Serum Levels Of TNF-α Research Articles

Baicalin inhibits PANoptosis by blocking mitochondrial Z-DNA formation and ZBP1-PANoptosome assembly in macrophages.

PANoptosis is an emerging form of regulated cell death (RCD) characterized by simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling that not only participates in pathologies of inflammatory diseases but also has a critical role against pathogenic infections. Targeting PANoptosis represents a promising therapeutic strategy for related inflammatory diseases, but identification of inhibitors for PANoptosis remains an unmet demand. Baicalin () is an active flavonoid isolated from Scutellaria baicalensis Georgi (Huangqin), a traditional Chinese medicinal herb used for heat-clearing and detoxifying. Numerous studies suggest that baicalin possesses inhibitory activities on various forms of RCD including apoptosis/secondary necrosis, pyroptosis, and necroptosis, thereby mitigating inflammatory responses. In this study we investigated the effects of baicalin on PANoptosis in macrophage cellular models. Primary macrophages (BMDMs) or J774A.1 macrophage cells were treated with 5Z-7-oxozeaenol (OXO, an inhibitor for TAK1) in combination with TNF-α or LPS. We showed that OXO plus TNF-α or LPS induced robust lytic cell death, which was dose-dependently inhibited by baicalin (50-200 μM). We demonstrated that PANoptosis induction was accompanied by overt mitochondrial injury, mitochondrial DNA (mtDNA) release and Z-DNA formation. Z-DNA was formed from cytosolic oxidized mtDNA. Both oxidized mtDNA and mitochondrial Z-DNA puncta were co-localized with the PANoptosome (including ZBP1, RIPK3, ASC, and caspase-8), a platform for mediating PANoptosis. Intriguingly, baicalin not only prevented mitochondrial injury but also blocked mtDNA release, Z-DNA formation and PANoptosome assembly. Knockdown of ZBP1 markedly decreased PANoptotic cell death. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), administration of baicalin (200 mg/kg, i.g., for 4 times) significantly mitigated lung and liver injury and reduced levels of serum TNF-α and IFN-γ, concomitant with decreased levels of PANoptosis hallmarks in these organs. Baicalin also abrogated the hallmarks of PANoptosis in liver-resident macrophages (Kupffer cells) in HLH mice. Collectively, our results demonstrate that baicalin inhibits PANoptosis in macrophages by blocking mitochondrial Z-DNA formation and ZBP1-PANoptosome assembly, thus conferring protection against inflammatory diseases. PANoptosis is a form of regulated cell death displaying simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling. This study shows that induction of PANoptosis is linked to mitochondrial dysfunction and mitochondrial Z-DNA formation. Baicalin inhibits PANoptosis in macrophages in vitro via blocking mitochondrial dysfunction and the mitochondrial Z-DNA formation and thereby impeding the assembly of ZBP1-associated PANoptosome. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), baicalin inhibits the activation of PANoptotic signaling in liver-resident macrophages (Kupffer cells) in vivo, thus mitigating systemic inflammation and multiple organ injury in mice.

Astragaloside IV suppresses the proliferation and inflammatory response of human epidermal keratinocytes and ameliorates imiquimod-induced psoriasis-like skin damage in mice.

The primary pathological features of psoriasis include excessive epidermal keratinocytes and infiltration of inflammatory cells, which are pivotal targets for psoriasis therapy. Astragaloside IV (AS-IV), the principal active compound of astragalus, exhibits anti-inflammatory, antioxidant, and immune-modulatory properties. This study aims to investigate AS-IV's anti--psoriatic effects and underlying mechanisms. Normal human epidermal keratinocytes (NHEKs) were stimulated with a combination of TNF-α, IL-17A, IL-1α, IL-22, and oncostatin M (M5) to replicate psoriatic keratinocyte pathology in vitro. Cell proliferation was assessed using CCK8 and EDU staining. Pro-inflammatory cytokine levels were measured via qRT-PCR. In addition, an imiquimod (IMQ)-induced psoriasis mouse model was utilized. Skin histology changes were evaluated with HE staining, while IL-6 and TNF-α levels in mouse serum were quantified using ELISA. NF-κB pathway protein expression was analyzed by western blotting. The results demonstrated that AS-IV inhibited M5-induced proliferation of NHEKs. AS-IV reduced M5-stimulated IL-1β, IL-6, IL-8, TNF-α, IL-23, and MCP-1 expression in NHEKs. Moreover, M5-induced phosphorylation of IκBα and p65 was significantly attenuated by AS-IV. Furthermore, AS-IV application ameliorated erythema, scale formation, and epidermal thickening in IMQ-induced psoriasis-like mouse models. AS-IV also decreased IL-6 and TNF-α levels in mouse serum and inhibited IκBα and p65 phosphorylation in skin tissues. However, prostratin treatment reversed these effects. These findings underscore AS-IV's capacity to mitigate M5-induced NHEK proliferation and inflammation. AS-IV shows promise in alleviating IMQ-induced psoriasis-like skin lesions and inflammation by suppressing the NF-κB pathway.

Effects of acupuncture on serotonin, histamine, substance P, and tryptase levels at sensitized points in model rats with knee osteoarthritis

ObjectiveTo elucidate the differences in manual acupuncture effectiveness at sensitized points by investigating the mechanisms of local skin action at different sensitization points in rats with knee osteoarthritis (KOA). MethodsForty Sprague–Dawley rats were equally divided into control, model (1 mg of monoiodoacetate into the right knee joint cavity), sham operation, manual acupuncture at right Tianjing acupoint (MAR-SJ 10), and left SJ 10 groups. Safranine-O and fast green staining were used to assess the modeling. The morphological and functional changes in mast cells (MCs) were assessed during acupoint sensitization using toluidine blue and immunofluorescence staining. The levels of serotonin, histamine, substance P (SP), and tryptase at skin acupoints and serum levels of IL-β, IL-6, and TNF-α were detected using ELISA. ResultsAfter 14 days of treatment, the number of MCs and their degranulation rates were statistically higher in the model group than in the control group (both P < .001). After applying acupuncture, the levels of 5-HT, HA, and SP at skin acupoints were lower than those in the model group (all P < .05), and tryptase level was higher (both P < .05). Tryptase level was higher on the skin at the MAL-SJ 10 acupoint than that on the MAR-SJ 10 acupoint (P = .004). Compared with the model group, the serum levels of IL-1β, IL-6, and TNF-α in the MAR-SJ 10 and MAL-SJ 10 groups were lower (all P < .05). ConclusionAcupuncture at KOA-sensitized acupoints mitigates joint injury in KOA rats and may bidirectionally regulate local MCs of these acupoints. This finding not only enhances the reference value of sensitizing points in clinical diagnosis and treatment, but also contributes to the understanding of the biological mechanisms underlying acupuncture intervention at sensitizing points.

In chronic spontaneous urticaria, increased Galectin-9 expression on basophils and eosinophils is linked to high disease activity, endotype-specific markers, and response to omalizumab treatment.

Galectin-9 (Gal-9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. To characterize the role and relevance of Gal-9 in the pathogenesis of CSU. We assessed 60 CSU patients for their expression of Gal-9 on circulating eosinophils and basophils as well as T cell expression of the Gal-9 receptor TIM-3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal-9 expression by eosinophils and basophils. Our CSU patients had markedly increased rates of circulating Gal-9+ eosinophils and basophils and high numbers of lesional Gal-9+ cells. High rates of blood Gal-9+ eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF-α were positively correlated with circulating Gal-9+ eosinophils/basophils, and TNF-α markedly upregulated Gal-9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal-9+ eosinophils/basophils than non-responders, and omalizumab reduced blood levels of Gal-9+ eosinophils/basophils in responders. Gal-9+ eosinophils/basophils were negatively correlated with TIM-3+TH17 cells. Our findings demonstrate a previously unrecognized involvement of the Gal-9/TIM-3 pathway in the pathogenesis CSU and call for studies that explore its relevance.

Alpinia officinarum Hance extract relieved sepsis-induced myocardial ferroptosis and inflammation by inhibiting lncRNA MIAT/TRAF6/NF-κB axis.

Sepsis is generally triggered by a dysfunctional host response to infection, and it can result in life-threatening organ dysfunction. Alpinia officinarum Hance (AO) exhibits regulatory functions in some diseases. However, whether AO extract (AOE) plays a promoting role in sepsis--triggered myocardial injury is unclear. This study was aimed at investigating the regulatory effects of AOE on myocardial ferroptosis and inflammation in sepsis, and the regulation effects on the lncRNA MIAT/TRAF6/NF-κB axis. Lipopolysaccharide (LPS) was used to treat mice for establishing an in vivo sepsis model. The pathological changes in heart tissues were observed through hematoxylin-eosin (HE) staining. The levels of CK-MB, cTnl, MDA, SOD, IL-1β, IL-18, IL-6, and TNF-α in serum were detected through enzyme-linked immunosorbent assay (ELISA). The level of Fe2+ was assessed, and the protein expressions (ACSL4, GPX4, TRAF6, p-P65, and P65) were examined through western blot. The expressions of lncRNA MIAT and TRAF6 were measured through real-time quantitative polymerase chain reaction (RT-qPCR). Our results demonstrated that AOE treatment ameliorated sepsis-triggered myocardial damage by reducing the disordered cardiomyocytes, the destroyed sarcolemma, and the CK-MB and cTnl levels. In addition, AOE treatment inhibited sepsis-induced myocardial ferroptosis and inflammation by regulating Fe2+, ACSL4, GPX4, IL-1β, IL-18, IL-6, and TNF-α levels. Moreover, the improvement effect of AOE was strengthened with the increase in the dose of AOE (25, 50, 100 mg/kg). It was also revealed that AOE treatment retarded the lncRNA MIAT/TRAF6/NF-κB axis. Rescue assays manifested that overexpression of MIAT reduced the cardioprotective effect of AOE. In conclusion, AOE relieved sepsis-induced myocardial ferroptosis and inflammation by inhibiting lncRNA MIAT/TRAF6/NF-κB axis. These findings may provide a potential therapeutic drug for the treatment of sepsis.

Buzhong Yiqi decoction attenuates acquired myasthenia by regulating the JAK2/STAT3/AKT signaling pathway, inhibiting inflammation, and improving mitochondrial function.

Acquired myasthenia (AM), a debilitating autoimmune disease, is typically characterized by skeletal muscle fatigue and weakness. Despite advances in myasthenia gravis treatment, current approaches remain unsatisfactory and many result in unexpected side effects. Traditional Chinese medicine has shown great potential in the treatment of myasthenia gravis, including relieving myasthenic symptoms, improving patients' quality of life, and reducing Western medicine side effects. This study investigates the protective effects and mechanism of BZYQD in mice with acquired myasthenia. BZYQD alleviates the reduced grip strength and increased expression of MAFbx and MuRF-1 in mice with acquired myasthenia. It also reduces levels of pro-inflammatory factors IL-1β, IL-6, and TNF-α in the mouse serum. In addition, BZYQD reduces ROS accumulation and the mitochondrial ROS production rate, while increasing ATP levels and mitochondrial membrane potential in mice with acquired myasthenia. Moreover, BZYQD decreases the expression of p-JAK2, p-STAT3, and p-AKT in the skeletal muscle of mice with acquired myasthenia. In summary, BZYQD reduces inflammation, enhances mitochondrial function, and regulates the JAK2/STAT3/AKT signaling pathway to treat acquired myasthenia.

Linoleyl acetate and mandenol alleviate HUA-induced ED via NLRP3 inflammasome and JAK2/STAT3 signalling conduction in rats.

Hyperuricemia (HUA) is characterized by elevated blood uric acid levels, which can increase the risk of erectile dysfunction (ED). Clinical studies have demonstrated satisfactory efficacy of a traditional Chinese medicine formula QYHT decoction in improving ED. Furthermore, the main monomeric components of this formula, linoleyl acetate and mandenol, demonstrate promise in the treatment of ED. This study established an ED rat model induced by HUA and the animals were administered with linoleyl acetate and mandenol. HE and TUNEL were performed to detect tissue changes, ELISA to measure the levels of serum testosterone (T), MDA, NO, CRP, and TNF-α and qPCR and WB to assess the expression levels of NLRP3, ASC, Caspase-1, JAK2, and STAT3 in whole blood. The findings showed that linoleyl acetate and mandenol improved kidney tissue morphology, reduced cell apoptosis in penile tissue, significantly increased T and NO levels, while substantially decreasing levels of MDA, CRP, and TNF-α. Meanwhile, the expression of NLRP3, ASC, and Caspase-1 mRNAs and proteins was markedly reduced, and the phosphorylation of JAK2 and STAT3 was inhibited. These findings were further validated through faecal microbiota transplantation results. Taken together, linoleyl acetate and mandenol could inhibit NLRP3 inflammasome activation, reduce inflammatory and oxidative stress responses, suppress the activity of JAK-STAT signalling pathway, ultimately providing a potential treatment for HUA-induced ED.

Unraveling the role of collateral circulation and serum ELAVL1 in carotid atherosclerosis and ischemic stroke: Insights from clinical observations.

The (embryonic lethal, abnormal vision, drosophila)-like protein 1 (ELAVL1) is a newly discovered protein associated with cerebral ischemic/reperfusion (I/R) injury. However, little is known of ELAVL1 in ischemic stroke patients. To investigate the clinical significance of collateral circulation and serum ELAVL1 in patients with carotid atherosclerosis (CAS) and ischemic stroke. The present prospective cohort investigation included 317 ischemic stroke patients and 300 CAS patients admitted between March 2020 and March 2022. Collateral circulation was measured using digital subtraction angiography (DSA) and graded using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading system. Enzyme-linked immunosorbent assays (ELISAs) were used to measure serum ELAVL1, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). The serum levels of total cholesterol (TC), triglyceride (TG), high-density leptin cholesterol (HDL-C), and low-density leptin cholesterol (LDL-C) were also measured. The serum levels of ELAVL1, CRP, IL-6, TNF-α, and LDL-C were all markedly higher, while HDL-C was significantly lower in ischemic stroke patients compared to the CAS patients. Serum ELAVL1 was markedly higher in ASITN/SIR grade 0-1 patients compared to grade 2-4 patients. Also, ELAVL1 correlated positively with serum CRP, IL-6, TNF-α, TC, and LDL-C, and negatively with HDL-C. Receiver operating characteristic (ROC) curves showed that ELAVL1 and collateral circulation have the potential to be used as biomarkers for the diagnosis of ischemic stroke. Meanwhile, CRP, IL-6, TNF-α, HDL-C, ASITN/SIR grading, and ELAVL1 were independent risk factors for ischemic stroke. We found that serum ELAVL1 was associated with clinical outcomes of ischemic stroke patients, while the combination of ELAVL1 and collateral circulation could be used as a potential biomarker for ischemic stroke diagnosis.

Correlation Analysis of Characteristics of Intestinal Microbiota and Cytokine Levels in Patients with Obstructive Sleep Apnea-Hypopnea Syndrome.

The aim of this study was to analyze the relationship between the characteristics of the intestinal microbiota and cytokine levels in individuals with different degrees of obstructive sleep apnea-hypopnea syndrome (OSAHS) as well as to investigate intestinal microbiota imbalances in patients with OSAHS and the associated mechanisms. Based on their sleep apnea hypopnea index (AHI), a total of 37 adults were assigned to a control group, a mild OSAHS group, or a moderate-to-severe OSAHS group. Fecal samples were collected to characterize the intestinal microbiota using metagenomic next-generation sequencing (mNGS), while blood samples were collected to detect levels of interleukin-17a (IL-17a), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in each group. 1. There was no significant difference in the Shannon index among the three groups (P > 0.05). The three groups showed significant difference in the relative abundance of Faecalibacterium prausnitzii and Bifidobacterium adolescentis (with F values of 3.955 and 7.24, respectively, P < 0.05), while showed no significant difference in the relative abundance of B. pseudocatenulatum, Bifidobacterium longum, Klebsiella pneumoniae, and Haemophilus parainfluenzae (P > 0.05). 2. The three groups showed significant difference in the expression of serum IL-17A and TNF-α levels (with F values of 18.119 and 10.691, respectively, P < 0.05), while showed no significant difference in the expression of IL-10, IL-6, and CRP levels (P > 0.05). 3. Multiple linear regression analysis revealed that the relative abundance of F. prausnitzii was correlated with changes in BMI and AHI (with β values of 2.585 and -0.157, respectively, P < 0.05), while the relative abundance of B. adolescentis was correlated with changes in IL-17a (with β value of -0.161, P < 0.05). The study revealed a significant correlation between intestinal microbiota abundance and cytokine levels, suggesting that gut microbiota disruption in OSAHS patients may be linked to systemic chronic inflammation.

Oleanolic acid attenuates obesity through modulating the lipid metabolism in high-fat diet-fed mice.

As a natural pentacyclic triterpenoid, oleanolic acid has hepatoprotective, anti-inflammatory, and antioxidant activities. This work performed the invitro experiments and animal assay to explore whether oleanolic acid alleviates lipid accumulation induced by high-fat diet by mediating PPARγ. Oil red O staining showed that oleanolic acid can reduce lipid accumulation in HepG2 cells, which were treated with oleic acid and palmitic acid. Immunofluorescence, western blot analysis, and RT-qPCR showed that oleanolic acid could promote nuclear translocation of PPARγ and reduce the expression level of PPARγ, C/EBP-β, and SREBP-1c. The results of invivo experiments indicated that dietary intervention with oleanolic acid can effectively improve the fat accumulation in liver tissue and attenuate the level of IL-6 and TNF-α in serum caused by high-fat diet. Meanwhile, oleanolic acid did not cause lesions in vital organs at the experimental concentrations. In addition, the computer simulation indicated that oleanolic acid could directly bind to PPARγ with a reasonable and stable docking conformation. The above research results can provide new evidence for oleanolic acid to prevent nonalcoholic fatty liver disease.

EFFECTS OF MANNAN-OLIGOSACCHARIDES ON GROWTH PERFORMANCE, SERUM BIOCHEMICAL INDICES, IMMUNE FUNCTION, AND INTESTINAL MORPHOLOGY IN FATTENING TAN SHEEP

This study examined the effects of dietary Mannan-Oligosaccharides (MOS) on growth performance, serum biochemical indices, immune function, and intestinal morphology in fattening Tan sheep. Twenty-eight four-month-old male Tan sheep were assigned to four groups and received a basal diet supplemented with 0%, 1%, 2%, or 3% MOS for 56 days following a 14-day adaptation period.Results indicated that MOS supplementation significantly increased average daily gain (ADG) in a dose-dependent manner (P ≤ 0.05). Serum biochemical analyses showed a linear and quadratic reduction in triglyceride (TG) levels, and a linear and quadratic increase in alkaline phosphatase (ALP) levels (P ≤ 0.05). Total cholesterol (TC) levels decreased linearly, whereas urea nitrogen (UN) levels increased linearly with higher MOS levels (P ≤ 0.05). Mannan-Oligosaccharides also enhanced total antioxidant capacity (T-AOC) and catalase (CAT) activity, with both parameters increasing linearly (P ≤ 0.05). Immune function was significantly improved, demonstrated by elevated levels of immunoglobulin A (IgA), interleukin-6 (IL-6), IL-10, and interferon-gamma (IFN-γ) (P ≤ 0.05). Additionally, 2% and 3% MOS groups showed increased immunoglobulin G (IgG) and tumor necrosis factor-alpha (TNF-α) levels (P ≤ 0.05). Linear increases were noted in serum IgG, IgA, IgM, IL-6, and TNF-α levels, while IL-10 and IFN-γ levels exhibited both linear and quadratic increases (P ≤ 0.05).Intestinal morphology analysis revealed significant improvements in jejunal villus height, crypt depth reduction, and the villus-to-crypt ratio, with these parameters showing both linear and quadratic changes in response to increasing MOS levels (P ≤ 0.05). In conclusion, 2% MOS supplementation is recommended for enhanced growth performance, metabolic health, immune function, and intestinal integrity in fattening Tan sheep. Keywords: Tan sheep; growth performance; antioxidant; immune function; intestinal morphology

Ziziphus Jujube Polysaccharides inhibit over-abundance of fecal butyric acid in mildly stressed growing mice to ameliorate depression-like behavior

The microbial-gut-brain axis is the main pathway that induces depression in adolescents. In Chinese medicine, Ziziphus Jujube Polysaccharides (ZJP) are recognized for their capacity to modulate gut microbiota and bolster immune function, suggesting their potential as a therapeutic agent for mitigating youth depression. In this study, a 44 d chronic unpredictable mild stress (CUMS) model was used to investigate how ZJP alleviates depression-like behavior in male C57BL/6 mice. The administration of ZJP ameliorated depression-like behavior, down-regulated serum levels of TNF-α, IL-1β, IL-2, IL-6, and up-regulated hippocampal 5-HT. Correlation analysis revealed that fecal butyric acid (BA) concentration was positively correlated with depression-like behavior index (P＜0.05). ZJP modified the gut microbiota by replenishing deficient saccharides (fructose, galactose, rhamnose, arabinose), diminishing the prevalence of SCFA-producing bacteria (Alistipes, Lachnospiraceae, Colidextribacter). Additionally, ZJP decreased the gene abundance of the sugar and SCFA metabolism pathways, and related enzymes in the gut of model mice, thereby reversing butyrate enrichment and ameliorating associated depression-like behavior. In summary, ZJP stabilized the intestinal microbiota structure and balanced the BA metabolism in CUMS mice by regulating the metabolism of gut microbiota-sugar-SCFAs, thereby improving depression-like behavior.

The clinical importance of IFN-γ and human epididymis protein 4 in Egyptian patients with epithelial ovarian cancer combined with HPV infection

BackgroundHigh-grade Epithelial Ovarian Cancer (HGEOC) is an aggressive disease that usually presents at an advanced stage. Thus, detecting the circulating cytokines (IFNγ and TNF-α) may serve as a biomarker to identify malignancy and manage therapeutic decisions. ObjectivesAssessing the clinical importance of inflammatory mediators and tumor markers in EOC Egyptian patients compared with benign cases. Moreover, identifying the distinct inflammatory mediators in EOC patients combined with HPV infection. MethodsThis study was conducted on 61 Egyptian patients, divided into 25 patients with HGEOC, 22 patients with LGEOC, and 14 benign ovarian tumor cases. Measurements of serum HE4, CA125, CEA, and CA19-9 were determined by Roche Elecsys immunoassays. Serum levels of TNF-α and IFN-γ were measured using quantitative sandwich ELISA. Quantitative genotyping of HPV DNA types 16, 18, and 45 was assessed for the HPV DNA-positive samples. ResultsHPV DNA was detected in 25.53 % of malignant cases, HPV 16 was detected in 50 % of HPV-positive cases, and only 1 case of HPV 18 was detected out of 12 positive cases. The Human Epididymis protein 4 (HE4) was statistically different between patients with EOC and benign cases (p-value = 0.007) and between HPV DNA positive and HPV DNA negative cases (p-value = 0.008). The serum levels of IFN- γ were statistically different between HGEOC and LGEOC (p-value < 0.001), while the serum levels of TNF-α didn’t differ statistically between the two groups. ConclusionIFN-γ could be used as a biomarker to discriminate HGEOC and LGEOC. Initial evidence for the possible association between HE4 and the progression of HPV-associated EOC was speculated.

Pharmacological Study of Guben Yifei-Tang on a Rat Model of Pneumoconiosis

Background Diffuse pulmonary fibrosis is a progressively worsening lung disease that poses a serious threat to human health. Current treatment options are limited and generally ineffective. Objectives This study aimed to investigate the therapeutic effects of GubenYifei-Tang (GB) in a rat model of pneumoconiosis. Materials and Methods We established a chronic pneumoconiosis model in rats through intratracheal injection of silica dust. Subsequently, the rats were randomly assigned to various groups, including the model group (NC group), Hanfangji Masu tablet group (TET group), high-dose GB group (GB-H group), low-dose GB group (GB-L group), and a blank control group comprising 12 normal rats (NC group). We assessed blood biochemical, vascular endothelial function, immunoinflammatory factors, and oxidative stress indices in four rats from each group at the 1st, 3rd, and 6th months of administration. Results Throughout the 6-month administration period, rats in the GB-L and GB-H groups displayed no significant abnormalities in their general condition or body weight. Both high and low doses of GB significantly reduced the respiratory rate and increased the respiratory amplitude of the pneumoconiosis model rats ( p &lt; 0.05). Additionally, they significantly decreased the mean pulmonary arterial pressure of these rats ( p &lt; 0.05). Moreover, we observed noteworthy improvements in blood gas indices and hypoxemia symptoms, including increased pH, decreased arterial partial pressure of carbon dioxide, increased arterial oxygen partial pressure, and arterial oxygen saturation. Compared to the NC group, the model group rats exhibited significantly elevated concentrations of serum transforming growth factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α), and interleukin-1 ( p &lt; 0.01). High-dose GB significantly reduced serum levels of TGF-β, TNF-α, and interleukin-10 in rats, while low-dose GB partially improved serum inflammatory factor levels. Additionally, the lung mass index, malondialdehyde (MDA) levels, and hydroxyproline levels were significantly increased in the model group rats compared to the NC group ( p &lt; 0.01), accompanied by decreased superoxide dismutase (SOD) levels. Both high and low doses of GB demonstrated substantial improvements in lung mass index, MDA, SOD, and hydroxyproline levels in rats ( p &lt; 0.05). Conclusion In the rat model of pneumoconiosis, GB exerts a positive therapeutic impact on lung tissue lesions and respiratory function, with its effectiveness being both time- and dose-dependent.

Tujia medicine Toddalia asiatica improves synovial pannus in rats with collagen-induced arthritis through the PI3K/Akt signaling pathway

To investigate the therapeutic mechanism of Tujia medicine Toddalia asiatica alcohol extract (TAAE) for synovial pannus formation in rats with college-induced arthritis (CIA). Sixty male SD rats were randomized into normal control group, CIA model group, TGT group, 3 TAAE treatment groups at low, medium and high doses (n=10). Except for those in the normal control group, all the rats were subjected to CIA modeling using a secondary immunization method and treatment with saline, TGT or TAAE by gavage once daily for 35 days. The severity of arthritis was assessed using arthritis index (AI) score, and knee joint synovium pathologies were examined with HE staining. Serum levels of TNF-α, IL-6, and IL-1β were detected with ELISA; the protein expressions of PI3K, Akt, p-PI3K, p-Akt, VEGF, endostatin, HIF-1α, MMP1, MMP3, and MMP9 in knee joint synovial tissues were determined using Western blotting, and the mRNA expressions of TNF‑α, IL-6, IL-1β, VEGF, HIF-1α, PI3K, and Akt were detected with RT-PCR. Treatment of CIA rat models with TAAE and TGT significantly alleviated paw swelling, lowered AI scores, and reduced knee joint pathology, neoangiogenesis, and serum levels of inflammatory factors. TAAE treatment obviously increased endostatin protein expression, downregulated p-PI3K, p-Akt, MMP1, MMP3, MMP9, VEGF, and HIF-1α proteins, and reduced TNF‑α, IL-6, IL-1β, PI3K, Akt, VEGF, and HIF-1α mRNA levels in the synovial tissues, and these changes were comparable between high-dose TAAE group and TGT group. TAAE can improve joint symptoms and inhibit synovial pannus formation in CIA rats by regulating the expressions of HIF-1α, VEGF, endostatin, MMP1, MMP3, and MMP9 via the PI3K/Akt signalling pathway.

MicroRNA-296-5p Expression in COVID-19 Patients and its Relationship with Inflammatory Cytokines

Objectives: The cytokine storm, triggered by the activation of certain pro-inflammatory genes in the second phase of COVID-19, is associated with severe acute respiratory disorder. Evidence suggests that microRNAs (miR) and cytokine levels can play pivotal roles in host cell antiviral defense mechanisms. This study aimed to investigate the changes in IFN-γ inducible protein 10 (IP-10) and miR-296-5p expression, as well as their relationship with some inflammatory cytokines and biochemical variables in COVID-19 patients. Methods: This retrospective single-center study was conducted on 30 COVID-19 patients and 30 controls. The expression of miR-296-5p and IP-10 genes in peripheral blood mononuclear cells (PBMCs) was evaluated using real-time PCR. Serum levels of IL-6, TNF-α, and CRP were measured by ELISA. Results: Higher expression levels of miR-296-5p and IP-10 genes were observed in COVID-19 patients compared to controls (P=0.001). Furthermore, IP-10, IL-6, and TNF-α levels were significantly higher (PP&lt;0.01) in COVID-19 patients than in controls. The results also showed positive correlations between miR-296-5p expression and serum levels of IL-6, CRP, and TNF-α in patients with COVID-19. ROC curve analysis of miR[1]296-5p in COVID-19 patients showed an area under the curve of 0.830, 95% CI (0.658-0.815), P&lt;0.001, with an optimal cut-off point of 0.32965. Conclusion: Our results suggest a regulatory role for miR-296-5p in cytokine secretion in COVID-19. The results indicate that the expression of miR-296-5p and IP-10 genes in PBMCs might serve as convenient novel biomarkers for the prognosis of COVID-19.

Effect of Saccharomyces boulardii on Liver Diseases: A Systematic Review.

We aimed to systematize the results of published studies on the use of Saccharomyces boulardii (SB) for the treatment of various liver disorders (CRD42022378050). Searches were conducted using PubMed and Scopus on 1 August 2022. The PubMed search was updated on 15 June 2024. The review included sixteen studies: ten experimental animal studies (EASs) and six randomized controlled trials (RCTs). The CNCM I-745 strain was used in 68.8% of the included studies. SB reduced the severity of many manifestations of cirrhosis, and lowered the Child-Pugh scores in RCT. SB reduced the serum concentrations of TNF-α, IL-1β, IL-6, and IL-4 in animals with metabolic dysfunction-associated steatotic liver disease (MASLD); lowered the serum TNF-α and IL-6 levels in experimental cirrhosis in rats; and reduced the CRP levels in decompensated cirrhosis. The EAS of MASLD revealed that SB reduced liver steatosis and inflammation and lowered the liver expression of genes of TNF-α, IL-1β, interferon-γ, and IL-10. In studies on experimental cirrhosis and MASLD, SB reduced the liver expression of genes of TGF-β, α-SMA, and collagen as well as liver fibrosis. SB reduced the abundance of Escherichia (Proteobacteria), increased the abundance of Bacteroidetes in the gut microbiota, prevented an increase in intestinal barrier permeability, and reduced bacterial translocation and endotoxemia.

Activating α7nAChR suppresses systemic inflammation by mitigating neuroinflammation of the medullary visceral zone in sepsis in a rat model.

Our previous studies have shown that activating α7nAChRs suppresses systemic inflammation and immunity through the cholinergic anti-inflammatory pathway (CAP) in early sepsis. Now that the medullary visceral zone (MVZ) is the center of CAP and responsible for regulating systemic inflammation, what changes will occur in MVZ's pathology and function in sepsis, especially when interfering with α7nAChRs? Does activation of MVZ's α7nAChRs contribute to the inhibition of systemic inflammation? To clarify these issues, we explored the systemic inflammation and immunity state by detecting serum levels of TNF-α, IL-6, HMGB1, sCD14, and CD4+CD25+Treg and TH17 lymphocytes percentage, meanwhile, we analyzed the apoptosis of cholinergic and catecholaminergic neurons and the expressions of tyrosine hydroxylase (TH) and choline acetyltransferase (CHAT) in MVZ in sepsis and the interfering effects on α7nAChRs. In this study, we found that in sepsis, serum TNF-α, IL-6, HMGB1, sCD14, CD4+CD25+Treg, and TH17 lymphocytes significantly increased and the ratio of Treg/TH17 significantly decreased, cholinergic and catecholaminergic neurons underwent apoptosis with low expressions of TH and CHAT in MVZ; activation of α7nAChRs not only significantly decreased the levels of septic serum TNF-α, IL-6, HMGB1, sCD14, and TH17 lymphocytes (P ＜ 0.05), but also significantly reduced cholinergic and catecholaminergic neurons' apoptosis, and promoted expressions of TH/CHAT. Our study reveals that sepsis undermines MVZ through neuroinflammation which contributes to the uncontrolled systemic inflammation. Activating central α7nAChRs is not only helpful to restore MVZ's structure and function but also beneficial to subside the inflammatory storm in sepsis. Even if MVZ is damaged in sepsis, cholinergic neurons in MVZ still regulate the systemic inflammation stably.

Fingolimod Alleviates Inflammation after Cerebral Ischemia via HMGB1/TLR4/NF-κB Signaling Pathway.

Clinically, ischemic reperfusion injury is the main cause of stroke injury. This study aimed to assess the effectiveness of fingolimod in suppressing inflammation caused by ischemic brain injury and explore its pharmacological mechanisms. In total, 75 male Sprague-Dawley rats were randomly and equally assigned to five distinct groups: sham, middle cerebral artery occlusion/reperfusion (MCAO/R) surgery, fingolimod low-dose (F-L), fingolimod medium-dose (F-M), and fingolimod high-dose (F-H). Neurobehavioral tests, 2,3,5-triphenyltetrazolium chloride staining, and the brain tissue drying-wet method were conducted to evaluate neurological impairment, cerebral infarction size, and brain water content. Enzyme-linked immunosorbent assay was employed to quantify pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) protein levels. Western blotting and immunohistochemical staining were performed to assess high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and nuclear factor kappa-B p65 (NF-κBp65) levels. Rats in the F-L, F-M, and F-H groups exhibited lower Longa scores, reduced infarction volumes, and decreased brain edema than those in the MCAO/R group. Additionally, the F-L, F-M, and F-H groups exhibited lower serum levels of IL-1β, IL-6, and TNF-α than those of the MCAO/R group. Additionally, F-L, F-M, and F-H treatments resulted in decreased HMGB1, TLR4, and NF-κBp65 protein expression levels in the hippocampus of MCAO/R rats. Fingolimod was found to reduce ischemic brain injury in a dose-dependent manner. Moreover, it was also found to alleviate inflammation following ischemic brain injury via the HMGB1/TLR4/NF‑κB signaling pathway.

Association between TMPRSS2 rs2070788 polymorphism and COVID-19 severity: a case-control study in multiple cities of Iran.

Host genetic variations have been identified as potential influencers of COVID-19 infection. This study aimed to examine the association between transmembrane serine protease type 2 (TMPRSS2) rs2070788 single nucleotide polymorphism (SNP) and the prognosis of COVID-19 in Iranian populations. This case-control study was performed on 756 COVID-19 patients and 59 healthy individuals across Iran. Clinical data, blood samples, and the presence of the TMPRSS2 rs2070788: G>A SNP were determined using T-ARMS-PCR. Additionally, serum levels of tumor necrosis factor α (TNF-α), C-reactive protein (CRP), interleukin-6 (IL-6), and IL-1β were evaluated in the collected blood samples. No significant association was found between the genotypes and allele frequencies of TMPRSS2 rs2070788 SNP and susceptibility to or mortality from COVID-19 infection. However, we observed a substantial increase in IL-6 and CRP levels associated with the severity of COVID-19, while no such trend was observed for IL-1β and TNF-α. This study showed a considerable rise in TNF-α and IL-1β serum levels exclusively in COVID-19 patients with TT rs2070788 TMPRSS2 SNP genotype compared to healthy controls. In this study conducted across multiple cities in Iran, no significant association was found between the TMPRSS2 rs2070788 SNP genotypes and COVID-19 severity or mortality.