Levels Of Pro-inflammatory Factors Research Articles

Serpina3n/serpina3 alleviates cyclophosphamide-induced interstitial cystitis by activating the Wnt/β-catenin signal

Background/objectiveSerpina3n/Serpina3 has been identified to be implicated in inflammatory diseases, but its role in interstitial cystitis/bladder pain syndrome (IC/BPS) remains unknown. Here, we aimed to reveal serpina3n/serpina3 role in IC/BPS in vivo and in vitro.MethodsThe IC/BPS model in mice was induced by intraperitoneal injection of 150 mg/kg of cyclophosphamide (CYP). HE and toluidine blue staining were used for histology assessment. Serpina3n/serpina3 expression in the bladder tissues from IC/BPS patients and mouse models were determined by qPCR, immunohistochemistry and western blotting. XAV-939 treatment was applied to inhibit β-catenin activation. Serpina3 role in modulating the growth and apoptosis of HBlEpCs, a human primary bladder epithelial cell line, was assessed by CCK-8 and flow cytometry assays.ResultsSerpina3n/serpina3 expression was decreased in both human and mice bladder tissues with IC/BPS. Upregulation of serpina3n significantly alleviated CYP-induced bladder injury, with decreased mast cells and pro-inflammatory factor levels, including IL-1β, IL-6, and TNF-α, while increased IL-10 level. In addition, serpina3 overexpression inhibited the apoptosis of HBlEpCs, and increased cell growth. In mechanism, we found that serpina3 overexpression promoted the activation of wnt/β-catenin signaling. And, the inhibition of wnt/β-catenin signaling with XAV-939 abolished serpina3n/serpina3 role in protecting bladder tissues from CYP-induced cystitis, as well as inhibiting HBlEpC apoptosis.ConclusionSerpina3n/serpina3 expression was decreased in IC/BPS. Overexpression of serpina3n could alleviate CYP-induced IC/BPS by activating the Wnt/β-catenin signal. This study may provide a new therapeutic strategy for IC/BPS.

Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain

BackgroundPeripheral nerve damage causes neuroinflammation, which plays a critical role in establishing and maintaining neuropathic pain (NeP). The mechanisms contributing to neuroinflammation remain poorly elucidated, and pharmacological strategies for NeP are limited. Thus, in this study, we planned to explore the possible link between astrocyte senescence and NeP disorders following chronic sciatic nerve injury.MethodsAn NeP animal model was established by inducing chronic constrictive injury (CCI) to the sciatic nerve in adult rats. A senolytic drug combination of dasatinib and quercetin was gavaged daily from the first postoperative day until the end of the study. Paw mechanical withdrawal threshold (PMWT) and paw thermal withdrawal latency (PTWL) were evaluated to assess behaviors in response to pain in the experimental rats. Senescence-associated β-galactosidase staining, western blot analysis, and immunofluorescence were applied to examine the levels of proinflammatory factors and severity of the senescence-like response in the spinal cord. Lipopolysaccharide (LPS) was administered to induce senescence of spinal astrocytes in primary cultures in vitro, to explore the potential impacts of senescence on the secretion of proinflammatory factors. Furthermore, single-cell RNA sequencing (scRNA-seq) was conducted to identify senescence-related molecular responses in spinal astrocytes under neuropathic pain.ResultsFollowing sciatic nerve CCI, rats exhibited reduced PMWT and PTWL, increased levels of spinal proinflammatory factors, and an enhanced degree of senescence in spinal astrocytes. Treatment with dasatinib and quercetin effectively attenuated spinal neuroinflammation and mitigated the hypersensitivities of the rats subjected to sciatic nerve CCI. Mechanistically, the dasatinib-quercetin combination reversed senescence in LPS-stimulated primary cultured astrocytes and decreased the levels of proinflammatory factors. The scRNA-seq data revealed four potential senescence-related genes in the spinal astrocyte population, and the expression of clusterin (CLU) protein was validated via in vitro experiments.ConclusionThe findings indicate the potential role of astrocyte senescence in neuroinflammation following peripheral nerve injury, and suggest that targeting CLU activation in astrocytes might provide a novel therapeutic strategy to treat NeP.Graphical abstract

Gypenoside-14 Reduces Depression via Downregulation of the Nuclear Factor Kappa B (NF-kB) Signaling Pathway on the Lipopolysaccharide (LPS)-Induced Depression Model.

Neuroinflammation is a common pathogenetic sign of depression and is closely linked to the development of depression. Many clinical anti-inflammatory drugs act as antidepressants by reducing the neuroinflammatory response. Previous research found that gypenosides and their bioactive compound gypenoside-14 (GP-14) had neuroprotective effects against hypoxia-induced injury and reduced neuroinflammation-related high-altitude cerebral edema. Here we investigated the effects of GP-14 on the lipopolysaccharide (LPS)-induced depression-like behavior model. LPS (0.5 mg/kg) was injected into mice intraperitoneally for 7 consecutive days to induce depression-like behavior, which is considered a model for the exacerbation of depression. GP-14 in the amount of 100 mg/kg was simultaneously administered by gavage for 7 days. In the LPS-induced depression model, GP-14 not only attenuated depression-like behavior but also improved the anxiety-like behavior of the mice. Additionally, GP-14 treatment mitigated learning and cognitive decline in depressed mice. ELISA and immunofluorescence staining results revealed that GP-14 inhibited the upregulation of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), and suppressed the activation of astrocytes induced with LPS, indicating its potent anti-inflammatory effect. GP-14 pretreatment in C8 cells and primary astrocytes can inhibit the activation of the NF-κB signaling pathway and downregulate the levels of pro-inflammatory factors. In summary, our findings showed that GP-14 had significant anti-inflammation and anti-depression properties; thus, GP-14 could be a promising lead compound for treating depression.

Ferulic acid attenuated difenoconazole-induced immunotoxicity in carp by inhibiting TRAF/TAK1/NF-κB, Nrf2 and p53 pathways

Difenoconazole (DFZ) is a classical triazole fungicide that causes immunosuppression in non-target organisms. Ferulic acid (FA) is a polyphenolic molecule found in nature that has antioxidant and anti-inflammatory activities. The purpose of this investigation was to see if FA could prevent DFZ-induced immunosuppression and to identify the potential mechanisms. Carp were exposed to 1/10 LC50 of DFZ as well as fed normal feed or feed containing dietary additive FA for 30 d. It was found that DFZ-induced immunosuppression could be improved by FA, as evidenced by upregulation of Hb, C3 and IgM and downregulation of LDH. It was then investigated that FA could ameliorate DFZ-induced splenic injury through p53-mediated apoptosis. At the same time, enhancing the levels of CAT, GSH and T-AOC in spleen and transcription levels Nrf2 signaling pathway related genes indicated that FA reduced oxidative damage caused by DFZ by blocking the Nrf2 signaling pathway. In addition, FA inhibited the inflammatory response triggered by TRAF/TAK1/NF-κB signaling pathway, downregulated the transcript levels of pro-inflammatory factors (il-1β, tnf-α, il-6) and the level of NLRP3 inflammasome (NRLP3, ASC, Caspase 1), and upregulated the transcript levels of anti-inflammatory factors (tgf-β1, il-10). In conclusion, the above results suggested that FA mediated TRAF/TAK1/NF-κB, Nrf2, and p53 pathways to attenuate DFZ-induced inflammation, oxidative stress, and apoptosis thereby enhancing the immune capacity of carp.

Coffea arabica Extract Attenuates Atopic Dermatitis-like Skin Lesions by Regulating NLRP3 Inflammasome Expression and Skin Barrier Functions.

Atopic dermatitis (AD) is a common skin disease worldwide. The major causes of AD are skin barrier defects, immune dysfunction, and oxidative stress. In this study, we investigated the anti-oxidation and anti-inflammation effects of Coffea arabica extract (CAE) and its regulation of the skin barrier and immune functions in AD. In vitro experiments revealed that CAE decreased the reactive oxygen species levels and inhibited the translocation of nuclear factor-κB (NF-κB), further reducing the secretion of interleukin (IL)-1β and IL-6 induced by interferon-γ (IFN-γ)/tumor necrosis factor-α (TNF-α). Moreover, CAE decreased IFN-γ/TNF-α-induced NLR family pyrin domain-containing 3 (NLRP3), caspase-1, high-mobility group box 1 (HMGB1), and receptor for advanced glycation end products (RAGE) expression levels. It also restored the protein levels of skin barrier function-related markers including filaggrin and claudin-1. In vivo experiments revealed that CAE not only reduced the redness of the backs of mice caused by 2,4-dinitrochlorobenzene (DNCB) but also reduced the levels of pro-inflammatory factors in their skin. CAE also reduced transepidermal water loss (TEWL) and immune cell infiltration in DNCB-treated mice. Overall, CAE exerted anti-oxidation and anti-inflammation effects and ameliorated skin barrier dysfunction, suggesting its potential as an active ingredient for AD treatment.

Dendrobium officinale Kimura & Migo polysaccharide and its multilayer emulsion protect skin photoaging

Ethnopharmacological relevanceDendrobium officinale Kimura & Migo is traditionally used to treat skin diseases, gastrointestinal diseases, and other diseases. Dendrobium officinale polysaccharides (DOP) are the main component of Dendrobium officinale that accounts for its bioactivity, which shows a variety of effects such as moisturizing, antioxidant and anti-fatigue. However, there is no comprehensive study on the effect of DOP on skin photoaging combined with in vitro and in vivo models, and its specific mechanism is still unclear. Aim of the studyOur study aimed to explore the effect and underlying mechanism of DOP on skin photoaging, as well as to improve the stability and transdermal absorption of DOP. Materials and methodsDOP was extracted, purified and structurally characterized. In vitro HaCaT cell photoaging model was used to examine the photoprotection effect of DOP. Cell viability was detected by CCK-8; Intracellular reactive oxygen species were determined by DCFH-DA; DNA damage, cell apoptosis and cell cycle arrest were examined by flow cytocytometry. For autophagy flux detection, the adenovirus loaded with mRFP-GFP-LC3 was introduced into cells. Further, to enhance the stability and absorption of DOP, we designed and prepared the W/O/W type DOP multilayer emulsions (ME) by a two-step emulsification method. The emulsion stability, drug loading and encapsulation rate, DOP stability and DOP transdermal rate were detected. In vivo photoaging animal model was applied to compare the difference of photoaging protection effect between DOP solution and DOP ME. Specifically, skin appearance, histological change, antioxidant system, proinflammatory indicators, matrix metalloproteinases and autophagy level of skin tissues were examined and compared. ResultsThe results showed that DOP achieve photoaging protection by inhibiting oxidative stress, alleviating cell cycle arrest and apoptosis, and enhancing autophagy flux in photoaged HaCaT cells. The W/O/W type DOP multilayer emulsion (ME) with high encapsulation rate and strong stability was found to significantly improve the stability and transdermal absorption of DOP. In addition, our results showed that DOP (ME) remarkably improved skin condition of photoaged mice. Specifically, DOP (ME) enhanced the expression of antioxidant enzymes and autophagy and decreased the levels of pro-inflammatory factors and matrix metalloproteinases in the skin of photoaged mice as compared with DOP solution. ConclusionsIn conclusion, DOP was effective in improving skin photoaging, and the DOP multilayer emulsion we designed enhanced the stability and skin absorption of DOP, boosting DOP's protective effect against photoaging.

Histone Deacetylase 3 Inhibition Ameliorates Microglia-Mediated Neuro-Inflammation Via the SIRT1/Nrf2 Pathway After Traumatic Spinal Cord Injury

Background Microglial-induced inflammation plays a crucial role in the pathophysiological process of nervous system injury, however, still lacks effective therapeutic agents. Previously, we discovered that the inhibition of histone deacetylase 3 (HDAC3) exerts anti-inflammatory effects after traumatic spinal cord injury (SCI), whereas little is known about its underlying mechanism. Therefore, the present study aimed to explore the effects and potential mechanisms of HDAC3 on neuroinflammation and microglial function. Methods Rats were randomized into 4 groups: sham group, SCI group, SCI + vehicle group, and SCI + RGF966 group. To examine the effect of HDAC3 on neurological deficit after SCI, we gathered data using the Basso Beattie Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, junction protein expression, and Nissl staining. We also evaluated microglial activation and inflammatory factor levels. Immunofluorescence analysis, immunohistochemical analysis, western blotting, and quantitative real-time polymerase chain reaction were performed to examine the regulation of the Sirtuin 1 (SIRT1)/nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. Results The results showed that HDAC3 inhibition significantly ameliorated Basso–Beattie–Bresnahan (BBB) permeability, brain edema, and improved neurological functions and junction protein levels. Additionally, HDAC3 inhibition significantly inhibited microglial activation, thereby reducing the levels of SCI-induced pro-inflammatory factors. Moreover, HDAC3 inhibition dramatically enhanced the expression of SIRT1 and increased both Nrf2 nuclear accumulation and transcriptional activity, thereby increasing downstream heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1 expression. Conclusions The results of this study suggest that HDAC3 inhibition protects the spinal cord from injury following SCI by inhibiting SCI-induced microglial activation and the subsequent inflammatory response via SIRT1/Nrf2 signaling pathway, highlighting HDAC3 as a potential therapeutic target for the treatment of SCI.

Procyanidin improves experimental colitis by regulating macrophage polarization

BackgroundInflammatory bowel disease (IBD) is a chronic disease with an unclear pathogenesis for which successful treatments are still lacking. It has been reported that procyanidin, a natural antioxidant, relieves colitis, but the specific mechanism is elusive. PurposeOur present study was designed to investigate the effects of procyanidin on colitis and the regulation of the M1 macrophage phenotype and related signaling pathways. MethodsIn vivo, we used two classic colitis models to observe the effect of procyanidin on macrophage polarization. In vitro, we further validated the therapeutic effect of procyanidin in the RAW264.7 cell line and peritoneal macrophages. ResultsThe current findings provide new evidence that procyanidin ameliorated dextran sulfate sodium (DSS)-induced colitis by preventing the polarization of macrophages to the M1 type and downregulating the levels of proinflammatory factors in cells. We also showed that procyanidin prevented lipopolysaccharide (LPS)-induced elevation of inflammatory cytokines and the activation of proinflammatory macrophages, which was achieved by activating the STAT3 and NF-κB pathways. ConclusionsThis is the first study to demonstrate that procyanidin alleviates experimental colitis by inhibiting the polarization of proinflammatory macrophages. These data reveal new ideas for the pathogenesis and treatment of inflammatory diseases.

Microbiota from healthy mice alleviates cognitive decline via reshaping the gut-brain metabolic axis in diabetic mice

Diabetic cognitive decline has been associated with the gut microbial disorders, but its potential gut-brain axis mechanisms remain unclear. Herein we transplanted the gut microbiota from healthy mice into type 1 diabetic (T1D) mice and then investigated the effect of fecal microbiota transplantation (FMT) on cognitive function and the gut-brain metabolic axis. The results demonstrate that FMT from healthy mice effectively improved the learning and memory abilities in T1D mice, and significantly reduced neuroinflammation and neuron injury in the cortex and hippocampus. Moreover, FMT partly reversed the gut microbiota and gut-brain metabolic disorders, particularly glutamate metabolism. In vitro study, we found that glutamate notably decreased microglia activation and the expression levels of proinflammatory factor. Hence, our study suggests that glutamate serves as a key signal metabolite connecting the gut to brain and affects cognitive functions.

Regulation of tight junction proteins and cell death by peroxisome proliferator-activated receptor γ agonist in brainstem of hypertensive rats.

The decrease in tight junction proteins and their adapter proteins in the hypertensive brain is remarkable. Here, we aimed to investigate tight junction proteins and peroxisome proliferator-activated receptor (PPARγ) activation as well as inflammation factors and cell death proteins in the brainstem of hypertension models, namely spontaneously hypertensive rats (SHR) and borderline hypertensive rats (BHR). At first, SHR and BHR groups were treated with PPARγ agonist, pioglitazone. Then, occludin, claudin-1, claudin-2, claudin-12, ZO-1, and NF-κB p65 gene expression levels; pIKKβ, NF-κB p65, TNF, IL-1β, caspase-3, caspase-9 levels, and PARP-1 cleavage were evaluated. Significantly lower pIKKβ, NF-κB p65, TNF, and IL-1β levels were measured in pioglitazone-treated SHR. Results from this study confirm higher occludin (1.35-fold), claudin-2 (7.45-fold), claudin-12 (1.12-fold), and NF-κB p65 subunit (4.76-fold) expressions in the BHR group when compared to the SHR group. Pioglitazone was found effective in terms of regulating gene expression in SHR. Pioglitazone significantly increased occludin (8.17-fold), claudin-2 (2.41-fold), and claudin-12 (1.85-fold) mRNA levels, which were accompanied by decreased cleaved caspase-3, caspase-9 levels, PARP-1 activation, and proinflammatory factor levels in SHR (p ˂ 0.05). Our work has led us to conclude that alterations in tight junction proteins, particularly occludin, and cell death parameters in the brainstem following PPARγ activation may contribute to neuroprotection in essential hypertension.

Inhibition of CREB promotes glucocorticoids action on airway inflammation in pediatric asthma by promoting ferroptosis of eosinophils.

Pediatric asthma is a common chronic disease of childhood with airway inflammation. Cyclic adenosine monophosphate response element binding protein (CREB) plays a significant role in the transcription of proinflammatory genes, but its role in pediatric asthma has remained unclear. Herein, we investigated the functions of CREB in pediatric asthma. Eosinophils were purified from the peripheral blood of interleukin 5 (IL5) transgenic (IL5T) neonatal mice. The contents of CREB, long-chain fatty-acid-CoA ligase 4, transferrin receptor protein 1, ferritin heavy chain 1, and glutathione peroxidase 4 in eosinophils were examined by Western blot analysis. The viability of eosinophils, and the mean fluorescence intensity of Siglec F, C-C motif chemokine receptor 3 (CCR3), and reactive oxygen species were examined by flow cytometry. The concentration of iron in eosinophils was assessed by a commercial kit. The contents of malondialdehyde, glutathione, glutathione peroxidase, IL-5, and IL-4 were discovered by enzyme-linked-immunosorbent serologic assay. The C57BL/6 mice were randomly divided into four groups: sham, ovalbumin (OVA), OVA+Ad-shNC, and OVA+Ad-shCREB. The bronchial and alveolar structures were evaluated by hematoxylin and eosin staining. Leukocytes and eosinophils in the blood were measured using a HEMAVET 950. The abundance of CREB in eosinophils was enhanced by CREB overexpression vector transfection, but reduced by short hairpin (sh)CREB transfection. Downregulation of CREB triggered the cell death of eosinophils. Knockdown of CREB could obviously contribute to ferroptosis of eosinophils. In addition, downregulation of CREB facilitated dexamethasone (DXMS, a type of glucocorticoid)-induced eosinophils death. Moreover, we established an asthma mouse model by OVA treatment. The CREB was upregulated in OVA group mice, but Ad-shCREB treatment obviously downregulated CREB level. Downregulation of CREB diminished OVA-induced asthmatic airway inflammation by reducing the number of inflammatory cells and the levels of proinflammatory factors. Downregulated CREB enhanced the anti-inflammatory effect of DXMS in OVA-induced mice. Inhibition of CREB promoted the effect of glucocorticoids on airway inflammation in pediatric asthma through promoting ferroptosis of eosinophils.

Inhibition of xCT by sulfasalazine alleviates the depression-like behavior of adult male mice subjected to maternal separation stress

Maternal separation (MS) can induce emotional disorders. Our previous study reported that MS resulted in depression-like behavior. In this study, we aimed to explore the role of xCT in depression-like behavior in adult mice subjected to MS stress. Pups were divided into the control group, the control + sulfasalazine (SSZ, 75 mg/kg/day, i.p.) group, the MS group, and the MS+SSZ group. After MS, all pups were raised until PD60. Then, the depression-like behavior was detected by the novelty suppressed feeding (NSF) test, the forced swimming test (FST), and the tail suspension test (TST). The synaptic plasticity was examined by electrophysiological recordings and molecular biotechnology. The data showed that, compared with the control group, the mice in the MS group presented depression-like behavior, impairment of long-term potentiation (LTP), a reduction in the number of astrocytes, and activation of the microglia. Moreover, the expression of xCT was increased in the prefrontal cortex of MS mice, the EAAT2 and the Group Ⅱ metabotropic glutamate receptors (mGluR2/3) were decreased, and the level of pro-inflammatory factors was increased in the prefrontal cortex. After the administration with SSZ, the depression-like behavior and the impairment of LTP were alleviated, the number of astrocytes was increased, and the microglial activation was inhibited. Moreover, the levels of EAAT2 and mGluR2/3 were ameliorated, the over-activation of the microglia was mitigated, and the levels of glutamate and pro-inflammatory factors were decreased. In conclusion, the inhibition of xCT by SSZ could alleviate depression-like behavior partly via modulating the homeostasis of the glutamate system and dampening neuroinflammation.

Hesperetin attenuates cognitive dysfunction via SIRT6/NLRP3 pathway in scopolamine-induced mice.

Neuroinflammation is a critical feature in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). Hesperetin can exert anti-inflammatory, antioxidant and other neuroprotective effects. In this study, the scopolamine (SCOP)-induced cognitive dysfunction in mice model was used to evaluate the neuroprotective effects of hesperetin. Behavioral tests (Morris water maze, open field, and novel object recognition tests) were conducted to evaluate the effect of hesperetin on cognitive dysfunction behaviors. Nissl staining and Immunofluorescence were used to evaluate hippocampal neuronal damage and microglial activation in mice. The levels of proinflammatory factors, oxidant stress, and the cholinergic neurotransmitter were detected by real-time quantitative fluorescence PCR (RT-qPCR) or biochemical reagent kits. Western blotting was used to detect the relative protein expression of the sirtuin 6 (SIRT6) / NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway. Results showed that hesperetin could ameliorate SCOP-induced cognitive impairment and neuronal damage, and regulate the levels of cholinergic neurotransmitters in the hippocampal of AD mice. Hesperetin could also enhance antioxidant defense by regulating the levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT). Hesperetin exerted anti-neuroinflammation effects through inhibiting of microglia activation and down-regulating the mRNA transcript levels of inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Meanwhile, hesperetin could attenuate the expression of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), thioredoxin-interacting protein (TXNIP), and caspase-1 p20 and upregulate the expression of SIRT6 in SCOP-induced mice. Overall, our study suggested that hesperetin might ameliorate SCOP-induced cognitive dysfunction by improving cholinergic system dysfunction and suppressing oxidative stress and attenuating neuroinflammation via SIRT6/NLRP3 pathway in mice.

Subcutaneous Injection of Allogeneic Adipose-Derived Mesenchymal Stromal Cells in Psoriasis Plaques: Clinical Trial Phase I.

Mesenchymal stromal cells (MSCs) play immunomodulatory role in various autoimmune diseases. Previous pre-clinical and clinical studies have shown that MSCs could be a therapeutic modality for psoriasis. However, the mechanisms of treatment and its possible side effects are under investigation. In this study, the safety and probable efficacy of injecting allogeneic adipose-derived mesenchymal stromal cells (ADSCs) in psoriatic patients were evaluated. In this phase I clinical study with six months of follow-up, total number of 1×106 or 3×106 cells/cm2 of ADSCs were injected into the subcutaneous tissue of each plaque as a single dose in three males and two females (3M/2F) with a mean age of 32.8 ± 8.18. The primary outcome was safety. Changes in clinical and histological indexes, the number of B and T lymphocytes in local and peripheral blood, and serum levels of inflammatory cytokines were assessed. Paired t test was used to compare variables at two time points (baseline and six months after injection) and repeated measures ANOVA test was utilized for variables at three time points in follow-up visits. No major adverse effects such as burning, pain, itching, or any systemic side effects were observed following ADSCs injection, and the lesions showed slight to considerable improvement after injection. The mRNA expression levels of pro-inflammatory factors were reduced in the dermis of the patients after injection. The increased expression level of Foxp3 transcription factor in the patient blood samples suggested modulation of inflammation after ADMSCs administration. Six months after the intervention, no major side effects were reported, but skin thickness, erythema, and scaling of the plaques, as well as the PASI score, were decreased in majority of patients. Our study suggested that ADSC injection could be considered as a safe and effective therapeutic approach for psoriatic plaques (registration number: IRCT20080728001031N24).

The role of peroxisome proliferator-activated receptor γ in lipid metabolism and inflammation in atherosclerosis.

Cardiovascular disease events are the result of functional and structural abnormalities in the arteries and heart. Atherosclerosis is the main cause and pathological basis of cardiovascular diseases. Atherosclerosis is a multifactorial disease associated with dyslipidemia, inflammation, and oxidative stress, among which dyslipidemia and chronic inflammation occur in all processes. Under the influence of lipoproteins, the arterial intima causes inflammation, necrosis, fibrosis, and calcification, leading to plaque formation in specific parts of the artery, which further develops into plaque rupture and secondary thrombosis. Foam cell formation from macrophages is an early event in the development of atherosclerosis. Lipid uptake causes a vascular inflammatory response, and persistent inflammatory infiltration in the lesion area further promotes the development of the disease. Inhibition of macrophage differentiation into foam cell and reduction of the level of proinflammatory factors in macrophages can effectively alleviate the occurrence and development of atherosclerosis. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor that plays an important antiatherosclerotic role by regulating triglyceride metabolism, lipid uptake, cholesterol efflux, macrophage polarity, and inhibiting inflammatory signaling pathways. In addition, PPARγ shifts its binding to ligands and co-activators or co-repressors of transcription of target genes through posttranslational modification, thereby affecting the regulation of its downstream target genes. Many ligand agonists have also been developed targeting PPARγ. In this review, we summarized the role of PPARγ in lipid metabolism and inflammation in development of atherosclerosis, the posttranslational regulatory mechanism of PPARγ, and further discusses the value of PPARγ as an antiatherosclerosis target.

Mechanisms of Si-Wu Decoction in the treatment of ulcerative colitis revealed by network pharmacology and experimental verification

Ethnopharmacological relevanceSi-Wu Decoction (SWD) is a traditional Chinese medicine decoction. SWD is commonly used to treat blood deficiency syndrome. It is also used to treat some ulcerative colitis (UC) patients now, but the mechanism of action remains unclear. Aim of the studyThis study explored the efficacy and mechanism of action of SWD in treating UC based on network pharmacology and related experimental validation. Materials and MethodsSeveral databases were used to screen SWD for major active ingredients, targets of the ingredients, and UC disease genes. Cytoscape 3.8.2 software was used for topological analysis to construct the drug-compound-disease gene-target relationship network. The String database platform was used to construct the target protein interaction network. The DAVID (Database for Annotation, Visualization and Integrated Discovery) database was used to perform the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for the key targets. DSS (Dextran Sulfate Sodium)-induced UC mouse model was used to evaluate the in-vivo activity of SWD. Western Blot analysis and quantitative polymerase chain reaction were performed to verify the targets in the related pathways. ResultsNetwork pharmacology revealed that the SWD targeted pathway network involved 12 core targets and 15 major pathways. SWD may play a part by targeting key targets such as nuclear factor-kappaB (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway, and several mitogenic pathways. We showed that SWD largely restored the colorectal structure in UC model mice. Compared to the model group, the SWD group showed reduced infiltration of inflammatory cells. SWD significantly decreased the mRNA levels of IL-6 (Interleukin-6), TNF-α (Tumor necrosis factor-alpha), IL-1b (Interleukin-1beta) and other pro-inflammatory factors. Western Blot results showed that SWD concentration-dependently inhibited STAT3 and NF-κB activation in DSS-treated colon tissue. ConclusionOur findings suggest that SWD treats UC by inhibiting STAT3 and NF-κB signaling pathways, reducing the expression of inflammatory cytokines, and improving epithelial repair in experimental colitis, thus shedding light on the mechanisms by which SWD exerts its effects on UC.

Difenoconazole disrupts carp intestinal physical barrier and causes inflammatory response via triggering oxidative stress and apoptosis

As a common fungicide, difenoconazole (DFZ) is widespread in the natural environment and poses many potential threats. Carp makes up a significant proportion of China's freshwater aquaculture population and are vulnerable to the DFZ. Therefore, this study investigated the effects of DFZ (0.488 mg/L and 1.953 mg/L) exposure for 4 d on the intestinal tissues of carp and explored the mechanisms. Specifically, DFZ exposure caused pathological damage to the intestinal tissues of carp, reducing the expression levels of intestinal tight junction proteins, and leading to damage to the intestinal barrier. In addition, DFZ exposure activated the NF-κB signaling pathway, increasing the levels of pro-inflammatory factors (TNF-α, IL-1β, IL-6) and decreasing the levels of anti-inflammatory factors (IL-10, TGF-β1). As disruption of the intestinal barrier is closely linked to oxidative stress and apoptosis, we have conducted research in both areas for this reason. The results showed that DFZ exposure elevated reactive oxygen species in carp intestines, decreased antioxidant enzyme activity, and suppressed the expression of oxidative stress-related genes. TUNEL results showed that DFZ induced the onset of apoptosis. In addition, the expression levels of apoptosis-related genes and proteins were examined. Western blotting results showed that DFZ could upregulate the protein expression levels of Bax, Cytochrome C and downregulate the protein levels of Bcl-2. qPCR results showed that DFZ could upregulate the transcript levels of Bax, Caspase-3, Caspase-8 and Caspase-9 and downregulate the transcript levels of Bcl-2 transcript levels. This suggests that DFZ can induce apoptosis of mitochondrial pathway in carp intestine. In conclusion, DFZ can induce oxidative stress and apoptosis in carp intestine, leading to the destruction of intestinal physical barrier and the occurrence of inflammation. Our data support the idea that oxidative stress and apoptosis are important triggers of pesticide-induced inflammatory bowel illness.

Influence of fish protein hydrolysate on intestinal health and microbial communities in turbot Scophthalmus maximus

This study aimed to investigate the effect of fish protein hydrolysate (FPH) on intestinal microbiota and health of turbot Scophthalmus maximus (average initial body weight 25.5 g). Two control diets were formulated to contain 360 g kg −1 (high fish meal, HFM) and 240 g kg−1 (low fish meal, LFM) of fish meal. Two experimental diets were derived from the HFM diet by replacing fish meal with FPH at levels of 100 g kg−1 (appropriate level, FPH10) or 300 g kg−1 (excessive level, FPH30). The supplementation of FPH at an appropriate level showed a positive effect on growth performance. According to chyme amino acid concentrations, moderate FPH in diets can alleviate the rate of amino acid absorption in middle intestine than excessive one (FPH30), and more thoroughly absorbed in distal intestine than fish meal (HFM) and plant protein (LFM). Histology of distal intestine showed that an appropriate level of FPH in diets could serve to alleviate the symptoms of structural damage (villi height and wall thickness) to the intestine caused by plant protein. The expressions of tight junction proteins and mucin 2 in the FPH10 and FPH30 diets was up-regulated in middle intestine compared to the LFM diet. FPH at a moderate level reduced the levels of pro-inflammatory factors (IL-1β and TNF-α) but didn't increased anti-inflammatory factors (IL-10 and TGF-β) in middle intestine compared with the LFM diet. To turbot, mucosa and chyme-associated microbiota from middle and distal intestine mainly belonged to Proteobacteria and Firmicutes. The bacterial richness, diversity and/or evenness decreased in middle intestine chyme, distal intestine mucosa and/or chyme when fish were fed diets containing FPH. Fish fed an appropriate level of FPH showed an increase of genera Bacillus in middle intestine mucosa and a decrease of genera Vibrio in distal intestine mucosa, while there was an inverse trend in fish fed an excessive level of FPH. Overall, FPH at an appropriate level showed a positive effect on intestinal health by improving middle or distal intestinal structure integrity and barrier function, as well as regulating immune-related inflammatory factors. Meanwhile, moderate FPH in diets may modulate the abundance of potentially probiotic (Bacillus) and pathogenic (Vibrio) in the intestine.

Glucocorticoid nanoformulations relieve chronic pelvic pain syndrome and may alleviate depression in mice

BackgroundChronic pelvic pain syndrome (CPPS) is a typical symptom of chronic prostatitis (CP) in males that may cause abnormal urination, sexual dysfunction, or depression and significantly affect the quality of life of the patient. Currently, there is no effective treatment for CPPS due to its recurrence and intractability. For synergistic CPPS therapy, we developed pH/reactive oxygen species (ROS) dual-responsive dexamethasone (Dex) nanoformulations using a ROS-responsive moiety and phytochemical modified α-cyclodextrin (α-CD) as the carrier.ResultsDex release from the nanoformulations can be controlled in acidic and/or ROS-rich microenvironments. The fabricated Dex nanoformulations can also be efficiently internalized by lipopolysaccharide (LPS)-stimulated macrophages, prostatic epithelial cells, and stromal cells. Moreover, the levels of proinflammatory factors (e.g., TNF-α, IL-1β, and IL-17 A) in these cells were significantly decreased by Dex nanoformulations treatment through the release of Dex, phytochemical and elimination of ROS. In vivo experiments demonstrated notable accumulation of the Dex nanoformulations in prostate tissue to alleviate the symptoms of CPPS through the downregulation of proinflammatory factors. Interestingly, depression in mice may be relieved due to alleviation of their pelvic pain.ConclusionWe fabricated Dex nanoformulations for the effective management of CPPS and alleviation of depression in mice.

Physiopathological mechanisms related to inflammation in obesity and type 2 diabetes mellitus.

Overweight, obesity, and type 2 diabetes mellitus pose global health problems that are ever-increasing. A chronic low-grade inflammatory status and the presence of various pro-inflammatory markers either in circulation or within dysfunctional metabolic tissues are well established. The presence of these factors can, to some extent, predict disease development and progression. A central role is played by the presence of dysfunctional adipose tissue, liver dysfunction, and skeletal muscle dysfunction, which collectively contribute to the increased circulatory levels of proinflammatory factors. Weight loss and classical metabolic interventions achieve a decrease in many of these factors' circulating levels, implying that a better understanding of the processes or even the modulation of inflammation may alleviate these diseases. This review suggests that inflammation plays a significant role in the development and progression of these conditions and that measuring inflammatory markers may be useful for assessing disease risk and development of future treatment methods.