An outbreak of a novel coronavirus was reported in Wuhan,China,in late 2019.It has spread rapidly through China and many other countries,causing a global pandemic.Since February 2020,over 28 countries/regions have rep...An outbreak of a novel coronavirus was reported in Wuhan,China,in late 2019.It has spread rapidly through China and many other countries,causing a global pandemic.Since February 2020,over 28 countries/regions have reported confirmed cases.Individuals with the infection known as coronavirus disease-19(COVID-19)have similar clinical features as severe acute respiratory syndrome first encountered 17 years ago,with fever,cough,and upper airway congestion,along with high production of proinflammatory cytokines(PICs),which form a cytokine storm.PICs induced by COVID-19 include interleukin(IL)-6,IL-17,and monocyte chemoattractant protein-1.The production of cytokines is regulated by activated nuclear factor-kB and involves downstream pathways such as Janus kinase/signal transducers and activators transcription.Protein expression is also regulated by post-translational modification of chromosomal markers.Lysine residues in the peptide tails stretching out from the core of histones bind the sequence upstream of the coding portion of genomic DNA.Covalent modification,particularly methylation,activates or represses gene transcription.PICs have been reported to be induced by histone modification and stimulate exudation of hyaluronic acid,which is implicated in the occurrence of COVID-19.These findings indicate the impact of the expression of PICs on the pathogenesis and therapeutic targeting of COVID-19.展开更多
Background:Increased proinflammatory cytokines and chemokines might contribute to infiltration of inflammatory cells and remodeling in airways of asthma.Although these molecules may be associated with asthma,there is...Background:Increased proinflammatory cytokines and chemokines might contribute to infiltration of inflammatory cells and remodeling in airways of asthma.Although these molecules may be associated with asthma,there is lack of systemic evidence showing which and how important these events are in the disease.We aimed to analyze the concentrations of these molecules in the airways and relationships with disease severity and with airway infiltration of inflammatory cells in a large cohort of asthmatics (n =70,including 37 mild and 33 moderate/severe asthmatics) compared with controls (n =30).Methods:Meso scale discovery system and commercial ELISA kits were used to measure the concentrations ofproinflammatory cytokines interleukin (IL)-1 β;tumor necrosis factor-alpha (TNF-α);IL-6;and IL-17 and CC and CXC chemokines CCL2,CCL4,CCL 11,CCL 13,CCL17,CCL22,and CCL26 and CXCL8,CXCL9,CXCL10,and CXCL1 1 in bronchoalveolar lavage fluid of asthmatics and controls.Results:The concentrations ofIL-1,TNF-α,IL-6,CXCL8 and CXCL 10,and CCL4,CCL 11,CCL 17,and CCL22 were significantly elevated in asthmatics compared with controls (P 〈 0.05).The concentrations of TNF-α and CXCL8,but not others,were negatively correlated with severity of disease (lung function forced expiratory volume in 1 s) (TNF-α vs.total:r =-0.359,P =0.002 vs.moderate/severe:r =-0.541,P =0.001;CXCL8 vs.total:r =-0.327,P =0.006 vs.moderate/severe:r =-0.625,P =0.0001,respectively).In addition,concentrations of these two molecules were also correlated with the absolute numbers of infiltrating eosinophils and neutrophils in asthmatic airways.Conclusions:Increased concentrations of TNF-α and CXCL8 are associated with pathogenesis of asthma.Targeting these molecules might provide an alternative therapeutic for this disease.展开更多
Mastitis is a common disease for mammals all around the world. Figuring out why mastitis mainly occurs around parturition may be helpful for dealing with the disease. Lipolytic activity and oxidative stress take place...Mastitis is a common disease for mammals all around the world. Figuring out why mastitis mainly occurs around parturition may be helpful for dealing with the disease. Lipolytic activity and oxidative stress take place around parturition, which may leads to alteration in fatty acids profile and proinflammatory cytokine expression. Thus, the aim of the present study was to further our understanding about the high incidence of mastitis around parturition by comparison of plasma fatty acid profile and mammary inflammation indicators at different reproductive stages. A total of 47 female rats were included in the present study. After mating, all the pregnant and non-pregnant rats began to receive the same experimental diet. Blood samples were collected at day 1 and 14 of gestation as well as day 3 postpartum.Mammary samples were collected at day 14 of gestation and day 3 postpartum from pregnant and nonpregnant rats. The results showed that rats at d 3 postpartum had greater(P < 0.05) plasma concentrations of non-esterified fatty acids(NEFA), arachidonic acid(ARA) and docosahexaenoic acid(DHA) as well as ARA: eicosapentaenoic acid(EPA) ratio than those at d 14 of gestation. The mRNA abundances of interleukin-1 β(IL-1β), tumor necrosis factor-α(TNF-α),IL-8 and xanthine oxidoreductase(XOR) in mammary of the pregnant rats were greater(P < 0.05) than those in age-matched non-pregnant rats.Rats at d 3 postpartum had higher(P < 0.05) protein expression levels of IL-1β and TNF-α as well as meloperoxidase(MPO) activity and polymorphonuclear neutrophils(PMN) prevalence than those at d 1 of gestation. The rats at d 3 postpartum also had greater(P < 0.05) IL-1β and MPO activity than those at d 14 of gestation. The results indicated that elevated mammary expression of proinflammatory cytokines and XOR as well as altered fatty acid profile around parturition might facilitate the recruitment of neutrophils into mammary glands.展开更多
Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in rats.Methods:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 m...Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in rats.Methods:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 mg/kg,i.p.)for four weeks.Behavioral tests such as Morris water maze and elevated plus maze were conducted to check memory impairment caused by cladribine.On day 29,all rats were sacrificed,and the brains were separated for estimation of neuroinflammatory factors,biochemical parameters,neurotransmitters,Aβ(1-42),blood-brain barrier permeability,nuclear factor erythroid 2-related factor 2(Nrf2),and brain-derived neurotrophic factor(BDNF).Results:Treatment with cryptotanshinone dose-dependently enhanced spatial memory,improved the levels of neurotransmitter and antioxidant enzymes,and suppressed proinflammatory cytokine release.Cryptotanshinone also decreased Aβ(1-42)accumulation and increased the levels of Nrf2 and BDNF in the hippocampus.Additionally,the histopathological results showed that cryptotanshinone reduced cladribine-induced neuronal death in the hippocampus.Conclusions:Cryptotanshinone exhibits a promising neuroprotective effect against cladribine-induced cognitive impairment in preclinical studies,and may be a potential phytochemical for the treatment and management of cognitive impairment.展开更多
Objective:To determine the neuroprotective effects of apigenin against streptozotocin(STZ)-induced diabetic neuropathy(DN).Methods:To induce DN,Wistar rats(150-200 g)were administered with STZ(55 mg/kg,i.p.).Then they...Objective:To determine the neuroprotective effects of apigenin against streptozotocin(STZ)-induced diabetic neuropathy(DN).Methods:To induce DN,Wistar rats(150-200 g)were administered with STZ(55 mg/kg,i.p.).Then they were randomly assigned to various groups,viz.,normal,diabetic control,insulin(10 IU/kg,s.c.),apigenin(5,10,and 20 mg/kg,p.o.),and insulin(10 IU/kg)plus apigenin(20 mg/kg,p.o.).Various behavioral,biochemical,and molecular markers[tumor necrosis factor-alpha(TNF-α),interleukin(IL)-1β,IL-6,Toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),and nuclear factor erythroid 2-related factor 2(Nrf2)]were assessed.Results:Apigenin(10 and 20 mg/kg,p.o.)substantially reduced plasma glucose levels,lipid profile,aspartate transaminase,alanine transaminase,glycated hemoglobin,and neural advanced glycation end products in STZ-induced DN rats(P<0.05).After apigenin intervention,STZ-induced changes in food and water intake,body weight,urine output,allodynia,hyperalgesia,and insulin levels were markedly improved(P<0.05).Neural antioxidant enzymes(superoxide dismutase and glutathione)and Na+K+ATPase activity were also considerably elevated(P<0.05)while the level of lipid peroxidation was diminished following apigenin therapy(P<0.05).Furthermore,apigenin markedly upregulated the Nrf2 mRNA level while downregulating the mRNA expressions of TNF-αand ILs and the protein expressions of TLR4 and MyD88(P<0.05).STZ-induced histological abnormalities in the sciatic nerve were also improved by apigenin treatment.Conclusions:Apigenin exerts its neuroprotective effect by modulating the inflammatory and oxidative stress pathways via regulating the TLR4-MyD88 signaling pathway.展开更多
Serotonin deficiency in major depressive disorder(MDD)has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan(Trp)-degrading enzyme,liver Trp 2,3-diox...Serotonin deficiency in major depressive disorder(MDD)has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan(Trp)-degrading enzyme,liver Trp 2,3-dioxygenase(TDO),by cortisol,leading to decreased Trp availability to the brain for serotonin synthesis.Subsequently,the serotonin deficiency was proposed to involve induction of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase(IDO)by proinflammatory cytokines,with inflammation being the underlying cause.Recent evidence,however,challenges this latter concept,as not all MDD patients are immune-activated and,when present,inflammation is mild and/or transient.A wide range of antidepressant drugs inhibit the activity of liver TDO and bind specifically to the enzyme,but not to IDO.IDO induction is not a major event in MDD,but,when it occurs,its metabolic consequences may be masked and overridden by upregulation of kynurenine monooxygenase(KMO),the gateway to production of modulators of immune and neuronal functions.KMO appears to be activated in MDD by certain proinflammatory cytokines and antidepressants with anti-inflammatory properties may block this activation.We demonstrate the ability of the antidepressant ketamine to dock(bind)to KMO.The pathophysiology of MDD may be underpinned by both the serotonin deficiency and glutamatergic activation mediated respectively by TDO induction and N-methyl-D-aspartate receptor activation.Inhibition of TDO and KMO should be the focus of MDD pharmacotherapy.展开更多
Microglial cells are important resident innate immune components in the central nervous system that are often activated during neuroinflammation.Activated microglia can display one of two phenotypes,M1 or M2,which eac...Microglial cells are important resident innate immune components in the central nervous system that are often activated during neuroinflammation.Activated microglia can display one of two phenotypes,M1 or M2,which each play distinct roles in neuroinflammation.Rutin,a dietary flavonoid,exhibits protective effects against neuroinflammation.However,whether rutin is able to influence the M1/M2 polarization of microglia remains unclear.In this study,in vitro BV-2 cell models of neuroinflammation were established using 100 ng/mL lipopolysaccharide to investigate the effects of 1-hour rutin pretreatment on microglial polarization.The results revealed that rutin pretreatment reduced the expression of the proinflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6 and increased the secretion of interleukin-10.Rutin pretreatment also downregulated the expression of the M1 microglial markers CD86 and inducible nitric oxide synthase and upregulated the expression of the M2 microglial markers arginase 1 and CD206.Rutin pretreatment inhibited the expression of Toll-like receptor 4 and myeloid differentiation factor 88 and blocked the phosphorylation of I kappa B kinase and nuclear factor-kappa B.These results showed that rutin pretreatment may promote the phenotypic switch of microglia M1 to M2 by inhibiting the Toll-like receptor 4/nuclear factor-kappa B signaling pathway to alleviate lipopolysaccharide-induced neuroinflammation.展开更多
Objective: To investigate the role of toll-like receptor 2(TLR2) in inflammatory activity of macrophage infected with the recombinant Mycobacterium bovis bacillus Calmette-Guerin(rBCG). Methods: Mouse macrophage cell ...Objective: To investigate the role of toll-like receptor 2(TLR2) in inflammatory activity of macrophage infected with the recombinant Mycobacterium bovis bacillus Calmette-Guerin(rBCG). Methods: Mouse macrophage cell line J774 A.1 was infected with Mycobacterium bovis bacillus Calmette-Guerin(BCG) and rBCG cultures for 48 h in the presence or absence of 10 μg/mL of TLR2 inhibitor. Untreated macrophages were used as a negative control while lipopolysaccharide-stimulated macrophages were used as a positive control. The ability of the macrophage to engulf the BCG and rBCG in the absence or presence of TLR2 inhibitor was assessed using a phagocytic assay, while the production of inflammatory cytokines and nitric oxide by the infected macrophages was evaluated using ELISA and Griess reagent method, while the expression of the inducible nitric oxide synthase was determined using Western blot analysis. Results: The results showed that blocking TLR2 function reduced the phagocytic activity, nitric oxide production and proinflammatory cytokine secretion such as TNF-α, IL-1β and IL-12 p40 as well as inducible nitric oxide synthase expression in the infected macrophages. These data showed the importance of TLR2 in the activation of macrophages following BCG and r BCG infections. Conclusions: Through exploring the immunological mechanism which underlies the protection conferred by the candidate vaccine, this study will improve our understanding of the vaccine candidate's mechanism to protect the host from malaria infection.展开更多
<i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"></span><span style="font-family:;" "=&q...<i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"></span><span style="font-family:;" "=""><span style="font-family:Verdana;"> used as an analgesic and anti-inflammatory. It is often used not only in Mongolian medicine but also in traditional Chinese medicine. However, there are few studies on its impact of inflammatory cytokines. This study explored the effects of </span><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i> <i><span style="font-family:Verdana;">in vitro</span></i><span style="font-family:Verdana;"></span></i></span><span style="font-family:Verdana;"> used human colon cancer (Caco-2) cells. Cytotoxicity was assessed by measuring effects on expression of IL-1</span><i><span style="font-family:Verdana;"><span style="white-space:nowrap;">β</span></span></i><span style="font-family:Verdana;">, IL-6, IL-8, and TNF-</span><i><span style="font-family:Verdana;"><span style="white-space:nowrap;">α</span></span></i><span style="font-family:Verdana;"> used enzyme-linked immun</span><span style="font-family:Verdana;">o</span><span style="font-family:;" "=""><span style="font-family:Verdana;">sorbent assay (ELISA). </span><span><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">In vitro</span></i><span style="font-family:Verdana;"></span></i></span></span><span style="font-family:Verdana;"> study demonstrated that incubation of Caco-2 cells with some kinds of</span><i> </i><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"></span></i><span style="font-family:Verdana;"> at some concentrations inhibit secretion of TNF-</span><i><span style="font-family:Verdana;"><span style="white-space:nowrap;">α</span></span></i><span style="font-family:Verdana;"> and FAXIU </span><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">ACONITUM</span></i> <i><span style="font-family:Verdana;">KUSNEZOFFII</span></i><span style="font-family:Verdana;"></span></i><span style="font-family:Verdana;"> could inhibit the secretion of IL-1</span><i><span style="font-family:Verdana;"><span style="white-space:nowrap;">β</span></span></i><span style="font-family:Verdana;">. While IL-6 and IL-8 levels were unaffected after 24 h of treatment with </span><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"><i></i></span><i><span style="font-family:Verdana;">, </span></i></i><span style="font-family:Verdana;"></span><span style="font-family:Verdana;"></span><span style="font-family:Verdana;">qujian </span><i><i><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"><i></i></span><i><span style="font-family:Verdana;">, </span></i></i></i></i><span style="font-family:Verdana;"></span><span style="font-family:Verdana;"></span><span style="font-family:Verdana;"></span><span style="font-family:Verdana;">faxiu </span><i><i><i><i><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"></span></i><span style="font-family:Verdana;">.</span></i></i></i></i>展开更多
Objectives: We set out to study cardiac autonomic tone in patients with idiopathic dilated cardio-myopathy (IDC), and whether it correlates with other established markers of disease progression and patient ultimate ou...Objectives: We set out to study cardiac autonomic tone in patients with idiopathic dilated cardio-myopathy (IDC), and whether it correlates with other established markers of disease progression and patient ultimate outcome. Design: Fifty-one IDC patients in sinus rhythm underwent extensive non-invasive and invasive evaluation during a three-day hospitalization period. The control group consisted of thirty-eight apparently healthy subjects who underwent 24-hour ambulatory ECG recording. Results: Heart rate variability (HRV) and heart rate turbulence (HRT) correlated with many previously established prognostic markers of IDC and congestive heart failure, especially measures of cardiorespiratory performance capacity and circulating neurohumoral factors (p < 0.05 for all). Furthermore, attenuated HRV correlated with worse prognosis during a median follow-up of 6.8 years (range 5.1 - 8.1). Additionally, 24-hour time domain, low and high frequency components of frequency domain and non-linear HRV, excluding scaling exponents (α), were lower in IDC patients as compared with controls (p < 0.05 for all);however, HRT was not significantly different. Conclusions: The magnitude of impairment in cardiac autonomic control correlates well with other prognostic markers of IDC, and is associated with unfavorable outcome.展开更多
Mesenchymal stem cells(MSCs)experience substantial viability issues in the stroke infarct region,limiting their therapeutic efficacy and clinical translation.High levels of deadly reactive oxygen radicals(ROS)and proi...Mesenchymal stem cells(MSCs)experience substantial viability issues in the stroke infarct region,limiting their therapeutic efficacy and clinical translation.High levels of deadly reactive oxygen radicals(ROS)and proinflammatory cytokines(PC)in the infarct milieu kill transplanted MSCs,whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs’viability.Based on the intrinsic hormesis effects in cellular biology,we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy.This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer.In this system,extracellular ROSscavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a microlivable niche at the level of a single MSC for transplantation.Meanwhile,the infarct’s inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing.The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days.This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.展开更多
Objective To study the effects and mechanism of lovastatin on cell proliferation and expression of proinflammatory cytokines in cultured human glomerular mesangial cells.Methods The influence of lovastatin on HMC prol...Objective To study the effects and mechanism of lovastatin on cell proliferation and expression of proinflammatory cytokines in cultured human glomerular mesangial cells.Methods The influence of lovastatin on HMC proliferation was evaluated with 3H-thymidine incorporation. mRNA expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α, and MCP-1) and activation of NF-KB of HMC were measured using Reverse transcription-polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA) respectively.Results Lovastatin was found to have inhibitory effects on human mesangial cell (HMC) proliferation and lipopolysaccharide ( LPS )-mediated human mesangine cell HMC mRNA expression of proinflammatory cytokines via activation of NF-KB. The effect of lovstatin on HMC could be prevented when the mevalonate and farnesol were added to the culture.Conclusion Lovastatin may decrease HMC proliferation and production of proinflammatory cytokines through the inhibition of NF-KB activation. This provided experimental evidence for further evaluation of the renal protective effect of HRI, suggesting that it may be a potent agent for prevention of progressive reanl diseases aside from its lipid-lowering effect.展开更多
The intestinal epithelium(IE) forms an indispensible barrier and interface between the intestinal interstitium and the luminal environment. The IE regulates water, ion and nutrient transport while providing a barrier ...The intestinal epithelium(IE) forms an indispensible barrier and interface between the intestinal interstitium and the luminal environment. The IE regulates water, ion and nutrient transport while providing a barrier against toxins, pathogens(bacteria, fungi and virus) and antigens. The apical intercellular tight junctions(TJ) are responsible for the paracellular barrier function and regulate transepithelial flux of ions and solutes between adjacent cells. Increased intestinal permeability caused by defects in the IE TJ barrier is considered an important pathogenic factor for the development of intestinal inflammation, diarrhea and malnutrition in humans and animals. In fact, defects in the IE TJ barrier allow increased antigenic penetration, resulting in an amplified inflammatory response in inflammatory bowel disease(IBD), necrotizing enterocolitis and ischemia-reperfusion injury. Conversely, the beneficial enhancement of the intestinal TJ barrier has been shown to resolve intestinal inflammation and apoptosis in both animal models of IBD and human IBD. Autophagy(self-eating mechanism) is an intracellular lysosome-dependent degradation and recycling pathway essential for cell survival and homeostasis.Dysregulated autophagy has been shown to be directly associated with many pathological processes,including IBD. Importantly, the crosstalk between IE TJ and autophagy has been revealed recently. We showed that autophagy enhanced IE TJ barrier function by increasing transepithelial resistance and reducing the paracellular permeability of small solutes and ions, which is, in part, by targeting claudin-2,a cation-selective, pore-forming, transmembrane TJ protein, for lysosome(autophagy)-mediated degradation. Interestingly, previous studies have shown that the inflamed intestinal mucosa in patients with active IBD has increased claudin-2 expression. In addition, inflammatory cytokines(for example,tumor necrosis factor-α, interleukin-6, interleukin-13, and interleukin-17) whose levels are increased in IBD patients cause an increase in claudin-2 expression and a claudin-2-dependent increase in TJ permeability. Thus, the role of claudin-2 in intestinal pathological processes has been attributed, in part, to the increase of intestinal TJ permeability. Claudin-2 represents a new therapeutic target in treating IBD,diarrhea and malnutrition in animals and humans.展开更多
Inflammation is an essential response provided by the immune systems that ensures the survival duringinfection and tissue injury. Inflammatory responses are essential for the maintenance of normal tissue homeostasis. ...Inflammation is an essential response provided by the immune systems that ensures the survival duringinfection and tissue injury. Inflammatory responses are essential for the maintenance of normal tissue homeostasis. Themolecular mechanism of inflammation is quite a complicated process which is initiated by the recognition of specificmolecular patterns associated with either infection or tissue injury. The entire process of the inflammatory response ismediated by several key regulators involved in the selective expression of proinflammatory molecules. Prolongedinflammations are often associated with severe detrimental side effects on health. Alterations in inflammatory responsesdue to persistent inducers or genetic variations are on the rise over the last couple of decades, causing a variety ofinflammatory diseases and pathophysiological conditions.展开更多
Immune cells, particularly macrophages, play critical roles in the hypoxia-induced inflammatory response. The small GTPase RhoB is usually rapidly induced by a variety of stimuli and has been described as an important...Immune cells, particularly macrophages, play critical roles in the hypoxia-induced inflammatory response. The small GTPase RhoB is usually rapidly induced by a variety of stimuli and has been described as an important regulator of cytoskeletal organization and vesicle and membrane receptor trafficking. However, it is unknown whether RhoB is involved in the hypoxia-induced inflammatory response. Here, we investigated the effect of hypoxia on the expression of RhoB and the mechanism and significance of RhoB expression in macrophages. We found that hypoxia significantly upregulated the expression of RhoB in RAW264.7 cells, mouse peritoneal macrophages, and the spleen of rats. Hypoxia-induced expression of RhoB was significantly blocked by a specific inhibitor of hypoxia-inducible factor-1α (HIF-1α), c-Jun N-terminal kinase (JNK), or extracellular-signal regulated protein kinase (ERK), indicating that hypoxia-activated HIF-1α, JNK, and ERK are involved in the upregulation of RhoB by hypoxia. Knockdown of RhoB expression not only significantly suppressed basal production of interleukin-1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in normoxia but also more markedly decreased the hypoxia-stimulated production of these cytokines. Furthermore, we showed that RhoB increased nuclear factor-kappa B (NF-κB) activity, and the inhibition of NF-κB transcriptional activity significantly decreased the RhoB-increased mRNA levels of IL-1β, IL-6, and TNF-α. Finally, we demonstrated that RhoB enhanced cell adhesion and inhibited cell migration in normoxia and hypoxia. Taken together, these results suggest that RhoB plays an important role in the hypoxia-induced activation of macrophages and the inflammatory response.展开更多
Background Bacterial lipopolysaccharide (LPS) can activate immunological cells to secrete various proinflammatory cytokines involved in the pathophysiological process of disseminated intravascular coagulation (DIC...Background Bacterial lipopolysaccharide (LPS) can activate immunological cells to secrete various proinflammatory cytokines involved in the pathophysiological process of disseminated intravascular coagulation (DIC) during infection. In recent years, it has been found that bone marrow-derived mesenchymal stem cells (BMSCs) can affect the activity of these immune cells and regulate the secretion of proinflammatory cytokines. Here, we report the possible protective effect of BMSCs pre-treatment in LPS-induced DIC rat model and the mechanism. Methods Forty-eight adult male rats were divided into five experimental groups and one control group with eight animals in each group. In the treatment groups, 0, 1×10^6, 2×10^6, 3×10^6, and 5×10^6 of BMSCs were injected intravenously for 3 days before LPS injection, while the control group was treated with pure cell culture medium injection. Then, the LPS (3 mg/kg) was injected via the tail vein in the treatment groups, while the control group received 0.9% NaCI. Blood was withdrawn before and 4 and 8 hours after LPS administration. The following parameters were monitored: platelets (PLT), fibrinogen (Fib), D-dimer (D-D), activated partial thromboplastin time (APTT), prothrombin time (PT), tumor necrosis factor-a (TNF-(a), interferon-y (IFN-a), interleukin-1β (IL-1β), creatinine (Cr), alanine aminotransferase (ALT), creatinine kinase-MB (CK-MB), and endothelin (ET). Results Compared with the control group, a significant change of coagulation parameters were found in the experimental groups. The plasma level of the inflammatory mediator (TNF-a, IFN-7, IL-1β), organ indicator (Cr, ALT, and CK-MB), and ET in the experimental groups were much lower (P〈0.05) than that in the control group. Furthermore, some of these effects were dose-dependent; the statistical comparison of the plasma levels between the groups (from group 2 to group 5) showed a significant difference (P 〈0.05), except the ALl and CK-MB levels (P 〉0.05). Conclusion Pre-treatment with BMSCs can attenuate organ dysfunction and inhibit systemic intravascular coagulation effectively via the regulatory effect on immune cells and proinflammatory cytokines in LPS-induced DIC rat model.展开更多
INTRODUCTION Severe acute pancreatitis (AP) remains a challenge in clinical practice, and there are no internationally agreed specific therapies. Severe AP typically presents with epigastric pain, abdominal distenti...INTRODUCTION Severe acute pancreatitis (AP) remains a challenge in clinical practice, and there are no internationally agreed specific therapies. Severe AP typically presents with epigastric pain, abdominal distention, vomiting, and constipation at the early stage and is similar to the Yangming-Fushi syndrome of traditional Chinese medicine (TCM). The Chinese herbal ointment Liu-He-Dan (LHD) has been adapted for the treatment of AP with Yangming-Fushi syndrome externally on belly for many years in our hospital. However, the potential mechanism of LHD in the treatment of severe AP has not been elucidated. Therefore, the present study sought to evaluate the effect of LHD on AP patients and preliminarily investigate its anti-inflammatory mechanism.展开更多
Discovery and functional identification of plant-derived small compounds as the immunosuppressant attract much attention these years. Albaconol is a new kind of small compound, prenylated resorcinol, isolated from the...Discovery and functional identification of plant-derived small compounds as the immunosuppressant attract much attention these years. Albaconol is a new kind of small compound, prenylated resorcinol, isolated from the fruiting bodies of the inedible mushroom Albatrellus confluens. Our previous studies showed that albaconol can inhibit tumor cell growth and dendritic cell maturation. However, the immunomodulatory roles and the underlying mechanisms of albaconol have not been fully understood. In this study we investigated the effects of albaconol on the proliferation and LPS-induced proinflammatory cytokine production of macrophages. Albaconol, when used at a dose higher than 1.0 μg/ml, inhibited proliferation of RAW264.7 cells in a doseand time-dependent manner, and could induce cellular apoptosis when used at high dosage (≥7.5 μg/ml). Furthermore, we found that albaconol used at a lower dosage without apoptosis induction could significantly inhibit LPS-induced TNF-α IL-6, IL-1β and NO production in RAW264.7 cells. The inhibition of NF-κB activation and enhancement of SOCS1 expression in LPS-stimulated macrophages by albaconol may contribute to the above immunosuppressive or anti-inflammatory activities of albaconol. Our results suggest that albaconol may be a potential immunosuppressive and anti- inflammatory drug. Cellular & Molecular Immunology. 2008;5(4):271-278.展开更多
Gut microbial dysbiosis has been linked to many noncommunicable diseases.However,little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying...Gut microbial dysbiosis has been linked to many noncommunicable diseases.However,little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection.Here,we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers,which have recently been identified as molecular signatures predicting the progression of the COVID-19.We demonstrate that in our cohort of 990 healthy individuals without infection,this proteomic risk score is positively associated with proinflammatory cytokines mainly among older,but not younger,individuals.We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals.Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation.Overall,our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals.These results may provide novel insights into the cross-talk between gut microbiota and host immune system.展开更多
基金Medical Scientific Research Foundation of Guangdong Province of China,Guangdong Provincial Health Commission,China,No.A2018356。
文摘An outbreak of a novel coronavirus was reported in Wuhan,China,in late 2019.It has spread rapidly through China and many other countries,causing a global pandemic.Since February 2020,over 28 countries/regions have reported confirmed cases.Individuals with the infection known as coronavirus disease-19(COVID-19)have similar clinical features as severe acute respiratory syndrome first encountered 17 years ago,with fever,cough,and upper airway congestion,along with high production of proinflammatory cytokines(PICs),which form a cytokine storm.PICs induced by COVID-19 include interleukin(IL)-6,IL-17,and monocyte chemoattractant protein-1.The production of cytokines is regulated by activated nuclear factor-kB and involves downstream pathways such as Janus kinase/signal transducers and activators transcription.Protein expression is also regulated by post-translational modification of chromosomal markers.Lysine residues in the peptide tails stretching out from the core of histones bind the sequence upstream of the coding portion of genomic DNA.Covalent modification,particularly methylation,activates or represses gene transcription.PICs have been reported to be induced by histone modification and stimulate exudation of hyaluronic acid,which is implicated in the occurrence of COVID-19.These findings indicate the impact of the expression of PICs on the pathogenesis and therapeutic targeting of COVID-19.
文摘Background:Increased proinflammatory cytokines and chemokines might contribute to infiltration of inflammatory cells and remodeling in airways of asthma.Although these molecules may be associated with asthma,there is lack of systemic evidence showing which and how important these events are in the disease.We aimed to analyze the concentrations of these molecules in the airways and relationships with disease severity and with airway infiltration of inflammatory cells in a large cohort of asthmatics (n =70,including 37 mild and 33 moderate/severe asthmatics) compared with controls (n =30).Methods:Meso scale discovery system and commercial ELISA kits were used to measure the concentrations ofproinflammatory cytokines interleukin (IL)-1 β;tumor necrosis factor-alpha (TNF-α);IL-6;and IL-17 and CC and CXC chemokines CCL2,CCL4,CCL 11,CCL 13,CCL17,CCL22,and CCL26 and CXCL8,CXCL9,CXCL10,and CXCL1 1 in bronchoalveolar lavage fluid of asthmatics and controls.Results:The concentrations ofIL-1,TNF-α,IL-6,CXCL8 and CXCL 10,and CCL4,CCL 11,CCL 17,and CCL22 were significantly elevated in asthmatics compared with controls (P 〈 0.05).The concentrations of TNF-α and CXCL8,but not others,were negatively correlated with severity of disease (lung function forced expiratory volume in 1 s) (TNF-α vs.total:r =-0.359,P =0.002 vs.moderate/severe:r =-0.541,P =0.001;CXCL8 vs.total:r =-0.327,P =0.006 vs.moderate/severe:r =-0.625,P =0.0001,respectively).In addition,concentrations of these two molecules were also correlated with the absolute numbers of infiltrating eosinophils and neutrophils in asthmatic airways.Conclusions:Increased concentrations of TNF-α and CXCL8 are associated with pathogenesis of asthma.Targeting these molecules might provide an alternative therapeutic for this disease.
基金supported by the National Natural Science Foundation of China (30901042)Sichuan Province Science Foundation for Fostering Youths Talents (2011JQ0015)+1 种基金Key Program Fundation of the Education Department of Sichuan ProvinceNovus Research Fellowship (NRF)
文摘Mastitis is a common disease for mammals all around the world. Figuring out why mastitis mainly occurs around parturition may be helpful for dealing with the disease. Lipolytic activity and oxidative stress take place around parturition, which may leads to alteration in fatty acids profile and proinflammatory cytokine expression. Thus, the aim of the present study was to further our understanding about the high incidence of mastitis around parturition by comparison of plasma fatty acid profile and mammary inflammation indicators at different reproductive stages. A total of 47 female rats were included in the present study. After mating, all the pregnant and non-pregnant rats began to receive the same experimental diet. Blood samples were collected at day 1 and 14 of gestation as well as day 3 postpartum.Mammary samples were collected at day 14 of gestation and day 3 postpartum from pregnant and nonpregnant rats. The results showed that rats at d 3 postpartum had greater(P < 0.05) plasma concentrations of non-esterified fatty acids(NEFA), arachidonic acid(ARA) and docosahexaenoic acid(DHA) as well as ARA: eicosapentaenoic acid(EPA) ratio than those at d 14 of gestation. The mRNA abundances of interleukin-1 β(IL-1β), tumor necrosis factor-α(TNF-α),IL-8 and xanthine oxidoreductase(XOR) in mammary of the pregnant rats were greater(P < 0.05) than those in age-matched non-pregnant rats.Rats at d 3 postpartum had higher(P < 0.05) protein expression levels of IL-1β and TNF-α as well as meloperoxidase(MPO) activity and polymorphonuclear neutrophils(PMN) prevalence than those at d 1 of gestation. The rats at d 3 postpartum also had greater(P < 0.05) IL-1β and MPO activity than those at d 14 of gestation. The results indicated that elevated mammary expression of proinflammatory cytokines and XOR as well as altered fatty acid profile around parturition might facilitate the recruitment of neutrophils into mammary glands.
基金funded by the Indian Council of Medical Research with Grant Number 2020-8817,New Delhi,India。
文摘Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in rats.Methods:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 mg/kg,i.p.)for four weeks.Behavioral tests such as Morris water maze and elevated plus maze were conducted to check memory impairment caused by cladribine.On day 29,all rats were sacrificed,and the brains were separated for estimation of neuroinflammatory factors,biochemical parameters,neurotransmitters,Aβ(1-42),blood-brain barrier permeability,nuclear factor erythroid 2-related factor 2(Nrf2),and brain-derived neurotrophic factor(BDNF).Results:Treatment with cryptotanshinone dose-dependently enhanced spatial memory,improved the levels of neurotransmitter and antioxidant enzymes,and suppressed proinflammatory cytokine release.Cryptotanshinone also decreased Aβ(1-42)accumulation and increased the levels of Nrf2 and BDNF in the hippocampus.Additionally,the histopathological results showed that cryptotanshinone reduced cladribine-induced neuronal death in the hippocampus.Conclusions:Cryptotanshinone exhibits a promising neuroprotective effect against cladribine-induced cognitive impairment in preclinical studies,and may be a potential phytochemical for the treatment and management of cognitive impairment.
文摘Objective:To determine the neuroprotective effects of apigenin against streptozotocin(STZ)-induced diabetic neuropathy(DN).Methods:To induce DN,Wistar rats(150-200 g)were administered with STZ(55 mg/kg,i.p.).Then they were randomly assigned to various groups,viz.,normal,diabetic control,insulin(10 IU/kg,s.c.),apigenin(5,10,and 20 mg/kg,p.o.),and insulin(10 IU/kg)plus apigenin(20 mg/kg,p.o.).Various behavioral,biochemical,and molecular markers[tumor necrosis factor-alpha(TNF-α),interleukin(IL)-1β,IL-6,Toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),and nuclear factor erythroid 2-related factor 2(Nrf2)]were assessed.Results:Apigenin(10 and 20 mg/kg,p.o.)substantially reduced plasma glucose levels,lipid profile,aspartate transaminase,alanine transaminase,glycated hemoglobin,and neural advanced glycation end products in STZ-induced DN rats(P<0.05).After apigenin intervention,STZ-induced changes in food and water intake,body weight,urine output,allodynia,hyperalgesia,and insulin levels were markedly improved(P<0.05).Neural antioxidant enzymes(superoxide dismutase and glutathione)and Na+K+ATPase activity were also considerably elevated(P<0.05)while the level of lipid peroxidation was diminished following apigenin therapy(P<0.05).Furthermore,apigenin markedly upregulated the Nrf2 mRNA level while downregulating the mRNA expressions of TNF-αand ILs and the protein expressions of TLR4 and MyD88(P<0.05).STZ-induced histological abnormalities in the sciatic nerve were also improved by apigenin treatment.Conclusions:Apigenin exerts its neuroprotective effect by modulating the inflammatory and oxidative stress pathways via regulating the TLR4-MyD88 signaling pathway.
文摘Serotonin deficiency in major depressive disorder(MDD)has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan(Trp)-degrading enzyme,liver Trp 2,3-dioxygenase(TDO),by cortisol,leading to decreased Trp availability to the brain for serotonin synthesis.Subsequently,the serotonin deficiency was proposed to involve induction of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase(IDO)by proinflammatory cytokines,with inflammation being the underlying cause.Recent evidence,however,challenges this latter concept,as not all MDD patients are immune-activated and,when present,inflammation is mild and/or transient.A wide range of antidepressant drugs inhibit the activity of liver TDO and bind specifically to the enzyme,but not to IDO.IDO induction is not a major event in MDD,but,when it occurs,its metabolic consequences may be masked and overridden by upregulation of kynurenine monooxygenase(KMO),the gateway to production of modulators of immune and neuronal functions.KMO appears to be activated in MDD by certain proinflammatory cytokines and antidepressants with anti-inflammatory properties may block this activation.We demonstrate the ability of the antidepressant ketamine to dock(bind)to KMO.The pathophysiology of MDD may be underpinned by both the serotonin deficiency and glutamatergic activation mediated respectively by TDO induction and N-methyl-D-aspartate receptor activation.Inhibition of TDO and KMO should be the focus of MDD pharmacotherapy.
基金This study was supported by the Natural Science and Technology Foundation of Zunyi City,China,No.201915(to GPL)Doctor Startup Foundation of Zunyi Medical University,Nos.[2017]5733-045(to GPL),[2017]5733-044(to YYH)Natural Science and Technology Foundation of Guizhou Province,China,No.[2020]1Y292(to YYH).
文摘Microglial cells are important resident innate immune components in the central nervous system that are often activated during neuroinflammation.Activated microglia can display one of two phenotypes,M1 or M2,which each play distinct roles in neuroinflammation.Rutin,a dietary flavonoid,exhibits protective effects against neuroinflammation.However,whether rutin is able to influence the M1/M2 polarization of microglia remains unclear.In this study,in vitro BV-2 cell models of neuroinflammation were established using 100 ng/mL lipopolysaccharide to investigate the effects of 1-hour rutin pretreatment on microglial polarization.The results revealed that rutin pretreatment reduced the expression of the proinflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6 and increased the secretion of interleukin-10.Rutin pretreatment also downregulated the expression of the M1 microglial markers CD86 and inducible nitric oxide synthase and upregulated the expression of the M2 microglial markers arginase 1 and CD206.Rutin pretreatment inhibited the expression of Toll-like receptor 4 and myeloid differentiation factor 88 and blocked the phosphorylation of I kappa B kinase and nuclear factor-kappa B.These results showed that rutin pretreatment may promote the phenotypic switch of microglia M1 to M2 by inhibiting the Toll-like receptor 4/nuclear factor-kappa B signaling pathway to alleviate lipopolysaccharide-induced neuroinflammation.
基金supported by the Universiti Sains Malaysia Fundamental Research Grant Scheme(No.203/PPSK/6171158)
文摘Objective: To investigate the role of toll-like receptor 2(TLR2) in inflammatory activity of macrophage infected with the recombinant Mycobacterium bovis bacillus Calmette-Guerin(rBCG). Methods: Mouse macrophage cell line J774 A.1 was infected with Mycobacterium bovis bacillus Calmette-Guerin(BCG) and rBCG cultures for 48 h in the presence or absence of 10 μg/mL of TLR2 inhibitor. Untreated macrophages were used as a negative control while lipopolysaccharide-stimulated macrophages were used as a positive control. The ability of the macrophage to engulf the BCG and rBCG in the absence or presence of TLR2 inhibitor was assessed using a phagocytic assay, while the production of inflammatory cytokines and nitric oxide by the infected macrophages was evaluated using ELISA and Griess reagent method, while the expression of the inducible nitric oxide synthase was determined using Western blot analysis. Results: The results showed that blocking TLR2 function reduced the phagocytic activity, nitric oxide production and proinflammatory cytokine secretion such as TNF-α, IL-1β and IL-12 p40 as well as inducible nitric oxide synthase expression in the infected macrophages. These data showed the importance of TLR2 in the activation of macrophages following BCG and r BCG infections. Conclusions: Through exploring the immunological mechanism which underlies the protection conferred by the candidate vaccine, this study will improve our understanding of the vaccine candidate's mechanism to protect the host from malaria infection.
文摘<i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"></span><span style="font-family:;" "=""><span style="font-family:Verdana;"> used as an analgesic and anti-inflammatory. It is often used not only in Mongolian medicine but also in traditional Chinese medicine. However, there are few studies on its impact of inflammatory cytokines. This study explored the effects of </span><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i> <i><span style="font-family:Verdana;">in vitro</span></i><span style="font-family:Verdana;"></span></i></span><span style="font-family:Verdana;"> used human colon cancer (Caco-2) cells. Cytotoxicity was assessed by measuring effects on expression of IL-1</span><i><span style="font-family:Verdana;"><span style="white-space:nowrap;">β</span></span></i><span style="font-family:Verdana;">, IL-6, IL-8, and TNF-</span><i><span style="font-family:Verdana;"><span style="white-space:nowrap;">α</span></span></i><span style="font-family:Verdana;"> used enzyme-linked immun</span><span style="font-family:Verdana;">o</span><span style="font-family:;" "=""><span style="font-family:Verdana;">sorbent assay (ELISA). </span><span><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">In vitro</span></i><span style="font-family:Verdana;"></span></i></span></span><span style="font-family:Verdana;"> study demonstrated that incubation of Caco-2 cells with some kinds of</span><i> </i><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"></span></i><span style="font-family:Verdana;"> at some concentrations inhibit secretion of TNF-</span><i><span style="font-family:Verdana;"><span style="white-space:nowrap;">α</span></span></i><span style="font-family:Verdana;"> and FAXIU </span><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">ACONITUM</span></i> <i><span style="font-family:Verdana;">KUSNEZOFFII</span></i><span style="font-family:Verdana;"></span></i><span style="font-family:Verdana;"> could inhibit the secretion of IL-1</span><i><span style="font-family:Verdana;"><span style="white-space:nowrap;">β</span></span></i><span style="font-family:Verdana;">. While IL-6 and IL-8 levels were unaffected after 24 h of treatment with </span><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"><i></i></span><i><span style="font-family:Verdana;">, </span></i></i><span style="font-family:Verdana;"></span><span style="font-family:Verdana;"></span><span style="font-family:Verdana;">qujian </span><i><i><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"><i></i></span><i><span style="font-family:Verdana;">, </span></i></i></i></i><span style="font-family:Verdana;"></span><span style="font-family:Verdana;"></span><span style="font-family:Verdana;"></span><span style="font-family:Verdana;">faxiu </span><i><i><i><i><span style="font-family:Verdana;"><i></i></span><i><i><span style="font-family:Verdana;">Aconitum kusnezoffii</span></i><span style="font-family:Verdana;"></span></i><span style="font-family:Verdana;">.</span></i></i></i></i>
基金supported by grants from the Finnish Foundation for Cardiovascular Research,the Finnish Foundation for Medicine,the Finnish Cultural Foundation,North Savo Regional fund and the research funds of Kuopio University Hospital,Finland.
文摘Objectives: We set out to study cardiac autonomic tone in patients with idiopathic dilated cardio-myopathy (IDC), and whether it correlates with other established markers of disease progression and patient ultimate outcome. Design: Fifty-one IDC patients in sinus rhythm underwent extensive non-invasive and invasive evaluation during a three-day hospitalization period. The control group consisted of thirty-eight apparently healthy subjects who underwent 24-hour ambulatory ECG recording. Results: Heart rate variability (HRV) and heart rate turbulence (HRT) correlated with many previously established prognostic markers of IDC and congestive heart failure, especially measures of cardiorespiratory performance capacity and circulating neurohumoral factors (p < 0.05 for all). Furthermore, attenuated HRV correlated with worse prognosis during a median follow-up of 6.8 years (range 5.1 - 8.1). Additionally, 24-hour time domain, low and high frequency components of frequency domain and non-linear HRV, excluding scaling exponents (α), were lower in IDC patients as compared with controls (p < 0.05 for all);however, HRT was not significantly different. Conclusions: The magnitude of impairment in cardiac autonomic control correlates well with other prognostic markers of IDC, and is associated with unfavorable outcome.
基金supported by National Natural Science Foundation of China(Nos.92068110,81973272 and 92068111)Shanghai Science and Technology Committee(Nos.20JC1411800,and 23S41900100,China)+4 种基金Programs of Shanghai Academic/Technology Research Leader(Nos.21XD1400200 and 21XD1422200,China)Innovation Program of Shanghai Municipal Education Commission(2023ZKZD21,China)the fund of Research Grant for Health Science and Technology of Shanghai Municipal Commission of Health Committee(No.20214Y0268,China)Science and Technology Development Fund of Shanghai Pudong New Area(No.PKJ2020-Y49,China)the Project of Key Medical Specialty and Treatment Center of Pudong Hospital of Fudan University(No.Zdzk2020-15,China)。
文摘Mesenchymal stem cells(MSCs)experience substantial viability issues in the stroke infarct region,limiting their therapeutic efficacy and clinical translation.High levels of deadly reactive oxygen radicals(ROS)and proinflammatory cytokines(PC)in the infarct milieu kill transplanted MSCs,whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs’viability.Based on the intrinsic hormesis effects in cellular biology,we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy.This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer.In this system,extracellular ROSscavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a microlivable niche at the level of a single MSC for transplantation.Meanwhile,the infarct’s inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing.The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days.This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.
基金This work was supported by the National Education Foundation of China (No. 1999002309).
文摘Objective To study the effects and mechanism of lovastatin on cell proliferation and expression of proinflammatory cytokines in cultured human glomerular mesangial cells.Methods The influence of lovastatin on HMC proliferation was evaluated with 3H-thymidine incorporation. mRNA expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α, and MCP-1) and activation of NF-KB of HMC were measured using Reverse transcription-polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA) respectively.Results Lovastatin was found to have inhibitory effects on human mesangial cell (HMC) proliferation and lipopolysaccharide ( LPS )-mediated human mesangine cell HMC mRNA expression of proinflammatory cytokines via activation of NF-KB. The effect of lovstatin on HMC could be prevented when the mevalonate and farnesol were added to the culture.Conclusion Lovastatin may decrease HMC proliferation and production of proinflammatory cytokines through the inhibition of NF-KB activation. This provided experimental evidence for further evaluation of the renal protective effect of HRI, suggesting that it may be a potent agent for prevention of progressive reanl diseases aside from its lipid-lowering effect.
基金supported, in part, by the Evergreen Scholarship of the Wuhan Polytechnic University (to CAAH) and Texas A&M Agri Life Research (H-8200 to GW)National Natural Science Foundation of China (No. 31372319 and 31402084)(to YH)
文摘The intestinal epithelium(IE) forms an indispensible barrier and interface between the intestinal interstitium and the luminal environment. The IE regulates water, ion and nutrient transport while providing a barrier against toxins, pathogens(bacteria, fungi and virus) and antigens. The apical intercellular tight junctions(TJ) are responsible for the paracellular barrier function and regulate transepithelial flux of ions and solutes between adjacent cells. Increased intestinal permeability caused by defects in the IE TJ barrier is considered an important pathogenic factor for the development of intestinal inflammation, diarrhea and malnutrition in humans and animals. In fact, defects in the IE TJ barrier allow increased antigenic penetration, resulting in an amplified inflammatory response in inflammatory bowel disease(IBD), necrotizing enterocolitis and ischemia-reperfusion injury. Conversely, the beneficial enhancement of the intestinal TJ barrier has been shown to resolve intestinal inflammation and apoptosis in both animal models of IBD and human IBD. Autophagy(self-eating mechanism) is an intracellular lysosome-dependent degradation and recycling pathway essential for cell survival and homeostasis.Dysregulated autophagy has been shown to be directly associated with many pathological processes,including IBD. Importantly, the crosstalk between IE TJ and autophagy has been revealed recently. We showed that autophagy enhanced IE TJ barrier function by increasing transepithelial resistance and reducing the paracellular permeability of small solutes and ions, which is, in part, by targeting claudin-2,a cation-selective, pore-forming, transmembrane TJ protein, for lysosome(autophagy)-mediated degradation. Interestingly, previous studies have shown that the inflamed intestinal mucosa in patients with active IBD has increased claudin-2 expression. In addition, inflammatory cytokines(for example,tumor necrosis factor-α, interleukin-6, interleukin-13, and interleukin-17) whose levels are increased in IBD patients cause an increase in claudin-2 expression and a claudin-2-dependent increase in TJ permeability. Thus, the role of claudin-2 in intestinal pathological processes has been attributed, in part, to the increase of intestinal TJ permeability. Claudin-2 represents a new therapeutic target in treating IBD,diarrhea and malnutrition in animals and humans.
文摘Inflammation is an essential response provided by the immune systems that ensures the survival duringinfection and tissue injury. Inflammatory responses are essential for the maintenance of normal tissue homeostasis. Themolecular mechanism of inflammation is quite a complicated process which is initiated by the recognition of specificmolecular patterns associated with either infection or tissue injury. The entire process of the inflammatory response ismediated by several key regulators involved in the selective expression of proinflammatory molecules. Prolongedinflammations are often associated with severe detrimental side effects on health. Alterations in inflammatory responsesdue to persistent inducers or genetic variations are on the rise over the last couple of decades, causing a variety ofinflammatory diseases and pathophysiological conditions.
文摘Immune cells, particularly macrophages, play critical roles in the hypoxia-induced inflammatory response. The small GTPase RhoB is usually rapidly induced by a variety of stimuli and has been described as an important regulator of cytoskeletal organization and vesicle and membrane receptor trafficking. However, it is unknown whether RhoB is involved in the hypoxia-induced inflammatory response. Here, we investigated the effect of hypoxia on the expression of RhoB and the mechanism and significance of RhoB expression in macrophages. We found that hypoxia significantly upregulated the expression of RhoB in RAW264.7 cells, mouse peritoneal macrophages, and the spleen of rats. Hypoxia-induced expression of RhoB was significantly blocked by a specific inhibitor of hypoxia-inducible factor-1α (HIF-1α), c-Jun N-terminal kinase (JNK), or extracellular-signal regulated protein kinase (ERK), indicating that hypoxia-activated HIF-1α, JNK, and ERK are involved in the upregulation of RhoB by hypoxia. Knockdown of RhoB expression not only significantly suppressed basal production of interleukin-1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in normoxia but also more markedly decreased the hypoxia-stimulated production of these cytokines. Furthermore, we showed that RhoB increased nuclear factor-kappa B (NF-κB) activity, and the inhibition of NF-κB transcriptional activity significantly decreased the RhoB-increased mRNA levels of IL-1β, IL-6, and TNF-α. Finally, we demonstrated that RhoB enhanced cell adhesion and inhibited cell migration in normoxia and hypoxia. Taken together, these results suggest that RhoB plays an important role in the hypoxia-induced activation of macrophages and the inflammatory response.
文摘Background Bacterial lipopolysaccharide (LPS) can activate immunological cells to secrete various proinflammatory cytokines involved in the pathophysiological process of disseminated intravascular coagulation (DIC) during infection. In recent years, it has been found that bone marrow-derived mesenchymal stem cells (BMSCs) can affect the activity of these immune cells and regulate the secretion of proinflammatory cytokines. Here, we report the possible protective effect of BMSCs pre-treatment in LPS-induced DIC rat model and the mechanism. Methods Forty-eight adult male rats were divided into five experimental groups and one control group with eight animals in each group. In the treatment groups, 0, 1×10^6, 2×10^6, 3×10^6, and 5×10^6 of BMSCs were injected intravenously for 3 days before LPS injection, while the control group was treated with pure cell culture medium injection. Then, the LPS (3 mg/kg) was injected via the tail vein in the treatment groups, while the control group received 0.9% NaCI. Blood was withdrawn before and 4 and 8 hours after LPS administration. The following parameters were monitored: platelets (PLT), fibrinogen (Fib), D-dimer (D-D), activated partial thromboplastin time (APTT), prothrombin time (PT), tumor necrosis factor-a (TNF-(a), interferon-y (IFN-a), interleukin-1β (IL-1β), creatinine (Cr), alanine aminotransferase (ALT), creatinine kinase-MB (CK-MB), and endothelin (ET). Results Compared with the control group, a significant change of coagulation parameters were found in the experimental groups. The plasma level of the inflammatory mediator (TNF-a, IFN-7, IL-1β), organ indicator (Cr, ALT, and CK-MB), and ET in the experimental groups were much lower (P〈0.05) than that in the control group. Furthermore, some of these effects were dose-dependent; the statistical comparison of the plasma levels between the groups (from group 2 to group 5) showed a significant difference (P 〈0.05), except the ALl and CK-MB levels (P 〉0.05). Conclusion Pre-treatment with BMSCs can attenuate organ dysfunction and inhibit systemic intravascular coagulation effectively via the regulatory effect on immune cells and proinflammatory cytokines in LPS-induced DIC rat model.
基金This work was supported by grants from the National Natural Science Foundation of China (No. 81374042 and No. 81370091).
文摘INTRODUCTION Severe acute pancreatitis (AP) remains a challenge in clinical practice, and there are no internationally agreed specific therapies. Severe AP typically presents with epigastric pain, abdominal distention, vomiting, and constipation at the early stage and is similar to the Yangming-Fushi syndrome of traditional Chinese medicine (TCM). The Chinese herbal ointment Liu-He-Dan (LHD) has been adapted for the treatment of AP with Yangming-Fushi syndrome externally on belly for many years in our hospital. However, the potential mechanism of LHD in the treatment of severe AP has not been elucidated. Therefore, the present study sought to evaluate the effect of LHD on AP patients and preliminarily investigate its anti-inflammatory mechanism.
基金grants from the National Natural Science Foundation of China (30721091)the National Key Basic Research Program of China (2007CB512403)
文摘Discovery and functional identification of plant-derived small compounds as the immunosuppressant attract much attention these years. Albaconol is a new kind of small compound, prenylated resorcinol, isolated from the fruiting bodies of the inedible mushroom Albatrellus confluens. Our previous studies showed that albaconol can inhibit tumor cell growth and dendritic cell maturation. However, the immunomodulatory roles and the underlying mechanisms of albaconol have not been fully understood. In this study we investigated the effects of albaconol on the proliferation and LPS-induced proinflammatory cytokine production of macrophages. Albaconol, when used at a dose higher than 1.0 μg/ml, inhibited proliferation of RAW264.7 cells in a doseand time-dependent manner, and could induce cellular apoptosis when used at high dosage (≥7.5 μg/ml). Furthermore, we found that albaconol used at a lower dosage without apoptosis induction could significantly inhibit LPS-induced TNF-α IL-6, IL-1β and NO production in RAW264.7 cells. The inhibition of NF-κB activation and enhancement of SOCS1 expression in LPS-stimulated macrophages by albaconol may contribute to the above immunosuppressive or anti-inflammatory activities of albaconol. Our results suggest that albaconol may be a potential immunosuppressive and anti- inflammatory drug. Cellular & Molecular Immunology. 2008;5(4):271-278.
基金supported by the National Natural Science Foundation of China(82073529,81903316,81773416,81972492,21904107,81672086)Zhejiang Ten-thousand Talents Program(2019R52039)+3 种基金Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars(LR19C050001)the 5010 Program for Clinical Researches(2007032)the Sun Yat-sen University,Hangzhou Agriculture and Society Advancement Program(20190101A04)Tencent foundation(2020)。
文摘Gut microbial dysbiosis has been linked to many noncommunicable diseases.However,little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection.Here,we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers,which have recently been identified as molecular signatures predicting the progression of the COVID-19.We demonstrate that in our cohort of 990 healthy individuals without infection,this proteomic risk score is positively associated with proinflammatory cytokines mainly among older,but not younger,individuals.We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals.Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation.Overall,our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals.These results may provide novel insights into the cross-talk between gut microbiota and host immune system.