Dear Editor,Idiopathic orbital inflammation(IOI),also known as orbital inflammatory pseudotumor,is a relatively common orbital disorder[1].Its pathogenesis remains unclear,often regarded as a nonspecific immune-mediat...Dear Editor,Idiopathic orbital inflammation(IOI),also known as orbital inflammatory pseudotumor,is a relatively common orbital disorder[1].Its pathogenesis remains unclear,often regarded as a nonspecific immune-mediated response[2].IOI presents with symptoms such as pain,photophobia,proptosis,eyelid swelling,edema,conjunctival congestion,and diplopia,with possible vision loss occurring in some cases.Based on the soft tissue structures involved,IOI can be classified into subtypes such as myositis,optic neuritis,dacryoadenitis,diffuse orbital inflammation,and orbital inflammatory masses[2].展开更多
Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response pla...Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response plays a crucial role in worsening brain injury.Neuroinflammation,a key player in the pathophysiology of stroke,has a dual role.In the acute phase of stroke,neuroinflammation exacerbates brain injury,contributing to neuronal damage and blood–brain barrier disruption.This aspect of neuroinflammation is associated with poor neurological outcomes.Conversely,in the recovery phase following stroke,neuroinflammation facilitates brain repair processes,including neurogenesis,angiogenesis,and synaptic plasticity.The transition of neuroinflammation from a harmful to a reparative role is not well understood.Therefore,this review seeks to explore the mechanisms underlying this transition,with the goal of informing the development of therapeutic interventions that are both time-and context-specific.This review aims to elucidate the complex and dual role of neuroinflammation in stroke,highlighting the main actors,biomarkers of the disease,and potential therapeutic approaches.展开更多
Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammat...Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs,which have a range of serious adverse effects.As an alternative,naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions.Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models,in the face of neuroinflammatory insults induced by lipopolysaccharide,through a systematic review and meta-analysis.A search of the preclinical literature was conducted across four databases(Pub Med,Web of Science,Scielo,and Google Scholar).Studies were selected based on inclusion and exclusion criteria,assessed for methodological quality using CAMARADES,and risk of bias using the SYRCLE tool,and data were extracted from the studies.The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis.A total of 384 potentially relevant articles were identified,of which 11 studies were included in the analysis.The methodological quality was assessed,resulting in an average score of 5.8/10,and the overall risk of bias analysis revealed a lack of methodological clarity in most studies.Furthermore,through the meta-analysis,it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines,such as tumor necrosis factor alpha,interleukin 6,interleukin 1β(n=89;SMD=–2.00;95%CI:–3.29 to–0.71),and microgliosis(n=33;SMD=–2.56;95%CI:–4.07 to–1.10).In terms of underlying mechanisms,quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties,possibly through the nuclear factor erythroid 2-related factor 2(Nrf2)/HO-1 pathways,increasing the expression of antioxidant enzymes and reducing reactive species,and modulating the caspase pathway,increasing levels of anti-apoptotic proteins and decreasing proapoptotic proteins.Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation.However,despite promising results in animal models,future directions should focus on well-designed clinical studies to assess the safety,bioavailability,and efficacy of quercetin and its derivatives in humans.Additionally,standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.展开更多
AIM:To report and analyze cases of sterile intraocular inflammation(IOI)following intravitreal faricimab injections in patients treated for neovascular age-related macular degeneration(nAMD)and diabetic macular edema(...AIM:To report and analyze cases of sterile intraocular inflammation(IOI)following intravitreal faricimab injections in patients treated for neovascular age-related macular degeneration(nAMD)and diabetic macular edema(DME).METHODS:This double-center case series included nine eyes of six patients who developed uveitis after faricimab therapy.Comprehensive clinical evaluation was performed,including slit-lamp examination,intraocular pressure(IOP)measurement,fluorescein and indocyanine green angiography(ICGA),and laboratory tests.Inflammatory responses were treated with topical or systemic corticosteroids,and patients were monitored for visual acuity and inflammatory activity.RESULTS:The incidence of IOI was 0.8%per patient(Innsbruck)and 0.23%(Czechia),with inflammation typically occurring between the third and sixth injection(mean interval:10d post-injection).Inflammator y presentations ranged from anterior uveitis to posterior segment involvement.One notable case demonstrated novel choroidal hypofluorescent lesions on angiography,suggesting deeper ocular involvement.The mean patient age was 76y;five of six affected patients were female.All cases responded to local and systemic corticosteroids,with full recovery of initial visual acuity.CONCLUSION:Sterile IOI after faricimab appears to be a rare but relevant adverse event.Although the incidence falls within expected ranges for anti-vascular endothelial growth factor(anti-VEGF)agents,the observed choroidal involvement represents a potentially new safety signal.Prompt diagnosis and corticosteroid therapy are effective in all cases.Our findings support the need for vigilant post-marketing surveillance and further studies to better understand the underlying mechanisms and risk factors of faricimab-associated inflammation.展开更多
Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,par...Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,particularly palmitic acid,are potent inducers of chronic low-grade inflammation,largely due to disruptions in glucose metabolism and the onset of insulin resistance(Qiu et al.,2022).While many organs are affected,the brain,specifically the hypothalamus,is among the first to exhibit inflammation in response to an unhealthy diet,suggesting that obesity may,in fact,be a brain-centered disease with neuroinflammation as a central factor(Thaler et al., 2012).展开更多
Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson'...Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).展开更多
Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated ...Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.展开更多
AIM:To define the prevalence and anatomical patterns of paranasal sinus abnormalities(PSA)in thyroid-associated ophthalmopathy(TAO)and to test the hypothesis that TAO is partially driven by contiguous orbital inflamma...AIM:To define the prevalence and anatomical patterns of paranasal sinus abnormalities(PSA)in thyroid-associated ophthalmopathy(TAO)and to test the hypothesis that TAO is partially driven by contiguous orbital inflammation rather than systemic autoimmunity or generalized orbital pressure.METHODS:Data included ophthalmic assessments and a panel of thyroid function and autoimmune biomarkers.Blinded radiological analysis of orbital computed tomography(CT)scans was performed to quantify sinus abnormalities and extraocular muscles(EOMs)involvement.Patients were categorized into two groups based on CT findings,those with no radiological evidence of sinus abnormalities(non-PSA control group)and those with identifiable PSA.Furthermore,ethmoid sinus mucosal biopsies from a subset of TAO patients and noninflammatory controls were subjected to histopathological analysis.RESULTS:Totally 121 TAO patients(mean age 42.4±12.8y,range 10-78y),male:female=42:79,were included.PSA was identified in 44.6%(n=54)of patients,with a distribution anatomically restricted to the maxillary(50.0%isolated)and ethmoid sinuses(18.5%isolated;29.6%combined).Compared to the non-PSA group(n=67),patients with PSA were significantly older(45.1±11.8 vs 40.3±13.2y;P=0.040)and were more likely to be male(55.6%vs 17.9%;P<0.001).They also had significantly higher proptosis(22.1±3.2 vs 20.7±2.9 mm;P<0.001).Medial/inferior rectus involvement was most frequent(88.4%vs 89.3%).Histopathological analysis of sinus mucosa from PSA patients provided direct evidence of pathology,revealing a dense,chronic lymphoplasmacytic infiltrate and submucosal edema,validating the radiological findings as a true inflammatory process.No significant correlation was found with systemic autoimmune markers,including thyroid-stimulating hormone(TSH)receptor antibodies(TRAb,median 4.86 vs 2.71 IU/L,P=0.104).CONCLUSION:TAO is associated with a high prevalence of PSA in a pattern consistent with the orbital anatomy.The correlation with ipsilateral muscle thickening combined with the lack of association with proptosis laterality or systemic biomarkers lend strong support to a model of contiguous inflammation over systemic autoimmunity,a hypothesis that warrants further validation through longitudinal and mechanistic studies.展开更多
Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered chitosan intragastrically to an MPTP-induced mouse...Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered chitosan intragastrically to an MPTP-induced mouse model of Parkinson's disease and found that it effectively reduced dopamine neuron injury, neurotransmitter dopamine release, and motor symptoms. These neuroprotective effects of chitosan were related to bacterial metabolites, specifically shortchain fatty acids, and chitosan administration altered intestinal microbial diversity and decreased short-chain fatty acid production in the gut. Furthermore, chitosan effectively reduced damage to the intestinal barrier and the blood–brain barrier. Finally, we demonstrated that chitosan improved intestinal barrier function and alleviated inflammation in both the peripheral nervous system and the central nervous system by reducing acetate levels. Based on these findings, we suggest a molecular mechanism by which chitosan decreases inflammation through reducing acetate levels and repairing the intestinal and blood–brain barriers, thereby alleviating symptoms of Parkinson's disease.展开更多
The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evi...The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evidence highlights that these diseases share similar pathophysiological features,including insulin resistance and chronic inflammation,which contribute to their rapid progression(Chen et al.,2022).Insulin resistance,a hallmark of T2DM,has been suggested to exacerbate neurodegeneration in AD.Similarly,chronic low-grade inflammation in T2DM parallels with neuroinflammation,which is observed in AD,suggesting overlapping pathophysiological mechanisms in T2DM and AD.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
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
Objective Safranal is a natural product from saffron(Crocus sativus L.)with anti-inflammatory and nephroprotective potential.This study aimed to explore the role of safranal in a cationic bovine serum albumin(C-BSA)-i...Objective Safranal is a natural product from saffron(Crocus sativus L.)with anti-inflammatory and nephroprotective potential.This study aimed to explore the role of safranal in a cationic bovine serum albumin(C-BSA)-induced rat model of membranous glomerulonephritis(MGN).Methods After model establishment,Sprague–Dawley rats were administered 100 or 200 mg/kg safranal by gavage.A biochemical analyser was used to measure the urine protein levels and serum levels of renal function parameters.Hematoxylin–eosin and immunofluorescence staining of kidney tissues were performed to examine histopathological changes and assess the expression of IgG,C3,and Sirt1.Western blotting was performed to measure the protein levels of podocin,nephrin,Sirt1,and factors involved in the NF-κB/p65 pathway.Inflammatory cytokine levels in renal homogenates were determined by ELISA.Results Safranal at 100 or 200 mg/kg reduced kidney weight(2.07±0.15 g and 2.05±0.15 g)and the kidney somatic index(0.83±0.08%and 0.81±0.08%)in MGN rats compared with those in the model group without drug administration(2.62±0.17 g and 1.05±0.1%).C-BSA increased the urine protein level to 117.68±10.52 mg/day(compared with the sham group,5.03±0.45 mg/day),caused dysregulation of renal function indicators,and induced glomerular expansion and inflammatory cell infiltration in the rat kidney samples.All the biochemical and histological changes were improved by safranal administration.Safranal at two doses also increased the fluorescence intensities of IgG(0.1±0.009 and 0.088±0.008)and C3(0.065±0.006 and 0.048±0.004)compared with those in the MGN group(0.15±0.013 and 0.086±0.008).Additionally,safranal reversed the downregulation of podocin,nephrin,and Wilms tumor protein-1(WT1)levels and reversed the high inflammatory cytokine levels in MGN rats.Mechanistically,safranal activated Sirt1 signalling to interfere with NF-κB signalling in the kidney tissues of MGN rats.Conclusions Safranal ameliorates renal damage,inflammation,and podocyte injury in MGN by upregulating SIRT1 and inhibiting NF-κB signalling.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
The intestinal tract,a complex organ responsible for nutrient absorption and digestion,relies heavily on a balanced gut microbiome to maintain its integrity.Disruptions to this delicate microbial ecosystem can lead to...The intestinal tract,a complex organ responsible for nutrient absorption and digestion,relies heavily on a balanced gut microbiome to maintain its integrity.Disruptions to this delicate microbial ecosystem can lead to intestinal inflammation,a hallmark of inflammatory bowel disease(IBD).While the role of the gut microbiome in IBD is increasingly recognized,the underlying mechanisms,particularly those involving endoplasmic reticulum(ER)stress,autophagy,and cell death,remain incompletely understood.ER stress,a cellular response to various stressors,can trigger inflammation and cell death.Autophagy,a cellular degradation process,can either alleviate or exacerbate ER stress-induced inflammation,depending on the specific context.The gut microbiome can influence both ER stress and autophagy pathways,further complicating the interplay between these processes.This review delves into the intricate relationship between ER stress,autophagy,and the gut microbiome in the context of intestinal inflammation.By exploring the molecular mechanisms underlying these interactions,we aim to provide a comprehensive theoretical framework for developing novel therapeutic strategies for IBD.A deeper understanding of the ER stress-autophagy axis,the gut microbial-ER stress axis,and the gut microbial-autophagy axis may pave the way for targeted interventions to restore intestinal health and mitigate the impact of IBD.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19...Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.展开更多
OBJECTIVE:To investigate the effect and mechanism of Yishen Tongluo formula(益肾通络方,YSTLF)in streptozotocin-induced diabetic kidney disease mice(DKD)mice.METHODS:Thirty Institute of Cancer Research mice(specific pa...OBJECTIVE:To investigate the effect and mechanism of Yishen Tongluo formula(益肾通络方,YSTLF)in streptozotocin-induced diabetic kidney disease mice(DKD)mice.METHODS:Thirty Institute of Cancer Research mice(specific pathogen free,SPF grade)were divided into five groups(n=6 per group):control,DKD model,DKD model with YSTLF(4.9 g/kg),DKD model with YSTLF(9.8 g/kg),and DKD model with captopril.DKD was induced through a single intraperitoneal injection of streptozotocin(150 mg/kg).Body weight,fasting blood glucose and urine C-peptide levels were measured to assess metabolic regulation by YSTLF.Renal function was evaluated using indicators of glomerular and tubular health.Liver function was assessed by measuring aspartate aminotransferase and alanine aminotransferase levels.Renal pathological changes were examined using hematoxylin/eosin staining and transmission electron microscopy.Inflammatory and apoptosis-related factors were analyzed through enzyme-linked immunosorbent assay,immunohistochemistry,and Western blot analysis.RESULTS:In DKD mice,fasting blood glucose,Cpeptide,24-hour urine protein(UP)levels,and renal damage were elevated,accompanied by increased inflammation and apoptosis.YSTLF significantly reduced 24-hour UP and C-peptide levels and improved kidney and liver function in DKD mice.YSTLF also mitigated glomerular hypertrophy,basement membrane thickening,and podocyte foot process effacement.It upregulated the expression of the podocyte marker podocalyxin.Furthermore,YSTLF alleviated inflammation and apoptosis,likely by reducing the overexpression of monocyte chemoattractant protein(MCP-1),Bax,and Caspase-3 in the kidneys of DKD mice.CONCLUSIONS:These findings suggest that YSTLF ameliorates kidney injury by modulating the expression of inflammatory cytokine MCP-1 and the Bax/Caspase-3 apoptosis pathway,providing a potential therapeutic approach for DKD.展开更多
Temporomandibular joint(TMJ)disc displacement is one of the most significant subtypes of temporomandibular joint disorders,but its etiology and mechanism are poorly understood.In this study,we elucidated the mechanism...Temporomandibular joint(TMJ)disc displacement is one of the most significant subtypes of temporomandibular joint disorders,but its etiology and mechanism are poorly understood.In this study,we elucidated the mechanisms by which destruction of inflamed collagen fibrils induces alterations in the mechanical properties and positioning of the TMJ disc.By constructing a rat model of TMJ arthritis,we observed anteriorly dislocated TMJ discs with aggravated deformity in vivo from five weeks to six months after a local injection of Freund’s complete adjuvant.By mimicking inflammatory conditions with interleukin-1 beta in vitro,we observed enhanced expression of collagen-synthesis markers in primary TMJ disc cells cultured in a conventional two-dimensional environment.In contrast,three-dimensional(3D)-cultivated disc cell sheets demonstrated the disordered assembly of inflamed collagen fibrils,inappropriate arrangement,and decreased Young’s modulus.Mechanistically,inflammation-related activation of the nuclear factor kappa-B(NF-κB)pathway occurs during the progression of TMJ arthritis.NF-κB inhibition reduced the collagen fibril destruction in the inflamed disc cell sheets in vitro,and early NF-κB blockade alleviated collagen degeneration and dislocation of the TMJ discs in vivo.Therefore,the NF-κB pathway participates in the collagen remodeling in inflamed TMJ discs,offering a potential therapeutic target for disc displacement.展开更多
OBJECTIVE:To evaluate the therapeutic effects of Xiahuo Pingwei San(夏藿平胃散,XHPWS)on ulcerative colitis(UC)in mice and to explore the underlying mechanisms through a network pharmacology approach.METHODS:Ultra-perf...OBJECTIVE:To evaluate the therapeutic effects of Xiahuo Pingwei San(夏藿平胃散,XHPWS)on ulcerative colitis(UC)in mice and to explore the underlying mechanisms through a network pharmacology approach.METHODS:Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF/MS)was utilized to identify the chemical composition and authenticate the active constituents of XHPWS,ensuring rigorous quality control across batches.A dextran sulfate sodium(DSS)-induced UC model was established in C57BL/6 mice,which were treated with XHPWS in vivo.The efficacy against UC was assessed by measuring parameters such as body weight,disease activity index(DAI)scores,and colon length.Levels of inflammatory cytokines,including interleukin-6(IL-6),interleukin-1β(IL-1β),and tumor necrosis factor-alpha(TNF-α),in colonic tissue were evaluated using enzymelinked immunosorbent assay(ELISA).Histological analysis of colon sections was conducted using hematoxylin and eosin staining.A network pharmacology approach was employed to explore the mechanisms of XHPWS and to predict its potential targets in UC treatment.Predicted protein expressions in colonic tissue were validated using immune-ohistochemistry(IHC)and Western blotting techniques.RESULTS:XHPWS effectively alle via ted DSS-induced UC symptoms in mice,as evidenced by restored body weight,reduced colon shortening,and decreased DAI scores.Histopathological examination revealed that XHPWS significantly reduced intestinal inflammatory infiltration,restored intestinal epithelial permeability,and increased goblet cell count.Network pharmacology analysis identified 63 active compounds in XHPWS and suggested that it might target 35 potential proteins associated with UC treatment.Functional enrichment analysis indicated that the protective mechanism of XHPWS could be related to the advanced glycation end products-receptor for advanced glycation end products(AGE-RAGE)signaling pathway.Notably,quercetin,kaempferol,wogonin,and nobiletin,the main components of XHPWS,showed strong correlations with the core targets.Additionally,experimental validation demonstrated that XHPWS significantly decreased levels of inflammatory cytokines interleukin 6(IL-6),interleukin 1 beta(IL-1β),and tumor necrosis factor alpha(TNF-α)in UC mice,while downregulating the expression of proteins related to the AGE-RAGE pathway.CONCLUSION:Our study demonstrated that XHPWS effectively alle via tes colitis symptoms and inflammation in UC mice,potentially through the regulation of the AGE-RAGE pathway.These findings provide strong evidence for the therapeutic potential of XHPWS in UC treatment,thereby broadening its clinical applications.展开更多
High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the ex...High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.展开更多
基金Supported by the National Natural Science Foundation of China(No.82388101,No.81930024)the Science and Technology Commission of Shanghai(No.22YS1400400,No.20DZ2270800).
文摘Dear Editor,Idiopathic orbital inflammation(IOI),also known as orbital inflammatory pseudotumor,is a relatively common orbital disorder[1].Its pathogenesis remains unclear,often regarded as a nonspecific immune-mediated response[2].IOI presents with symptoms such as pain,photophobia,proptosis,eyelid swelling,edema,conjunctival congestion,and diplopia,with possible vision loss occurring in some cases.Based on the soft tissue structures involved,IOI can be classified into subtypes such as myositis,optic neuritis,dacryoadenitis,diffuse orbital inflammation,and orbital inflammatory masses[2].
基金supported by European Union-NextGeneration EU under the Italian University and Research(MUR)National Innovation Ecosystem grant ECS00000041-VITALITY-CUP E13C22001060006(to MdA)。
文摘Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response plays a crucial role in worsening brain injury.Neuroinflammation,a key player in the pathophysiology of stroke,has a dual role.In the acute phase of stroke,neuroinflammation exacerbates brain injury,contributing to neuronal damage and blood–brain barrier disruption.This aspect of neuroinflammation is associated with poor neurological outcomes.Conversely,in the recovery phase following stroke,neuroinflammation facilitates brain repair processes,including neurogenesis,angiogenesis,and synaptic plasticity.The transition of neuroinflammation from a harmful to a reparative role is not well understood.Therefore,this review seeks to explore the mechanisms underlying this transition,with the goal of informing the development of therapeutic interventions that are both time-and context-specific.This review aims to elucidate the complex and dual role of neuroinflammation in stroke,highlighting the main actors,biomarkers of the disease,and potential therapeutic approaches.
基金supported by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil(CAPES)[Finance Code 001](to MGS)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico(CNPq)fellowship[research grants 309840/2022-8]。
文摘Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs,which have a range of serious adverse effects.As an alternative,naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions.Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models,in the face of neuroinflammatory insults induced by lipopolysaccharide,through a systematic review and meta-analysis.A search of the preclinical literature was conducted across four databases(Pub Med,Web of Science,Scielo,and Google Scholar).Studies were selected based on inclusion and exclusion criteria,assessed for methodological quality using CAMARADES,and risk of bias using the SYRCLE tool,and data were extracted from the studies.The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis.A total of 384 potentially relevant articles were identified,of which 11 studies were included in the analysis.The methodological quality was assessed,resulting in an average score of 5.8/10,and the overall risk of bias analysis revealed a lack of methodological clarity in most studies.Furthermore,through the meta-analysis,it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines,such as tumor necrosis factor alpha,interleukin 6,interleukin 1β(n=89;SMD=–2.00;95%CI:–3.29 to–0.71),and microgliosis(n=33;SMD=–2.56;95%CI:–4.07 to–1.10).In terms of underlying mechanisms,quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties,possibly through the nuclear factor erythroid 2-related factor 2(Nrf2)/HO-1 pathways,increasing the expression of antioxidant enzymes and reducing reactive species,and modulating the caspase pathway,increasing levels of anti-apoptotic proteins and decreasing proapoptotic proteins.Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation.However,despite promising results in animal models,future directions should focus on well-designed clinical studies to assess the safety,bioavailability,and efficacy of quercetin and its derivatives in humans.Additionally,standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.
文摘AIM:To report and analyze cases of sterile intraocular inflammation(IOI)following intravitreal faricimab injections in patients treated for neovascular age-related macular degeneration(nAMD)and diabetic macular edema(DME).METHODS:This double-center case series included nine eyes of six patients who developed uveitis after faricimab therapy.Comprehensive clinical evaluation was performed,including slit-lamp examination,intraocular pressure(IOP)measurement,fluorescein and indocyanine green angiography(ICGA),and laboratory tests.Inflammatory responses were treated with topical or systemic corticosteroids,and patients were monitored for visual acuity and inflammatory activity.RESULTS:The incidence of IOI was 0.8%per patient(Innsbruck)and 0.23%(Czechia),with inflammation typically occurring between the third and sixth injection(mean interval:10d post-injection).Inflammator y presentations ranged from anterior uveitis to posterior segment involvement.One notable case demonstrated novel choroidal hypofluorescent lesions on angiography,suggesting deeper ocular involvement.The mean patient age was 76y;five of six affected patients were female.All cases responded to local and systemic corticosteroids,with full recovery of initial visual acuity.CONCLUSION:Sterile IOI after faricimab appears to be a rare but relevant adverse event.Although the incidence falls within expected ranges for anti-vascular endothelial growth factor(anti-VEGF)agents,the observed choroidal involvement represents a potentially new safety signal.Prompt diagnosis and corticosteroid therapy are effective in all cases.Our findings support the need for vigilant post-marketing surveillance and further studies to better understand the underlying mechanisms and risk factors of faricimab-associated inflammation.
文摘Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,particularly palmitic acid,are potent inducers of chronic low-grade inflammation,largely due to disruptions in glucose metabolism and the onset of insulin resistance(Qiu et al.,2022).While many organs are affected,the brain,specifically the hypothalamus,is among the first to exhibit inflammation in response to an unhealthy diet,suggesting that obesity may,in fact,be a brain-centered disease with neuroinflammation as a central factor(Thaler et al., 2012).
基金supported by grants from the Deutsche Forschungsgemeinschaft(HU 2614/1-1(Project No.462650276))the Fritz Thyssen Foundation(10.21.1.021MN)the Medical faculty of the University of Saarland(HOMFOR2016,HOMFORexzellent2017,HOMFOR2024 Anschubfinanzierung)to WH。
文摘Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).
基金supported by FWO(Fonds voor Wetenschappelijk Onderzoek),grant number G07562NFWO(to BB)。
文摘Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.
基金Supported by The National Natural Science Foundation of China(No.82101180)the Fund for Beijing Science&Technology Development of TCM(No.BJZYYB-2023-17)the Beijing Municipal Natural Science Foundation grant(No.7252093).
文摘AIM:To define the prevalence and anatomical patterns of paranasal sinus abnormalities(PSA)in thyroid-associated ophthalmopathy(TAO)and to test the hypothesis that TAO is partially driven by contiguous orbital inflammation rather than systemic autoimmunity or generalized orbital pressure.METHODS:Data included ophthalmic assessments and a panel of thyroid function and autoimmune biomarkers.Blinded radiological analysis of orbital computed tomography(CT)scans was performed to quantify sinus abnormalities and extraocular muscles(EOMs)involvement.Patients were categorized into two groups based on CT findings,those with no radiological evidence of sinus abnormalities(non-PSA control group)and those with identifiable PSA.Furthermore,ethmoid sinus mucosal biopsies from a subset of TAO patients and noninflammatory controls were subjected to histopathological analysis.RESULTS:Totally 121 TAO patients(mean age 42.4±12.8y,range 10-78y),male:female=42:79,were included.PSA was identified in 44.6%(n=54)of patients,with a distribution anatomically restricted to the maxillary(50.0%isolated)and ethmoid sinuses(18.5%isolated;29.6%combined).Compared to the non-PSA group(n=67),patients with PSA were significantly older(45.1±11.8 vs 40.3±13.2y;P=0.040)and were more likely to be male(55.6%vs 17.9%;P<0.001).They also had significantly higher proptosis(22.1±3.2 vs 20.7±2.9 mm;P<0.001).Medial/inferior rectus involvement was most frequent(88.4%vs 89.3%).Histopathological analysis of sinus mucosa from PSA patients provided direct evidence of pathology,revealing a dense,chronic lymphoplasmacytic infiltrate and submucosal edema,validating the radiological findings as a true inflammatory process.No significant correlation was found with systemic autoimmune markers,including thyroid-stimulating hormone(TSH)receptor antibodies(TRAb,median 4.86 vs 2.71 IU/L,P=0.104).CONCLUSION:TAO is associated with a high prevalence of PSA in a pattern consistent with the orbital anatomy.The correlation with ipsilateral muscle thickening combined with the lack of association with proptosis laterality or systemic biomarkers lend strong support to a model of contiguous inflammation over systemic autoimmunity,a hypothesis that warrants further validation through longitudinal and mechanistic studies.
基金supported by the National Natural Science Foundation of China,Nos. 32260196 (to JY), 81860646 (to ZY) and 31860274 (to JY)a grant from Yunnan Department of Science and Technology,Nos. 202101AT070251 (to JY), 202201AS070084 (to ZY), 202301AY070001-239 (to JY), 202101AZ070001-012, and 2019FI016 (to ZY)。
文摘Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered chitosan intragastrically to an MPTP-induced mouse model of Parkinson's disease and found that it effectively reduced dopamine neuron injury, neurotransmitter dopamine release, and motor symptoms. These neuroprotective effects of chitosan were related to bacterial metabolites, specifically shortchain fatty acids, and chitosan administration altered intestinal microbial diversity and decreased short-chain fatty acid production in the gut. Furthermore, chitosan effectively reduced damage to the intestinal barrier and the blood–brain barrier. Finally, we demonstrated that chitosan improved intestinal barrier function and alleviated inflammation in both the peripheral nervous system and the central nervous system by reducing acetate levels. Based on these findings, we suggest a molecular mechanism by which chitosan decreases inflammation through reducing acetate levels and repairing the intestinal and blood–brain barriers, thereby alleviating symptoms of Parkinson's disease.
基金supported by grants from NIH T32(DK007260,to WC)the Steno North American Fellowship awarded by the Novo Nordisk Foundation(NNF23OC0087108,to WC).
文摘The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evidence highlights that these diseases share similar pathophysiological features,including insulin resistance and chronic inflammation,which contribute to their rapid progression(Chen et al.,2022).Insulin resistance,a hallmark of T2DM,has been suggested to exacerbate neurodegeneration in AD.Similarly,chronic low-grade inflammation in T2DM parallels with neuroinflammation,which is observed in AD,suggesting overlapping pathophysiological mechanisms in T2DM and AD.
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.
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supported by the National Natural Science Foundation of China(Nos.82474412 and 82074364)the Innovation Program of Wuhan-Basic Research in 2022(No.2022020801020506)the Natural Science Foundation of Hubei Province(No.2022CFC024).
文摘Objective Safranal is a natural product from saffron(Crocus sativus L.)with anti-inflammatory and nephroprotective potential.This study aimed to explore the role of safranal in a cationic bovine serum albumin(C-BSA)-induced rat model of membranous glomerulonephritis(MGN).Methods After model establishment,Sprague–Dawley rats were administered 100 or 200 mg/kg safranal by gavage.A biochemical analyser was used to measure the urine protein levels and serum levels of renal function parameters.Hematoxylin–eosin and immunofluorescence staining of kidney tissues were performed to examine histopathological changes and assess the expression of IgG,C3,and Sirt1.Western blotting was performed to measure the protein levels of podocin,nephrin,Sirt1,and factors involved in the NF-κB/p65 pathway.Inflammatory cytokine levels in renal homogenates were determined by ELISA.Results Safranal at 100 or 200 mg/kg reduced kidney weight(2.07±0.15 g and 2.05±0.15 g)and the kidney somatic index(0.83±0.08%and 0.81±0.08%)in MGN rats compared with those in the model group without drug administration(2.62±0.17 g and 1.05±0.1%).C-BSA increased the urine protein level to 117.68±10.52 mg/day(compared with the sham group,5.03±0.45 mg/day),caused dysregulation of renal function indicators,and induced glomerular expansion and inflammatory cell infiltration in the rat kidney samples.All the biochemical and histological changes were improved by safranal administration.Safranal at two doses also increased the fluorescence intensities of IgG(0.1±0.009 and 0.088±0.008)and C3(0.065±0.006 and 0.048±0.004)compared with those in the MGN group(0.15±0.013 and 0.086±0.008).Additionally,safranal reversed the downregulation of podocin,nephrin,and Wilms tumor protein-1(WT1)levels and reversed the high inflammatory cytokine levels in MGN rats.Mechanistically,safranal activated Sirt1 signalling to interfere with NF-κB signalling in the kidney tissues of MGN rats.Conclusions Safranal ameliorates renal damage,inflammation,and podocyte injury in MGN by upregulating SIRT1 and inhibiting NF-κB signalling.
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.
基金supported by the fund for the Project of the National Key Research and Development Program of China(2024YFD1300203)Project support was provided by the Fund opened from Key Laboratory of Fujian Universities Preventive Veterinary Medicine and Biotechnology,Longyan University(grant No.2021KF01)the Cyanine Project of Yangzhou University(2020)。
文摘The intestinal tract,a complex organ responsible for nutrient absorption and digestion,relies heavily on a balanced gut microbiome to maintain its integrity.Disruptions to this delicate microbial ecosystem can lead to intestinal inflammation,a hallmark of inflammatory bowel disease(IBD).While the role of the gut microbiome in IBD is increasingly recognized,the underlying mechanisms,particularly those involving endoplasmic reticulum(ER)stress,autophagy,and cell death,remain incompletely understood.ER stress,a cellular response to various stressors,can trigger inflammation and cell death.Autophagy,a cellular degradation process,can either alleviate or exacerbate ER stress-induced inflammation,depending on the specific context.The gut microbiome can influence both ER stress and autophagy pathways,further complicating the interplay between these processes.This review delves into the intricate relationship between ER stress,autophagy,and the gut microbiome in the context of intestinal inflammation.By exploring the molecular mechanisms underlying these interactions,we aim to provide a comprehensive theoretical framework for developing novel therapeutic strategies for IBD.A deeper understanding of the ER stress-autophagy axis,the gut microbial-ER stress axis,and the gut microbial-autophagy axis may pave the way for targeted interventions to restore intestinal health and mitigate the impact of IBD.
基金supported by GILO Foundation.This research is in part supported by Korea Drug Development Fund funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2023-00282595,Republic of Korea).
文摘Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.
基金National Key Research and Development Plan:Evidence-Based Evaluation and Therapeutic Mechanism Cooperation Study of Yishen Tongluo Formula for Preventing Diabetes Kidney Disease(Phase 3)(No.2020YFE0201800)Key Science and Technology Projects of Henan Province:Research on Innovative Drug Cooperation of Traditional Chinese Medicine Yishen Tongluo Concentrated Pills(益肾通络浓缩丸)(No.221111520300)+1 种基金Key scientific and technological projects of Henan province:Study on the Pharmacodynamic Mechanism of Yishen Tongluo Formula in Treatment of Diabetes Kidney Disease based on the Interaction Regulation of Protein Phosphorylation and Acylation Modification(No.212102310347)to WU SuhuiNational Natural Science Foundation of China:the Mechanism of Yishen Tongluo Formula Intervention in Diabetic Kidney Disease based on(Yin-Yang-1/Nuclear Factor Erythroid 2-Related Factor 2 Mediated Endothelial Podocyte Interaction Response(No.82474495)to XU Jiangyan。
文摘OBJECTIVE:To investigate the effect and mechanism of Yishen Tongluo formula(益肾通络方,YSTLF)in streptozotocin-induced diabetic kidney disease mice(DKD)mice.METHODS:Thirty Institute of Cancer Research mice(specific pathogen free,SPF grade)were divided into five groups(n=6 per group):control,DKD model,DKD model with YSTLF(4.9 g/kg),DKD model with YSTLF(9.8 g/kg),and DKD model with captopril.DKD was induced through a single intraperitoneal injection of streptozotocin(150 mg/kg).Body weight,fasting blood glucose and urine C-peptide levels were measured to assess metabolic regulation by YSTLF.Renal function was evaluated using indicators of glomerular and tubular health.Liver function was assessed by measuring aspartate aminotransferase and alanine aminotransferase levels.Renal pathological changes were examined using hematoxylin/eosin staining and transmission electron microscopy.Inflammatory and apoptosis-related factors were analyzed through enzyme-linked immunosorbent assay,immunohistochemistry,and Western blot analysis.RESULTS:In DKD mice,fasting blood glucose,Cpeptide,24-hour urine protein(UP)levels,and renal damage were elevated,accompanied by increased inflammation and apoptosis.YSTLF significantly reduced 24-hour UP and C-peptide levels and improved kidney and liver function in DKD mice.YSTLF also mitigated glomerular hypertrophy,basement membrane thickening,and podocyte foot process effacement.It upregulated the expression of the podocyte marker podocalyxin.Furthermore,YSTLF alleviated inflammation and apoptosis,likely by reducing the overexpression of monocyte chemoattractant protein(MCP-1),Bax,and Caspase-3 in the kidneys of DKD mice.CONCLUSIONS:These findings suggest that YSTLF ameliorates kidney injury by modulating the expression of inflammatory cytokine MCP-1 and the Bax/Caspase-3 apoptosis pathway,providing a potential therapeutic approach for DKD.
基金supported by the National Natural Science Foundation of China Nos.82370983,81671015(X.W.),82230030(Y.L.),82101043(S.C.)and 82370922(Y.F.)Beijing International Science and Technology Cooperation Project No.Z221100002722003(Y.L.)+4 种基金Beijing Natural Science Foundation Nos.L234017,JL23002(Y.L.),No.7242282(S.C.)and 7232217(Y.G.)Clinical Medicine Plus X-Young Scholars Project of Peking University No.PKU2024LCXQ039(Y.L.)National Program for Multidisciplinary Cooperative Treatment on Major Diseases No.PKUSSNMP-202013(X.W.)Hygiene and Health Development Scientific Research Fostering Plan of Haidian District Beijing No.HP2023-12-509001(J.Z.)Young Clinical Research Fund of the Chinese Stomatological Association No.CSA-02022-03(J.Z.).
文摘Temporomandibular joint(TMJ)disc displacement is one of the most significant subtypes of temporomandibular joint disorders,but its etiology and mechanism are poorly understood.In this study,we elucidated the mechanisms by which destruction of inflamed collagen fibrils induces alterations in the mechanical properties and positioning of the TMJ disc.By constructing a rat model of TMJ arthritis,we observed anteriorly dislocated TMJ discs with aggravated deformity in vivo from five weeks to six months after a local injection of Freund’s complete adjuvant.By mimicking inflammatory conditions with interleukin-1 beta in vitro,we observed enhanced expression of collagen-synthesis markers in primary TMJ disc cells cultured in a conventional two-dimensional environment.In contrast,three-dimensional(3D)-cultivated disc cell sheets demonstrated the disordered assembly of inflamed collagen fibrils,inappropriate arrangement,and decreased Young’s modulus.Mechanistically,inflammation-related activation of the nuclear factor kappa-B(NF-κB)pathway occurs during the progression of TMJ arthritis.NF-κB inhibition reduced the collagen fibril destruction in the inflamed disc cell sheets in vitro,and early NF-κB blockade alleviated collagen degeneration and dislocation of the TMJ discs in vivo.Therefore,the NF-κB pathway participates in the collagen remodeling in inflamed TMJ discs,offering a potential therapeutic target for disc displacement.
基金the Guangdong Provincial Basic and Applied Basic Research Project:Mechanistic Study on the Regulation of Inflammatory Microenvironment and Improvement of Ulcerative Colitis by Lingnan Traditional Medicine Ficus Pandurata Hance through Wilms'Tumor 1-associating Protein-Mediated RNA Methyltransferase Promoting Toll Like Receptor 4 m6A Modification(2023A1515011699)the Zhongshan Medical Research Project:Mechanistic Study on the Action of Xiahuo Pingwei San in the Treatment of Ulcerative Colitis(2022A020446)。
文摘OBJECTIVE:To evaluate the therapeutic effects of Xiahuo Pingwei San(夏藿平胃散,XHPWS)on ulcerative colitis(UC)in mice and to explore the underlying mechanisms through a network pharmacology approach.METHODS:Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF/MS)was utilized to identify the chemical composition and authenticate the active constituents of XHPWS,ensuring rigorous quality control across batches.A dextran sulfate sodium(DSS)-induced UC model was established in C57BL/6 mice,which were treated with XHPWS in vivo.The efficacy against UC was assessed by measuring parameters such as body weight,disease activity index(DAI)scores,and colon length.Levels of inflammatory cytokines,including interleukin-6(IL-6),interleukin-1β(IL-1β),and tumor necrosis factor-alpha(TNF-α),in colonic tissue were evaluated using enzymelinked immunosorbent assay(ELISA).Histological analysis of colon sections was conducted using hematoxylin and eosin staining.A network pharmacology approach was employed to explore the mechanisms of XHPWS and to predict its potential targets in UC treatment.Predicted protein expressions in colonic tissue were validated using immune-ohistochemistry(IHC)and Western blotting techniques.RESULTS:XHPWS effectively alle via ted DSS-induced UC symptoms in mice,as evidenced by restored body weight,reduced colon shortening,and decreased DAI scores.Histopathological examination revealed that XHPWS significantly reduced intestinal inflammatory infiltration,restored intestinal epithelial permeability,and increased goblet cell count.Network pharmacology analysis identified 63 active compounds in XHPWS and suggested that it might target 35 potential proteins associated with UC treatment.Functional enrichment analysis indicated that the protective mechanism of XHPWS could be related to the advanced glycation end products-receptor for advanced glycation end products(AGE-RAGE)signaling pathway.Notably,quercetin,kaempferol,wogonin,and nobiletin,the main components of XHPWS,showed strong correlations with the core targets.Additionally,experimental validation demonstrated that XHPWS significantly decreased levels of inflammatory cytokines interleukin 6(IL-6),interleukin 1 beta(IL-1β),and tumor necrosis factor alpha(TNF-α)in UC mice,while downregulating the expression of proteins related to the AGE-RAGE pathway.CONCLUSION:Our study demonstrated that XHPWS effectively alle via tes colitis symptoms and inflammation in UC mice,potentially through the regulation of the AGE-RAGE pathway.These findings provide strong evidence for the therapeutic potential of XHPWS in UC treatment,thereby broadening its clinical applications.
基金supported by a grant of the M.D.-Ph.D./Medical Scientist Training Program through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(to HK)+3 种基金supported by National Research Foundation of Korea(NRF)grants funded by the Korean government(MSITMinistry of Science and ICT)(NRF2019R1A5A2026045 and NRF-2021R1F1A1061819)a grant from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(HR21C1003)New Faculty Research Fund of Ajou University School of Medicine(to JYC)。
文摘High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.
