophysiology of AP. Mitochondrial dysfunction is closely related to calcium (Ca^(2+)) overload, intracellular adenosine triphosphate depletion, mitochondrial permeability transition pore openings, loss of mitochondrial membrane potential, mitophagy damage and inflammatory responses. Mitochondrial dysfunction is an early triggering event in the initiation and development of AP,and this organelle damage may precede the release of inflammatory cytokines, intracellular trypsin activation and vacuole formation of pancreatic acinar cells. This review provides further insight into the role of mitochondria in both physiological and pathophysiological aspects of AP, aiming to improve our understanding of the underlying mechanism which may lead to the development of therapeutic and preventive strategies for AP.展开更多
Rheumatoid arthritis(RA)is a chronic autoimmune disease that affects approxi-mately 0.46%of the global population.Conventional therapeutics for RA,including disease-modifying antirheumatic drugs(DMARDs),nonsteroidal a...Rheumatoid arthritis(RA)is a chronic autoimmune disease that affects approxi-mately 0.46%of the global population.Conventional therapeutics for RA,including disease-modifying antirheumatic drugs(DMARDs),nonsteroidal anti-inflammatory drugs(NSAIDs),and corticosteroids,frequently result in unintended adverse effects.Dexamethasone(DEX)is a potent glucocorticoid used to treat RA due to its anti-inflammatory and immunosuppressive properties.Liposomal delivery of DEX,particu-larly when liposomes are surface-modified with targeting ligands like peptides or sialic acid,can improve drug efficacy by enhancing its distribution to inflamed joints and minimizing toxicity.This study investigates the potential of liposomal drug delivery systems to enhance the efficacy and targeting of DEX in the treatment of RA.Results from various studies demonstrate that liposomal DEX significantly inhibits arthritis progression in animal models,reduces joint inflammation and damage,and alleviates cartilage destruction compared to free DEX.The liposomal formulation also shows better hemocompatibility,fewer adverse effects on body weight and immune organ index,and a longer circulation time with higher bioavailability.The anti-inflammatory mechanism is associated with the downregulation of pro-inflammatory cytokines like tumor necrosis factor-α(TNF-α)and B-cell-activating factor(BAFF),which are key players in the pathogenesis of RA.Additionally,liposomal DEX can induce the expres-sion of anti-inflammatory cytokines like interleukin-10(IL-10),which has significant anti-inflammatory and immunoregulatory properties.The findings suggest that lipo-somal DEX represents a promising candidate for effective and safe RA therapy,with the potential to improve the management of this debilitating disease by providing targeted delivery and sustained release of the drug.展开更多
BACKGROUND: Sepsis is a life-threatening inflammatory condition in which the invading pathogen avoids the host's defense mechanisms and continuously stimulates and damages host cells. Consequently, many immune res...BACKGROUND: Sepsis is a life-threatening inflammatory condition in which the invading pathogen avoids the host's defense mechanisms and continuously stimulates and damages host cells. Consequently, many immune responses initially triggered for protection become harmful because of the failure to restore homeostasis, resulting in ongoing hyperinflammation and immunosuppression. METHODS: A literature review was conducted to address bacterial sepsis, describe advances in understanding complex immunological reactions, critically assess diagnostic approaches, and emphasize the importance of studying bacterial bottlenecks in the detection and treatment of sepsis.RESULTS: Diagnosing sepsis via a single laboratory test is not feasible;therefore, multiple key biomarkers are typically monitored, with a focus on trends rather than absolute values. The immediate interpretation of sepsis-associated clinical signs and symptoms, along with the use of specific and sensitive laboratory tests, is crucial for the survival of patients in the early stages. However, long-term mortality associated with sepsis is now recognized, and alongside the progression of this condition, there is an in vivo selection of adapted pathogens.CONCLUSION: Bacterial sepsis remains a significant cause of mortality across all ages and societies. While substantial progress has been made in understanding the immunological mechanisms underlying the inflammatory response, there is growing recognition that the ongoing host-pathogen interactions, including the emergence of adapted virulent strains, shape both the acute and long-term outcomes in sepsis. This underscores the urgent need for novel high-throughput diagnostic methods and a shift toward more pre-emptive, rather than reactive, treatment strategies in sepsis care.展开更多
Objective:To investigate the protective effects of naringin on doxorubicin(DOX)-induced liver injury.Methods:A total of 50 male rats were allocated into five groups:the control group,the DOX group,the DOX groups treat...Objective:To investigate the protective effects of naringin on doxorubicin(DOX)-induced liver injury.Methods:A total of 50 male rats were allocated into five groups:the control group,the DOX group,the DOX groups treated with 50 mg/kg and 100 mg/kg of naringin by gastric lavage for 10 days,as well as the group treated with 100 mg/kg of naringin alone.Liver and serum samples were collected for biochemical,histopathological,and molecular analyses,including liver enzyme activity,oxidative stress markers,inflammation,apoptosis-related proteins,and DNA damage indicators.Results:Naringin attenuated DOX-induced elevation in liver enzyme activity and inflammation markers while enhancing antioxidant activities.Naringin also activated the Nrf2-HO-1 signaling pathway,with the most pronounced effect in the high-dose naringin group.In addition,naringin modulated apoptotic signaling by downregulating the expression of PI3K-AKT and BAX,and upregulating Bcl-2,as well as reduced the level of 8-OHdG.Histopathological evaluation showed that DOX-induced structural liver alterations,such as cellular degeneration and necrosis,were notably attenuated by naringin treatment.Conclusions:Naringin treatment exerts protective effects against DOX-induced liver injury through its antioxidative,anti-inflammatory,and anti-apoptotic effects.展开更多
Objective Radiation-induced pulmonary fibrosis(RIPF)is a dynamic,complex and long-term process involving multiple chemokines and cytokines that lead to irreversible and severe lung tissue damage and even failure.Salid...Objective Radiation-induced pulmonary fibrosis(RIPF)is a dynamic,complex and long-term process involving multiple chemokines and cytokines that lead to irreversible and severe lung tissue damage and even failure.Salidroside,the main active component of Rhodiola rosea,exhibits distinct pharmacological actions including an anti-fibrotic effect.The purpose of this study is to investigate the therapeutic effect of salidroside(SAL)on RIPF via Nr1d2 regulation,which may affect inflammation response and epithelial mesenchymal transformation(EMT).Methods The key genes involved in RIPF development were identified by combining differentially expressed gene(DEG)analysis(mRNA microarray dataset GSE41789 downloaded from the Gene Expression Ombibus database,GEO)with Quantitative real time polymerase chain reaction(qRT-PCR)validation.Mouse type II lung epithelial cells(MLE-12)were divided into control group(control),radiation-exposure group(IR),group with postradiation exposure plus SAL treatment(AIR+SAL),and group with pre/post-radiation exposure plus SAL treatment(ABIR+SAL).The MLE-12 cells in the IR,AIR+SAL,and ABIR+SAL groups were irradiated with a single dose of 6 Gy X-rays,and the latter two groups were treated with SAL at three concentrations(5,10,and 20μg/mL)for 24 h.A total of 48 C57BL/6J mice were randomly allocated into control group(control),radiation-exposure group(IR),group with post-radiation exposure plus SAL treatment(AIR+SAL),and group with pre/post-radiation exposure plus SAL treatment(ABIR+SAL).The mice in the IR,AIR+SAL,and ABIR+SAL groups were irradiated with a single thorax dose of 17 Gy X-rays.At 24 h after irradiation,the mice in the AIR+SAL group were intraperitoneally injected with SAL(10,20,and 40 mg/kg)for 21 days.The mice in the ABIR+SAL group were intraperitoneally injected with SAL(10,20,and 40 mg/kg)for 10 days before thorax irradiation and for 11 days after thorax irradiation.Results The mice in the IR group incurred lung injuries including haemorrhage,oedema,inflammatory cell infiltration,increased release of proinflammatory cytokines,and pulmonary fibrosis.SAL treatment evidently alleviated radiationinduced inflammation and pulmonary fibrosis in the irradiated MLE-12 and mice.Moreover,SAL hindered the expression of Nr1d2,which influencedα-SMA and E-cadherin expression.Notably,pre-treatment with SAL in the irradiated mice exhibited a significant preventive effect on RIPF development.Conclusions Salidroside alleviated pulmonary fibrosis development through multiple mechanisms,including relieving inflammation response.Moreover,the downregulation of Nr1d2 might suppressα-SMA and promote E-cadherin,which affected EMT.展开更多
基金Supported by National Natural Science Foundation of China:Effect and Mechanisms Research of Hua-shi-Bai-Du Formula on the Cytokine Storm in COVID-19 Based on Innate and Acquired Immunity(No.82074091)Beijing Natural Science Foundation:Effects and Mechanisms research of Qing-Fei-Pai-Du-Tang on the Cytokine Storm in COVID-19 Based on TLRs Signaling(No.M21014)CAMS Innovation Fund for Medical Sciences(CIFMS)[No.2021-I2M-1-028(New Technology Research on Discovery and Evaluation of Unknown Small Molecular Effective Substances in Natural Products)and 2021-I2M-1-031(Key Technology Research on Quality Evaluation and Resource Guarantee of Rare Medicinal Plants)]。
文摘OBJECTIVE:To compare the anti-inflammatory effects of three decoctions for coronavirus disease 2019(COVID-19)[Qingfei Paidu Tang(清肺排毒汤),QF;Huashi Baidu Fang(化湿败毒方),HS;Xuanfei Baidu Fang(宣肺败毒方),XF]in parallelly experimental models by using severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-related toll-like receptors(TLRs)ligands and its spike(S)protein as stimulators.METHODS:RAW264.7 macrophages were used to investigate the effects of three decoctions on the inflammations induced by R848,poly(I:C),lipopolysaccharide(LPS),as well as SARS-CoV-2 S protein,in vitro.Mouse endotoxemia model was used for evaluating their anti-inflammatory actions in vivo.The levels of monocyte chemoattractant protein-1(MCP-1),interleukin-6(IL-6),tumor necrosis factorα(TNF-α),and interferon-β(IFN-β)were determined by enzyme-linked immunosorbent assay.RESULTS:Three decoctions could decrease supernatant IL-6,MCP-1,nitric oxide(NO)and TNF-αto varying degrees in activated macrophages.Meanwhile,they did not increase the level of antiviral cytokine IFN-βinduced by TLR3 and TLR4 ligands,but rather suppressed it,suggesting that externally administrated type I interferons(IFN-Is)may be needed for the severe COVID-19 cases characterized by deficient IFN-Is.In mouse endotoxemia model,all three decoctions could suppress serum pro-inflammatory cytokines,but only QF could relieve hypothermia and antagonize diarrhea.CONCLUSIONS:Collectively,our study compared,for the first time,the effects of three decoctions on SARSCoV-2-related TLRs-mediated inflammations.In vitro,three decoctions exert similar suppressive effects on inflammatory cytokines induced by SARS-CoV-2-related TLRs ligands,as well as S protein.In vivo,QF possesses the strongest effects compared with HS and XF.These findings may provide not only experimental basis for the clinical use of three decoctions,but also a rationale for the combination therapy with IFN-Is.
文摘<b><span style="font-family:Verdana;">Background</span></b><span style="font-family:""><span style="font-family:Verdana;">: The recognition of human blood microbiota, consisting of cell wall-deficient microbes (L-forms), is a major challenge today in the field of microbiology. There are accumulating data confirming the concept of “internal” blood L-form microbiota and its significance for health and diseases. Finding out whether the blood microbiota can be of diagnostic and prognostic importance for detection and evaluation of chronic infections anywhere in </span><span style="font-family:Verdana;">the body is a major objective. In the context of chronically infected upper</span> <span style="font-family:Verdana;">respiratory tract (URT), the aim of the current study was to understand</span><span style="font-family:Verdana;"> wheth</span><span style="font-family:Verdana;">er a local infection can be a source for entry of bacteria and fungi in th</span><span style="font-family:Verdana;">e blood. </span><b><span style="font-family:Verdana;">Methods: </span></b><span style="font-family:Verdana;">Blood samples from six persons with chronic inflammations</span><span style="font-family:Verdana;"> in URT diagnosed with hypertrophied adenoids, chronic sinusitis, nasal polyps, chronic naso-pharyngitis and one control healthy person were studied. Blood microbiota assessment methodology that be used, included three phases: </span></span><span style="font-family:Verdana;">1</span><span style="font-family:""><span style="font-family:Verdana;">) </span><span style="font-family:Verdana;">isolation of L-form cultures from blood-development and propagation;</span></span><span style="font-family:Verdana;">2</span><span style="font-family:""><span style="font-family:Verdana;">) cultivation directed to conversion of L-forms into bacterial and fungal cul</span><span style="font-family:Verdana;">tures;</span></span><span style="font-family:Verdana;">3</span><span style="font-family:Verdana;">) isolation of pure classical bacterial and fungal cultures and their</span><span style="font-family:""> <span><span style="font-family:Verdana;">identification by MALDI-TOF method. </span><b><span style="font-family:Verdana;">Results:</span></b><span style="font-family:Verdana;"> From the patients were isolated </span></span><span style="font-family:Verdana;">L-forms of opportunistic bacteria (</span><i><span style="font-family:Verdana;">Streptococcus mitis</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Roseomonas mucosa</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Dermacoccus nishinomiyaensis</span></i><span><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Enterococcus faecalis</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Acinetobacter johnsonii</span></i><span style="font-family:Verdana;">, </span></span><i><span style="font-family:Verdana;">Pseudomonas putida</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Staphylococcus aureus</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Pseudomonas luteola</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Enterobacter cloacae</span></i><span style="font-family:Verdana;">) and fungi such as </span><i><span style="font-family:Verdana;">Rhodotorula mucilaginosa</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Aspergillus niger</span></i><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Aspergillus fumigatus and Mucorales.</span></i> <b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> The novel innovative methodology for assessment of blood L-form microbiota was successfully applied for detection of microbes responsible for chronic infections at URT.
基金supported by the National Natural Science Foundation of China(Nos.52173129,52373140,and 52103157)the China Postdoctoral Science Foundation(No.2023T160301).
文摘Compared to fluorescence imaging,chemiluminescence imaging does not need external excitation light,and hence presents high imaging depth and signal-to-noise ratio without autofluorescence and phototoxicity,making it a promising tool for biological detection and analysis.However,the target-specific activatable near-infrared emission chemiluminescent probes still need to be developed for the precise diagnosis of diseases.In this paper,we synthesized four direct near-infrared emission Schaap’s chemiluminophores(AINCL,AIFCL,ABTCL,and APYCL)by incorporating different electronic acceptors,respectively,and studied the effect of the acceptors on the optical properties of the chemiluminophores.To achieve the specific detection of hydrogen sulfide(H_(2)S)-related diseases,we used H_(2)S-cleavable 2,4-dinitrophenylsulfonate to cage the phenol groups in the chemiluminophores.It was demonstrated that the endogenous H_(2)S in inflammations and tumors could activate effectively the chemiluminescence with high specificity,which provided the precise location of nidus in chemiluminescence imaging and allowed us to perform surgical resection.
文摘Erratum to:Nano Research,2024,17(7):6332-6341.https://doi.org/10.1007/s12274-024-6547-z.One of the authors’affiliations,Sino-Danish College,Sino-Danish Center for Education and Research,University of Chinese Academy of Sciences,Beijing 100049,China,was unfortunately omitted.And the online version of this paper is corrected.
基金supported by the National Key Research and Development Program of China(No.2023YFD2400900)the National Natural Science Foundation of China(Nos.32171619 and 32201388)+2 种基金the Youth project of the Natural Science Foundation of Hubei Province(No.2021CFB243)Hubei Province Excellent Young and Middle aged Science and Technology Innovation Team Project(No.T2022028)the Youth Talent Project of Science and Technology Research Program of Hubei Provincial Department of Education(No.Q20212503)。
文摘Microcystin-LR(MC-LR)is a highly toxic category of biotoxins that can damage eye development and retinal structure in zebrafish,while probiotics can largely benefit the function of the retina.Although they both act on the visual system,whether probiotics can alleviate the visual damage caused by MC-LR in fish and the underlying mechanisms remains unclear.In this study,we exposed adult zebrafish for 28 days at MC-LR concentrations of 0,2.20,and 22.00μg/L with or without the probiotic Lactobacillus rhamnosus in the diet.MC-LR exposure alone resulted in structural damage to the retina and abnormal phototropic behavior,whereas L.rhamnosus could alleviate these damages.Biochemical analyses showed thatMCLR-induced abnormalities in apoptosis of ocular cells,retinal inflammatory responses,neurotransmission,and phototransduction were restored in the L.rhamnosus treatment group,indicating L.rhamnosus alleviated MC-LR-induced defects in the visual system and dysfunctions.This study underlines the defensive role of probiotics in protecting the host from environmental pollutants,which may provide guidance for the application of probiotics in aquaculture.
基金supported by the National Natural Science Foundation of China,Nos.82104560(to CL),U21A20400(to QW)the Natural Science Foundation of Beijing,No.7232279(to XW)the Project of Beijing University of Chinese Medicine,No.2022-JYB-JBZR-004(to XW)。
文摘The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke,which promotes neuronal death and inhibits nerve tissue regeneration.As the first immune cells to be activated after an ischemic stroke,microglia play an important immunomodulatory role in the progression of the condition.After an ischemic stroke,peripheral blood immune cells(mainly T cells)are recruited to the central nervous system by chemokines secreted by immune cells in the brain,where they interact with central nervous system cells(mainly microglia)to trigger a secondary neuroimmune response.This review summarizes the interactions between T cells and microglia in the immune-inflammatory processes of ischemic stroke.We found that,during ischemic stroke,T cells and microglia demonstrate a more pronounced synergistic effect.Th1,Th17,and M1 microglia can co-secrete proinflammatory factors,such as interferon-γ,tumor necrosis factor-α,and interleukin-1β,to promote neuroinflammation and exacerbate brain injury.Th2,Treg,and M2 microglia jointly secrete anti-inflammatory factors,such as interleukin-4,interleukin-10,and transforming growth factor-β,to inhibit the progression of neuroinflammation,as well as growth factors such as brain-derived neurotrophic factor to promote nerve regeneration and repair brain injury.Immune interactions between microglia and T cells influence the direction of the subsequent neuroinflammation,which in turn determines the prognosis of ischemic stroke patients.Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke.However,such studies have been relatively infrequent,and clinical experience is still insufficient.In summary,in ischemic stroke,T cell subsets and activated microglia act synergistically to regulate inflammatory progression,mainly by secreting inflammatory factors.In the future,a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells,along with the activation of M2-type microglia.These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.
基金supported by the National Natural Science Foundation of China, Nos.82201474 (to GL), 82071330 (to ZT), and 92148206 (to ZT)Key Research and Discovery Program of Hubei Province, No.2021BCA109 (to ZT)。
文摘Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as ‘cell polarization.’ There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations(microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.
基金supported by the National Natural Science Foundation of China,Nos.82274313(to YD),82204746(to ML),82003982(to TL).
文摘It has been reported that the PI3K/AKT signaling pathway plays a key role in the pathogenesis of ischemic stroke.As a result,the development of drugs targeting the PI3K/AKT signaling pathway has attracted increasing attention from researchers.This article reviews the pathological mechanisms and advancements in research related to the signaling pathways in ischemic stroke,with a focus on the PI3K/AKT signaling pathway.The key findings include the following:(1)The complex pathological mechanisms of ischemic stroke can be categorized into five major types:excitatory amino acid toxicity,Ca^(2+)overload,inflammatory response,oxidative stress,and apoptosis.(2)The PI3K/AKT-mediated signaling pathway is closely associated with the occurrence and progression of ischemic stroke,which primarily involves the NF-κB,NRF2,BCL-2,mTOR,and endothelial NOS signaling pathways.(3)Natural products,including flavonoids,quinones,alkaloids,phenylpropanoids,phenols,terpenoids,and iridoids,show great potential as candidate substances for the development of innovative anti-stroke medications.(4)Recently,novel therapeutic techniques,such as electroacupuncture and mesenchymal stem cell therapy,have demonstrated the potential to improve stroke outcomes by activating the PI3K/AKT signaling pathway,providing new possibilities for the treatment and rehabilitation of patients with ischemic stroke.Future investigations should focus on the direct regulatory mechanisms of drugs targeting the PI3K/AKT signaling pathway and their clinical translation to develop innovative treatment strategies for ischemic stroke.
基金supported by the Natural Science Foundation of Fujian Province,No.2021J02035(to WX).
文摘Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
基金supported by the National Natural Science Foundation of China,No.82071442 (to LS)a grant from the Jilin Provincial Department of Finance,No.JLSWSRCZX2021-004 (to LS)。
文摘Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
基金funded by FEDER/Ministerio de Ciencia,Innovación y Universidades Agencia Estatal de Investigación/Project(PID2020-119729GB-100,REF/AEI/10.13039/501100011033)(to EP)a predoctoral fellowship from the Spanish Ministry of Universities(FPU)and Amigos de la Universidad de Navarra(to NSS)“Programa MRR Investigo 2023”(to MGB and MMD)。
文摘Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3(NLRP3). However, whether sirtuin 2-mediated pathways induce a pro-or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.
基金supported by Fondo Nacional de Desarrollo Científico y Tecnológico(FONDECYT)#1200836,#1210644,and#1240888,and Agencia Nacional de Investigación y Desarrollo(ANID)-FONDAP#15130011(to LL)FONDECYT#3230227(to MFG).
文摘Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.
文摘Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition;this phenomenon is known as cerebral ischemia-reperfusion injury.Current studies have elucidated the neuroprotective role of the sirtuin protein family(Sirtuins)in modulating cerebral ischemia-reperfusion injury.However,the potential of utilizing it as a novel intervention target to influence the prognosis of cerebral ischemia-reperfusion injury requires additional exploration.In this review,the origin and research progress of Sirtuins are summarized,suggesting the involvement of Sirtuins in diverse mechanisms that affect cerebral ischemia-reperfusion injury,including inflammation,oxidative stress,blood-brain barrier damage,apoptosis,pyroptosis,and autophagy.The therapeutic avenues related to Sirtuins that may improve the prognosis of cerebral ischemia-reperfusion injury were also investigated by modulating Sirtuins expression and affecting representative pathways,such as nuclear factor-kappa B signaling,oxidative stress mediated by adenosine monophosphate-activated protein kinase,and the forkhead box O.This review also summarizes the potential of endogenous substances,such as RNA and hormones,drugs,dietary supplements,and emerging therapies that regulate Sirtuins expression.This review also reveals that regulating Sirtuins mitigates cerebral ischemia-reperfusion injury when combined with other risk factors.While Sirtuins show promise as a potential target for the treatment of cerebral ischemiareperfusion injury,most recent studies are based on rodent models with circadian rhythms that are distinct from those of humans,potentially influencing the efficacy of Sirtuinstargeting drug therapies.Overall,this review provides new insights into the role of Sirtuins in the pathology and treatment of cerebral ischemia-reperfusion injury.
基金supported by the National Natural Science Foundation of China(Key Program),No.11932013the National Natural Science Foundation of China(General Program),No.82272255+2 种基金Armed Police Force High-Level Science and Technology Personnel ProjectThe Armed Police Force Focuses on Supporting Scientific and Technological Innovation TeamsKey Project of Tianjin Science and Technology Plan,No.20JCZDJC00570(all to XC)。
文摘Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.
基金supported by a grant from the Fund of Chengdu Medical College (CYZYB22-03)。
文摘The mechanism of cell damage during acute pancreatitis (AP) has not been fully elucidated, and there is still a lack of specific or effective treatments. Increasing evidence has implicated mitochondrial dysfunction as a key event in the pathophysiology of AP. Mitochondrial dysfunction is closely related to calcium (Ca^(2+)) overload, intracellular adenosine triphosphate depletion, mitochondrial permeability transition pore openings, loss of mitochondrial membrane potential, mitophagy damage and inflammatory responses. Mitochondrial dysfunction is an early triggering event in the initiation and development of AP,and this organelle damage may precede the release of inflammatory cytokines, intracellular trypsin activation and vacuole formation of pancreatic acinar cells. This review provides further insight into the role of mitochondria in both physiological and pathophysiological aspects of AP, aiming to improve our understanding of the underlying mechanism which may lead to the development of therapeutic and preventive strategies for AP.
文摘Rheumatoid arthritis(RA)is a chronic autoimmune disease that affects approxi-mately 0.46%of the global population.Conventional therapeutics for RA,including disease-modifying antirheumatic drugs(DMARDs),nonsteroidal anti-inflammatory drugs(NSAIDs),and corticosteroids,frequently result in unintended adverse effects.Dexamethasone(DEX)is a potent glucocorticoid used to treat RA due to its anti-inflammatory and immunosuppressive properties.Liposomal delivery of DEX,particu-larly when liposomes are surface-modified with targeting ligands like peptides or sialic acid,can improve drug efficacy by enhancing its distribution to inflamed joints and minimizing toxicity.This study investigates the potential of liposomal drug delivery systems to enhance the efficacy and targeting of DEX in the treatment of RA.Results from various studies demonstrate that liposomal DEX significantly inhibits arthritis progression in animal models,reduces joint inflammation and damage,and alleviates cartilage destruction compared to free DEX.The liposomal formulation also shows better hemocompatibility,fewer adverse effects on body weight and immune organ index,and a longer circulation time with higher bioavailability.The anti-inflammatory mechanism is associated with the downregulation of pro-inflammatory cytokines like tumor necrosis factor-α(TNF-α)and B-cell-activating factor(BAFF),which are key players in the pathogenesis of RA.Additionally,liposomal DEX can induce the expres-sion of anti-inflammatory cytokines like interleukin-10(IL-10),which has significant anti-inflammatory and immunoregulatory properties.The findings suggest that lipo-somal DEX represents a promising candidate for effective and safe RA therapy,with the potential to improve the management of this debilitating disease by providing targeted delivery and sustained release of the drug.
基金funded by the Deanship of Scientific Research (DSR) at King Abdulaziz UniversityJeddah+1 种基金Saudi Arabiaunder grant number G-150-248-1443。
文摘BACKGROUND: Sepsis is a life-threatening inflammatory condition in which the invading pathogen avoids the host's defense mechanisms and continuously stimulates and damages host cells. Consequently, many immune responses initially triggered for protection become harmful because of the failure to restore homeostasis, resulting in ongoing hyperinflammation and immunosuppression. METHODS: A literature review was conducted to address bacterial sepsis, describe advances in understanding complex immunological reactions, critically assess diagnostic approaches, and emphasize the importance of studying bacterial bottlenecks in the detection and treatment of sepsis.RESULTS: Diagnosing sepsis via a single laboratory test is not feasible;therefore, multiple key biomarkers are typically monitored, with a focus on trends rather than absolute values. The immediate interpretation of sepsis-associated clinical signs and symptoms, along with the use of specific and sensitive laboratory tests, is crucial for the survival of patients in the early stages. However, long-term mortality associated with sepsis is now recognized, and alongside the progression of this condition, there is an in vivo selection of adapted pathogens.CONCLUSION: Bacterial sepsis remains a significant cause of mortality across all ages and societies. While substantial progress has been made in understanding the immunological mechanisms underlying the inflammatory response, there is growing recognition that the ongoing host-pathogen interactions, including the emergence of adapted virulent strains, shape both the acute and long-term outcomes in sepsis. This underscores the urgent need for novel high-throughput diagnostic methods and a shift toward more pre-emptive, rather than reactive, treatment strategies in sepsis care.
基金supported by the Atatürk University Scientific Research Projects Coordinator(Project No:2020/8737)。
文摘Objective:To investigate the protective effects of naringin on doxorubicin(DOX)-induced liver injury.Methods:A total of 50 male rats were allocated into five groups:the control group,the DOX group,the DOX groups treated with 50 mg/kg and 100 mg/kg of naringin by gastric lavage for 10 days,as well as the group treated with 100 mg/kg of naringin alone.Liver and serum samples were collected for biochemical,histopathological,and molecular analyses,including liver enzyme activity,oxidative stress markers,inflammation,apoptosis-related proteins,and DNA damage indicators.Results:Naringin attenuated DOX-induced elevation in liver enzyme activity and inflammation markers while enhancing antioxidant activities.Naringin also activated the Nrf2-HO-1 signaling pathway,with the most pronounced effect in the high-dose naringin group.In addition,naringin modulated apoptotic signaling by downregulating the expression of PI3K-AKT and BAX,and upregulating Bcl-2,as well as reduced the level of 8-OHdG.Histopathological evaluation showed that DOX-induced structural liver alterations,such as cellular degeneration and necrosis,were notably attenuated by naringin treatment.Conclusions:Naringin treatment exerts protective effects against DOX-induced liver injury through its antioxidative,anti-inflammatory,and anti-apoptotic effects.
文摘Objective Radiation-induced pulmonary fibrosis(RIPF)is a dynamic,complex and long-term process involving multiple chemokines and cytokines that lead to irreversible and severe lung tissue damage and even failure.Salidroside,the main active component of Rhodiola rosea,exhibits distinct pharmacological actions including an anti-fibrotic effect.The purpose of this study is to investigate the therapeutic effect of salidroside(SAL)on RIPF via Nr1d2 regulation,which may affect inflammation response and epithelial mesenchymal transformation(EMT).Methods The key genes involved in RIPF development were identified by combining differentially expressed gene(DEG)analysis(mRNA microarray dataset GSE41789 downloaded from the Gene Expression Ombibus database,GEO)with Quantitative real time polymerase chain reaction(qRT-PCR)validation.Mouse type II lung epithelial cells(MLE-12)were divided into control group(control),radiation-exposure group(IR),group with postradiation exposure plus SAL treatment(AIR+SAL),and group with pre/post-radiation exposure plus SAL treatment(ABIR+SAL).The MLE-12 cells in the IR,AIR+SAL,and ABIR+SAL groups were irradiated with a single dose of 6 Gy X-rays,and the latter two groups were treated with SAL at three concentrations(5,10,and 20μg/mL)for 24 h.A total of 48 C57BL/6J mice were randomly allocated into control group(control),radiation-exposure group(IR),group with post-radiation exposure plus SAL treatment(AIR+SAL),and group with pre/post-radiation exposure plus SAL treatment(ABIR+SAL).The mice in the IR,AIR+SAL,and ABIR+SAL groups were irradiated with a single thorax dose of 17 Gy X-rays.At 24 h after irradiation,the mice in the AIR+SAL group were intraperitoneally injected with SAL(10,20,and 40 mg/kg)for 21 days.The mice in the ABIR+SAL group were intraperitoneally injected with SAL(10,20,and 40 mg/kg)for 10 days before thorax irradiation and for 11 days after thorax irradiation.Results The mice in the IR group incurred lung injuries including haemorrhage,oedema,inflammatory cell infiltration,increased release of proinflammatory cytokines,and pulmonary fibrosis.SAL treatment evidently alleviated radiationinduced inflammation and pulmonary fibrosis in the irradiated MLE-12 and mice.Moreover,SAL hindered the expression of Nr1d2,which influencedα-SMA and E-cadherin expression.Notably,pre-treatment with SAL in the irradiated mice exhibited a significant preventive effect on RIPF development.Conclusions Salidroside alleviated pulmonary fibrosis development through multiple mechanisms,including relieving inflammation response.Moreover,the downregulation of Nr1d2 might suppressα-SMA and promote E-cadherin,which affected EMT.
