Including Interleukin Research Articles

Sarcoidosis: molecular mechanisms and therapeutic strategies.

Sarcoidosis, a multisystemic granulomatous disease with unknown etiology, is characterized by formation of noncaseating granulomas, which can affect all organs. Recent studies have made outstanding achievement in understanding the pathology, etiology, genetics, and immune dysregulation involved in granuloma formation of sarcoidosis. Antigen stimulation in genetically predisposed individuals enhances the phagocytic activity of antigen-presenting cells, including macrophages and dendritic cells. CD4 + T cells initiate dysregulated immune responses and secrete significant quantities of inflammatory cytokines, including interleukin (IL)-2 and interferon-gamma (IFN-γ), which play a crucial role in modulating the aggregation and fusion of macrophages to form granulomas. The current therapeutic strategies focus on blocking the formation and spread of granulomas to protect organ function and alleviate symptoms. The efficacy of traditional treatments, such as glucocorticoids and immunosuppressants, has been confirmed in the management of sarcoidosis. Promising therapeutic agents encompass inhibitors of cytokines, like those targeting tumor necrosis factor (TNF)-α, as well as inhibitors of signaling pathways, such as Janus kinase (JAK) inhibitors, which exhibit favorable prospects for application. Although there has been progress in the identification of biomarkers for the diagnosis, prognosis, activity and severity of sarcoidosis, specific and sensitive biomarkers have yet to be identified. This review outlines recent advancements in the molecular mechanisms and therapeutic strategies for the sarcoidosis.

Lysoglycerophospholipid metabolism alterations associated with ambient fine particulate matter exposure: Insights into the pro-atherosclerotic effects.

The biological pathways connecting ambient fine particulate matter (PM2.5)-induced initial adverse effects to the development of atherosclerotic cardiovascular diseases are not fully understood. We hypothesize that lysoglycerophospholipids (LysoGPLs) are pivotal mediators of atherosclerosis induced by exposure to PM2.5. This study investigated the changes of LysoGPLs in response to PM2.5 exposure and the mediation role of LysoGPLs in the pro-atherosclerotic effects of PM2.5 exposure. In this longitudinal panel study, 110 adults aged 50-65 years from Beijing, China, were followed between 2013 and 2015. Targeted metabolomics analyses were utilized to quantify 18 LysoGPLs from five subclasses in 579 plasma samples. Daily PM2.5 mass concentration was monitored at a station. We used linear mixed-effect models to estimate the responses of LysoGPLs to PM2.5 exposure. Subsequently, mediation analyses were conducted to investigate the mediating role of LysoGPLs in PM2.5-associated changes in non-high density lipoprotein-cholesterol (Non-HDL-C), a biomarker for pro-atherosclerotic apolipoprotein B-containing lipoproteins, and various inflammatory biomarkers, including interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1), soluble CD40 ligand, and interferon (IFN)-γ. Short-to medium-term (1-30 days) PM2.5 exposure was associated with significant increases in six lysophosphatidic acids (LPAs), three lysoalkylphosphatidylcholines [LPC(O)s], and three lysophosphatidylglycerols (LPGs), as well as decreases in two LPAs and one lysophosphatidylserine (LysoPS), with maximus changes of 0.5-2.1%, 0.8-2.1%, 1.9-3.0%, -1.4-3.7%, and -8.0%, respectively. Furthermore, the elevated levels of LPA 18:1/18:2, LPC(O) 18:0/18:1, and LPG 16:0/16:1/18:0 significantly mediated the PM2.5-associated increase in Non-HDL-C (18-49%), IL-8 (9-24%), MCP-1 (12-26%), and IFN-γ (4-12%) over 30 days. In conclusion, short-to medium-term PM2.5 exposure was associated with altered metabolism of LysoGPLs, which mediated the PM2.5-associated pro-atherosclerotic response.

NLRP3: a key regulator of skin wound healing and macrophage-fibroblast interactions in mice

Wound healing is a highly coordinated process driven by intricate molecular signaling and dynamic interactions between diverse cell types. Nod-like receptor pyrin domain-containing protein 3 (NLRP3) has been implicated in the regulation of inflammation and tissue repair; however, its specific role in skin wound healing remains unclear. This study highlights the pivotal role of NLRP3 in effective skin wound healing, as demonstrated by delayed wound closure and altered cellular and molecular responses in NLRP3-deficient (NLRP3−/−) mice. Histological analysis revealed impaired healing processes, accompanied by reduced expression of key inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2). Deficiencies in apoptosis were evident through altered expression of cysteine-aspartic acid protease 3 (Caspase-3), P53, and B-cell lymphoma-2 (Bcl-2). Furthermore, critical growth factors such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and matrix metalloproteinase-9 (MMP-9) were significantly decreased at the excisional skin wound sites. Furthermore, using co-culture systems, we found that NLRP3 mediated the interaction between macrophages and myofibroblasts. Wild-type fibroblast-conditioned media (MFbCM) enhanced nitric oxide (NO), IL-6, and tumor necrosis factor-α (TNF-α) production in M1 macrophages and arginase activity, chitinase 3-like protein 1 (Ym1), and IL-10 expression in M2 macrophages, effects significantly diminished with NLRP3−/− MFbCM. Similarly, conditioned media from wild-type M1 or M2 macrophages promoted the expression of FGF-2, VEGF, and MMP-2 expression in myofibroblasts, which was attenuated when using NLRP3−/− macrophage-conditioned media. PGE2 levels were reduced in both NLRP3−/− macrophages and myofibroblasts. Supplementing NLRP3−/− conditioned media with PGE2 partially restored the impaired functions, suggesting that PGE2 acts as a downstream mediator of NLRP3-regulated macrophage-myofibroblast interactions. These findings indicate that NLRP3 is a key regulator of skin wound healing, facilitating macrophage-myofibroblast communication.

Modeling the response to interleukin-21 to inform natural killer cell immunotherapy.

Natural killer (NK) cells are emerging agents for cancer therapy. Several different cytokines are used to generate NK cells for adoptive immunotherapy including interleukin (IL)-2, IL-12, IL-15 and IL-18 in solution, and membrane-bound IL-21. These cytokines drive NK cell activation through the integration of signal transducers and activators of transcription (STAT) and nuclear factor-kappa B (NF-κB) pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations for both proliferation and cytotoxicity. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with mathematical modeling using feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for different cytokine combinations and indicates synergy of activated STATs and NF-κB transcription factors between priming and post-priming phases. The use of IL-21 in solution in the priming of NK cell culture resulted in an improved NK cell proliferation, without compromising cytotoxicity potential or interferon gamma secretion against hepatocellular carcinoma cell lines. Our work provides an integrative framework for interrogating NK cell proliferation and activation for cancer immunotherapy.

Interleukin-6 is significantly increased in severe pneumonia after allo-HSCT and might induce lung injury via IL-6/sIL-6R/JAK1/STAT3 pathway.

Severe pneumonia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with high mortality. Given that cytokine, including Interleukin-6 (IL-6), play a critical role in immune-mediated organ injury in patients with severe COVID-19, we hypothesized that cytokines may also contribute to the pathogenesis of severe pneumonia after allo-HSCT. This study aimed to investigate the role of IL-6 in severe pneumonia post-allo-HSCT and explore its underlying mechanism. Serum cytokine levels were prospectively measured in patients with severe and non-severe pneumonia following allo-HSCT. A mouse model of acute lung injury (ALI) and in vitro experiment using primary murine pulmonary microvascular endothelial cells (PMVECs) were conducted to assess the effects of IL-6 blockade, the mechanism of IL-6 in ALI, and immune-induced ALI. Serum IL-6 and sIL-6R levels were higher in the severe pneumonia group than in the non-severe group and were associated with disease progression. In a mouse model, preventive IL-6 blockade reduced ALI and improved survival. In vitro, the IL-6 trans-signaling complex caused more severe damage to mouse PMVECs than the classical signaling pathway. Soluble glycoprotein 130 and ruxolitinib effectively blocked the JAK1/STAT3 pathway activated by IL-6 trans-signaling in mouse PMVECs and reduced downstream inflammatory responses. IL-6 levels were elevated in patients with severe pneumonia after allo-HSCT and were linked to disease progression. This injury may be driven by the IL-6/sIL-6R/JAK1/STAT3 pathway. This preliminary study suggests that targeting the IL-6 trans-signaling pathway may be a promising therapeutic approach for severe pneumonia/ALI following allo-HSCT.

Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early-stage NSCLC

B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.

Novel Cinnamic Acid Derivatives Containing Naproxen as NLRP3 Inhibitors: Synthesis and Evaluation of Their Biological Activity.

Long-term use of naproxen can lead to serious side effects. Inspired by the biological activity of cinnamic acid, a series of cinnamic acid derivatives containing naproxen were designed and synthesized, and their anti-inflammatory activities and mechanisms were explored in vitro. Our results indicated that all of naproxen derivatives showed more significant inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) production and had a lower degree of cytotoxicity than that of naproxen. The present studies revealed that compound 23 (IC50 = 5.66 ± 1.66 µM) markedly inhibited the LPS-induced NO production and the over-expression of pro-inflammatory cytokines, including interleukin (IL)-1β, inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2). Furthermore, it blocked the activation of NF-κB signaling pathway and pyrin domain-containing protein 3 (NLRP-3) inflammasome in a concentration-dependent manner. Additionally, docking studies confirmed that compound 23 exhibited awell-fittinginto the NLRP3 active site. Considering these results, compound 23 might be a novel NLRP3 inhibitor to treat inflammatory diseases.

Cortical thickness correlated with peripheral inflammatory cytokines in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons, resulting in muscle atrophy, spasticity, hyperreflexia, and paralysis. Inflammation plays an important role in the development of ALS, and associated with rapid disease progression. Current observational studies indicate the thinning of cortical thickness in patients with ALS is associated with rapid disease progression and cognitive changes. However, the effects of inflammatory cytokines on cortical thickness in patients with ALS are unclear. Here, we investigated the relationship between inflammatory cytokines and cortical thickness in patients with ALS. We evaluated 51 patients with ALS for inflammatory cytokines including interleukin (IL)-4, interferon (IFN)-α, IL-1β, IL-2, IL-5, IL-12, tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-8, IL-17, and IFN-γ and analyzed the correlation between these indicators and the ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score). Twenty-six patients with ALS and 26 controls were studied using whole-cortex analysis, and post-hoc analyses were performed to examine the correlation between brain cortical thickness and ALSFRS-R or ΔFS scores. IL-4, IFN-α, IL-1β, and IL-2 levels were significantly correlated with ALSFRS-R scores, and the IL-2 level was significantly correlated with ΔFS scores. After controlling for age and sex, the ALS group had thinner cortexes in multiple clusters across the brain than the control group. Further analyses revealed that cortical thickness in the right superior temporal and lingual gyrus regions was inversely correlated with ΔFS scores. There was a significant positive correlation between the clusters in the right lingual cortex and IL-2 level. These results suggest cortical thickness was reduced in patients with ALS in motor and non-motor cortical areas. Inflammatory factors (especially IL-2) were correlated with cortical thickness, and both were related to the disease progression rate, suggesting IL-2 plays an important role in ALS.

The Role of IL-6 and TNF-Alpha Biomarkers in Predicting Disability Outcomes in Acute Ischemic Stroke Patients.

Inflammatory biomarkers, including Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-alpha), play a significant role in influencing stroke outcomes, particularly in the progression of post-stroke disability. While numerous studies have suggested a correlation between elevated levels of these cytokines and poor functional recovery, further investigation is needed to understand their prognostic value in acute ischemic stroke. We conducted a prospective study on 56 patients diagnosed with acute ischemic stroke, evaluating IL-6 and TNF-alpha levels on days 1 and 7 post symptom onset. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and functional outcomes were measured with the modified Rankin Scale (mRS). Statistical analyses were performed to evaluate the association between biomarker levels and stroke severity and recovery. Our study demonstrated that elevated levels of IL-6 and TNF-alpha on both days 1 and 7 were significantly correlated with greater stroke severity and poorer functional outcomes, as indicated by higher NIHSS and mRS scores. These findings are consistent with broader research indicating strong associations between inflammatory cytokines and post-stroke disability, further reinforcing their relevance as prognostic indicators. IL-6 and TNF-alpha are promising biomarkers for predicting stroke severity and functional recovery in acute ischemic stroke. Monitoring these cytokines in the early stages of stroke could aid in identifying patients at higher risk for long-term disability, potentially guiding personalized therapeutic strategies. Further research into anti-inflammatory therapies targeting these cytokines may improve stroke rehabilitation and outcomes.

Total alkaloids in Fritillaria cirrhosa D. Don alleviate OVA-induced allergic asthma by inhibiting M2 macrophage polarization

Fritillaria cirrhosa D. Don (FCD) is a traditional Chinese medicine used to treat respiratory disorders, known for its effects in clearing heat, moistening the lungs, resolving phlegm, and relieving cough. Additionally, the total alkaloids extracted from FCD can alleviate asthma symptoms and reduce airway inflammation. However, no studies have investigated the effects of total alkaloids on lung macrophages. This study explored whether the total alkaloids of FCD (TAs-FCD) reduce M2 macrophage polarization and, consequently, attenuate airway remodeling in asthmatic mice. This study further elucidated its mechanism of action in treating allergic asthma. The extracted TAs-FCD was analyzed for its composition using UPLC-Q-TOF/MS. Network pharmacology was employed to identify the active ingredients and potential mechanisms of TAs-FCD in the treatment of allergic asthma. A mouse model of ovalbumin-induced allergic asthma was established, adopted, and validated through in vivo experiments. Hematoxylin-eosin staining (H&E), immunohistochemistry (IHC), immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), and real-time fluorescence quantitative polymerase chain reaction (q-PCR) were used to investigate the role of TAs-FCD in inhibiting M2 macrophage polarization in the context of allergic asthma. A total of 66 active ingredients were screened from 116 compounds using SWISSADME. The targets of these 66 compounds were predicted by SwissTargetPrediction, resulting in 808 unique drug targets after excluding duplicates. Additionally, 1756 targets related to allergic asthma were identified from the DisGeNET, Genecard, and OMIM databases. This led to 267 cross-targets between the active ingredient targets and allergic asthma targets, including interleukin (IL)-1β, tumor necrosis factor (TNF), and STAT3. Animal experiments demonstrated that TAs-FCD improved histopathological injury in mouse lungs, reduced peri-airway collagen fiber accumulation, airway mucus secretion, and airway smooth muscle proliferation. TAs-FCD also lowered IL-1β, TNF-α and IL-4 levels in lung tissues and alleviated airway inflammation. Furthermore, TAs-FCD significantly reduced levels of Arg1 and CD206, which are closely associated with M2 macrophages, and downregulated the expression of p-STAT3 and p-JAK2. TAs-FCD may inhibit M2 macrophage polarization by regulating the JAK2/STAT3 pathway, thereby alleviating airway remodeling and inflammation in allergic asthmatic mice.

Modified Jiaoqi Powder enhances epithelial autophagy against TNF-triggered apoptosis in chronic ulcerative colitis

A vicious cycle of dysregulated intestinal epithelial cell death, intestinal barrier defect, and subsequent inflammation response is core to chronic ulcerative colitis (UC). Modified Jiaoqi Powder (MJQP), a traditional Chinese medicine formula, has been clinically applied to treat chronic relapsing and chronic persistent types of UC. Nevertheless, the underlying mechanisms of MJQP in chronic UC remains unknown. The present study aimed to demonstrate the favorable effects and potential molecular mechanisms of MJQP in chronic UC. The chemical components of MJQP and MJQP drug serum were identified by LC-MS/MS. The curative effects of MJQP were evaluated in a well-established DSS-induced chronic UC mice model by measuring body weight, colon length, disease activity index (DAI) and histological scores. Serum cytokines, including interleukin (IL)-1β, IL-12, IL-13, IL-4, tumor necrosis factor-alpha (TNF-α), and IFN-γ were measured using enzyme-linked immunosorbent assay. Western blotting, immunofluorescence, and MTT assay were used to analyze the effects of MJQP on colonic barrier function in chronic UC mice and human epithelial cell lines. TUNEL assay, western blotting, and flow cytometry were used to examine the related apoptosis indicators. An electron microscope was used to observe autophagosomes and autolysosomes, while western blotting and immunofluorescence were used to detect autophagy-associated proteins. Network pharmacology was used to predict potential targets and pathways of MJQP in UC. Finally, the TNF pathway-related proteins were detected by immunohistochemistry and western blotting. MJQP administration prevented the UC progression, as evidenced by faster weight gain, longer colon length, lower histological scores and DAI, and up-/down- regulation of inflammatory factors. The expression of tight junction proteins, ki67, and E-cadherin increased dose-dependently after MJQP intervention. Moreover, MJQP treatment promoted the viability of NCM460 and Caco2 cells in a concentration-dependent manner. MJQP dose-dependently decreased the proportion of TUNEL-positive cells and attenuated the pro-apoptotic proteins cleaved-caspase 8 and cleaved-caspase 3 in colonic tissues. Flow cytometry also showed that MJQP dose-dependently decreased the apoptotic cell population of LPS-induced NCM460 and Caco2 cells. Electron microscopy revealed that autophagosomes and autolysosomes were significantly improved in the MJQP-treated groups. Additionally, autophagy-related proteins were significantly expressed after MJQP treatment. Network pharmacological analysis predicted that MJQP may alleviate chronic UC by promoting intestinal epithelial cell proliferation and affecting TNF-related signaling pathways. As anticipated, the TNF pathway-associated proteins were attenuated dose-dependently in colonic tissues after MJQP treatment. These results provide novel therapeutic strategies indicating that MJQP may be a promising candidate treatment for chronic UC by promoting epithelial barrier restitution by enhancing epithelial autophagy against TNF-mediated apoptosis.

Effect of immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS.

Autoantibodies (AABs) are currently being investigated as causative or aggravating factors during post-COVID. In this study, we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection. This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptor (ANSR) autoantibodies and neurological impairments. We found that following immunoadsorption therapy, the ANSR AABs were nearly eliminated from the patients' blood. The removal of immunoglobulin G antibodies was accompanied by a decrease of pro-inflammatory cytokines including interleukin (IL)-4, IL-2, IL-1β, tumor necrosis factor, and IL-17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatorycytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients. Thirty days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a modest but statistically significant amelioration ofhand grip strength was observed. However, neither self-reportedsymptoms nor scores on ME/CFS questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.

The pathogenesis of depression: Roles of connexin 43-based gap junctions and inflammation.

Depression is a leading chronic mental illness worldwide, characterized by anhedonia and pessimism. Connexin is a kind of widely distributed protein in the body. Connexin 43 (Cx43) plays an important role in the pathogenesis of depression. Growing evidence has indicated that inflammation is closely associated with neuropsychiatric diseases such as depression. Inflammation occurs in patients with mood disorders, and symptomatic relief after multiple treatments is often accompanied by proinflammatory restoration. In this study, we sought to determine the upstream and downstream relationship of Cx43 abnormalities and peripheral inflammation in inducing depression. Gap27, as a Cx43 mimetic peptide, specifically blocks Cx43 gap junction channels in the brain. The mice were treated with injection of Gap27 into the prefrontal cortex (PFC), conditional knockout of Cx43 in the PFC, and lipopolysaccharide (LPS) intraperitoneal injection. Our results revealed that the treatments gave rise to the depressive-like behavior occurrence in mice, including reducing the sucrose preference and spontaneous activities, and increasing immobility time in the forced swimming test. Functional blockade of Cx43 induced abnormal expression of peripheral inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, IL-2, IL-10, and IL-18. Furthermore, depression associated with peripheral inflammation derived from LPS intraperitoneal injection significantly reduced the Cx43 expression and the diffusion distance of gap junction channel permeability dye in the PFC. These results showed that blockade of Cx43 in the PFC and peripheral inflammation are complicatedly intertwined, and reinforcing each other during the induction of depression.

Ameliorative Effect of Raspberry Ketone on Hypothalamic Inflammation in High Fat Diet-Induced Obese Mice

This study aimed to investigate the regulatory effects of raspberry ketone on hypothalamic inflammation and its mechanism. Mouse microglia cells (BV2 cells) were cultured in vitro with palmitic acid (100 μM) to induce inflammation model and then incubated with raspberry ketone (5, 20, 50 μM) alone or raspberry ketone (50 μM) and the specific inhibitor of uncoupling protein 2 (UCP2), genipin (10 μM), to test the role of UCP2 in raspberry ketone regulatory of inflammation. Meanwhile, C57BL/6J mice were fed a high-fat diet containing raspberry ketone (0.2%, wt/wt) for 16 wk or 7 d to observe the effects of raspberry ketone on the body weights and hypothalamic inflammation of mice. The expression levels of inflammatory factors, including interleukin-6 (IL-6), interleukin-1beta (IL-1β) and tumour necrosis factor alpha (TNF-α), were detected using RT-qPCR, Elisa, and Western blotting, respectively. At the cellular level, raspberry ketone reduced the content of inflammatory factors in BV2 cells and in the cell culture medium. Genipin inhibited the anti-inflammatory effect of raspberry ketone on BV2 cells. At the animal level, after 16 wk of feeding, raspberry ketone-containing diets significantly reduced the body weight of mice, but had no significant effect on the mRNA expression level of hypothalamic inflammatory factors. On the other hand, 7 d of raspberry ketone gavage significantly reduced mRNA and protein expression of hypothalamic inflammatory factors. The results of this study suggest that raspberry ketone could regulate high-fat diet-induced obesity in mice, and the specific mechanism may be to inhibit hypothalamic inflammation in mice by regulating UCP2 gene expression.

Mechanisms of breast cancer treatment using Gentiana robusta: evidence from comprehensive bioinformatics investigation

This study investigates the potential treatment of breast cancer utilizing Gentiana robusta King ex Hook. f. (QJ) through an integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulation. Building upon prior research on QJ’s chemical constituents, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the DAVID database. Network interactions and core genes were identified using Cytoscape 3.9.1. Key target genes, including Interleukin-6 (IL-6), tumour suppressor gene P53 (TP53), and epidermal growth factor receptor (EGFR), were selected for molecular docking with QJ’s active components, 2′-O-β-D-glucopyranosyl-gentiopicroside and macrophylloside D, employing Schrodinger Maestro 13.5. Molecular dynamics (MD) simulations were performed using the Desmond program. A total of 270 intersection targets of active ingredients and diseases were identified, with three core targets determined through network topology screening. Enrichment analysis highlighted the involvement of QJ in breast cancer treatment, primarily through the hsa05200 cancer signaling pathway and the hsa04066 HIF-1 signaling pathway. Molecular docking and dynamics simulations demonstrated the close interaction of 2′-O-β-D-glucopyranosyl-gentiopicroside (QJ17) and macrophylloside D (QJ25) with IL6, TP53, and EGFR, and other target genes, showcasing a stabilizing effect. In conclusion, this study unveils the effective components and potential mechanisms of 2′-O-β-D-glucopyranosyl-gentiopicroside and macrophylloside D in breast cancer prevention and treatment. The identified components act on target genes such as IL6, TP53, and EGFR, regulating crucial pathways including the cancer signaling and Hypoxia-inducible factor 1 (HIF-1) signaling pathways. These findings provide valuable insights into the therapeutic potential of QJ in breast cancer management. However, further experimental research are needed to validate the computational findings of QJ.

Luteolin Exhibits Anxiolytic and Antidepressant Potential in Parkinson's Disease Rat: Antioxidant and Anti-Inflammatory Effects.

Parkinson's disease (PD) is accompanied by a complex array of nonmotor and motor manifestations. The exploration of anti-inflammatory and antioxidant active ingredient as potential therapeutic interventions in PD-associated mood alterations has gained significant attention. This study aimed to assess the antidepressant and anxiolytic properties of luteolin (LTN), a potent antioxidant and anti-inflammatory component, using a 6-hydroxydopamine (6-OHDA)-induced animal model of PD. Rats were administered LTN (10, 25, and 50 mg/kg, per oral) and fluoxetine (10 mg/kg/per oral) over a 28-day period. Behavioral tests were employed to estimate the depression- and anxiety-like behaviors. Rats treated with LTN exhibited significant improvement in 6-OHDA-induced mood alterations, as per behavioral tests. Additionally, LTN treatment led to increased hippocampal levels of catalase and superoxide dismutase, and a reduction in malondialdehyde. LTN downregulated the gene expression of nuclear factor kappa B (NF-κB)/nod-like receptor (NLR) pyrin domain-containing 3 (NLRP3) axis components, including NF-κB, NLRP3, ASC, and Caspase1 and reduced the protein level of pro-inflammatory cytokines, including interleukin (IL)-6, interleukin (IL)-1β, and tumor necrosis factor alpha (TNF-α), in addition to augmenting the protein levels of TNF-α, IL-1β, and IL-6. Furthermore, LTN exhibited an upregulatory effect on the anti-inflammatory cytokine IL-10 within the hippocampus of 6-OHDA-induced PD rats. Also, molecular docking showed higher affinity between LTN and NF-κB/NLRP3 axis components. These findings highlight the potential anxiolytic and antidepressant impacts of LTN through its antioxidant and anti-inflammatory mechanisms against 6-OHDA-induced alterations in a rat PD model.

Berberine Attenuates Cerulein-Induced Acute Pancreatitis by Modulating Nrf2/NOX2 Signaling Pathway via AMPK Activation.

AMP-activated protein kinase (AMPK) is the master regulator of cellular energy which gets activated during energy stress and restores tissue homeostasis. AMPK is widely expressed in the pancreas and is involved in protein synthesis. In cerulein-induced acute pancreatitis (AP), diminished AMPK activity in the pancreatic tissue may be associated with pancreatic inflammation and oxidative stress. Our results demonstrated that berberine (BR) treatment produced significant decrease in plasma amylase and lipase levels and improved histopathological features in AP mice model. Myeloperoxidase (MPO) activity indicated that BR suppressed the infiltration of neutrophils in pancreas. BR treatment markedly decreased the levels of proinflammatory cytokines including interleukins (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α) via inhibition of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression. In addition, BR activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and inhibits cerulein-induced oxidative-nitrosative stress. Mechanistically, we found inhibition of AMPK activity in cerulein-induced AP, while BR-treated animals showed marked increase in the AMPK expression. Together, our study indicated that BR-mediated AMPK activation in pancreatic tissues demonstrated attenuation of cerulein-induced oxidative stress and inflammation. Based on our observations, further exploration of this promising natural product against AP and associated complications may lead to promising therapeutic options.

Relationship Between the Biomarkers of Collagen Regulation and Echocardiography Parameters in Patients With Heart Failure With Preserved Ejection Fraction.

To study the relationship between laboratory markers and echocardiography (EchoCG) parameters in heart failure with preserved ejection fraction (HFpEF) depending on the results of the diastolic stress test (DST). The diagnostic algorithm provided by the current guidelines for the assessment of left ventricular (LV) diastolic function was used to select patients. If there were not enough criteria to make a conclusion about increased LV filling pressure (FP) based on standard resting echocardiography data in patients with arterial hypertension and ischemic heart disease, DST was performed to detect HFpEF. 80 patients (50.0% men, mean age 66.3±5.4 years) were included. Group 1 consisted of 41 patients with a positive DST, and group 2 included 39 patients with a negative DST. Concentrations of the markers of immune inflammation, endothelial dysfunction, collagen homeostasis, and myocardial stress were measured. The DST showed significant differences in the E/e' ratio (15.1 [13.4; 15.9] in group 1 and 9.5 [7.9; 10.3] in group 2, respectively, p<0.001) and the diastolic functional reserve index (DFRI) (9.8 [6.8; 14.0] and 21.0 [13.0; 29.0], p < 0.001). Resting EchoCG revealed significant differences in the left atrial reservoir strain (LASr) (22.8 [19.6; 25.6]% and 28.0 [24.8; 30.2]%, p<0.001) and the left atrial stiffness index (LASI) (0.50 [0.40; 0.57] and 0.34 [0.27; 0.41], p<0.001). In patients with HFpEF, the laboratory parameters of collagen regulation had the greatest number of relationships. Correlations were found between the concentrations of matrix metalloproteinase-9 and other biomarkers, including interleukin-10 (IL-10) (r=0.311; p=0.048), myeloperoxidase (r=0.382; p=0.014), N-terminal propeptide of procollagen type I (procollagen I N-terminal propeptide, PINP) (r=0.722; p<0.001) and type III (r=0.591; p<0.001), C-terminal propeptide of procollagen type I (r=0.330; p=0.035), tissue inhibitor of metalloproteinases type 1 (r=0.410; p=0.008), EchoCG parameters, including left atrial volume index (LAVI) (r=0.414; p=0.007) and DFRI (r=0.354; p=0.025). In addition, correlations were found for the concentrations of PINP with IL-10 (r=0.401; p=0.009) and endothelin-1 (r= -0.337; p=0.031); PINP with LAVI (r=0.498; p=0.001) and DFRI (r=0.420; p=0.007). Patients with HFpEF have a greater number of relationships between markers of collagen homeostasis disorders and EchoCG parameters characterizing an increase in LV FP.

Predictive Role and Clinical Value of Serum Cytokines in COVID-19.

Cytokines and chemokines are clinically relevant for severity prediction and treatment of COVID-19 caused by SARS-CoV-2. We aimed to demonstrate the potential cytokines for severity prediction in the five days after symptom onset and describe the importance of serum cytokine levels for patients with different disease severity. Hospitalized COVID-19 patients and healthy control participants were recruited, and serial sera were collected from COVID-19 patients. Thirteen cytokines, including interleukin (IL) 1β, interferon (IFN) α2, IFN- γ, tumor necrosis factor (TNF) α, monocyte chemoattractant protein (MCP-1/CCL2), IL-6, IL-8 (CXCL8), IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33, were studied by bead-based multiplex assay by flow cytometry. Data regarding routine laboratory test results (leucocyte count, neutrophil count, lymphocyte count, platelet count, hemoglobin, liver transaminases, C-reactive protein [CRP], procalcitonin, and creatinine) were collected. We demonstrated that COVID-19 patients had elevated serum levels of IFN-α2, TNF-α, MCP-1/CCL2, IL-6, IL-8, IL-18, IL-33 compared to healthy participants. Elevated levels of CRP and decreased lymphocyte count were observed in the critical disease group. Longitudinal analysis revealed a statistically significant increase in IL-6, IL-18, and MCP-1 serum levels of critical patients compared to healthy controls. MCP-1, IL-6, and IL-18 were found to be the best predictors of critical COVID-19 disease, and MCP-1 has the highest level of predictive performance.

Elevated visfatin levels illuminate the inflammatory path in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants caused by an imbalance between lung injury and lung repair in the developing immature lungs of the newborn. Pulmonary inflammation is an important feature in the pathogenesis of BPD. The aim of this study was to evaluate the relationship between the inflammatory microenvironment and the levels of visfatin and nesfatin-1, which are among the new adipocytokines, in BPD patients. The groups consisted of 30 patients with BPD and 30 healthy children. Plasma levels of visfatin and nesfatin-1 and inflammation-related markers including interleukin-4 (IL-4), interleukin-10 (IL-10), nuclear factor kappa B (Nf-κB) and matrix metalloproteinase-9 (MMP-9) were determined by enzyme-linked immunosorbent assay (ELISA). RT-PCR was performed to evaluate the change in mRNA expression of visfatin and nesfatin-1 in the groups. Visfatin levels were significantly higher in the BPD group compared to the healthy control (7.05±4.07 ng/ml vs. 2.13±1.66 ng/ml, p<0.0001). There was a 1.36±0.12 fold increase in visfatin mRNA expression (p<0.05) in the BPD group. There was no significant difference in plasma levels of nesfatin-1, IL-4, and IL-10 between the groups. Although MMP-9 and Nf-κB levels were significantly higher in the BPD group (p<0.0001), there was no correlation between visfatin levels and MMP-9 and Nf-κB levels in BPD patients. This study showed that significant changes in visfatin levels in BPD patients might be associated with the risk of developing inflammation in BPD.