Levels Of IL-6 Research Articles

Inhibition of PDE4B ameliorates cognitive defects in the model of alcoholic dementia in 3×Tg-AD mice via PDE4B/cAMP/PKA signaling.

Chronic, heavy alcohol use may lead to permanent brain damage, cognitive impairment, and dementia. One of the most serious consequences is alcoholic dementia (AlD). Phosphodiesterase-4 (PDE4) inhibitors have been shown to exhibit beneficial effects on cognition deficits and alcoholism. However, it is not known whether PDE4 inhibitors can be used to treat AlD. A33, a relatively selective PDE4B inhibitor, is absent of the emetic effect associated with PDE4D. The effect of A33 on memory and cognition in AlD remains unclear. We investigated the effects of A33 and the PDE4 inhibitor rolipram on memory and cognition using an AlD animal model, i.e., APP/PS1/Tau mice drinking alcohol in the two-bottle choice test, with or without A33 or rolipram treatment for 3wk. The animal groups were compared in behavioral tests related to learning and memory. Neurochemical measures were conducted to explore the underlying mechanism of A33. Compared to WT controls, AlD mice showed impairments of learning ability and memory in the behavior tests; this was attenuated by treatment of rolipram or A33. In addition, administration of rolipram or A33 in AlD mice further alleviated neuropathological alterations in the hippocampus, including Aβ expression and deposition; rolipram or A33 also decreased the levels of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, as well as NF-κB. Further, rolipram or A33 decreased the activation of microglia while increased cAMP levels in the hippocampus of AlD mice. These results revealed that the alleviation of the cognitive impairment of AlD in APP/PS1/Tau triple transgenic mice by rolipram or A33 was linked to the action of the PDE4B/cAMP/PKA signaling pathway. A33 can be a promising therapeutic agent for AlD-related cognitive dysfunction.

Mitigating effects of Jiawei Chaihu Shugan decoction on necroptosis and inflammation of hippocampal neurons in epileptic mice

Jiawei Chaihu Shugan decoction (JWCHSGD) is a traditional Chinese medicine well-known for its beneficial effects in treating epilepsy (Xianzheng in ancient Chinese), but the molecular mechanism of its action remains unclear. To investigate the molecular mechanism of JWCHSGD’s prevention of epilepsy-mediated neuron from necroptosis and inflammation via the circRNA-Csnk1g3/Csnk1g3-85aa/ CK1γ3/TNF-α signal pathway. In vitro, murine neuronal HT22 cells were treated in six groups: control, model, carbamazepine, and three JWCHSGD doses (high, medium, low). Viability and apoptosis were assessed via CCK-8 and flow cytometry. In vivo, 60 C57BL/6J mice were divided into six groups: control, model, carbamazepine, JWCHSGD, JWCHSGD + Sh Circ_Csnk1g3, and JWCHSGD + Sh NC. An epilepsy model was induced, and treatments were administered for two weeks. Outcomes included EEG, hippocampal histopathology, apoptosis (TUNEL), and mRNA/protein expression of key pathway markers. In HT22 cells, the model group showed reduced viability, increased apoptosis, and elevated mRNA/protein levels of Csnk1g3-85aa, RIP1, RIP3, MLKL, TNF-α, IL-6, and IL-1β (P < 0.05). JWCHSGD and carbamazepine increased viability and decreased apoptosis, reversing these molecular changes (P < 0.05). In mice, the model group had heightened epileptic discharges, neuronal damage, and apoptosis, along with increased expression of the same markers (P < 0.05). JWCHSGD and carbamazepine mitigated these effects (P < 0.05). JWCHSGD reduces epileptic events by regulating the circRNA-Csnk1g3/Csnk1g3-85aa/CK1γ3/TNF-α signaling pathway, impacting necroptosis and inflammation in hippocampal neurons and HT22 cells.

Neospora caninum Inhibits Lewis Cancer and B16f10 Melanoma Lung Metastasis Development by Activating the Immune Response in Murine Models.

Malignant tumors are prevalent with high mortality rates in humans, dogs, and cats. Some microorganisms have been shown to inhibit cancer progression. The objective of this study is to evaluate the inhibitory effects of Neospora caninum, a livestock parasite, on three different tumor models in C57BL/6 mice, including Lewis subcutaneous tumors, Lewis and B16F10 melanoma lung metastasis. The results showed that a sufficient amount of N. caninum tachyzoites can significantly inhibit the development of subcutaneous tumors and lung metastasis (P < 0.001), and induce more than 50% tumor cell death in Lewis subcutaneous tumors. N. caninum treatment can significantly increases the infiltration of macrophages, NK cells, and CD8+ T cells (P < 0.0001) in Lewis subcutaneous tumors detected by immunohistochemistry, and the percentage of these immunocytes in the spleen (P < 0.05) of mice bearing B16F10 melanoma metastasis detected by flow cytometry. And with these changes, the mRNA expression levels of IL-12, IFN-γ, IL-2, IL-10, TNF-α and PD-L1 in tumor microenvironment and IL-12, IFN-γ, IL-2 in spleen were also significantly increased (P < 0.05). Altogether, our results indicate that a sufficient amount N. caninum tachyzoites not only inhibits the growth of Lewis subcutaneous tumors, but inhibits the development of Lewis and B16F10 melanomas lung metastatic in mice by activating potent immune responses. N. caninum and its anti-tumor properties may be an effective anti-tumor tool.

Quetiapine combined with escitalopram in the treatment of bipolar depression along with effects on inflammation and oxidative stress.

To assess the efficacy of escitalopram combined with quetiapine vs quetiapine alone in the treatment of depressive episodes of bipolar disorder (BPD). 88 hospitalized patients with a BPD depressive episode were recruited into the study. All patients were randomized to a control group (n = 44) or the intervention group (n = 44). Members of the control group received quetiapine fumarate alone, with an initial dose 50mg/time twice/day; the dose was increased by 50-100mg daily until 300-600mg/d was reached. The treatment group received quetiapine at the same doses plus escitalopram, with the initial dose of escitalopram 10mg/d, adjusting the dose to 20mg/d after 1week. Both groups were treated for 8weeks. The scores on the Hamilton Depression Scale (HAMD) and Young Mania Rating Scale (YMRS), along with levels of IL-6, IL-1β, MIF, SOD, CAT, MDA and GSH-Px, were compared between groups. Among those in the intervention group, 88.6% of participants experienced a 50% or greater reduction in HAMD score compared to 70.5% in the control group (P < .05). Participants in the intervention group also experienced a significantly greater reduction in IL-6, IL-1β, MIF and MDA levels (P < .05), and a significant increase in SOD, CAT and GSH-Px levels compared to the control group (P < .05). Escitalopram oxalate combined with quetiapine is more effective than quetiapine alone in the treatment of patients with bipolar depressive episodes, which can effectively improve the symptoms of depression, inhibit the body's inflammatory response, regulate the state of oxidative stress, and does not increase the risk of mania.

Downstream Link of Vitamin D Pathway with Inflammation Irrespective of Plasma 25OHD3: Hints from Vitamin D-Binding Protein (DBP) and Receptor (VDR) Gene Polymorphisms

Background: Vitamin D insufficiency/deficiency is a highly prevalent condition worldwide. At the same time, chronic inflammation is a versatile pathophysiological feature and a common correlate of various disorders, including vitamin D deficiency. Methods: We investigated the possible association of inflammation with 25-hydroxyvitamin D3 (25OHD3) levels and its down-stream pathway by exploring vitamin D-binding protein (DBP) and vitamin D receptor (VDR) genes for single-nucleotide polymorphisms (SNPs), in healthy non-elderly Bahraini adults. Plasma levels of 25OHD3 were measured by chemiluminescence, and six SNPs, four in the GC gene (rs2282679AC, rs4588CA, rs7041GT, and rs2298849TC) and two in the VDR gene (rs731236TC and rs12721377AG) were genotyped by real-time PCR. The concentrations of five inflammatory biomarkers, IL6, IL8, procalcitonin (PCT), TREM1, and uPAR, were measured by ELISA. Results: The results showed no association between the 25OHD3 level and any of the inflammatory markers’ levels. However, three tested SNPs were significantly associated with the concentrations of tested biomarkers except for IL6. The TT mutant genotype of rs2298849TC was associated with lower levels of IL8 and higher levels of PCT and TREM1, the AA mutant genotype of rs2282679AC was associated with decreased levels of IL8 (p ≤ 0.001) and increased levels of TREM1 (p = 0.005), and the GG wild genotype of rs12721377AG was associated with increased levels of 25OHD3 (p = 0.026). Conclusions: Although chronic inflammation is not associated with the vitamin D system in the blood, it is downstream, as revealed by DBP and VDR genotyping. Alternatively, DBP and VDR pursue other functions beyond the vitamin D pathway.

Inflammatory cytokine levels in Rheumatic Heart Disease and their association with use of Benzathine Penicillin: A Case-Control Pilot Study.

Valvular inflammation plays an important role in the progression of Rheumatic Heart Disease. We report the association between inflammatory markers and use of Benzathine Penicillin G in patients with Rheumatic mitral valve disease. The levels of inflammatory cytokines; IL-1β, IL-6, TNF-α and inflammatory marker hs- CRP were measured using ELISA method in 32 patients with RHD receiving Benzathine Penicillin as secondary prophylaxis and 31 patients not receiving secondary prophylaxis, in a case-control study. The severity and type of valvular dysfunction were assessed with echocardiogram. The median level of IL-1β was significantly lower in patients on BPG (0.95 pg/ml vs. 5.47 pg/ml) p<0.002. The median levels of IL-6, TNF-α and hs-CRP were not significantly different between study groups. The adjusted odds of raised IL-1β were lower in patients on BPG (odds ratio 0.40, 95% C.I. 0.11, 1.45) p 0.16. There was a trend of inverse association between the use of BPG and mitral stenosis (odds ratio 0.42, 95% C.I. (0.12, 1.46) p 0.17. Patients with RHD on BPG had lower levels of IL-1β and a trend toward a lower prevalence of mitral stenosis. Role of IL-1β in progression of incompetent to stenotic mitral valve dysfunction needs to be explored in future studies.

Oral lactoferrin as a treatment of pediatrics’ anemia resulted from chronic kidney diseases: a randomized controlled trial

Anemia in pediatrics is often associated with chronic conditions such as chronic kidney disease (CKD). It can worsen the disease prognosis and affect quality of life. Injectable dosage forms are predominantly used in its treatment with various side effects. This randomized and parallel clinical trial aimed to compare the effectiveness of oral lactoferrin with intravenous (IV) iron dextran in managing anemia resulted from CKD in pediatrics. The study involved 60 children diagnosed with CKD-related anemia who were allocated into two separate groups. Group 1 consisted of 30 pediatric patients who received 100 mg of oral lactoferrin daily for a period of 3 months. Group 2 included 30 pediatric patients who were given IV iron dextran at a dosage of 50 mg three times weekly for 3 months. Both treatments are effective in treating CKD-induced anemia in pediatrics; however, oral lactoferrin demonstrated superior efficacy as there was a significant change within that group in levels of Hb, RBCs, MCH, iron, RDW-SD, MCHC, IL-6, and GDF-15 before and after treatment. In contrast, IV iron dextran showed significant changes within its group in iron, GFR, IL-6, GDF-15, and RDW-SD. After 3 months of treatment, no significant differences were observed between the two groups.

Batryticatus bombyx improved atopic dermatitis in NC/Nga mice and impact on inflammation and recovery of skin barrier via STAT1/P38/NF-κB downregulation and HO-1/Nrf2 activation in HaCaT keratinocytes.

Batryticatus bombyx (BB) (Beauveria bassiana Vuill.) is used as an herbal medicine and food additive. Although BB has neuroprotective and anti-apoptotic effects, its impacts on atopic dermatitis (AD) are unknown. We evaluated the effects of BB in an NC/Nga mouse model of house dust mite (HDM)-induced AD, in TNF-α and IFN-γ (TI)-stimulated HaCaT keratinocytes, and in a 3D human skin model. NC/Nga mice were induced with HDM and treated with BB for 6 weeks. We assessed skin symptoms, serum levels of IgE, histamine, and IL-6, immune cell counts, and performed histological analysis of dorsal skin tissue. Additionally, we induced inflammation in HaCaT cells and a 3D human skin model using TNF-α/IFN-γ. We measured inflammatory cytokine levels, skin hydration factors, and delved into underlying mechanisms via ELISA, real-time PCR, and Western blot. BB improved skin lesions, reduced thickness, and inflammatory cell infiltration in HDM-induced mice. It alleviated scratching, improved moisture retention, and reduced IgE, histamine, and IL-6 levels. In HaCaT cells, BB inhibited thymic stromal lymphopoietin and increased hyaluronan content. It also upregulated aquaporin-3, hyaluronan synthase-1/3, filaggrin, involucrin, and occludin, enhancing skin hydration and tight junction stability. BB decreased STAT1, p38 MAPK, and NF-κB p65 levels in HaCaT cells and exhibited antioxidant effects by increasing HO-1/Nrf2 expression. BB may serve as a therapeutic alternative for AD treatment by inhibiting skin inflammation.

Identification of growth differentiation factor 15 as an early predictive biomarker for metabolic dysfunction-associated steatohepatitis: A nested case-control study of UK Biobank proteomic data.

This study aims to determine the predictive capability for metabolic dysfunction-associated steatohepatitis (MASH) long before its diagnosis by using six previously identified diagnostic biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) with proteomic data from the UK Biobank. A nested case-control study comprising a MASH group and three age- and sex-matched control groups (metabolic dysfunction-associated steatosis, viral hepatitis and normal liver controls) was conducted. Olink proteomics, anthropometric and biochemical data at baseline levels were obtained from the UK Biobank. The baseline levels of CDCP1, FABP4, FGF21, GDF15, IL-6 and THBS2 were analysed prospectively to determine their predictive accuracy for subsequent diagnosis with a mean lag time of over 10 years. At baseline, GDF15 demonstrated the best performance for predicting MASH occurrence at 5 and 10 years later, with AUCs of 0.90 at 5 years and 0.86 at 10 years. A predictive model based on four biomarkers (GDF15, FGF21, IL-6 and THBS2) showed AUCs of 0.88 at both 5 and 10 years. Furthermore, a protein-clinical model that included these four circulating protein biomarkers along with three clinical factors (BMI, ALT and TC) yielded AUCs of 0.92 at 5 years and 0.89 at 10 years. GDF15 at baseline levels outperformed other individual circulating protein biomarkers for the early prediction of MASH. Our data suggest that GDF15 and the GDF15-based model may be used as easy-to-implement tools to identify patients with high risks of developing MASH at a mean lag time of over 10 years.

Effects of increasing levels of rubber seed cake on growth performance, nutrient digestion metabolism, serum biochemical parameters, and rumen microbiota of Hu sheep

This study aimed to reveal the effects of increasing levels of rubber seed cake (RSC) on growth performance, nutrient digestion metabolism, serum biochemical parameters, and rumen microbiota in Hu sheep. In this study, 48 Hu sheep, weighing 17.01 ± 0.57 kg at 3 months of age, were randomly divided into four treatments: 0% rubber seed cake (RSC0%), 6% rubber seed cake (RSC6%), 12% rubber seed cake (RSC12%) and 18% rubber seed cake (RSC18%), with 12 sheep per group. Compared to the RSC0%, the ADG and DMI of the RSC6% and RSC12% were increased (P > 0.05). The apparent digestibility of OM and EE quadratically (P < 0.05) changed with the increase of RSC supplementation, with the greatest apparent digestibility of OM and EE observed in the RSC6% diet. With increased RSC supplementation, the N intake and fecal N increased linearly (P < 0.05), and the apparent digestibility of N reduced linearly (P < 0.05). As the increase of RSC supplementation, the serum levels of IgA, IgM, IgG, IL-4, T-AOC, and GSH-Px increased linearly (P < 0.05), and the serum level of IL-6 reduced linearly (P < 0.05). The serum level of IL-1β reduced quadratically (P < 0.05) with the increased RSC dose, and the serum level of SOD increased quadratically (P < 0.05) with the increased RSC dose. The ruminal NH3-N and the relative abundance of norank_Muribaculaceae quadratically (P < 0.05) changed with increased RSC supplementation, and the greatest relative abundance of norank_Muribaculaceae was observed in the RSC6% diet. In general, incorporating RSC into the diet of Hu sheep did not adversely affect growth performance and rumen fermentation characteristics. Supplementing with 6% RSC enhanced the relative abundance of norank_Muribaculacea in the rumen fluid and the immune and antioxidant capabilities. However, supplementing with 12 and 18% RSC might have negatively impacted nutrient digestion and metabolism. Therefore, this study recommended replacing corn and soybean meal with 6% RSC in the diet of Hu sheep.

Cytokines and Depressive Symptoms Among Adolescents.

Background: Inflammation has been linked to an increased risk of depression, but there is limited and conflicting research on the role of inflammatory markers in adolescent depression. The purpose of this study was to examine associations between cytokines TNF-α, IL-1β, IL-6, and IL-8 and depression among a community-based sample of adolescents (13-19years of age). Methods: Salivary samples were self-collected by adolescents for assay of cytokines. The Patient Health Questionnaire-9 (PHQ-9) was used to measure depressive symptoms and clinical depression, where a score ≥11 indicated the threshold for experiencing clinical depression. Multiple linear and logistic regression models were used to examine the relationships between cytokines and depression, adjusting for age, sex, ethnicity, income, and body mass index. Results: The mean age of the 83 participants was 15.86years. Eight participants screened positive for depression; the mean depressive symptom score was 5.11. Higher levels of IL-6 (Coef = 1.33, p < .001) and IL-8 (Coef = 0.69, p = .025) were associated with more frequent depressive symptoms while higher levels of TNF-α (OR = 2.50, p = .002), IL-1β (OR = 1.98, p = .001), and IL-8 (OR = 2.44, p = .008) were associated with greater odds of meeting criteria for clinical depression. Conclusions: Future research should focus on factors that induce higher cytokine levels and the mechanisms underlying their effects on depression. Cytokines assessed in this study may ultimately have implications as methods for depression screening or targets for biologic interventions to prevent and treat adolescent depression.

Effects of high-intensity interval training on physical performance, systolic blood pressure, oxidative stress and inflammatory markers in skeletal muscle of spontaneously hypertensive rats.

To investigate whether high-intensity interval training (HIIT) improves physical performance, systolic blood pressure, and markers of oxidative stress and inflammation in skeletal muscle of spontaneously hypertensive rats (SHR). Nineteen male SHR rats were randomly assigned to two groups: sedentary (SHRC) and trained (SHR+T). The SHR+T group trained five times a week for eight weeks on a treadmill, while the SHR group remained without any exercise stimulus throughout the experimental period. Maximum physical performance and systolic blood pressure (SBP) were assessed before and after the training period. The following variables were measured in the tibialis anterior (TA) muscle: gene expression of the NADPH oxidase complex (NOX2, NOX4, p22phox, p47phox) and the NF-kB pathway (NF-kB and Ik-B), lipid peroxidation (malonaldehyde; MDA), protein carbonylation, hydrophilic antioxidant capacity (HAC) and pro-inflammatory cytokines (IL-6 and TNF-α). SHR+T rats showed higher physical performance and levels of IL-6, and lower SBP and protein carbonylation (p<0.05), compared with SHRC rats. No significant differences (p>0.05) were observed in the other variables. Our results indicate that HIIT is an effective non-pharmacologic strategy to improve physical performance, reduce SBP, and modulate the skeletal muscle oxidative damage and inflammation in hypertensive rats.

Exosomal PINK1 from Human Umbilical Cord Mesenchymal Stem Cells Attenuates Neurological Deficits and Inflammatory Responses after Intracerebral Hemorrhage in Mice.

This study investigated the therapeutic potential of exosomes from human umbilical cord mesenchymal stem cells (huMSCs), focusing on PTEN-induced kinase 1 (PINK1) and its impact on exosome efficacy. Postmodification, exosomes were administered to a murine model of intracranial hemorrhage (ICH). Assessments included brain edema, neurological function, anxiety-like behaviors, inflammatory responses, and microglial polarization. We observed that administration of exosomes from control huMSCs significantly reduced brain water content, indicating a reduction in brain edema, as quantitatively assessed through water content analysis. Neurological function, evaluated using a standard scoring system, showed marked improvement in animals treated with control exosomes compared with those receiving PINK1-deficient exosomes, highlighting the importance of PINK1 in mediating neurological recovery. Additionally, control exosomes substantially decreased anxiety-like behaviors in the Open Field Test, demonstrated by reduced immobility times and increased exploratory behavior. Inflammatory response assessments showed a favorable shift with decreased levels of pro-inflammatory cytokines (MCP-1, IL-1β, TNF-α) and increased levels of the anti-inflammatory cytokine IL-10 in the exosome-treated groups. Furthermore, analysis of microglial polarization revealed a shift toward the anti-inflammatory M2 phenotype, evidenced by decreased M1 markers (Cd86, Iba1) and increased M2 markers (Arg1, Cd206) in the control exosome-treated group. Taken together, we found that PINK1-deficient exosomes showed reduced therapeutic efficacy in ICH treatment compared with the exosomes with normal PINK1 expression. Our findings underscore the critical role of PINK1 in enhancing the therapeutic potential of huMSC-derived exosomes in ICH treatment.

Normal butanol fraction of Polygonum hydropiper L. flavonoids reduces inflammation caused by PCV2 infections in cell and mouse models

IntroductionThe normal butanol fraction of Polygonum hydropiper L. flavonoids (FNB) exhibits significant anti-inflammatory effects. This study investigated FNB's impact on inflammatory responses induced by Porcine circovirus type 2 (PCV2) in cell and mouse models.MethodsAn inflammatory model was established in RAW264.7 cells infected with varying PCV2 concentrations. And assigning both RAW264.7 cells and 108 SPF-grade KM mice to Control, PCV2, Rutin, and various dosages of FNB groups. Inflammatory factors such as Monocyte Chemoattractant Protein-1 (MCP-1), interleukin-6 (IL-6), IL-8, IL-10, Tumor Necrosis Factor-alpha (TNF-α), Reactive Oxygen Species (ROS), and Nitric Oxide (NO) were quantified using ELISA, RT-qPCR and immunohistochemistry.ResultsResults showed that a PCV2 titer of 104.5 TCID50/0.1 mL when applied to RAW264.7 cells effectively established an in vitro inflammatory model at 12 and 24 h post-infection. Following PCV2 infection, all the inflammatory factors displayed a significant increased both in culture supernatant and intracellular mRNA expression levels (p &amp;lt; 0.05 or p &amp;lt; 0.01), but these levels were reduced by FNB treatment (p &amp;lt; 0.05 or p &amp;lt; 0.01). In mouse sera post-PCV2 infection also showed elevated levels of IL-6, IL-8 IL-10, TNF-α, and MCP-1 (p &amp;lt; 0.05 or p &amp;lt; 0.01). Additionally, mRNA and protein levels for TNF-α, IL-8, IL-10, IL-6, and iNOS rose significantly in lung tissues (p &amp;lt; 0.01) but decreased with FNB treatment (p &amp;lt; 0.05 or p &amp;lt; 0.01).DiscussionThese findings suggest that FNB reduces inflammatory factor production and modulates the inflammatory response triggered by PCV2 infection, potentially enhancing host resistance against it.

IL-6 mediated CD206+ARG-1+ tumor associated macrophage polarization induces Treg infiltration in non-responder luminal A breast cancer.

Drug non-responsiveness is the major reason for the poor prognosis of hormonal receptor-positive breast cancer (ER+/PR+ BCa), particularly the luminal A subtype. However, the underlying mechanism of drug non-responsiveness remains unknown. Flow cytometry and t-SNE analysis followed by ELISA validation of responder and non-responder unveiled lower secretion of IFN-γ, IL-12, and higher levels of IL-6 and TGF-β in CD4+ Tcells (P < 0.001), CD8+ Tcells (P < 0.001), FOXP3+ Tregs (P < 0.001) and CD206+ TAMs (P < 0.001) in non-responders. Treatment of isolated CD206+ TAMs with recombinant IL-6 upregulated the expression of ARG-1 (arginase-1) and subsequent increase of TGF-β+ Tregs (P < 0.001) and IL-6+ Tregs (P < 0.001) in luminal A BCa. Our findings showed IL-6 mediated ARG-1+CD206+ TAMs polarization induced FOXP3+ Tregs infiltration in TME of non-responder in luminal A BCa.

Study on the Mechanism of Anti-Atopic Dermatitis by Herba Siegesbeckiae Based on Metabolomics.

Atopic dermatitis is a common inflammatory skin disease worldwide that is characterized by skin barrier dysfunction, itching, and a reduced quality of life. The research at hand aimed to delve into the anti-atopic dermatitis mechanism of Herba Siegesbeckiae, a traditional medicinal herb, using a metabolomic approach. The molecular mechanism by which Herba Siegesbeckiae acts against atopic dermatitis was investigated by establishing a mouse model of atopic dermatitis while conducting a metabolomics analysis on its metabolites. Interleukin IL-13, IL-17A, IL-3, IL-31, IL-33, IL4, IL-5, TSLP, IgE, and histamine levels in serum, participating in inhibiting itching and regulating immunity signaling were found to be restored to varying degrees in AD treating with HS. A total of 31 differential metabolites were selected from metabolomics results, among which N-acetyl-L-alanine (VIP = 1.62), Nacetyl- L-methionine (VIP = 1.5), uracil (VIP = 1.47), and prostaglandin E2 (VIP = 1.4) play important roles in the anti-AD regulatory mechanisms of HS and can be used as biomarkers. In addition, the mechanisms of HS anti-AD have been shown to be associated with seven metabolic pathways, including β-alanine metabolism, glycerophospholipid metabolism, histidine metabolism, and so on. In conclusion, HS demonstrated properties that counteract Atopic Dermatitis by suppressing itchiness and boosting the immune system, subsequently controlling the concentrations of related metabolites.

Intranasal delivery of hMSC-derived supernatant for treatment of ischemic stroke by inhibiting the pro-inflammatory polarization of neutrophils

BackgroundStem cells utilized for ischemic stroke treatment often display unstable homing capabilities and diminished activity in vivo, limiting their neuroprotective efficacy. Furthermore, the optimal delivery route for stem cells remains undetermined. While the cytokines secreted by stem cells show promise in modulating post-stroke inflammation, the direct application of these supernatants in ischemic stroke treatment and the underlying mechanisms are still unclear.MethodsSecretory supernatants (hMSC-L) and cell lysate products (hMSC-M) from primary human umbilical cord mesenchymal stem cells-cultured medium were administered intranasally to mice with cerebral ischemia. The neuroprotective effects of hMSC-L and hMSC-M were assessed with TTC staining, behavioral tests and pathological staining. Flow cytometry and qPCR evaluated the expression of immune cells and cytokines in the CNS and peripheral immune organs. In vitro, flow cytometry and ELISA measured the effects of hMSC-L and hMSC-M on N2 polarization and inflammatory cytokines expression in primary murine neutrophils. Western blot analysis determined the impact of hMSC-L and hMSC-M on the PPAR-γ/STAT6/SOCS1 pathway, which is crucial for N2 neutrophil polarization.ResultsTTC staining, behavioral experiments, and pathological assessments reveal intranasal delivery of hMSC-L and hMSC-M significantly reduces the infarct volume of mice with cerebral ischemia, improves neurological function scores, and promotes motor function recovery. Higher concentrations of hMSC-M contributed a more pronounced effect on neuropathological improvements in ischemic mice. Intranasal delivery of hMSC-L and hMSC-M significantly reduces neutrophil infiltration in the brain post-stroke and increases the proportion of anti-inflammatory N2-subtype neutrophils, boosting the expression levels of IL-10 and TGF-β. In vitro experiments demonstrate that hMSC-L and hMSC-M promote nuclear translocation of PPAR-γ in neutrophils stimulated with PMA, activating the downstream STAT6/SOCS1 signaling pathway to encourage N2-subtype neutrophil polarization.ConclusionsIntranasal delivery of hMSC-L and hMSC-M effectively ameliorates cerebral ischemic injury in mice, comparable to traditional administration routes like intravenous delivery. Treatment with hMSC-L and hMSC-M enhances the PPAR-γ/STAT6/SOCS1 pathway and improves the neuroinflammatory response post-stroke by increasing N2 neutrophil infiltration. These results provide a theoretical basis for a deeper understanding of the mechanisms of stem cell therapy and for exploring suitable delivery pathways of stem cell treatment.

CCR2 signaling regulates anti-chlamydia T cell immune responses in the airway.

CCR2, a member of the G protein-coupled receptor (GPCR) superfamily, is widely expressed on monocytes, macrophages, activated T cells, and other cell types, and plays a critical role in coordinating the immune response to various infections. Here we demonstrate that CCR2 expression is significantly elevated during Chlamydia muridarum (C. muridarum) respiratory infection, and its absence leads to exacerbated susceptibility, as evidenced by significant weight loss, higher bacterial loads, severe lung pathology, and elevated levels of inflammatory cytokines (il-1β, tnfα, and il-6). The absence of ccr2 impairs both myeloid cell infiltration and T cell responses, which are crucial for effective immune defense. Specifically, ccr2 deficiency disrupts the differentiation and response of Th1 cells, which are the primary effector lineage responsible for clearing chlamydia through secretion of interferon-gamma (IFN-γ). As a result, there is a significant decrease in CD3+CD4+IFN-γ+ T cells in the lung and spleen, accompanied by reduced levels of IFN-γ protein and mRNA, as well as downregulated mRNA expression of Th1-promoting cytokines (il-12p35, il-12p40) and transcription factors (stat4, T-bet), which play crucial roles in Th1 differentiation. Moreover, ccr2 deficiency greatly diminishes STAT1 phosphorylation, a key regulator of IFN-γ secretion by Th1 cells. Meanwhile, we also observed a significant reduction in IFN-γ secretion by CD8+ T cells following ccr2 deficiency. Conversely, ccr2-/- mice exhibit an exaggerated Th2-type immune response, with elevated levels of Th2-promoting cytokines (IL-4), transcription factors (STAT6 and gata3), and il-5, which together lead to more severe lung tissue damage and increased susceptibility to infection. Furthermore, these mice show higher levels of IL-17 along with an enhanced Th17-type immune response, characterized by increased Th17-promoting cytokines TGFB, transcription factors stat3 and RORγt, and il-21, suggesting a compensatory mechanism that drives neutrophil infiltration to exacerbate lung inflammation. These findings underscore the pivotal role of CCR2, a chemokine receptor, in orchestrating the immune response to Chlamydia infection by facilitating Th1 cells differentiation while restraining Th2-type and Th17-type immune responses, thereby alleviating pulmonary inflammation.

Analysis of intracranial lesions in patients with HIV-associated cryptococcal meningitis

BackgroundIntracranial imaging abnormalities are commonly observed in patients suffering from HIV-associated cryptococcal meningitis, both before and during the treatment period. This study aims to analyze the prevalence, origins, radiological characteristics, treatments, and prognosis of intracranial lesions in patients with HIV-associated cryptococcal meningitis, thereby providing references for future clinical decision-making.MethodsThe clinical data of patients diagnosed with HIV-associated cryptococcal meningitis and admitted to the Shanghai Public Health Clinical Centre between 2013 and 2019 were collected. Logistic regression analysis was subsequently conducted to identify potential risk factors associated with the development of intracranial lesions in this patient group.ResultsOf 211 patients analyzed, 64.5% (136/211) had intracranial lesions during treatment and follow-up. Initial cranial imaging showed 60% had lesions pre-treatment. Throughout treatment, 32.7% (52/159) developed new or worsened lesions. Mortality rates at 2 weeks, 8 weeks, and 2 years for those with detected lesions were 3%, 7.6%, and 13.2%, respectively. Lesions were primarily caused by Cryptococcus (70.5%) and Mycobacterium (24.3%). Lacunar infarcts, especially in the basal ganglia, were the most common type. Patients aged 50 years or older, and those presenting with altered mental status upon admission, were found to be more likely to have intracranial lesions at baseline, with adjusted odds ratios of 5.364 (95% CI: 1.468-19.591, P=0.011) and 7.970 (95% CI: 2.241-28.337, P=0.001), respectively. Patients with lesion progression showed higher levels of IFN-γ, IL-4, IL-5, IL-6, IL-1Ra, IL-1β, GM-CSF, Eotaxin, and Basic FGF in cerebrospinal fluid after four weeks of treatment.ConclusionIntracranial lesions in HIV-associated cryptococcal meningitis patients are mostly due to Cryptococcus and Mycobacterium infections. They often appear as lacunar infarcts, predominantly in the basal ganglia, and can worsen with treatment initiation, possibly due to higher baseline cytokine levels in cerebrospinal fluid.

Angel or devil: the dual roles of 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucopyranoside in the development of liver injury based on integrating pharmacological techniques: a systematic review

Background and purpose2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) exhibits a dualistic pharmacological profile, acting as both a hepatoprotective and hepatotoxic agent, which is intricately linked to its interaction with multiple signaling pathways and its stereoisomeric forms, namely, cis-SG and trans-SG. The purpose of this study is to evaluate both the hepatoprotective and hepatotoxic effects of TSG and give therapeutic guidance.MethodsThis study performed a systematic search of eight databases to identify preclinical literature up until March 2024. The CAMARADES system evaluated evidence quality and bias. STATA and Python were used for statistical analysis, including dose-effect maps, 3D maps and radar charts to show the dose-time-effect relationship of TSG on hepatoprotection and hepatotoxicity.ResultsAfter a rigorous screening process, a total of 24 studies encompassing 564 rodents were selected for inclusion in this study. The findings revealed that TSG exhibited bidirectional effects on the levels of ALT and AST, while also regulating the levels of ALT, AST, TNF-α, IL-6, serum TG, serum TC, SOD, MDA, IFN-γ, and apoptosis rate. The histological analysis of liver tissue confirmed the regulatory effects of TSG, and a comprehensive analysis revealed the optimal protective dosage range was 27.27–38.81 mg/kg/d and the optimal toxic dosage range was 51.93–76.07 mg/kg/d. TSG exerts the dual effects on liver injury (LI) through the network of Keap1/Nrf2/HO-1/NQO1, NF-κB, PPAR, PI3K/Akt, JAK/STAT and TGF-β pathways.ConclusionTSG could mediate the pathways of oxidation, inflammation, and metabolism to result in hepatoprotection (27.27–38.81 mg/kg/d) and hepatotoxicity (51.93–76.07 mg/kg/d).