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Hypertension is the key leading risk factor for death globally, affecting ∼1.3 billion adults, particularly in low- and middle-income countries. Most people living with hypertension have uncontrolled high blood pressure, increasing their likelihood of cardiovascular events. Significant issues preventing blood pressure control include lack of diagnosis, treatment, and response to existing therapy. For example, monotherapy and combination therapy are often unable to lower blood pressure to target levels. New therapies are urgently required to tackle this issue, particularly those that target the mechanisms behind hypertension instead of treating its symptoms. Acting via an increase in systemic and tissue-specific inflammation, the immune system is a critical contributor to blood pressure regulation and is considered an early mechanism leading to hypertension development. Here, we review the immune system's role in hypertension, evaluate clinical trials that target inflammation, and discuss knowledge gaps in pre-clinical and clinical data. We examine the effects of anti-inflammatory drugs colchicine and methotrexate on hypertension and evaluate the blockade of pro-inflammatory cytokines IL-1β and TNF-α on blood pressure in clinical trials. Lastly, we highlight how we can move forward to target specific components of the immune system to lower blood pressure. This includes targeting isolevuglandins, which accumulate in dendritic cells to promote T cell activation and cytokine production in salt-induced hypertension. We discuss the potential of the dietary fibre-derived metabolites short-chain fatty acids, which have anti-inflammatory and blood pressure-lowering effects via the gut microbiome. This would limit adverse events, leading to improved medication adherence and better blood pressure control., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Huperzine A (Hup A), an extract from Huperzia serrata, exerted its anti-inflammation and anti-oxidation effect to protect against neurodegenerative disorders and organ injury. Ferroptosis was indicated to involve in the development of acute lung injury (ALI) accompanying by lipid reactive oxygen species (ROS) overexpressed. However, there is little research focused on the protective effect of Hup A on ALI, and the underlying molecular mechanism remains elusive. This study aims to determine the therapeutic effect of Hup A on ALI in vivo and in vitro. Hup A attenuated lung injury and cellular damage in lipopolysaccharide-induced ALI (LPS-ALI) models, both in vivo and in vitro, accompanied by the upregulation of ferroptosis-associated proteins (SLC7A11 and GPX4). Furthermore, the pretreatment with Hup A decreased the abundance of inflammation factors (IL-6, TNF-α), MDA, lipid ROS, and Fe 2+ in the LPS-ALI model, while it also promoted the secretion of SOD and GSH to antagonize peroxidation. Mechanistically, RNA sequencing and network pharmacological analysis synergistically revealed the PI3K/Akt signaling pathway as a potential target of Hup A. In vitro experiments demonstrated that Hup A effectively activated GPX4 through the PI3K/Akt signaling pathway, which was subsequently reversed by LY294002, an inhibitor of the PI3K/Akt signaling pathway. Consequently, our results revealed that Hup A inhibited ferroptosis in LPS-ALI by activating the PI3K-Akt signaling pathway which indicated the potential therapeutical effect of Hup A and further emphasized the pivotal role of ferroptosis in ALI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Toll-like receptors (TLRs) play a pivotal role in initiating immune responses, particularly in the context of inflammation. However, an excessive inflammation can detrimentally affect the immune homeostasis Thus, it is important to regulate TLR signaling pathways appropriately. Gingerenone A (GIA), a bioactive compound derived from ginger, has garnered significant attention due to its potential anti-inflammatory properties. In this study, we investigate modulatory effects of GIA on TLR signaling pathways. Results showed that GIA effectively suppressed TLR-mediated inflammatory responses by modulating key signaling molecules such as nuclear factor kappa B and interferon regulatory factor 3. These results indicate that GIA is a novel regulator of TLR signaling, offering promising avenues for the development of new anti-inflammatory agents., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Bacterial keratitis is a common cause of blindness. Antibiotic treatment leads to the rapid release of lipopolysaccharide (LPS), which can activate corneal fibroblasts and cause persistent and excessive inflammatory responses. The anti-inflammatory drugs currently used to treat keratitis have serious side effects. Therefore, the ability of sodium butyrate (NaB), which can suppress the production of proinflammatory cytokines and promote the production of anti-inflammatory cytokines, to ameliorate keratitis was assessed in the present study., Methods: The effect of NaB on the viability of primary human corneal fibroblasts was assayed with a CCK-8 kit. Cell migration was assessed by an in vitro scratch assay. Cell phenotypes were assessed by Western blotting and immunofluorescence staining. An antibody array was used to measure the production of proinflammatory cytokines and chemokines., Results: At 0-1 mM, NaB had no significant effect on cell viability, promoted the expression of the keratocyte marker keratocan and inhibited the fibroblast marker vimentin. Inhibition of cell migration was observed in the wound healing assay. By targeting the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway, NaB decreased the levels of inflammation-related cytokines and chemokines whose expression was induced by LPS., Conclusions: NaB maintained the keratocyte phenotype, inhibited cell migration, and relieved LPS-induced inflammatory responses through the JAK/STAT signalling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depression is a complex neurological disease that holds many theories on its aetiology and pathophysiology. The monoamine strategy of treating depression with medications to increase levels of monoamines in the (extra)synapse, primarily through the inhibition of monoamine transporters, does not always work, as seen in patients that lack a response to multiple anti-depressant exposures, as well as a lack of depressive symptoms in healthy volunteers exposed to monoamine reduction. Depression is increasingly being understood not as a single condition, but as a complex interplay of adaptations in various systems, including inflammatory responses and neurotransmission pathways in the brain. This understanding has led to the development of the neurodegenerative hypothesis of depression. This hypothesis, which is gaining widespread acceptance posits that both oxidative stress and inflammation play significant roles in the pathophysiology of depression. This article is a review of the literature focused on neuroinflammation in depression, as well as summarised studies of anti-inflammatory and antioxidant effects of antidepressants., Competing Interests: Declaration of competing interest We confirm that the paper has been seen and reviewed by co-authors, approved the submission to the journal. We confirm that there are no conflicts of interest in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Acute kidney injury (AKI) is a severe medical condition that can lead to illness and death. A disintegrin and metalloprotease (ADAM) protein family is a potential treatment target for AKI due to its involvement in inflammation, growth, and differentiation. While ADAM10 and ADAM17 have been identified as significant contributors to inflammation, it is unclear whether they play a critical role in AKI. In this study, we induced AKI in male and female mice using lipopolysaccharide, a bacterial endotoxin that causes inflammation and oxidative stress. The role of kaempferol, which is found in many natural products and known to have antioxidant and anti-inflammatory activity in many pre-clinical studies, was investigated through ADAM10/17 enzymes in AKI. We also investigated the efficacy of a selective synthetic inhibitor named GW280264X for ADAM10/17 inhibition in AKI. Blood urea nitrogen and creatinine levels were measured in serum, while tumor necrosis factor-α, vascular adhesion molecule, interleukin (IL)-1β, glucose regulatory protein-78, IL-10, nuclear factor κ-B, thiobarbituric acid reactive substances, total thiol, ADAM10, and ADAM17 levels were measured in kidney tissue. We also evaluated kidney tissue histologically using hematoxylin and eosin, periodic acid-schiff, and caspase-3 staining. This research demonstrates that GW280264X and kaempferol reduces inflammation and oxidative stress, as evidenced by biochemical and histopathological results in AKI through ADAM10/17 inhibition. These findings suggest that inhibiting ADAM10/17 may be a promising therapeutic approach for treating acute kidney injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Constant efforts have been made to move towards maintaining the positive anti-inflammatory functions of glucocorticoids (GCs) while minimizing side effects. The anti-inflammatory effect of GCs is mainly attributed to the inhibition of major inflammatory pathways such as NF-κB through GR transrepression, while its side effects are mainly mediated by transactivation. Here, we investigated the selective glucocorticoid receptor modulator (SGRM)-like properties of a plant-derived compound. In this study, glucocorticoid receptor (GR)-mediated alleviation of inflammation by SP-8 was investigated by a combination of in vitro, in silico, and in vivo approaches. Molecular docking and cellular thermal shift assay suggested that SP-8 bound stably to the active site of GR via hydrogen bonding and hydrophobic interactions. SP-8 activated GR, induced GR nuclear translocation, and inhibited NF-κB pathway activation. Furthermore, SP-8 did not up-regulate the gene and protein expression of PEPCK and TAT in HepG2 cells, and it did not induce fat deposition like GC and has little effect on bone metabolism. Interestingly, SP-8 upregulated GR protein expression and did not cause GR phosphorylation at Ser211 in RAW264.7 cells. This work proved that SP-8 dissociated characteristics of transrepression and transactivation can be separated. In addition, the in vitro and in vivo anti-inflammatory effects of SP-8 were confirmed in LPS-induced RAW 264.7 cells and in a mouse model of DSS-induced ulcerative colitis, respectively. In conclusion, SP-8 might serve as a potential SGRM and might hold great potential for therapeutic use in inflammatory diseases., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We the undersigned declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We understand that the Corresponding Author is the sole contact for the Editorial process. She is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs., (Copyright © 2024. Published by Elsevier B.V.)

Spinal cord injury (SCI) is a serious and disabling injury that is often accompanied by neuropathic pain (NeP), which severely affects patients' motor and sensory functions and reduces their quality of life. Currently, there is no specific treatment for treating SCI and relieving the accompanying pain, and we can only rely on medication and physical rehabilitation, both of which are ineffective. Researchers have recently identified a novel class of glial cells, olfactory ensheathing cells (OECs), which originate from the olfactory system. Transplantation of OECs into damaged spinal cords has demonstrated their capacity to repair damaged nerves, improve the microenvironment at the point of injury, and They can also restore neural connectivity and alleviate the patient's NeP to a certain extent. Although the effectiveness of OECs transplantation has been confirmed in experiments, the specific mechanisms by which it repairs the spinal cord and relieves pain have not been articulated. Through a review of the literature, it has been established that the ability of OECs to repair and relieve pain is inextricably linked to its anti-inflammatory and immunomodulatory effects. In this regard, it is imperative to gain a deeper understanding of how OECs exert their anti-inflammatory and immunomodulatory effects. The objective of this paper is to provide a comprehensive overview of the mechanisms by which OECs exert anti-inflammatory and immunomodulatory effects. We aim to manipulate the immune microenvironment at the transplantation site through the intervention of cytokines and immune cells, with the goal of enhancing OECs' function or creating a conducive microenvironment for OECs' survival. This approach is expected to improve the therapeutic efficacy of OECs in clinical settings. However, numerous fundamental and clinical challenges remain to be addressed if OEC transplantation therapy is to become a standardized treatment in clinical practice., Competing Interests: Declaration of competing interest We confirmed that the paper has been seen and admitted by co-authors, approved the submission to the journal. We confirmed that there are no conflicts of interest in this paper. Thank you very much., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Human neutrophil elastase (HNE) is an important contributor to lung diseases such as acute lung injury (ALI) or acute respiratory distress syndrome. Therefore, this study aimed to identify natural HNE inhibitors with anti-inflammatory activity through machine learning algorithms, in vitro assays, molecular dynamic simulation, and an in vivo ALI assay., Methods: Based on the optimized Discovery Studio two-dimensional molecular descriptors, combined with different molecular fingerprints, six machine learning models were established using the Naïve Bayesian (NB) method to identify HNE inhibitors. Subsequently, the optimal model was utilized to screen 6925 drug-like compounds obtained from the Traditional Chinese Medicine Systems Pharmacy Database and Analysis Platform (TCMSP), followed by ADMET analysis. Finally, 10 compounds with reported anti-inflammatory activity were selected to determine their inhibitory activities against HNE in vitro, and the compounds with the best activity were selected for a 100 ns molecular dynamics simulation and its anti-inflammatory effect was evaluated using Poly (I:C)-induced ALI model., Results: The evaluation of the in vitro HNE inhibition efficiency of the 10 selected compounds showed that the flavonoid tricetin had the strongest inhibitory effect on HNE. The molecular dynamics simulation indicated that the binding of tricetin to HNE was relatively stable throughout the simulation. Importantly, in vivo experiments indicated that tricetin treatment substantially improved the Poly (I:C)-induced ALI., Conclusion: The proposed NB model was proved valuable for exploring novel HNE inhibitors, and natural tricetin was screened out as a novel HNE inhibitor, which was confirmed by in vitro and in vivo assays for its inhibitory activities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis is an inflammatory condition primarily affecting the joints. Nuciferine (NCF), a key bioactive aporphine alkaloid biosynthesized in lotus leaves, exhibits promising anti-inflammatory and antioxidant properties. In this study, we investigated whether NCF could alleviate inflammatory arthritis conditions in a complete Freund's adjuvant (CFA)-mediated arthritis model in rats. The arthritis model was established through intradermal injection of CFA (100 μL) in the sub-plantar region of the right hind paw. The arthritic animals were treated orally with NCF at 5 and 10 mg/kg and indomethacin (Indo) at 5 mg/kg body weight as reference control. NCF treatment remarkably alleviated inflammatory joint swelling and arthritic index. The radiological and histological analysis revealed evidence of the beneficial effects of NCF. NCF treatment decreased the content of pro-inflammatory cytokines (TNF-α and IL-1β) and myeloperoxidase (MPO) activity and restored the anti-inflammatory cytokine (IL-10) in the paw joints. The serum levels of pro-inflammatory cytokines were also markedly reduced in the NCF (10 mg/kg) treatment group. Moreover, the arthritis-induced inflammatory mediators, including cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) and the toll-like receptor (TLR)-4, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling proteins were substantially decreased in the NCF treatment groups. NCF treatment also restored the antioxidant defense enzymes and abrogated lipid peroxidation in the paw tissue. Our findings strongly suggest that NCF is a promising therapeutic molecule for rheumatoid arthritis, inspiring further research, and development in this area., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glaucine is an aporphine alkaloid with anti-inflammatory, bronchodilator and anti-cancer activities. However, the effects of glaucine in the regulation of age-related macular degeneration (AMD) remain unclear. Herein, we aimed to investigate the anti-angiogenetic and anti-inflammatory effects of glaucine in ARPE-19 cells. ARPE-19 cells were treated with N-(methoxyoxoacetyl)-glycine, methyl ester (DMOG) and cobalt chloride (CoCl 2 ) for induction of hypoxia, while lipopolysaccharide (LPS) treatment was used for elicitation of inflammatory response. Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The expression of hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by Western blot. The secretion of VEGF, interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1) was detected using enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs) were used for tube formation analysis. Expression of HIF-1α and secretion of VEGF were significantly increased under DMOG and CoCl 2 induction, whereas glaucine significantly attenuated both HIF-1α expression and VEGF secretion by DMOG- and CoCl 2 -induced ARPE-19 cells. In addition, glaucine suppressed the tube formation by DMOG- and CoCl 2 -induced HUVEC cells. Moreover, glaucine also attenuated the production of IL-6 and MCP-1 by LPS-induced ARPE-19 cells. This study indicated that glaucine exhibited anti-angiogenic and anti-inflammatory effects, suggesting that glaucine might have benefits for the treatment of AMD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dysregulated host response against infection triggers sepsis that leads to multiple organ dysfunction due to uncontrolled inflammatory responses. Despite marked progress in understanding of sepsis, numerous clinical trials for treatment of sepsis have proven daunting and a new therapeutic approach is highly needed. CE9A215 (inotodiol), a fungal secondary metabolite, has been researched for its pharmacological activities and has shown potent anti-allergic effects. In this study, we evaluated the anti-inflammatory activities of CE9A215 upon lipopolysaccharide (LPS) stimulation in vivo and in vitro for the first time. CE9A215 decreased the production of interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and IL-1β in a concentration-dependent manner in LPS-stimulated RAW264.7 cells. Intriguingly, in human mast cell line LUVA, CE9A215 significantly lowered IL-4 and IL-10, and this effect could be beneficial for the clearance of bacterial infection. In addition, administration of CE9A215 improved the survival rate of LPS-stimulated mice and inhibited the pro-inflammatory cytokines, IL-6, TNF-α, and IL-1β in blood. Moreover, CE9A215 enhanced the expression levels of plasma phospholipid transfer protein (PLTP), apolipoprotein E (ApoE), and ATP-binding cassette transporter (ABCA1) in LPS-stimulated RAW246.7 cells. Liver PLTP level increased significantly in the CE9A215-administered group compared with the control group, which implies that CE9A215 promotes LPS clearance and neutralization by reverse transport of LPS by increasing the expressions of PLTP, ApoE, and ABCA1. Our results highlight CE9A215's potential as a novel therapeutic option for the treatment of sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is an idiopathic disease caused by the loss or degeneration of the dopaminergic (dopamine-producing) neurons in the brain and characterized by various inflammatory and apoptotic responses in the neuronal cells. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) axis is responsible for neuronal survival by providing a number of anti-inflammatory and anti-apoptotic milieu that prevent the progression of PD. Alpha-lipoic acid (ALA) is a natural cofactor that has antioxidant capacity and contributes to various metabolic processes. ALA can penetrate the blood-brain barrier and contribute to numerous neuroprotective effects. It can activate PI3K/AKT pathway with consequent reduction of different inflammatory and oxidative biomarkers. Our work aims to unfold the neuroprotective effects of ALA via targeting PI3k/AKT pathway. Forty male mice were divided into four groups: control, ALA (100 mg/kg/day; i.p.), rotenone (ROT) (1.5 mg/kg/2 days, i.p.) and rotenone + ALA for 21 days. ALA showed obvious neuroprotective effects via significant activation of PI3K/AKT pathway with subsequent decreasing level of Caspase-3. ALA resulted in prominent anti-inflammatory actions by decreasing interlukin-1β (IL-1β), tumor necrosis factor (TNF)-α and nuclear factor kabba (NFk)-B. ALA remarkably induced antioxidant activities via increasing reduced glutathione (GSH) and superoxide dismutase (SOD) levels as well as decreasing malondialdehyde (MDA) level. The substantial behavioral improvement reflected in these results was noticed in the ALA-treated mice as a reflection of the neuroprotective activities of ALA. In conclusion, ALA showed promising neuroprotective effects in rotenone-induced PD via activating the PI3K/AKT pathway and consequent inhibition of apoptotic and inflammatory biomarkers., Competing Interests: Declaration of competing interest none., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Allergic asthma is a major health burden on society as a chronic respiratory disease characterized by inflammation and muscle tightening around the airways in response to inhaled allergens. Daphne kiusiana Miquel is a medicinal plant that can suppress allergic airway inflammation; however, its specific molecular mechanisms of action are unclear. In this study, we aimed to elucidate the mechanisms by which D. kiusiana inhibits allergic airway inflammation. We evaluated the anti-inflammatory effects of the ethyl acetate (EA) fraction of D. kiusiana and its major compound, daphnetin, on murine T lymphocyte EL4 cells stimulated with phorbol 12-myristate 13-acetate and ionomycin in vitro and on asthmatic mice stimulated with ovalbumin in vivo. The EA fraction and daphnetin inhibited T-helper type 2 (Th2) cytokine secretion, serum immunoglobulin E production, mucus secretion, and inflammatory cell recruitment in vivo. In vitro, daphnetin suppressed intracellular Ca 2+ mobilization (a critical regulator of nuclear factor of activated T cells) and functions of the activator protein 1 transcription factor to reduce interleukin (IL)-4 and IL-13 expression. Daphnetin effectively suppressed the IL-4/-13-induced activation of Janus kinase (JAK)/signal transducer and activator of transcription 6 (STAT6) signaling in vitro and in vivo, thereby inhibiting the expression of GATA3 and PDEF, two STAT6-target genes responsible for producing Th2 cytokines and mucins. These findings indicate that daphnetin suppresses allergic airway inflammation by stabilizing intracellular Ca 2+ levels and subsequently inactivating the JAK/STAT6/GATA3/PDEF pathway, suggesting that daphnetin is a promising alternative to existing asthma treatments., Competing Interests: Declaration of competing interest None: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Microglia are primarily involved in inflammatory reactions and oxidative stress in the brain; as such reducing microglial activation has been proposed as a potential therapeutic strategy for neurodegenerative disorders. Herein, we investigated the anti-inflammatory and antioxidant activities of coniferaldehyde (CFA), a naturally occurring cinnamaldehyde derivative, on activated microglia to evaluate its therapeutic potential. CFA inhibited the production of nitric oxide (NO) and proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. CFA also inhibited intracellular reactive oxygen species levels and oxidative stress markers such as 4-HNE and 8-OHdG. Detailed mechanistic studies showed that CFA exerted anti-inflammatory effects by inhibiting TAK1-mediated MAP kinase/NF-κB activation and upregulating AMPK signaling pathways. In addition, CFA exerted antioxidant effects by inhibiting the NADPH oxidase subunits and by increasing the expression of antioxidant enzymes such as HO-1, NQO1, and catalase by upregulating Nrf2 signaling. Finally, we confirmed the effects of CFA on the brains of the LPS-injected mice. CFA inhibited microglial activation and the expression of proinflammatory markers and increased Nrf2-driven antioxidant enzymes. Furthermore, CFA inhibited the production of 4-HNE and 8-OHdG in the brains of LPS-injected mice. As a result, CFA's significant anti-inflammatory and antioxidant properties may have therapeutic applications in neuroinflammatory disorders related with oxidative stress and microglial activation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Psoriasis is a prevalent immune-mediated inflammatory skin disease characterized by excessive abnormal proliferation of keratinocytes and infiltration of immune cells, which have significant impact on the life quality of individuals. Although biological agents and small molecule targeted drugs have brought significant clinical benefits to psoriasis patients, adverse reactions and high prices remains key issues in clinical medication of psoriasis, while natural product monomers possess high efficiency, low toxicity, anti-inflammatory and immunomodulatory properties, and bring new hope for the clinical treatment of psoriasis. Sappanone A (SA), a small molecule compound isolated from Caesalpinia sappan L, exhibits significant anti-inflammatory properties in various models, such as kidney inflammation and LPS-induced mice inflammation. Among these effects, the anti-inflammatory property of SA has received significant attention. In our study, we found that SA exhibited anti-proliferation and anti-inflammatory effects in HaCaT cells, and significantly alleviated imiquimod-induced psoriasis-like skin lesions via the inhibition of the excessive proliferation of keratinocytes and the infiltration of lymphocytes. Furthermore, the combinational analysis of network pharmacology and transcriptome sequencing revealed that SA exerted anti-psoriasis effects by inhibiting the matrix metalloproteinase 8 (Mmp8) expression and IL-17 pathway activation. In summary, we have first demonstrated that SA can be used as a novel anti-psoriasis drug, which may provide a novel strategy for the clinical treatment of psoriasis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The increased incidence of obesity, which become a global health problem, requires more functional food products with minor side and excellent effects. Calebin A (CbA) is a non-curcuminoid compound, which is reported to be an effective treatment for lipid metabolism and thermogenesis. However, its ability and mechanism of action in improving obesity-associated hyperglycemia remain unclear. This study was designed to explore the effect and mechanism of CbA in hyperglycemia via improvement of inflammation and glucose metabolism in the adipose tissue and liver in high-fat diet (HFD)-fed mice. After 10 weeks fed HFD, obese mice supplemented with CbA (25 and 100 mg/kg) for another 10 weeks showed a remarkable reducing adiposity and blood glucose. CbA modulated M1/M2 macrophage polarization, ameliorated inflammatory cytokines, and restored adiponectin as well as Glut 4 expression in the adipose tissue. In the in vitro study, CbA attenuated pro-inflammatory markers while upregulated anti-inflammatory IL-10 in LPS + IFNγ-generated M1 phenotype macrophages. In the liver, CbA attenuated steatosis, inflammatory infiltration, and protein levels of inflammatory TNF-α and IL-6. Moreover, CbA markedly upregulated Adiponectin receptor 1, AMPK, and insulin downstream Akt signaling to improve glycogen content and increase Glut2 protein. These findings indicated that CbA may be a novel therapeutic approach to treat obesity and hyperglycemia phenotype targeting on adipose inflammation and hepatic insulin signaling., Competing Interests: Declaration of competing interest The authors confirm that no conflicts of interest for the work described in this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium of joints. Fibroblast-like synoviocytes (FLS) play an important role in RA pathogenesis. We aimed to investigate the effect of N-(4-methoxyphenyl) quinoline-8-sulfonamide (QS-3g) on the inflammatory response of FLS and explore the potential underlying mechanisms., Methods: We screened and found that QS-3g exhibits the best anti-inflammatory response against FLS using the CCK8 assay. To investigate the therapeutic effects of QS-3g on K/BxN STA mice, we used H&E staining, immunofluorescence, immunohistochemistry, micro-CT, and other techniques. Additional investigations, including RNA-seq, molecular docking, and CETSA, revealed that QS-3g binds to RAMP1., Results: Among a series of 8-quinoline sulfonyl amide derivatives, QS-3g reduced the inflammatory response in TNF-α stimulated FLS, such as the release of interleukin (IL)-1β and IL-6. H&E staining and micro-CT showed that QS-3g inhibited synovial hypertrophy, inflammatory cell infiltration, and bone destruction. RNA-seq and CETSA analyses revealed the targeted inhibition of RAMP1 by QS-3g. Inhibition of RAMP1 expression could reduce IL-6 and IL-1β levels. Compared with RAMP1-si, combined administration of QS-3g and RAMP1-si reduced the TNF-α-induced inflammation in TNF-α stimulated FLS without statistically significant differences. Finally, the results of in vitro experiments showed that QS-3g could restore the balance of Gαi/Gαs by inhibiting Gαi and activating Gαs and up-regulate the expression of cAMP protein, thus inhibiting the RAMP1-mediated inflammatory response in FLS., Conclusion: QS-3g could inhibit RAMP1 activity and mediate the Gαs/Gαi-cAMP pathway to reduce FLS inflammatory response. Therefore, QS-3g may serve as a novel anti-inflammatory compound for treating RA., Competing Interests: Declaration of competing interest This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acute lung injury (ALI) is an inflammatory disorder accompanied by higher morbidity and mortality. The pathological mechanism of ALI has been reported to be associated with the release of inflammatory cytokines by macrophages. Sesquiterpene lactones (SLs) represent the principal anti-inflammatory components of many natural products. Tulipalin A is a natural small molecule and a conserved moiety in anti-inflammatory SLs. However, the anti-inflammatory potential of Tulipalin A has yet to be fully disclosed. The present study aims to investigate TulipalinA's anti-inflammatory activity and underlying mechanisms in vitro and in vivo. Tulipalin A suppressed inflammatory responses in lipopolysaccharide (LPS)-stimulated bone marrow-derived primary macrophages and ameliorated LPS-induced ALI in mice. Mechanistically, Tulipalin A directly targets the NF-κB p65 and disrupts its DNA binding activity, thereby impeding the activation of NF-κB. Inhibition of NF-κB attenuated M1 polarization of macrophages, consequently suppressing the production of pro-inflammatory mediators and ameliorating the onset and progression of ALI. These findings suggest Tulipalin A's potential to mitigate inflammatory disorders like ALI via targeting NF-κB p65 and disrupting its DNA binding activity., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oxidative stress and inflammation significantly contribute to the pathogenesis of diabetic cardiomyopathy (DCM). Persistent inflammatory stimuli drive the progression of myocardial fibrosis and impaired cardiac function. Phloridzin (Phl), a natural compound, demonstrates both anti-inflammatory and antioxidant properties. Nevertheless, its therapeutic potential and underlying mechanisms in DCM remain unclear. This study aimed to elucidate the mechanisms through which Phl inhibited myocardial fibrosis and exerted its antioxidative effects. The impact of Phl on DCM was evaluated using a high-fat/high-sugar diet combined with streptozotocin to induce an animal model and an in vitro H9C2 cell model stimulated by high glucose (HG). Untargeted metabolomics identified potential mechanisms underlying myocardial fibrosis. Phl treatment significantly enhanced left ventricular ejection fraction (EF%) and shortening fraction (FS%), while reducing myocardial injury markers, such as lactate dehydrogenase and creatine phosphokinase-MB, and suppressing myocardial collagen fiber accumulation. Simultaneously, Phl attenuated myocardial inflammation via inhibition of MyD88/NF-κB signaling, modulated the Nrf2/GPX4 axis to counter oxidative stress, and mitigated ferroptosis. In vitro, Phl inhibited high glucose-induced myocardial hypertrophy and fibrosis in H9C2 cells, while also repressing NF-κB activation in cardiomyocytes. Metabolomic profiling revealed that Phl ameliorated DCM through modulation of glycerophospholipid metabolic pathways, linking these metabolic shifts to enhanced antioxidant capacity, thereby reflecting its ability to reduce oxidative stress in the myocardium. Collectively, Phl provides cardioprotective effects by alleviating inflammation and oxidative damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (pregabalin/gabapentin) were designed and assessed in inflammatory, osteoarthritis and neuropathic pain. Isobolographic analysis was performed to analyze the interactions between nefopam and gabapentinoids in carrageenan-induced inflammatory pain, mono-iodoacetate-induced osteoarthritis pain and paclitaxel-induced peripheral neuropathic pain in mice. The anti-inflammatory effect and motor performance of monotherapy or their combinations were evaluated in the carrageenan-induced inflammatory responses and rotarod test, respectively. Nefopam (1, 3, 5, 10, 30 mg/kg, p.o.), pregabalin (3, 6, 12, 24 mg/kg, p.o.) or gabapentin (25, 50, 75, 100 mg/kg, p.o.) dose-dependently reversed mechanical allodynia in three pain models. Isobolographic analysis indicated that the combinations of nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis, and neuropathic pain mouse models, as evidenced by the experimental ED 50 (median effective dose) falling below the predicted additive line. Moreover, the combination of nefopam-pregabalin/gabapentin alleviated carrageenan-induced inflammation and edema, and also prevented gabapentinoids-related sedation or ataxia by lowering their effective doses. Collectively, the co-administration of nefopam and gabapentinoids showed synergistic analgesic effects and may result in improved therapeutic benefits for treating pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dry eye disease (DED) is a complex disorder driven by several factors like reduced tear production, increased evaporation, or poor tear quality. Oxidative stress plays a key role by exacerbating the inflammatory cycle. Previous studies explored antioxidants for DED treatment due to the link between oxidative damage and inflammation. Biochanin A (BCA) is a bioisoflavone from red clover with potent anti-inflammatory effects. This study investigated BCA's therapeutic potential for DED. Human corneal epithelial cells were cultured under hyperosmotic conditions to mimic DED. BCA treatment increased cell viability and decreased apoptosis and inflammatory cytokine expression. A DED mouse model was developed using female C57BL/6 mice in a controlled low-humidity environment combined with scopolamine injections. Mice received eye drops containing phosphate-buffered saline, low-dose BCA, or high-dose BCA. The effectiveness was evaluated by measuring tear volume, fluorescein staining, eye-closing ratio, corneal sensitivity and PAS staining. The levels of inflammatory components in corneas and conjunctiva were measured to assess DED severity. Maturation of antigen-presenting cells in cervical lymph nodes was analyzed by flow cytometry. BCA eye drops effectively reduced inflammation associated with DED in mice. BCA also decreased oxidative stress levels by reducing reactive oxygen species and enhancing the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2). These findings demonstrate that BCA ameliorates oxidative stress and ocular surface inflammation, indicating potential as a DED treatment by relieving oxidative damage and mitigating inflammation., Competing Interests: Declaration of competing interest The authors declared that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Recently, managing the chronic skin wounds has become increasingly challenging for healthcare professionals due to the intricate orchestration of cellular and molecular processes involved that lead to the uncontrollable inflammatory reactions which hinder the healing process. Therefore, different types of wound dressings with immunomodulatory properties have been developed in recent years to effectively regulate the immune responses, enhance angiogenesis, promote re-epithelialization, and accelerate the wound healing process. This study aims to develop a new type of immunomodulatory wound dressing utilizing carboxymethyl cellulose (CMC)/sodium alginate (Alg)-simvastatin (SIM) to simultaneously enhance the inflammatory responses and the wound healing ratio. The CMC/Alg-SIM hydrogels exhibited appropriate swelling ratio, water vapor transmission rate, and desirable degradation rate, depending on the SIM content. The fabricated dressing showed sustained release of SIM (during 5 days) that improved the proliferation of skin cells. According to the in vitro findings, the CMC/Alg-SIM hydrogel exhibited controlled pro-inflammatory responses (decreased 2.5- and 1.6-times IL-6 and TNF-α, respectively) and improved secretion of anti-inflammatory cytokines (increased 1.5- and 1.3-times IL-10 and TGF-β, respectively) in comparison with CMC/Alg. Furthermore, the CMC/Alg-SIM hydrogel facilitated rapid wound healing in the rat model with a full-thickness skin defect. After 14 days post-surgery, the wound healing ratio in the CMC/Alg hydrogel group (∼93%) was significantly greater than the control group (∼58%). Therefore, the engineered CMC/Alg-SIM hydrogel with desired immunomodulatory properties possesses the potential to enhance and accelerate skin regeneration for the management of chronic wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Sepsis is frequently complicated by neuroinflammation. Gibberellic acid (GA3) is recognized for its anti-inflammatory properties. In this study, our objective was to investigate whether GA3 could alleviate Nuclear factor-kappa B (NF-κB) -dependent inflammatory stress in sepsis-induced neuroinflammation., Methods: C57BL/6 J mice were administered 10 mg/kg lipopolysaccharide (LPS) to induce sepsis. BV2 cells were pre-incubated with GA3 and subjected lipopolysaccharide stimulation to replicate the inflammatory microglia during sepsis. Subsequently, we assessed the release of IL-6, TNF-α, and IL-1β, along with the expression of Zbtb16, NF-κB, and IκB. To investigate whether any observed anti-inflammatory effects of GA3 were mediated through a Zbtb16-dependent mechanism, Zbtb16 was silenced using siRNA., Results: GA3 improved the survival of sepsis mice and alleviated post-sepsis cognitive impairment. Additionally, GA3 attenuated microglial M1 activation (pro-inflammatory phenotype), inflammation, and neuronal damage in the brain. Moreover, GA3 inhibited the release of TNF-α, IL-6, and IL-1β in microglia stimulated with LPS. The NF-κB signaling pathway emerged as one of the key molecular pathways associated with the impact of GA3 on LPS-stimulated microglia. Lastly, GA3 upregulated Zbtb16 expression in microglia that had been downregulated by LPS. The inhibitory effects of GA3 on microglial M1 activation were partially reversed through siRNA knockdown of Zbtb16., Conclusions: Pre-incubation of microglia with GA3 led to the upregulation of the NF-κB regulator, Zbtb16. This process counteracted LPS-induced microglial M1 activation, resulting in an anti-inflammatory effect upon subsequent LPS stimulation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with immune dysregulation affecting colon inflammatory response. Recent studies have highlighted that neutrophil extracellular traps (NETs) play an important role in the pathogenesis of UC. Berbamine (BBM), one of the bioactive ingredients extracted from Chinese herbal medicine Berberis vulgaris L, has attracted intensive attentions due to its significant anti-inflammatory activity and a marketing drug for treating leukemia in China. However, the exact role and potential molecular mechanism of BBM against UC remains elusive. In the present study, our results showed that BBM could markedly improve the pathological phenotype and the colon inflammation in mice with dextran sulfate sodium (DSS)-induced colitis. Then, comprehensive approaches combining network pharmacology and molecular docking analyses were employed to predict the therapeutic potential of BBM in treating UC by peptidyl-arginine deiminase 4 (PAD4), a crucial molecule involved in NETs formation. The molecular docking results showed BBM had a high affinity for PAD4 with a binding energy of -9.3 kcal/mol Moreover, PAD4 expression and NETs productions, including citrullination of histone H3 (Cit-H3), neutrophil elastase (NE), myeloperoxidase (MPO) in both neutrophils and colonic tissue were reduced after BBM administration. However, in the mice with DSS-induced colitis pretreated with GSK484, a PAD4-specific inhibitor, BBM could not further reduce disease related indexes, expression of PAD4 and NETs productions. Above all, the identification of PAD4 as a potential target for BBM to inhibit NETs formation in colitis provides novel insights into the development of BBM-derived drugs for the clinical management of UC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships in this publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Wogonoside (WG) is a natural flavonoid extracted from Scutellariae Radix, recognized for its established anti-inflammatory properties. However, the role of WG in the context of neuroinflammation after spinal cord injury (SCI) remains inadequately elucidated. This study employed in silico, in vitro, and in vivo methodologies to investigate the impact of WG on microglia-mediated neuroinflammation after SCI. In the in silico experiment, we identified 15 potential target genes of WG associated with SCI. These genes were linked to the regulation of inflammatory response and immune defense. Molecular docking maps revealed toll-like receptor 4 as a molecular target for WG, demonstrating binding through a hydrogen bond (Lys263, Ser120). In lipopolysaccharide-stimulated BV2 cells and SCI mice, WG significantly attenuated microglial activation and facilitated a phenotype shift from M1 to M2. This was evidenced by the reversal of the increased expressions of Iba1, GFAP, and iNOS, as well as the decreased expression of Arg1. WG also suppressed the production of pro-inflammatory mediators (NO, TNF-α, IL-6, IL-1α, IL-1β, C1q). WG exerted these effects by suppressing the TLR4/MyD88/NF-κB signaling axis in microglia. Furthermore, by reducing levels of TNF-α, IL-1α, and C1q in supernatant of LPS-induced microglia, WG indirectly induced astrocytes change to A2 phenotype, evidenced by transcriptome sequencing result of primary mouse astrocytes. All these events above collectively created a favorable microenvironment, contributing to a significant alleviation of weight loss and neuronal damage at the lesion site of SCI mice. Our findings substantiate the efficacy of WG in mitigating neuroinflammation after SCI, thereby warranting further exploration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The spinal cord microglia play a pivotal role in neuroinflammation and neuropathic pain (NP). Sodium tanshinone IIA sulfonate (STS), a derivative of tanshinone IIA, has anti-inflammatory and anti-hyperalgesic effects. However, its underlying mechanism in NP remains unclear. This study aimed to investigate the effect of STS and elucidate possible mechanisms in a rat model of spared nerve injury. In vivo experiments, STS and AG490 were administered intraperitoneally once daily for 14 consecutive days after surgery. The results showed that the expression of miR-125b-5p in the spinal dorsal horn was substantially reduced, whereas signal transducer and activator of transcription 3 (STAT3) signaling was increased. After treatment with STS, the mechanical thresholds, expression of miR-125b-5p, and microglial M2 marker such as Arg-1 in the spinal cord horn increased significantly, whereas multiple pro-inflammatory cytokines and apoptosis were significantly reduced. Moreover, STAT3 pathway-related proteins and expression of the microglial M1 marker, CD68, were appreciably inhibited. In vitro, lipopolysaccharide (LPS) was used to induce an inflammatory response in BV-2 microglial cells. STS pretreatment inhibited LPS-stimulated pro-inflammatory cytokine secretion, reduced STAT3 pathway related-proteins and apoptosis, increased miR-125b-5p and proopiomelanocortin expression, and enhanced microglia transformation from M1 to M2 phenotype in BV-2 cells. These effects were reversed after the inhibition of miR-125b-5p expression in BV-2 cells. A dual-luciferase reporter assay confirmed that STAT3 binds to miR-125b-5p. In summary, these results suggest that STS exerts anti-hyperalgesic and anti-neuroinflammatory effects in rats with NP possibly via the miR-125b-5p/STAT3 axis., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in this work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Coronary atherosclerotic heart disease (CHD) is a primary cardiovascular disease caused by atherosclerosis (AS), which is characterized by chronic inflammation and lipid oxidative deposition. Molecular hydrogen (H 2 ) is an effective anti-inflammatory agent and has potential to ameliorate glycolipid metabolism disorders, which is believed to exert beneficial effects on the prevention and treatment of CHD. It is suggested that H 2 reduces inflammation in CHD by regulating multiple pathways, including NF-κB inflammatory pathway, pyroptosis, mitophagy, endoplasmic reticulum (ER) stress, and Nrf2 antioxidant pathway. Additionally, H 2 may improve glycolipid metabolism by mediation of PI3K and AMPK signalling pathways, contributing to inhibition of the occurrence and development of CHD. This review elaborates pathogenesis of CHD and evaluates the role of H 2 in CHD. Moreover, possible molecular mechanisms have been discussed and speculated, aiming to provide more strategies and directions for subsequent studies of H 2 in CHD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Spinal cord injury (SCI), a fatal condition, is characterized by progressive tissue degradation and extreme functional deficits with limited treatment options. Hesperetin, a natural flavonoid with potent antioxidant, antiapoptotic and anti-inflammatory properties, has yet to be systematically investigated for its therapeutic effects on neurological damage in rat models of SCI. In this study, rats were given oral hesperetin once daily for 28 days, and their locomotion and histopathological changes were assessed. The findings demonstrated that hesperetin alleviates neurological damage caused by SCI. The observed behavioral improvement could be due to an increase in the survival rate of neurons and oligodendrocytes. This improvement further boosted the ability to repair tissue and form myelin after SCI, ultimately resulting in better neurological outcomes. Furthermore, the present study revealed that hesperetin possesses potent antioxidant capabilities in the context of SCI, reducing the levels of harmful oxygen free radicals and increasing the activity of antioxidant enzymes. Additionally, hesperetin markedly inhibited injury-induced apoptosis, as assessed by caspase-3 immunofluorescence staining and the expression level of caspase-3, indicating the ability of hesperetin to prevent cell death after SCI. Finally, after SCI, hesperetin treatment effectively reduced the expression of inflammatory factors, including IL-1β, TNFα, and NF-kB, demonstrating the anti-inflammatory effect of hesperetin. Together, our results suggest that hesperetin should be considered a valuable therapeutic aid following SCI, as its positive effects on the nervous system, including antioxidant, anti-inflammatory and antiapoptotic effects, may be crucial mechanisms through which hesperetin exerts neuroprotective effects against SCI., Competing Interests: Declaration of competing interest The authors declare no financial conflicts of interest. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us., (Copyright © 2024. Published by Elsevier B.V.)

Ropinirole used to treat Parkinson's disease highly targets the dopaminergic receptor D3 over the D2 receptor but although both are expressed in the kidneys the ropinirole potential to treat kidney injury provoked by ischemia/reperfusion (I/R) is undraped. We investigated whether ropinirole can alleviate renal I/R by studying its anti-inflammatory, antioxidant, and anti-pyroptotic effects targeting its aptitude to inhibit the High-mobility group box 1/Toll-like receptor 4/Nuclear factor-kappa B (HMGB1/TLR4/NF-κB) cue and the canonical/non-canonical NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome trajectories. Herein, bilateral I/R surgery was induced in animals to be either untreated or treated with ropinirole for three days after the insult. Ropinirole successfully improved the histopathological picture and renal function which was confirmed by reducing cystatin C and the standard parameters creatinine and blood urea nitrogen (BUN). Ropinirole achieved this through its anti-inflammatory capacity mediated by reducing the HMGB1/TLR4 axis and inactivating NF-κB, which are upstream regulators of the NLRP3 pathway. As a result, the injurious inflammasome markers (NLRP3, apoptosis-associated speck-like protein (ASC), active caspase-1) and their target cytokines interleukin-1 beta (IL-1β) and IL-18 were decreased. Ropinirole also reduced the pyroptotic cell death markers caspase-11 and gasdermin-D. Furthermore, ropinirole by replenishing antioxidants and decreasing malondialdehyde helped to reduce oxidative stress in the kidneys. The docking findings confirmed that ropinirole highly binds to the dopaminergic D3 receptor more than to the D2 receptor. In conclusion, ropinirole has the potential to be a reno-therapeutic treatment against I/R insult by abating the inflammatory NLRP3 inflammasome signal, pyroptosis, and oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inflammation is a driver of human disease and an unmet clinical need exists for new anti-inflammatory medicines. As a key cell type in both acute and chronic inflammatory pathologies, macrophages are an appealing therapeutic target for anti-inflammatory medicines. Drug repurposing - the use of existing medicines for novel indications - is an attractive strategy for the identification of new anti-inflammatory medicines with reduced development costs and lower failure rates than de novo drug discovery. In this study, FDA-approved medicines were screened in a murine macrophage NF-κB reporter cell line to identify potential anti-inflammatory drug repurposing candidates. The multi-tyrosine kinase inhibitor sunitinib was found to be a potent inhibitor of NF-κB activity and suppressor of inflammatory mediator production in murine bone marrow derived macrophages. Furthermore, oral treatment with sunitinib in mice was found to reduce TNFα production, inflammatory gene expression and organ damage in a model of endotoxemia via inhibition of NF-κB. Finally, we revealed sunitinib to have immunomodulatory effects in a model of chronic cardiovascular inflammation by reducing circulating TNFα. This study validates drug repurposing as a strategy for the identification of novel anti-inflammatory medicines and highlights sunitinib as a potential drug repurposing candidate for inflammatory disease via inhibition of NF-κB signalling., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ginger has been used for thousands of years for the treatment of many illnesses, from nausea to migraines. Recently, an interest has grown in ginger compounds in the context of autoimmune and inflammatory diseases due to their significant anti-inflammatory effects. Nevertheless, the effects and mechanism of action of these phytochemicals in human immune cells, particularly in dendritic cells (DCs) are unclear. In the present study, we investigated the effects of 6-gingerol and 6-shogaol, the major compounds found in ginger rhizome, on the functionality of primary human monocyte-derived DCs (moDCs). Here we report for the first time that 6-gingerol and 6-shogaol dampen the immunogenicity of human DCs by inhibiting their activation, cytokine production and T cell stimulatory ability. In particular, the bioactive compounds of ginger dose-dependently inhibited the upregulation of activation markers, and the production of different cytokines in response to synthetic Toll-like receptor (TLR) ligands. Moreover, both compounds could significantly reduce the Escherichia coli-triggered cytokine production and T cell stimulatory capacity of moDCs. We also provide evidence that the ginger-derived compounds attenuate DC functionality via inhibiting the nuclear factor-κB (NF-kB), mitogen activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) signaling cascades. Further, 6-shogaol but not 6-gingerol activates the AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (NRF2) pathways that might contribute to its anti-inflammatory action. Altogether, our results indicate that ginger-derived phytochemicals exert their anti-inflammatory activities via multiple mechanisms and suggest that 6-shogaol is more potent in its ability to suppress DC functionality than 6-gingerol., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

At least seven dominantly inherited spinocerebellar ataxias (SCA) are caused by expansions of polyglutamine (polyQ)-encoding CAG repeat. The misfolded and aggregated polyQ-expanded proteins increase reactive oxygen species (ROS), cellular toxicity, and neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of coumarin derivatives LM-021, LMDS-1, LMDS-2, and pharmacological chaperone tafamidis using mouse BV-2 microglia and SCA3 ataxin-3 (ATXN3)/Q 75 -GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing nitric oxide (NO), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α production, and CD68 antigen (CD68) and histocompatibility-2 (MHCII) expression in lipopolysaccharides (LPS)/interferon (IFN)-γ-stimulated BV-2 microglia. In retinoic acid-differentiated ATXN3/Q 75 -GFP-expressing SH-SY5Y cells inflamed with LPS/IFN-γ-primed BV-2 conditioned medium, treatment with test compounds mitigated the increased caspase 1 activity and lactate dehydrogenase release, reduced ROS and ATXN3/Q 75 aggregation, and promoted neurite outgrowth. Examination of IL-1β and IL-6-mediated signaling pathways revealed that LM-021, LMDS-1, LMDS-2, and tafamidis decreased NLR family pyrin domain containing 1 (NLRP1), c-Jun N-terminal kinase/c-Jun proto-oncogene (JNK/JUN), inhibitor of kappa B (IκBα)/P65, mitogen-activated protein kinase 14/signal transducer and activator of transcription 1 (P38/STAT1), and/or Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling. The study results suggest the potential of LM-021, LMDS-1, LMDS-2, and tafamidis in treating SCA3 and probable other polyQ diseases., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Inflammation regulates ventricular remodeling after myocardial infarction (MI), and gabapentin exerts anti-inflammatory effects. We investigated the anti-inflammatory role and mechanism of gabapentin after MI., Methods: Rats were divided into the sham group (n = 12), MI group (n = 20), and MI + gabapentin group (n = 16). MI was induced by left coronary artery ligation. The effects of gabapentin on THP-1-derived macrophages were examined in vitro., Results: In vivo, 1 week after MI, gabapentin significantly reduced inducible nitric oxide synthase (iNOS; M1 macrophage marker) expression and decreased pro-inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1β). Gabapentin upregulated the M2 macrophage marker arginase-1, as well as CD163 expression, and increased the expression of anti-inflammatory factors, including chitinase-like 3, IL-10, and transforming growth factor-β. Four weeks after MI, cardiac function, infarct size, and cardiac fibrosis improved after gabapentin treatment. Gabapentin inhibited sympathetic nerve activity and decreased ventricular electrical instability in rats after MI. Tyrosine hydroxylase and growth-associated protein 43 were suppressed after gabapentin treatment. Gabapentin downregulated nerve growth factor (NGF) and reduced pro-inflammatory factors (iNOS, TNF-α, and IL-1β). In vitro, gabapentin reduced NGF, iNOS, TNF-α, and IL-1β expression in lipopolysaccharide-stimulated macrophages. Mechanistic studies revealed that the peroxisome proliferator-activated receptor-γ antagonist GW9662 attenuated the effects of gabapentin. Moreover, gabapentin reduced α2δ1 expression in the macrophage plasma membrane and reduced the calcium content of macrophages., Conclusion: Gabapentin attenuates cardiac remodeling by inhibiting inflammation via peroxisome proliferator-activated receptor-γ activation and preventing calcium overload., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Diabetic nephropathy (DN) is a serious concern in patients with diabetes mellitus. Prolonged hyperglycemia induces oxidative damage, chronic inflammation, and build-up of extracellular matrix (ECM) components in the renal cells, leading to kidney structural and functional changes. Imperatorin (IMP) is a naturally occurring furanocoumarin derivative with proven antioxidative and anti-inflammatory properties. We investigated whether IMP could improve DN and employed high glucose (HG)-induced HK-2 cells and high-fat diet-fed streptozotocin (HFD/STZ)-generated DN experimental model in C57BL/6 mice. In vitro, IMP effectively reduced the HG-activated reactive oxygen species generation, disturbance in the mitochondrial membrane potential (MMP) and epithelial-to-mesenchymal transition (EMT)-related markers, and the transforming growth factor (TGF)-β and collagen 1 expression in HK-2 cells. In vivo, we found an elevation of serum creatinine, kidney histology alterations, and collagen build-up in the kidneys of the DN control group. Also, we found an altered expression of EMT-related markers, upregulation of the TGF-β/Smad2/3 axis, and elevated pro-inflammatory molecules, TNF-α, IL-1β, IL-18 and phospho-NF-kB (p65) in the DN control group. IMP treatment did not significantly reduce the blood glucose level compared to the DN control group. However, IMP treatment effectively improved renal damage by ameliorating kidney histological changes and serum renal injury markers. IMP treatment restored renal antioxidants and exhibited anti-inflammatory effects in the kidneys. Moreover, the abnormal manifestation of EMT-related attributes and elevated levels of TGF-β, phospho-Smad2/3, and collagen 1 were also normalized in the IMP treatment group. Our findings highlight that IMP may be a potential candidate for treating DN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) represents a multifaceted syndrome related to complex pathologic mechanisms. Sacubitril/valsartan (Sac/val) has demonstrated therapeutic efficacy in HFpEF treatment. However, additional research is required to elucidate its pharmacological mechanisms. Accordingly, this study aimed to explore the potential therapeutic effects of Sac/val in HFpEF rats and the underlying molecular mechanisms. In this study, rats with HFpEF were induced by subjecting spontaneously hypertensive rats to a diet rich in fats, salts, and sugars, along with administering streptozotocin. Subsequently, they were administered Sac/val at a daily dosage of 18 mg/kg. Finally, cardiac structure and function were assessed using echocardiography; Hematoxylin and eosin staining and Masson's trichrome staining were employed to evaluate the pathological changes; Quantitative real-time polymerase chain reaction and Western blot analysis were conducted to determine the expression of pertinent mRNA and proteins. Sac/val treatment attenuated left ventricular (LV) remodeling and diastolic dysfunction in HFpEF rats, possibly related to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic efficacy. Mechanistically, Sac/val might inhibit inflammation by down-regulating cell adhesion molecule (intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)) expression. Additionally, it blocked the phosphorylation of glycogen synthase kinase 3β (GSK-3β) to prevent cardiomyocyte hypertrophy. Furthermore, it effectively suppressed myocardial fibrosis by inhibiting the transforming growth factor-beta1 (TGF-β1)/Smads pathway. Our findings suggest that Sac/val improved LV remodeling and diastolic dysfunction, potentially attributed to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic effects. These results provide a sound theoretical rationale for the clinical application of Sac/val in patients with HFpEF., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Inflammation is associated with the development and progression of a plethora of diseases including joint, metabolic, neurological, hepatic, and renal disorders. Sesamol, derived from the seeds of Sesamum indicum L., has received considerable attention due to its well-documented multipotent phytotherapeutic effects, including its anti-inflammatory and immunomodulatory properties. However, to date, no comprehensive review has been established to highlight or summarize the anti-inflammatory and immunomodulatory properties of sesamol. Herein, we aim to address this gap in the literature by presenting a thorough review encapsulating evidence surrounding the range of inflammatory mediators and cytokines shown to be targeted by sesamol in modulating its anti-inflammatory actions against a range of inflammatory disorders. Additionally, evidence highlighting the role that sesamol has in modulating components of adaptive immunity including cellular immune responses and Th1/Th2 balance is underscored. Moreover, the molecular mechanisms and the signaling pathways underlying such effects are also highlighted. Findings indicate that this seemingly potent lignan mediates its anti-inflammatory actions, at least in part, via suppression of various pro-inflammatory cytokines like IL-1β and TNFα, and downregulation of a multitude of signaling pathways including NF-κB and MAPK. In conclusion, we anticipate that sesamol may be employed in future therapeutic regimens to aid in more effective drug development to alleviate immune-related and inflammatory conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Neuroinflammation mediated by microglia made a significant contribution in the pathophysiology of epilepsy. Icariin (ICA), a bioactive ingredient isolated from Epimedium, has been shown to present both antioxidant and anti-inflammatory properties. This study was to explore the potential therapeutic effects of icariin on mouse pilocarpine model of epilepsy and its underlying mechanisms in vivo and in vitro. To this end, we firstly measured the serum concentrations of the proinflammatory cytokines IL-1β and IL-6 from patients with temporal lobe epilepsy and found that patients with a higher seizure frequency showed correspondingly higher inflammatory reaction. Mouse pharmacokinetic study, transmembrane transportation assay, and cell viability assay collectively demonstrated that ICA was able to cross the blood-brain barrier and has good biocompatibility. The acute and chronic epilepsy models were next established in a pilocarpine mouse model of acquired epilepsy. Icariin has been identified that it could cross the blood-brain barrier and enter the hippocampus to exhibit therapeutic effects. ICA treatment dramatically promoted microglial polarization to the M2 phenotype in epilepsy mice both in the acute and chronic phases. Reduced release of M1-associated proinflammatory factors, such as IL-1β and IL-6, corroborates the altered glial cell polarization. Furthermore, ICA alleviated seizure intensity and mortality in acute phase epileptic mice. Models in the chronic group also showed improved general condition, cognition ability, and memory function after ICA treatment. Taken together, our research strongly suggested that icariin has the potential to treat epilepsy via inhibiting neuroinflammation by promoting microglial polarization to the M2 phenotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Intestinal inflammation is a common clinical intestinal disease. Catalpol, a natural iridoid compound, has been shown to have anti-inflammatory, anti-oxidant and anti-apoptotic functions, but the mechanism of its protection against intestinal inflammation is still unclear. This study investigated the protective effect and potential mechanism of catalpol on the lipopolysaccharide (LPS)-induced inflammatory response of intestinal epithelial cell-6 (IEC-6). The results showed that catalpol could inhibit LPS-induced inflammatory response by dose-dependently reducing the release of inflammatory factors, such as tumor necrosis (TNF)-α, interleukin (IL)-1β and IL-6, and inhibiting the nuclear factor kappa-B (NF-κB) signaling pathway. Catalpol ameliorated cellular oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) expression. Meanwhile, catalpol also inhibited cell apoptosis, decreased the expression of B-cell lymphoma 2 (Bcl-2) - associated X (Bax), caspase 3 and caspase 9, and increased the expression of Bcl-2. This study found that catalpol activates AMP-activated protein kinase (AMPK) signaling pathway and inhibit mammalian target of rapamycin (mTOR) phosphorylationthe. In a further study, after inhibiting AMPK with dorsomorphin, the anti-inflammatory effects of catalpol were significantly reduced. Therefore, catalpol ameliorates LPS-induced inflammatory response by activating AMPK/mTOR signaling pathway in IEC-6 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Astrocytes and the activation of inflammatory factors are associated with depression. Tetrahydrocurcumin (THC), the principal metabolite of natural curcumin, is renowned for its anti-inflammatory properties. In this research, we explored the impact of THC on the expression of inflammatory factors, neurotrophins, and transforming growth factor β1 (TGF-β1) in the prefrontal cortex after chronic restraint stress (CRS) in mice and in lipopolysaccharide (LPS)-induced TNC1 astrocytes. Our findings indicated that THC mitigated the anxiety and depression-like behaviours observed in CRS mice. It also influenced the expression of TGF-β1, p-SMAD3/SMAD3, sirtuin 1 (SIRT1), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), inducible nitric oxide synthase (iNOS), and tumour necrosis factor α (TNF-α). Specifically, THC augmented the expressions of TGF-β1, p-SMAD3/SMAD3, SIRT1, BDNF, and GDNF, whilst diminishing the expressions of iNOS and TNF-α in LPS-induced astrocytes. However, when pre-treated with SB431542, a TGF-β1 receptor inhibitor, it nullified the aforementioned effects of THC on astrocytes. Our results propose that THC delivers its anti-depressive effects through the activation of TGF-β1, enhancement of p-SMAD3/SMAD3 and SIRT1 expression, upregulation of BDNF and GDNF, and downregulation of iNOS and TNF-α. This research furnishes new perspectives on the anti-inflammatory mechanism that underpins the antidepressant-like impact of THC., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Coronavirus disease 2019 (COVID-19) has been declared a new pandemic in March 2020. Although most patients are asymptomatic, those with underlying cardiovascular comorbidities may develop a more severe systemic infection which is often associated with fatal pneumonia. Nonetheless, neurological and cardiovascular manifestations could be present even without respiratory symptoms. To date, no COVID-19-specific drugs are able for preventing or treating the infection and generally, the symptoms are relieved with general anti-inflammatory drugs. Angiotensin-converting-enzyme 2 (ACE2) may function as the receptor for virus entry within the cells favoring the progression of infection in the organism. On the other hand, ACE2 is a relevant enzyme in renin angiotensin system (RAS) cascade fostering Ang1-7/Mas receptor activation which promotes protective effects in neurological and cardiovascular systems. It is known that RAS is composed by two functional countervailing axes the ACE/AngII/AT1 receptor and the ACE/AngII/AT2 receptor which counteracts the actions mediated by AngII/AT1 receptor by inducing anti-inflammatory, antioxidant and anti-growth functions. Subsequently an "alternative" ACE2/Ang1-7/Mas receptor axis has been described with functions similar to the latter protective arm. Here, we discuss the neurological and cardiovascular effects of COVID-19 highlighting the role of the stimulation of the RAS "alternative" protective arm in attenuating pulmonary, cerebral and cardiovascular damages. In conclusion, only two clinical trials are running for Mas receptor agonists but few other molecules are in preclinical phase and if successful these drugs might represent a successful strategy for the treatment of the acute phase of COVID-19 infection., Competing Interests: Declaration of competing interest The co-authors that worked to write this manuscript entitled “From cardiovascular system to brain, the potential protective role of Mas Receptors in COVID-19 infection” do not have any conflict of interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pancreatic β-cell dysfunction plays a vital role in the development of diabetes. IL-33 exerts anti-diabetic effects via its anti-inflammatory properties and has been demonstrated to increase insulin secretion in animal models. However, IL-33, as a pleiotropic cytokine, may also exert a deleterious effect on β-cells, which has not been rigorously studied. In the present study, we found that IL-33 promoted cell survival and insulin secretion in MIN6 (a mouse pancreatic β-cell line) cells under diabetogenic conditions. IL-33 increased the expression of its receptor ST2 and the transcription factor PPARγ, whereas PPARγ inhibition impaired IL-33-mediated β-cell survival and insulin release. IL-33 did not repress the expression of pro-inflammatory mediators, including Tf, Icam1, Cxcl10, and Il1b, whereas it significantly reduced the expression of Ccl2. IL-33 decreased TNF-α secretion and increased IL-10 secretion; these effects were completely reversed by PPARγ inhibition. IL-33 increased glucose uptake and expression of Glut2. It upregulated the expression of glycolytic enzyme genes, namely, Pkm2, Hk2, Gpi1, and Tpi, and downregulated the expression of Gck, Ldha, and Mct4. However, it did not alter hexokinase activity. Moreover, IL-33 increased the number and activity of mitochondria, accompanied by increased ATP production and reduced accumulation of ROS. IL-33 upregulated the expression of PGC-1α and cytochrome c, and mitochondrial fission- and fusion-associated genes, including Mfn1, Mfn2, and Dnm1l. IL-33-mediated mitochondrial homeostasis was partially reversed by PPARγ inhibition. Altogether, IL-33 protects β-cell survival and insulin secretion that could be partially driven via PPARγ, which regulates glucose uptake and promotes mitochondrial function and anti-inflammatory responses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Three novel cytosine-derived α,β-methylene diphosphonates designated MRS4598, MRS4552, and MRS4602 were tested in the range of 1 × 10 -9 to 1 × 10 -3  M for their efficacy and potency in inhibiting membrane-bound ecto-5'-nucleotidase/CD73 activity in primary astrocytes in vitro. The compounds were also tested for their ability to attenuate the reactive astrocyte phenotype induced by proinflammatory cytokines. The main findings are as follows: A) The tested compounds induced concentration-dependent inhibition of CD73 activity, with maximal inhibition achieved at ∼1 × 10 -3 M; B) All compounds showed high inhibitory potency, as reflected by IC 50 values in the submicromolar range; C) All compounds showed high binding capacity, as reflected by Ki values in the low nanomolar range; D) Among the tested compounds, MRS4598 showed the highest inhibitory efficacy and potency, as reflected by IC 50 and Ki values of 0.11 μM and 18.2 nM; E) Neither compound affected astrocyte proliferation and cell metabolic activity at concentrations near to IC 50 ; E) MRS4598 was able to inhibit CD73 activity in reactive astrocytes stimulated with TNF-α and to induce concentration-dependent inhibition of CD73 in reactive astrocytes stimulated with IL-1β, with an order of magnitude higher IC 50 value; F) MRS4598 was the only compound tested that was able to induce shedding of the CD73 from astrocyte membranes and to enhance astrocyte migration in the scratch wound migration assay, albeit at concentration well above its IC 50 value. Given the role of CD73 in neurodegenerative diseases, MRS4598, MRS4552, and MRS4602 are promising pharmacological tools for the treatment of neurodegeneration and neuroinflammation., Competing Interests: Declaration of competing interest The authors' individual contributions are listed in a separate section of the manuscript. The authors declare no professional, financial, personal, or other conflicts of interest. All authors have approved the manuscript and submission to European Journal of Pharmacology and agree with the order of authors in the manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Empagliflozin, a selective inhibitor of Na + -glucose cotransporter-2, has been reported to exert anti-inflammatory and anti-fibrotic effects in addition to autophagy modulation. Addressing the role of autophagy in allergic asthma revealed controversial results. The potential effect of empagliflozin treatment on airway inflammation and remodelling as well as autophagy modulation in a murine model of allergic asthma was investigated. Over a 7-week period, male BALB/c mice were sensitized and challenged by intraperitoneal injection and inhalation of ovalbumin, respectively. Animals were treated with empagliflozin (10 mg/kg; orally) and/or rapamycin (an autophagy inducer; 4 mg/kg; intraperitoneally) before every challenge. Methacholine-induced airway hyperresponsiveness was evaluated one day after the last challenge. After euthanasia, serum, bronchoalveolar lavage fluid, and lung tissues were collected for biochemical, histopathological, and immunohistochemical assessment. Results revealed that empagliflozin decreased airway hyperresponsiveness, serum ovalbumin-specific immunoglobulin E, and bronchoalveolar lavage total and differential leukocytic counts. Levels of inflammatory and profibrotic cytokines (IL-4, IL-5, IL-13, IL-17, and transforming growth factor-β1) were all inhibited. Moreover, empagliflozin preserved pulmonary microscopic architecture and alleviated bronchiolar epithelial thickening, goblet cell hyperplasia, fibrosis and smooth muscle hypertrophy. These effects were associated with inhibition of ovalbumin-activated autophagic flux, as demonstrated by decreased LC3B expression and LC3BII/I ratio, as well as increased P62 expression. However, the therapeutic potential of empagliflozin was inhibited when rapamycin was co-administered. In conclusion, this study demonstrates that empagliflozin has immunomodulatory, anti-inflammatory, and anti-remodelling properties in ovalbumin-induced allergic asthma and suggests that autophagic flux inhibition may play a role in empagliflozin's anti-asthmatic effects., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Berberine is approved for the treatment of intestinal infections and diarrhea and has been shown to have anti-inflammatory and anti-tumor effects in pathological intestinal tissues. However, it is unclear whether the anti-inflammatory effect of berberine contributes to its anti-tumor effect on colitis-associated colorectal cancer (CAC). In this study, we found that berberine effectively inhibited tumorigenesis and protected against colon shortening in CAC mouse model. Immunohistochemistry results showed a reduction in the number of macrophage infiltrations in the colon following berberine treatment. Further analysis revealed that most of the infiltrated macrophages were pro-inflammatory M1 type, which berberine effectively limited. However, in another CRC model without chronic colitis, berberine had no significant effect on tumor number or colon length. In vitro studies demonstrated that berberine treatment significantly reduced the percentage of M1 type and levels of Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Additionally, miR-155-5p level was down-regulated, and suppressor of cytokine signaling 1 (SOCS1) expression was up-regulated in berberine-treated cells. Notably, the miR-155-5p inhibitor attenuated the regulatory effects of berberine on SOCS1 signaling and macrophage polarization. Altogether, our findings suggest that the inhibitory effect of berberine on CAC development is dependent on its anti-inflammatory activity. Moreover, miR-155-5p may be involved in the pathogenesis of CAC by regulating M1 macrophage polarization, and berberine could be a promising protective agent against miR-155-5p-mediated CAC. This study provides new insights into pharmacologic mechanisms of berberine and supports the possibility that other anti-miR-155-5p drugs may be beneficial in the treatment of CAC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Fungal keratitis (FK) is a blinding ocular disease, which mainly results from fungal damage and excessive inflammation. Pentoxifylline, a kind of methylxanthine, has been discovered to have anti-inflammatory properties in various infectious diseases, hinting a potential therapeutic effect on treating corneal fungal infection. Whereas, the therapeutic impact of pentoxifylline on fungal keratitis is still uncertain. This study investigated the antifungal capability against Aspergillus fumigatus and the anti-inflammatory role of pentoxifylline by activating nuclear factor, erythroid 2 like 2 (Nrf2)/heme oxygenase1 (HO1) pathway in the process of FK. In our research, we demonstrated that pentoxifylline could effectively inhibit fungal growth and inflammatory reaction. Pentoxifylline reduced the production of pro-inflammatory factors by stimulating the Nrf2/HO1 pathway. Although there was no statistical difference between the curative efficacy of pentoxifylline and natamycin application to FK, pentoxifylline could promote corneal epithelial repair and was less toxicity to the ocular surface than natamycin. In conclusion, pentoxifylline performs antifungal and anti-inflammatory effects by lessening the fungus burden and activating the Nrf2/HO1 pathway, hinting that it has the potential to be a new therapeutic medication for Aspergillus fumigatus keratitis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Polycystic ovary syndrome (PCOS) is a complex reproductive disorder that seriously harms female reproductive health and decreases quality of life. Although spontaneous or assisted ovulation occurs, women with PCOS suffer from poor-quality oocytes and embryos and lower fertilization and final pregnancy rates. Therefore, it is urgent to identify new pathological mechanisms and discover the underlying therapeutic targets for reproductive disorders associated with PCOS. Berberine, one of the famous traditional Chinese medicines, has been shown to improve ovulation and live birth rates in women with PCOS. The effects of berberine on insulin resistance and abnormal glucose and lipid metabolism for restoring the reproductive health of women with PCOS are well recognized and have been widely studied, but much less attention has been given to its anti-inflammatory properties. Chronic low-grade inflammation is the unifying feature of PCOS and may contribute to reproductive disorders in PCOS. Berberine can modulate the inflammatory state of the ovaries and uterus in PCOS. The anti-inflammatory properties of berberine may provide new insight into the mechanisms by which berberine alleviates reproductive disorders associated with PCOS. Here, we summarized the most recent insights into the anti-inflammatory properties of berberine in PCOS reproductive disorders to inspire researchers to pursue new study directions involving berberine., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, “New Insights into Mechanisms of Berberine in Alleviating Reproductive Disorders of Polycystic Ovary Syndrome: Anti-inflammatory Properties”., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Severe pathological damage caused by the influenza virus is one of the leading causes of death. However, the prevention and control strategies for influenza virus infection have certain limitations, and the exploration for new influenza antiviral drugs has become the major research direction. This study evaluated the antiviral activities of four theaflavin derivatives (TFs). Cytopathic effect (CPE) reduction assay revealed that theaflavin-3'-gallate (TF2b) and theaflavin (TF1) could effectively inhibit the replication of influenza viruses H1N1-UI182, H1N1-PR8, H3N2, and H5N1, and TF2b exhibited the most significant antiviral activity in vivo. Intraperitoneal injection of TF2b at 40 mg/kg/d effectively alleviated viral pneumonia, maintained body weight, and improved the survival rate of mice infected with a lethal dose of H1N1-UI182 to 55.56%. Hematological analysis of peripheral blood further showed that TF2b increased the number of lymphocytes and decreased the number of neutrophils, monocytes, and platelets in the blood of infected mice. RT-qPCR results showed that TF2b reduced the mRNA expression levels of inflammatory cytokines (IL-6, TNF-α, and IL-1β), chemokines (CXCL-2 and CCL-3), and interferons (IFN-α and IFN-γ) after influenza virus infection. In addition, TF2b significantly down-regulated the expression levels of TLR4, p-p38, p-ERK, and cytokines IL-6, TNF-α, IL-1β, and IL-10. These results suggest that TF2b not only significantly inhibits viral replication and proliferation in vitro, but also alleviates pneumonia injury in vivo. Its antiviral effect might be attributed to the down-regulation of influenza virus-induced inflammatory cytokines by regulating the TLR4/MAPK/p38 signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Diabetic wound healing, characterized by chronic inflammation, remains a medical challenge. The failure of prompt conversion from pro-inflammatory M1-like macrophage to pro-healing M2-like macrophage is the main obstacle to diabetic wounds. Emodin, an anthraquinone derivative, has multiple bioactivities, including antibacterial, anticancer, and anti-inflammatory. Recently, emodin has shown potential in promoting wound healing. However, the underlying molecular mechanism remains unclear. In this study, we examined the effects of emodin on wound healing in db/db diabetic mice using a full-thickness excision model. Our results showed that emodin can remarkably accelerate healing by enhancing extracellular matrix (ECM) synthesis and granulation tissue formation. We identified 32 potential targets of emodin by network pharmacology analysis, and our transcriptome analysis highlighted the down-regulation of the NF-κB signaling pathway mediated by emodin. Mechanistically, emodin was shown to inhibit the p65-NF-κB complex and promote the proportion of M2 (anti-inflammatory)-like phenotype macrophages both in vitro and vivo. Then, bone-marrow-derived macrophages were co-cultured with fibroblasts (mouse dermal fibroblasts cells). Treatment of emodin significantly increased the proportion of M2-polarized macrophages and the expression level of TGF-β, a typical ECM formation-related cytokine secreted by the M2 macrophages in the co-cultured supernatant. We further revealed that emodin improved the proliferation of mouse dermal fibroblasts (MDFs) cells and upregulated the expression levels of collagen III, fibronectin and α-SMA in MDFs cells in emodin-treated co-culture systems. 1D11, a neutralizing antibody for all three major TGF-β isoforms, diminished the biological effects of emodin on proliferation and ECM formation in MDFs cells. Taken together, our study suggests emodin may serve as an effective therapeutic agent for diabetic wounds., Competing Interests: Declaration of competing interest Authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Being at the important pathological stage and the critical treatment period of non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) which is associated with fibrosis, hepatic and liver cancer has become a serious medical problem. As one of the major effective components in Scutellaria baicalensis, baicalin takes on anti-oxidant and anti-inflammatory activities. Nevertheless, its effects on NASH and its underlying molecular mechanism have not been thoroughly understood yet. In previous study, we have clarified baicalin could inhibit pyroptosis of hepatocytes mediated by NLRP3 in vitro, but the verification in vivo and upstream mechanism still need further work. Here the NASH mouse model was induced by feeding with a high fat diet (HFD) for 8-12 weeks. Thereafter, in the following weeks, NASH mice were given with HFD plus baicalin. We, subsequently, examined their hepatic function and inflammatory response and conducted the HE staining of liver samples. Furthermore, the underlying molecular mechanism was revealed through diverse molecular biological experiments including quantitative real-time PCR (qRT-PCR), Western blotting (WB), siRNA and CCK8 assays in HepG2 cells incubated with free fatty acid, and was verified in NASH mice. The in vivo findings indicated that baicalin decreased lipid accumulation and inflammation in the liver tissues of NASH mice, as evidenced by the enhanced NRF2/HO-1 expression and the reduced NLRP3/Caspase1/GSDMD levels, and these factors were involved in the pyroptosis pathway. Meanwhile, baicalin also contributed greatly against oxidative injury. The anti-inflammatory effect of baicalin was confirmed by experiments in vitro. For another, knockdown of NRF2 obviously weakened the protective effects of baicalin and reduced the NLRP3/Caspase1/GSDMD-mediated pyroptosis. This study indicates that baicalin is able to attenuate hepatic cell pyroptosis in vivo and in vitro in the case of NASH by regulating the NRF2/HO-1/NRLP3 pathway., Competing Interests: Declaration of competing interest We believe that the findings of this study are relevant to the scope of your journal and will be of interest to its readership. We have approved the manuscript and agree with submission to EUROPEAN JOURNAL OF PHARMACOLOGY. There are no conflicts of interest to declare. No part of this work has been published or under consideration by any other publication or electronic medium. Thank you very much for your consideration of this manuscript for publication in EUROPEAN JOURNAL OF PHARMACOLOGY Sincerely., (Copyright © 2022. Published by Elsevier B.V.)