Inflammatory Signaling Pathways Research Articles

Neuroinflammation and iron metabolism after intracerebral hemorrhage: a glial cell perspective

Intracerebral hemorrhage (ICH) is the most common subtype of hemorrhagic stroke causing significant morbidity and mortality. Previously clinical treatments for ICH have largely been based on a single pathophysiological perspective, and there remains a lack of curative interventions. Following the rupture of cerebral blood vessels, blood metabolites activate resident immune cells such as microglia and astrocytes, and infiltrate peripheral immune cells, leading to the release of a series of inflammatory mediators. Degradation of hemoglobin produces large amounts of iron ions, leading to an imbalance of iron homeostasis and the production of large quantities of harmful hydroxyl radicals. Neuroinflammation and dysregulation of brain iron metabolism are both important pathophysiological changes in ICH, and both can exacerbate secondary brain injury. There is an inseparable relationship between brain iron metabolism disorder and activated glial cells after ICH. Glial cells participate in brain iron metabolism through various mechanisms; meanwhile, iron accumulation exacerbates neuroinflammation by activating inflammatory signaling pathways modulating the functions of inflammatory cells, and so on. This review aims to explore neuroinflammation from the perspective of iron metabolism, linking the complex pathophysiological changes, delving into the exploration of treatment approaches for ICH, and offering insights that could enhance clinical management strategies.

Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy

Glucose-sensing ChREBP and MondoA are transcriptional factors involved in the lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in the pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBPRP mice with constitutively active (ca) ChREBP. These mice underwent retinal functional testing, which was followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19ChREBP) and subjected to global proteomics. Our results demonstrate that both proteins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photoreceptor degeneration, as we observed diminished scotopic ERG amplitudes in caChREBPRP mice at P35. The retinal proteomic landscape revealed a decline in the KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific caChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19ChREBP cells exhibit a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprogramming triggering retinal functional loss in mice.

Pharmacological action of Angelica sinensis polysaccharides: a review

Angelica sinensis, a traditional Chinese herbal medicine and food, which has a long history of clinical application, is used to improve health conditions and treat various diseases. Angelica sinensis polysaccharides (ASP), the main active component of this traditional Chinese medicine, have multicomponent, multitarget characteristics and very broad pharmacological activities. They play important roles in the treatment of several diseases. In addition, the effect is significant, which may provide a more comprehensive database and theoretical support for applying ASP in the treatment of disease and could be considered a promising candidate for preventing disease. This review summarizes the research progress on the extraction, chemical structure, pharmacological effects, and mechanisms of ASP and its derivatives by reviewing relevant national and international literature and provides comprehensive information and a reliable basis for the exploration of new treatment strategies involving botanical drugs for disease therapy. Literature information was obtained from scientific ethnobotany and ethnomedicine databases (up to September 2024), mainly from the PubMed, Web of Science, and CNKI databases. The literature has explored the extraction, purification, structure, and pharmacological effects of Angelica sinensis polysaccharides. The search keywords for such work included “Angelica sinensis” or “Angelica sinensis polysaccharides,” and “pharmacological effects,” “extraction” and “structure.” Multiple studies have shown that ASP has important pharmacological effects, such as antitumor, anemia-improving, anti-inflammatory, antioxidative, immunomodulatory, hepatoprotective, antifibrotic, hypoglycemic, antiradiation, and antiviral effects, the mechanisms of which appear to involve the regulation of inflammation, oxidative stress, and profibrotic signaling pathways. As a natural polysaccharide, ASP has potential applications as a drug. However, further research should be undertaken to clarify the unconfirmed regulatory mechanisms, conduct standard clinical trials, and evaluate the possible side effects. This review establishes a theoretical foundation for future studies on the structure, mechanism, and clinical use of ASP.

Matrine disturbs the eimeria necatrix-induced loop of tuft cell-intestinal stem cell-goblet cell by inactivating IL-13/JAK2/STAT3 signaling.

As sensors in the gut, tuft cells integrate a complex array of luminal signals to regulate the differentiation fate of intestinal stem cells (ISCs), which trigger a loop of tuft cell-ISC-goblet cell after parasitic infection. As a plant-derived alkaloid, Matrine plays a prominent role for standardizing ISC functions in Eimeria necatrix (EN)-exposed chicks. In this study, we investigated the modulation effects of Matrine on the specific intestinal epithelial cell loop in EN-exposed chicks in vivo and intestinal organoids (IOs) ex vivo. The results showed that EN infection resulted in swelling and hemorrhage of the jejunum, accompanied by the increase in levels of sIgA and inflammatory cytokines (IL-6, IL-1β, and TNF-α). And these inflammatory symptoms were effectively relieved by Matrine intervention. Concurrently, Matrine resisted the EN-induced increase in tuft cell numbers and levels of crucial pro-inflammatory factors (IL-25 and IL-13), while also reversing the differentiation of secretory cell progenitors into goblet cells. Importantly, Matrine impeded the upregulation of the inflammatory signaling pathway JAK2/STAT3 in EN-infected chicks and IOs. Conversely, exogenous supplementation of IL-13 or activation of STAT3 via Colivelin eliminated the standardization of the tuft cell-ISC-goblet cell loop by Matrine. Overall, our findings suggested that Matrine intercepted the tuft cell-ISC-goblet cell loop by reinstating IL-13/JAK2/STAT3 signaling after EN infection.

Mechanisms Underlying the Anti-Atherosclerotic Effects of EGCG.

Atherosclerosis (AS) is a chronic inflammatory vascular disease and the primary pathological basis of cardiovascular diseases. Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol compound in green tea, has garnered significant attention in recent years for its protective effects against AS. EGCG possesses properties that lower lipid levels, exhibit antioxidant and anti-inflammatory activities, enhance plaque stability, and promote the recovery of endothelial function. The regulatory mechanisms of EGCG in AS primarily involve inhibiting apoptosis, modulating autophagy, improving gut microbiota, and regulating the Nrf2 and inflammatory signaling pathways. This review summarizes the role of EGCG in the prevention and treatment of AS and its potential mechanisms, providing a scientific basis for future research directions and therapeutic applications.

The major roles of intestinal microbiota and TRAF6/NF-κB signaling pathway in acute intestinal inflammation in mice, and the improvement effect by Hippophae rhamnoides polysaccharide.

Acute enteritis, an intestinal disease with intestinal inflammation and injury as the main pathological manifestations. Inhibiting the inflammatory response is critical to the treatment of acute enteritis. Previous studies have shown that the Hippophae rhamnoides polysaccharide (HRP) has strong immune-enhancing effects. However, their functions regarding the intestines and the underlying mechanism are still unclear. In this study, the role of HRP in lipopolysaccharide (LPS)-induced acute enteritis in mice and its related mechanisms are discussed from two aspects: intestinal inflammation and intestinal microbiota. Kunming mice were inoculated with LPS to establish animal models of acute enteritis. The results showed that HRP attenuated the histological damage and maintained the intestine mucosal barrier via up-regulating the expression of occludin, claudin-1, and zona occludens-1 (ZO-1), and suppressing the levels of pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β)). The relative mRNA and protein levels of nuclear factor-kappa B p65 (NF-κBp65) and tumor necrosis factor-receptor-associated factor 6 (TRAF6) in the intestine tissues of LPS-induced acute enteritis mice significantly increased, whereas these adverse changes were alleviated in the HRP intervention groups. Notably, HRP may regulate the expression of the TRAF6/NF-κB signaling pathway by affecting the diversity of the intestinal microbiota. Microbiota analysis showed that HRP promoted the proliferation of beneficial bacteria, including Clostridia_UCG-014, Candidatus_Saccharimonas, Lachnospiraceae_NK4A136_group, Bacteroidota, Deferribacterota, and reduced the abundance of Atopostipes, Corynebacterium, Actinobacteriota, and Desulfobacterota. The studies conformed that the gut microbiota is crucial in HRP-mediated immunity regulation. HRP shows great potential as an immune enhancer and a natural medicine for treating intestinal inflammatory diseases.

The Putative Antidiabetic Effect of Hypericum perforatum on Diabetes Mellitus.

Diabetes mellitus (DM), a global disease that significantly impacts public health, has become increasingly common over time. In this review, we aim to determine the potential benefits of St. John's Wort (SJW) as an adjunct therapy for DM. We gathered information from studies conducted in vitro, in vivo, and in humans. In vitro studies investigated the concentrations of SJW extracts capable of inhibiting certain enzymes or factors involved in the inflammatory pathway, such as the β-signal transducer and activator of transcription 1, nuclear factor κB, methylglyoxal, and oxidative stress (OS). The extract was found to have positive effects on OS and anti-inflammatory properties in DM, suggesting it could serve as a protective agent against diabetic vascular complications, cell damage, and apoptosis. According to in vivo research, the essential components of the extract can stimulate thermogenesis in adipose tissue, inhibit several key inflammatory signaling pathways, and delay the early death of pancreatic β cells, all of which contribute to combating obesity. The extract may also help treat prediabetes and significantly reduce neuropathic pain. Human studies have also confirmed some of these results. However, some of the plant's side effects need further investigation through clinical research before it can be used to treat DM.

Mitigating intubation stress, mucosa injury, and inflammatory response in nasogastric tube intubation via suppression of the NF-κB signaling pathway by engineering a hydration lubrication coating.

Nasogastric tube (NGT) intubation is a common yet critical clinical procedure. However, complications arising from tube friction result in awful pain and morbidity. Here, we report a straightforward surface modification of slender NGT utilizing highly hydrated micelles that were composed of hyaluronic acid and Pluronic. The strong intermolecular hydrogen bonding facilitated the assembly of the micelles on NGT via a one-step dip coating process. The micelle coating conferred excellent hydrophilic, lubrication, anti-protein adhesive, and biocompatible properties. The in vivo efficacy of the micelle coating in alleviating catheterization irritation and mucosal injury was demonstrated using an NGT intubation model of rabbits. More importantly, compared to the paraffin oil coating (the current clinical means), the micelle coating possessed superior capability to reduce the inflammatory reaction caused by NGT intubation. The underlying mechanism was attributed to the suppression of the TLR4-IKBα-NF-κB inflammatory signaling pathway. This work provides a promising solution for developing lubricant medical coatings.

Aspirin-based PROTACs as COX-2 degraders for anti-inflammation.

Cyclooxygenase-2 (COX-2) is a key enzyme in the biosynthesis of prostaglandins and plays a special role in the process of inflammatory response. COX-2 is a target of non-steroidal anti-inflammatory drugs (NSAIDs), which can effectively relieve inflammation, pain and fever responses by inhibiting COX-2. Despite the significant study progress of inhibitors targeting COX-2, the development of COX-2 degraders remains insufficient. Proteolysis targeting chimaeras (PROTACs) have recently emerged as a fascinating technology for targeted protein degradation and drug discovery. In this report, we present the design, synthesis and detection of aspirin-based PROTACs that demonstrate effective ubiquitin-proteasome pathway degradation of COX-2 in lipopolysaccharide-stimulated RAW264.7 cells, and the aspirin-based negative PROTACs does not promote the degradation of COX-2. Moreover, we show AspPROTACs could significantly affect proteasome degradation and inflammatory signaling pathways through quantitative proteomic data analysis. These COX-2 degraders offer valuable chemical tools and novel insights for research in anti-inflammatory drugs.

Molecular insights into the therapeutic mechanisms of Bushen-Qiangdu-Zhilv decoction for ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic rheumatic immune disease characterized by high disability rates, significantly affecting patients' quality of life. BuShen-QiangDu-ZhiLv Decoction (BQZD), developed by the renowned traditional Chinese medicine practitioner Jiao Shude, has been traditionally used for AS treatment. However, the bioactive components and the precise mechanisms underlying BQZD's therapeutic effects remain largely unexplored. To investigate the protective effects and elucidate the molecular mechanisms of BQZD in treating ankylosing spondylitis. Ultra Performance Liquid Chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) was used to identify active compounds in BQZD. Bulk RNA-seq and Gene Set Variation Analysis (GSVA) were conducted to assess changes in pathway activity in AS patients before and after three months of BQZD treatment. We also utilized network pharmacology and molecular docking analyses to predict potential mechanisms, identifying key target genes such as IL-6, NFATc1, and c-FOS. Animal experiments were performed to validate these findings. UPLC-MS/MS identified 28 active compounds in BQZD capable of entering the bloodstream, with potential anti-inflammatory, immunomodulatory, and bone metabolism-regulating effects. BQZD treatment led to a significant reduction in ESR, CRP, and ASDAS-CRP scores, indicating clinical improvement in AS patients. RNA-seq analysis showed decreased GSVA scores for the ossification pathway, with moderate reductions in inflammatory response and RANKL signaling pathways. Positive correlations were found between pathway activity and clinical indicators. Network pharmacology and transcriptomic analysis identified IL-6, NFATc1, and c-FOS as key targets. In vivo experiments confirmed that BQZD reduced TNF-α and IL-1β levels, inhibited ectopic ossification, and modulated the expression of DKK-1, MMP-9, and OPN in the CAIA model. BQZD exerts therapeutic effects in AS by regulating inflammation and abnormal ossification through multi-pathway, multi-target mechanisms. The identification of key target genes such as IL-6, NFATc1, and c-FOS provides a solid foundation for future research and clinical applications of BQZD in AS management.

Clozapine Induces Agranulocytosis via Inflammatory and Hematopoietic Cytokine Induction of the JAK-STAT Signaling Pathway: Evidence From Network Pharmacology and Molecular Docking.

Clozapine exhibits significant therapeutic efficacy in schizophrenia, especially treatment-resistant schizophrenia. However, clozapine can cause agranulocytosis, a fatal adverse effect, and the aim of this study is to explore this mechanism based on network pharmacology and molecular docking. Six and two databases were used to identify targets associated with clozapine and agranulocytosis, respectively. The bioinformatics online platform was used to identify overlaps between the drug and disease targets. The protein-protein interaction (PPI) network was characterized using Cystoscope 3.10.1 and STRING. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were analyzed using the DAVID online platform. A drug-target-pathway-disease network was constructed utilizing Cystoscope 3.10.1. The Auto Dock Vina and PyMOL software were used to verify the molecular docking of clozapine and core targets. The analysis revealed 188 overlapping targets. The PPI and KEGG enrichment pathway analyses demonstrated that clozapine induces agranulocytosis by modulating the hematopoietic cell lineage and JAK-STAT signaling pathways via interleukin-3 (IL3), IL6, IL2 receptor subunit alpha (IL2RA), and granulocyte colony-stimulating factor. Binding energies between clozapine and core targets were favorable (< -7.0 kcal/mol). Clozapine-induced agranulocytosis may be linked to the JAK-STAT inflammatory signaling pathway through inflammatory and hematopoietic-related cytokines. Our findings enhance our comprehension of the potential mechanisms underlying clozapine-induced agranulocytosis.

Dorzolamide Intermediates with Potential Anti-Inflammatory Activity

Dorzolamide (DZD), a Carbonic anhydrase (CA) inhibitor clinically used to lower intraocular pressure, exhibits anti-inflammatory effects owing to the drug’s ability to inhibit the TIR domain-containing adaptor protein (TIRAP)-mediated signalling in macrophages. Here, we investigated whether DZD intermediates also demonstrate any anti-inflammatory property like DZD but with a reduced inhibition of CA. We found that several intermediates of DZD show increased binding to TIRAP at the common interface of kinases, such as Protein kinase C-delta (PKCδ) and Bruton's tyrosine kinase (BTK). Such binding results in a decreased activity of TIRAP, p38 Mitogen-activating protein kinases (MAPK), and p65, which are essential for major inflammatory signaling pathways. Remarkably, the DZD intermediates were more effective than DZD in decreasing the mRNA expression levels of pro-inflammatory cytokines in Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The DZD intermediates also exhibit a reduced binding energy to CA II and CA IV, highlighting their improved specificity as anti-inflammatory compounds with decreased unwanted biological effects. Furthermore, we validated the anti-inflammatory effect of the most efficient DZD intermediate, DRZ V, in a model of mouse sepsis. DRZ V-treated septic mice exhibited improved survival compared to DZD-treated septic mice. Our data indicate that the tested DZD intermediates are more effectual in dampening TIRAP-mediated inflammatory signaling as compared to DZD. Thus, DZD intermediates may be a promising option for developing novel anti-inflammatory therapeutics.

Evaluating the Evidence for Neuroprotective and Axonal Regenerative Activities of Different Inflammatory Cell Types After Optic Nerve Injury

AbstractThe optic nerve contains retinal ganglion cell (RGC) axons and functions to transmit visual stimuli to the brain. Injury to the optic nerve from ischemia, trauma, or disease leads to retrograde axonal degeneration and subsequent RGC dysfunction and death, causing irreversible vision loss. Inflammatory responses to neurological damage and axonal injuries in the central nervous system (CNS) are typically harmful to neurons and prevent recovery. However, recent evidence indicates that certain inflammatory cell types and signaling pathways are protective after optic nerve injury and promote RGC survival and axonal regeneration. The objective of this review is to examine the evidence for diverse effects of inflammatory cell types on the retina and optic nerve after injury. Additionally, we highlight promising avenues for further research.

A novel biomarker of COVI-19: MMP8 emerged by integrated bulk RNAseq and single-cell sequencing

COVID-19 has been emerging as the most influential illness which has caused great costs to the heath of population and social economy. Sivelestat sodium (SS) is indicated as an effective cure for lung dysfunction, a characteristic symptom of COVID-19 infection, but its pharmacological target is still unclear. Therefore, a deep understanding of the pathological progression and molecular alteration is an urgent issue for settling the diagnosis and therapy problems of COVID-19. In this study, the bulk ribonucleic acid sequencing (RNA-seq) data of healthy donors and non-severe and severe COVID-19 patients were collected. Then, target differentially expressed genes (DEGs) were screened through integrating sequencing data and the pharmacological database. Besides, with the help of functional and molecular interaction analyses, the potential effect of target gene alteration on COVID-19 progression was investigated. Single-cell sequencing was performed to evaluate the cell distribution of target genes, and the possible interaction of gene-positive cells with other cells was explored by intercellular ligand-receptor pattern analysis. The results showed that matrix metalloproteinase 8 (MMP8) was upregulated in severe COVID-19 patients, which was also identified as a targeting site to SS. Additionally, MMP8 took a core part in the regulatory interaction network of the screened DEGs in COVID-19 and was dramatically correlated with the inflammatory signaling pathway. The further investigations indicated that MMP8 was mainly expressed in myelocytes with a high degree of heterogeneity. MMP8-positive myelocytes interacted with other cell types through RETN-TLR4 and RETN-CAP1 ligand-receptor patterns. These findings emphasize the important role of MMP8 in COVID-19 progression and provide a potential therapeutic target for COVID-19 patients.

Bioinformatics based exploration of the anti-NAFLD mechanism of Wang’s empirical formula via TLR4/NF-κB/COX2 pathway

BackgroundNonalcoholic fatty liver disease (NAFLD) has developed as a leading public wellness challenge as a result of changes in dietary patterns. Unfortunately, there is still a lack of effective pharmacotherapy methods for NAFLD. Wang’s empirical formula (WSF) has demonstrated considerable clinical efficacy in treating metabolic disorders for years. Nevertheless, the protective effect of WSF against NAFLD and its underlying mechanism remains poorly understood.MethodsThe NAFLD model was established using a 17-week high-sucrose and high-fat (HSHF) diet with 32 ICR mice. In assessing the therapeutic efficacy of WSF on NAFLD, we detected changes in body weight, viscera weight, biomarkers of glycolipid metabolism in serum and liver, transaminase levels and histopathology of liver with H&E and Oil Red O staining after oral administration. The chemical components in WSF were extensively identified and gathered utilizing the HPLC-Q-TOF/MS system, database mining from HMDB, MassBank, and TCMSP databases, alongside literature searches from CNKI, Wanfang and VIP databases. The forecast of network pharmacology approach was then utilized to investigate the probable mechanisms by which WSF improves NAFLD based on the performance of prospective target identification and pathway enrichment analysis. Besides, molecular docking was also conducted for the verification of combination activities between active components of WSF and core proteins related to NAFLD. In final, validation experiments of obtained pathways were conducted through ELISA, immunohistochemistry (IHC), and western blot (WB) analysis.ResultsPharmacodynamic outcomes indicated that WSF intervention effectively mitigated obesity, fat accumulation in organs, lipid metabolism disorders, abnormal transaminase levels and liver pathology injury in NAFLD mice (P < 0.05, 0.01). A total of 72 existent ingredients of WSF were acquired by HPLC-Q-TOF/MS and database, and 254 common targets (11.6% in total targets) of NAFLD and WSF were identified. Network pharmacology revealed that WSF presses NAFLD via modulating TNF, IL6, AKT1, IL1B, PTGS2 (COX2), and other targets, and the probable pathways were primarily inflammatory signaling pathways, as confirmed by molecular docking. Molecular biology experiments further conformed that WSF could decrease levels of inflammatory factors like IL-1β, IL-6 and TNF-α (P < 0.01) and expression of TLR4, NF-κB and COX-2 (P < 0.05, 0.01) in the liver.ConclusionWSF treatment effectively protects against lipid metabolism disorders and liver inflammation injury in HSHF diet-induced NAFLD mice, and its molecular mechanism might be via suppressing the TLR4/NF-κB/COX-2 inflammatory pathway to reduce the release of inflammatory cytokines in the liver.Graphical abstract

Temporal therapy utilizing exosomes derived from M2 macrophages demonstrates enhanced efficacy in alleviating neuropathic pain in diabetic rats.

Diabetic pain patients have increased pain at night. Exosomes can relieve neuropathic pain. This study aimed to investigate the efficacy of exosome administration at different time points in relieving diabetic neuropathic pain (DNP) in rats. M2 macrophages from bone marrow were induced in mice and exosomes were extracted. A diabetic rat model was induced using streptozotocin, with the mechanical withdrawal threshold (MWT) of the rats being measured at ≤ 80% of the basal value after 14 days, indicating successful construction of the DNP rat model. Exosomes were administered on three consecutive days at ZT0 (zeitgeber time) and ZT12. Parameters including blood glucose levels, body weight, MWT, and thermal withdrawal latency (TWL) were assessed in the rats. The lumbar spinal cord of rats was examined on days 21 and 28 to measure inflammatory factors and observe the expression of M1 and M2 microglia. Furthermore, microglia were exposed to lipopolysaccharide (LPS) and LPS + exosomes in a controlled in vitro setting to assess alterations in microglia phenotype involving the NF-kB p65 and IKBα inflammatory signaling pathways. The findings revealed that administration of exosomes during the rat resting period at ZT12 resulted in increased MWT and TWL, as well as a shift in microglia polarization towards the M2 phenotype. In vitro analysis indicated that exosomes influenced microglia polarization and suppressed the phosphorylation of NF-kB p65 and IKBα. Temporal therapy with exosomes effectively reduces pain in DNP rats by polarizing microglia and affecting NF-kB p65 and IKBα signaling pathways.

Berberine in rheumatoid arthritis: a comprehensive review and meta-analysis of its anti-inflammatory and immunomodulatory mechanisms in animal models.

Berberine (BBR), an alkaloid derivative mostly found in Oregon grapes and barberry shoots, has several medical properties, including anti-microbial, anti-tumorigenic, and anti-inflammatory properties. As such, it is a superior alternative to presently recommended medications. From previous researches, which showed that BBR has anti-arthritic qualities by blocking a number of inflammatory signalling pathways. Furthermore, it has been demonstrated that BBR attenuates Beclin-1, which reduces autophagy-mediated survival of mature adipocytes. BBR has also been identified as an AhR inducer and a promoter of Treg differentiation. Berberine has been shown in earlier studies to be useful in treating rheumatoid arthritis (RA) in animal models. The pharmacological effects and possible action pathway of Berberine were evaluated in this study. We looked through three databases-PubMed, Web of Science, and Google Scholar-for pertinent research published from the time the databases were created and August 2024. This risk-of-bias measure was used to evaluate the methodological quality. Utilising RevMan 5.4, the statistical analysis was conducted. There were 12 studies in this research with 175 animals. The findings showed that Berberine lowers the levels of IL-1β, IL-17, IL-6, IL-10, and TNF-α), paw swelling, and histopathological scores. These connected to the anti-inflammatory, anti-oxidative stress, and osteoprotective qualities of berberine. Nonetheless, further superior animal research is required to evaluate berberine impact on rheumatoid arthritis (RA). Additionally, more research is needed to validate berberine safety. Considering the significance of the active component, further research is needed to determine the best dose and increase berberine bioavailability.

PS-MPs Induced Inflammation and Phosphorylation of Inflammatory Signalling Pathways in Liver.

As new pollutants, microplastics (MPs) have attracted much attention worldwide because they cause serious environmental pollution and pose potential health risks to humans. However, the toxic effects of MPs are still unclear. In this study, we analysed the inflammatory effects of 0.1 μm polystyrene microplastics (PS-MPs) on mouse and human liver cell lines. After 28 days of exposure to PS-MPs, the mice presented decreased liver index values and increased AST/ALT values. HL7702 and HepG2 were treated with PS-MPs for 24 h, and the cytotoxicity, the expression levels of inflammatory factors, and the phosphorylation of proteins in inflammation related pathways were confirmed. Compared with the control, the cell viability of these two cells significantly decreased after exposure to the PS-MPs at 1000 μm/cm2, and the BMD model also exhibited a similar dose. LDH leakage and AST also increased in a dose-dependent increase after PS-MPs exposure. The relative levels of chemokines such as GM-CSF, IL-6, IL-8, and IL-12p70 were significantly greater than those in the control. Furthermore, the PS-MPs can increase the expression levels of TLR4, MyD88, and NF-κB and activate the phosphorylation of NF-κB and STATs. Based on these results, exposure to PS-MPs can stimulate liver inflammation and activate the TLR4/MyD88/NF-κB and JAK-STAT pathways.

Network Toxicology and Molecular Docking Analysis of Tetracycline-Induced Acute Pancreatitis: Unveiling Core Mechanisms and Targets.

Acute pancreatitis (AP), induced by tetracycline, a widely used antibiotic, poses significant clinical and toxicological challenges, yet its molecular mechanisms remain unclear. This study aims to promote drug toxicology strategies for the effective investigation of the putative toxicity and potential molecular mechanisms of antibiotic drugs through the study of tetracycline in AP. Using the SwissTargetPrediction, SEA Search, Super-PRED, GeneCards, Drugbank, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD), we identified 259 potential targets associated with tetracycline exposure and AP. Further refinement via the STRING database and Cytoscape (version 3.10.1) software highlighted 22 core targets, including TP53, TNF, and AKT1. Functional enrichment via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) identified pathways through Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, highlighting PI3K-Akt, MAPK, HIF-1, and AGE-RAGE as critical mediators in tetracycline-induced AP. Molecular docking confirmed the strong binding between tetracycline and the core targets. Overall, these findings suggest that tetracycline may affect the occurrence and progression of pancreas-related inflammation by regulating pancreatic cell apoptosis and proliferation, activating inflammatory signaling pathways, and regulating lipid metabolic pathways. This study provides a theoretical basis for understanding the molecular mechanism of tetracycline-induced AP and lays the foundation for the prevention and treatment of digestive system diseases associated with excessive exposure to tetracycline antibiotics and certain tetracyclines. In addition, our network toxicology approach has accelerated the elucidation of toxic pathways in antibiotic drugs that lack specific characteristics.

A review on multiple sclerosis: Unravelling the complexities of pathogenesis, progression, mechanisms and therapeutic innovations.

Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disorder of the central nervous system (CNS) targeting myelinated axons. Pathogenesis of MS entails an intricate genetic, environmental, and immunological interaction. Dysregulation of immune response i.e. autoreactive T & B-Cells and macrophage infiltration into the CNS leads to inflammation, demyelination, and neurodegeneration. Disease progression of MS varies among individuals transitioning from one form of relapsing-remitting to secondary progressive MS (SPMS). Research advances have unfolded various molecular targets involved in MS from oxidative stress to blood-brain barrier (BBB) disruption. Different pathways are being targeted so far such as inflammatory and cytokine signaling pathways to overcome disease progression. Therapeutic innovations have significantly transformed the management of MS, especially the use of disease-modifying therapies (DMTs) to reduce relapse rates and control disease progression. Advancements in research, neuroprotective strategies, and remyelination strategies hold promising results in reversing CNS damage. Various mice models are being adopted for testing new entities in MS research.