Corticosteroids for the prevention and treatment of bronchopulmonary dysplasia: an overview of systematic reviews.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD, explaining the rationale for investigating postnatal corticosteroids. Multiple systematic reviews (SRs) have summarised the evidence from numerous randomised controlled trials (RCTs) investigating different aspects of administrating postnatal corticosteroids. Besides beneficial effects on the outcome of death or BPD, potential short- and long-term harms have been reported. OBJECTIVES: The primary objective of this overview was to summarise and appraise the evidence from SRs regarding the efficacy and safety of postnatal corticosteroids in preterm infants at risk of developing BPD. METHODS: We searched the Cochrane Database of Systematic Reviews, MEDLINE, Embase, CINAHL, and Epistemonikos for SRs in April 2023. We included all SRs assessing any form of postnatal corticosteroid administration in preterm populations with the objective of ameliorating pulmonary disease. All regimens and comparisons were included. Two review authors independently checked the eligibility of the SRs comparing corticosteroids with placebo, and corticosteroids with different routes of administration and regimens. The included outcomes, considered key drivers in the decision to administer postnatal corticosteroids, were the composite outcome of death or BPD at 36 weeks' postmenstrual age (PMA), its individual components, long-term neurodevelopmental sequelae, sepsis, and gastrointestinal tract perforation. We independently assessed the methodological quality of the included SRs by using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) and ROBIS (Risk Of Bias In Systematic reviews) tools. We assessed the certainty of the evidence using GRADE. We provided a narrative description of the characteristics, methodological quality, and results of the included SRs. MAIN RESULTS: We included nine SRs (seven Cochrane, two non-Cochrane) containing 87 RCTs, 1 follow-up study, and 9419 preterm infants, investigating the effects of postnatal corticosteroids to prevent or treat BPD. The quality of the included SRs according to AMSTAR 2 varied from high to critically low. Risk of bias according to ROBIS was low. The certainty of the evidence according to GRADE ranged from very low to moderate. Early initiated systemic dexamethasone (< seven days after birth) likely has a beneficial effect on death or BPD at 36 weeks' PMA (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.81 to 0.95; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 10 to 41; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA (RR 0.72, 95% CI 0.63 to 0.82; NNTB 13, 95% CI 9 to 21; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence). Early initiated systemic hydrocortisone may also have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.90, 95% CI 0.82 to 0.99; NNTB 18, 95% CI 9 to 594; I2 = 43%; 9 studies; 1376 infants; low-certainty evidence). However, these benefits are likely accompanied by harmful effects like cerebral palsy or neurosensory disability (dexamethasone) or gastrointestinal perforation (both dexamethasone and hydrocortisone). Late initiated systemic dexamethasone (≥ seven days after birth) may have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.75, 95% CI 0.67 to 0.84; NNTB 5, 95% CI 4 to 9; I2 = 61%; 12 studies; 553 infants; low-certainty evidence), mostly contributed to by a beneficial effect on BPD at 36 weeks' PMA (RR 0.76, 95% CI 0.66 to 0.87; NNTB 6, 95% CI 4 to 13; I2 = 14%; 12 studies; 553 infants; low-certainty evidence). No harmful side effects were shown in the outcomes chosen as key drivers to the decision to start or withhold late systemic dexamethasone. No effects, either beneficial or harmful, were found in the subgroup meta-analyses of late hydrocortisone studies. Early initiated inhaled corticosteroids probably have a beneficial effect on death and BPD at 36 weeks' PMA (RR 0.86, 95% CI 0.75 to 0.99; NNTB 19, 95% CI not applicable; I2 = 0%; 6 studies; 1285 infants; moderate-certainty evidence), with no apparent adverse effects shown in the SRs. In contrast, late initiated inhaled corticosteroids do not appear to have any benefits or harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier likely has a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.60, 95% CI 0.49 to 0.74; NNTB 4, 95% CI 3 to 6; I2 = 0%; 2 studies; 381 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA. No evidence of harmful effects was found. There was little evidence for effects of different starting doses or timing of systemic corticosteroids on death or BPD at 36 weeks' PMA, but potential adverse effects were observed for some comparisons. Lowering the dose might result in a more unfavourable balance of benefits and harms. Moderately early initiated systemic corticosteroids, compared with early systemic corticosteroids, may result in a higher incidence of BPD at 36 weeks' PMA. Pulse dosing instead of continuous dosing may have a negative effect on death and BPD at 36 weeks' PMA. We found no differences for the comparisons of inhaled versus systemic corticosteroids. AUTHORS' CONCLUSIONS: This overview summarises the evidence of nine SRs investigating the effect of postnatal corticosteroids in preterm infants at risk for BPD. Late initiated (≥ seven days after birth) systemic administration of dexamethasone is considered an effective intervention to reduce the risk of BPD in infants with a high risk profile for BPD, based on a favourable balance between benefits and harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is a promising intervention, based on the beneficial effect on desirable outcomes without (so far) negative side effects. Pending results of ongoing large, multicentre RCTs investigating both short- and long-term effects, endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is not appropriate for clinical practice at present. Early initiated (< seven days after birth) systemic dexamethasone and hydrocortisone and late initiated (≥ seven days after birth) hydrocortisone are considered ineffective interventions, because of an unfavourable balance between benefits and harms. No conclusions are possible regarding early and late inhaled corticosteroids, as more research is needed.

A series of indole-derived γ-hydroxy propiolate esters as potent anti-inflammatory agents: Design, synthesis, in-vitro and in-vivo biological studies.

A variety of novel indole-derived γ-hydroxy propiolate esters were designed, synthesized, and evaluated for their anti-inflammatory activity in-vitro and in-vivo. According to the nitric oxide (NO) inhibitory analysis, all compounds showed potent NO inhibitory ability in a dose-dependent manner, with no apparent cytotoxicity. The model compound, L-37, also exhibited significant potency in PGE2 inhibition. In addition, compounds L-37 and L-39 can downregulate the expression of COX-2 enzyme at 5 µM via ELISA experiment. Compound L-37 (1 µM) also inhibited the PGF1 production as well as the expression of COX-1, but displayed weak inhibition activity towards the Leukotrienes (LT) and Thromboxane-B2 (TXB-2) production. However, the expression of 5-LOX was significantly inhibited by compound L-39 at 5 µM. Xylene-induced ear edema model was explored for in-vivo anti-inflammatory evaluation, compound L-37 showed similar inhibitory activity compared with celecoxib, approximately 80% at 50 mg/kg dosage. Every outcome showed that the newly synthesized compounds can effectively inhibit inflammation.

Compatibility of Caffeine Clobetasol Propionate Dutasteride Nicotinamide and Progesterone in TrichoFoam™, a Natural Vehicle for Hair Foams.

BACKGROUND: Alopecia is a chronic dermatological disorder affecting men and women worldwide. Given the high incidence and significant impact on patients' well-being, options for managing and treating alopecia are essential. Topical available options remain limited and oral products may result in adverse effects. TrichoFoam™ is a ready-to-use foaming vehicle developed for compounding pharmacies and formulated with gentle, non-irritating, and sensory-pleasant ingredients. OBJECTIVE: The purpose of this study was to assess topical foams' physicochemical and microbiological stabilities of formulations compounded with TrichoFoam™ as the ready-touse vehicle. METHODS: HPLC analyses were conducted in a bracketed study covering concentrations of 0.1% to 2.0% of caffeine, 0.01% to 0.1% of clobetasol propionate, 0.1% to 0.25% of dutasteride, 0.25% to 0.50% of nicotinamide, and 0.25% to 2.5% of progesterone compounded with TrichoFoam™. Antimicrobial Effectiveness Testing was conducted at the beginning and end of the studies. RESULTS: Most formulations presented a beyond-use date of at least 90-180 days, except for clobetasol propionate, which showed compatibility for 14 days, and dutasteride 0.25%, which showed a BUD of 30 days. CONCLUSION: This validates the stability of the active pharmaceutical ingredients from different pharmacological classes with TrichoFoam™, suggesting that this ready-to-use vehicle can be an excellent alternative for personalized alopecia treatment.

Use of high-dose steroid therapy: addition of anakinra in the treatment of severe COVID-19.

OBJECTIVE: The aim of this study was to compare the clinical effects of the addition of anakinra to high-dose steroid therapy in COVID-19 patients with macrophage activation syndrome. METHODS: This was a single-center retrospective study conducted in Ümraniye Training and Research Hospital between March 11, 2020, and April 28, 2021. Patients receiving only high-dose steroid or anakinra+steroid were enrolled. The first day of anakinra was considered as day 0. Laboratory values and oxygen requirements were followed up for 7 days. Patients were divided into two groups: 66 patients in the high-dose steroid group and 67 patients in the anakinra+steroid group. The primary outcome was 28-day mortality. RESULTS: After treatment, a significant decrease in ferritin levels was detected only in the anakinra+steroid group (p=0.001). In both groups, there were significant changes in lymphocytes, C-reactive protein, lactate dehydrogenase, and fibrinogen levels during the 7-day follow-up. Changes in oxygen status according to the World Health Organization clinical scale on day 3 and day 7 between high-dose steroid and anakinra+steroid groups were similar (p=0.976). Complications were higher in the anakinra+steroid group than in the steroid group (26% vs. 12%, p=0.03). The rates of 28-day mortality were 57% in the anakinra+steroid group and 42% in the high-dose steroid group (p=0.48). In multivariate regression, anakinra did not affect 28-day mortality (p=0.67). CONCLUSION: The addition of anakinra to steroid treatment resulted in a significant decrease in biochemical parameters. However, no significant difference was observed in the oxygen status between the groups. The addition of anakinra to steroid treatment did not decrease mortality. Clinicians should be aware of the complications of anti-inflammatory therapies.

A novel quinoline with airway relaxant effects and anti-inflammatory properties.

BACKGROUND: In chronic pulmonary diseases characterized by inflammation and airway obstruction, such as asthma and COPD, there are unmet needs for improved treatment. Quinolines is a group of small heterocyclic compounds that have a broad range of pharmacological properties. Here, we investigated the airway relaxant and anti-inflammatory properties of a novel quinoline (RCD405). METHODS: The airway relaxant effect of RCD405 was examined in isolated airways from humans, dogs, rats and mice. Murine models of ovalbumin (OVA)-induced allergic asthma and LPS-induced airway inflammation were used to study the effects in vivo. RCD405 (10 mg/kg) or, for comparisons in selected studies, budesonide (3 mg/kg), were administered intratracheally 1 h prior to each challenge. Airway responsiveness was determined using methacholine provocation. Immune cell recruitment to bronchi was measured using flow cytometry and histological analyses were applied to investigate cell influx and goblet cell hyperplasia of the airways. Furthermore, production of cytokines and chemokines was measured using a multiplex immunoassay. The expression levels of asthma-related genes in murine lung tissue were determined by PCR. The involvement of NF-κB and metabolic activity was measured in the human monocytic cell line THP-1. RESULTS: RCD405 demonstrated a relaxant effect on carbachol precontracted airways in all four species investigated (potency ranking: human = rat > dog = mouse). The OVA-specific IgE and airway hyperresponsiveness (AHR) were significantly reduced by intratracheal treatment with RCD405, while no significant changes were observed for budesonide. In addition, administration of RCD405 to mice significantly decreased the expression of proinflammatory cytokines and chemokines as well as recruitment of immune cells to the lungs in both OVA- and LPS-induced airway inflammation, with a similar effect as for budesonide (in the OVA-model). However, the effect on gene expression of Il-4, IL-5 and Il-13 was more pronounced for RCD405 as compared to budesonide. Finally, in vitro, RCD405 reduced the LPS-induced NF-κB activation and by itself reduced cellular metabolism. CONCLUSIONS: RCD405 has airway relaxant effects, and it reduces AHR as well as airway inflammation in the models used, suggesting that it could be a clinically relevant compound to treat inflammatory airway diseases. Possible targets of this compound are complexes of mitochondrial oxidative phosphorylation, resulting in decreased metabolic activity of targeted cells as well as through pathways associated to NF-κB. However, further studies are needed to elucidate the mode of action.

Anti-inflammatory effects and related mechanisms in vitro and in vivo of Hedychium coccineum rhizome essential oil.

ETHNOPHARMACOLOGICAL RELEVANCE: Hedychium coccineum rhizome is an anti-inflammatory ethnomedicine used to remedy inflammation-related swelling and bronchial asthma. AIM OF THE STUDY: The study aimed to analyze the phytochemical constituents of H. coccineum rhizome essential oil (EO) and evaluate its in vitro and in vivo anti-inflammatory effects and underlying mechanisms. MATERIALS AND METHODS: Phytochemical constituents of H. coccineum rhizome EO were analyzed using GC-FID/MS. In RAW264.7 macrophages induced by LPS, blockade of PGE2, NO, IL-1ß, IL-6, and TNF-α secretion by H. coccineum rhizome EO was measured, and then Western blot, qRT-PCR, and immunofluorescent staining were used to evaluate its underlying mechanisms. Moreover, we used the xylene-induced ear edema model for testing anti-inflammatory potential in vivo and examined auricular swelling as well as tissue and serum contents of IL-1ß, IL-6, and TNF-α. RESULTS: EO's main components were E-nerolidol (40.5%), borneol acetate (24.8%), spathulenol (4.5%), linalool (3.8%), elemol (3.5%), and borneol (3.4%). In RAW264.7 cells stimulated by LPS, EO downregulated the expression of pro-inflammatory enzyme (iNOS and COX-2) genes and proteins, thereby suppressing pro-inflammatory mediators (NO and PGE2) secretion. Simultaneously, it reduced TNF-α, IL-1ß, and IL-6 release by downregulating their mRNA expression. Besides, H. coccineum EO attenuated LPS-stimulated activation of NF-κB (by reducing IκBα phosphorylation and degradation to inhibit NF-κB nuclear translocation) and MAPK (by downregulating JNK, p38, and ERK phosphorylation). In xylene-induced mouse ear edema, EO relieved auricular swelling and lowered serum and tissue levels of TNF-α, IL-1ß, and IL-6. CONCLUSIONS: H. coccineum EO had powerful in vivo and in vitro anti-inflammatory effects by inhibiting MAPK and NF-κB activation. Hence, H. coccineum EO should have great potential for application in the pharmaceutical field as a novel anti-inflammatory agent.

Triterpenes G-A and G-E from Galphimia glauca with anti-inflammatory and anti-arthritic activity in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Galphimia glauca is a medicinal plant that treats inflammatory and anti-rheumatic problems. Its anti-inflammatory capacity has been reported pharmacologically, attributed to the triterpenes G-A and G-E. AIM: The objective of the present work was to measure the anti-inflammatory and immunomodulatory effect of the methanolic extract (GgMeOH) of Galphimia glauca and the isolated galphimines G-A and G-E, first in an acute test of plantar edema with carrageenan, and later in the model of experimental-induced arthritis with CFA. The effect was measured by quantifying joint inflammation, the concentration of pro- (TNF-α, IL-6, IL-17) and anti-inflammatory (IL-10, and IL-4) cytokines, and the ADA enzyme in joints, kidneys, and spleen from mice with experimental arthritis. METHOD: The extract and the active triterpenes were obtained according to established methods using different chromatographic techniques. Female ICR strain mice were subjected to intraplantar administration with carrageenan and treated with different doses of GgMeOH, G-A, and G-E; edema was monitored at different times. Subsequently, the concentration of TNF-a and IL-10 in the spleen and swollen paw was quantified. Meloxicam (MEL) was used as an anti-inflammatory control drug. The most effective doses of each treatment were analyzed using a complete Freunds adjuvant (CFA)-induced experimental arthritis model. Joint inflammation was followed throughout the experiment. Ultimately, the concentration of inflammation markers, oxidant stress, and ADA activity was quantified. In this experimental stage, methotrexate (MTX) was used as an antiarthritic drug. RESULTS: Treatments derived from G. glauca, GgMeOH (DE50 = 158 mg/kg), G-A (DE50 = 2 mg/kg), and G-E (DE50 = 1.5 mg/kg) caused an anti-inflammatory effect in the plantar edema test with carrageenan. In the CFA model, joint inflammation decreased with all natural treatments; GgMeOH and G-A inhibited the ADA enzyme in all organs analyzed (joints, serum, spleen, left and right kidneys), while G-E inhibited the enzyme in joints, serum, and left kidney. CFA caused an increase in the weight index of the organs, an effect that was counteracted by the administration of G. glauca treatments, which also modulate the response to the cytokines analyzed in the different organs (IL-4, IL-10, IL-17, IL-6, and TNF- α). CONCLUSION: It is shown, for the first time, that the GgMeOH extract and the triterpenes G-A and G-E of Galphimia glauca have an anti-arthritic effect (anti-inflammatory, immunomodulatory, antioxidant, and ADA inhibitor), using an experimental arthritis model with CFA. Therefore, knowledge of the plant as a possible therapeutic agent for this rheumatic condition is expanding.

Gigantol ameliorates DSS-induced colitis via suppressing ß2 integrin mediated adhesion and chemotaxis of macrophage.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium, recognized as "Shihu" in traditional Chinese medicine, holds a rich history of medicinal utilization documented in the Chinese Pharmacopoeia. Ancient texts like "Shen Nong Ben Cao Jing" extol Dendrobium's virtues as a superior herbal medicine fortifying "Yin" and invigorating the five viscera. Dendrobium is extensively employed for the treatment of gastrointestinal inflammatory disorders, showcasing significant therapeutic efficacy, particularly against ulcerative colitis (UC), within the realm of Chinese ethnopharmacology. Dendrobium plays crucial pharmacological roles due to its rich content of polysaccharides, alkaloids, phenanthrenes, and bibenzyls. Gigantol, a prominent bibenzyl compound, stands out as one of the most vital active constituents within Dendrobium, the gigantol content of Dendrobium leaves can reach approximately 4.79 µg/g. Its significance lies in being recognized as a noteworthy anti-inflammatory compound derived from Dendrobium. AIM OF THE STUDY: Given the pivotal role of gigantol as a primary active substance in Dendrobium, the therapeutic potential of gigantol for gastrointestinal diseases remains enigmatic. Our present investigation aimed to evaluate the therapeutic effects of gigantol on dextran sulfate sodium (DSS)-induced colitis and reveal its potential mechanism in countering UC activity. MATERIALS AND METHODS: The protective efficacy of gigantol against colitis was assessed by examining the histopathological changes and conducting biochemical analyses of colon from DSS-challenged mice. Assessments focused on gigantol's impact on improving the intestinal epithelial barrier and its anti-inflammatory effects in colonic tissues of colitis mice. Investigative techniques included the exploration of the macrophage inflammatory signaling pathway via qPCR and Western blot analyses. In vitro studies scrutinized macrophage adhesion, migration, and chemotaxis utilizing transwell and Zigmond chambers. Furthermore, F-actin and Rac1 activation assays detailed cellular cytoskeletal remodeling. The potential therapeutic target of gigantol was identified and validated through protein binding analysis, competitive enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assay. The binding sites between gigantol and its target were predicted via molecular docking. RESULTS: Gigantol ameliorated symptoms of DSS-induced colitis, rectified damage to the intestinal barrier, and suppressed the production of pro-inflammatory cytokines in colonic tissues. Intriguingly, gigantol significantly curtailed NF-κB signaling activation in the colons of DSS-induced colitis mice. Notably, gigantol impaired the ß2 integrin-dependent adhesion and migratory capacity of RAW264.7 cells. Moreover, gigantol notably influenced the cytoskeleton remodeling of RAW264.7 cells by suppressing Vav1 phosphorylation and Rac1 activation. Mechanistically, gigantol interacted with ß2 integrin, subsequently diminishing binding affinity with intercellular adhesion molecule-1 (ICAM-1). CONCLUSIONS: In conclusion, these findings elucidate that gigantol ameliorates DSS-induced colitis by antagonizing ß2 integrin-mediated macrophage adhesion, migration, and chemotaxis, thus it may impede macrophage recruitment and infiltration into colonic tissues. This study suggests that gigantol shows promise as a viable candidate for clinical colitis therapy.

Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial.

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown. Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD. Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023. Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months. Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified. Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn. Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.

Bone marrow-derived mesenchymal stem cells mitigate chronic colitis and enteric neuropathy via anti-inflammatory and anti-oxidative mechanisms.

Current treatments for inflammatory bowel disease (IBD) are often inadequate due to limited efficacy and toxicity, leading to surgical resection in refractory cases. IBD's broad and complex pathogenesis involving the immune system, enteric nervous system, microbiome, and oxidative stress requires more effective therapeutic strategies. In this study, we investigated the therapeutic potential of bone marrow-derived mesenchymal stem cell (BM-MSC) treatments in spontaneous chronic colitis using the Winnie mouse model which closely replicates the presentation and inflammatory profile of ulcerative colitis. The 14-day BM-MSC treatment regimen reduced the severity of colitis, leading to the attenuation of diarrheal symptoms and recovery in body mass. Morphological and histological abnormalities in the colon were also alleviated. Transcriptomic analysis demonstrated that BM-MSC treatment led to alterations in gene expression profiles primarily downregulating genes related to inflammation, including pro-inflammatory cytokines, chemokines and other biomarkers of inflammation. Further evaluation of immune cell populations using immunohistochemistry revealed a reduction in leukocyte infiltration upon BM-MSC treatment. Notably, enteric neuronal gene signatures were the most impacted by BM-MSC treatment, which correlated with the restoration of neuronal density in the myenteric ganglia. Moreover, BM-MSCs exhibited neuroprotective effects against oxidative stress-induced neuronal loss through antioxidant mechanisms, including the reduction of mitochondrial-derived superoxide and attenuation of oxidative stress-induced HMGB1 translocation, potentially relying on MSC-derived SOD1. These findings suggest that BM-MSCs hold promise as a therapeutic intervention to mitigate chronic colitis by exerting anti-inflammatory effects and protecting the enteric nervous system from oxidative stress-induced damage.

Anti-inflammatory, healing and antiophidic potential of Jatropha mollissima (Pohl) Baill. (Euphorbiaceae): From popular use to pharmaceutical formulation in gel.

Jatropha mollissima (Pohl) Baill. (Euphorbiaceae) is widely used in traditional medicine to treat inflammatory disorders. So, a topical gel containing the hydroethanolic extract of its leaves was developed and evaluated for its anti-inflammatory, wound healing, and antiophidic properties in mice. First, the chemical profile of different parts of the plant was characterized by liquid chromatography coupled to mass spectrometry (LC-MS) using molecular networking. In the leaf extract, 11 compounds were characterized, with a particular emphasis on the identification of flavonoids. The gel efficiently inhibited carrageenan-induced paw edema, as well as acute and chronic croton oil-induced ear edema models, thereby reducing inflammatory and oxidative parameters in inflamed tissues. Besides anti-inflammatory activity, the herbal gel showed significant wound healing activity. The edematogenic, hemorrhagic and dermonecrotic activities induced by Bothrops jararaca snake venom were effectively inhibited by the treatment with J. mollissima gel. The association with the herbal gel improved in up to 90% the efficacy of commercial snake antivenom in reduce venom-induced edema. Additionally, while antivenom was not able to inhibit venom-induced dermonecrosis, treatment with herbal gel reduced in 55% the dermonocrotic halo produced. These results demonstrate the pharmacological potential of the herbal gel containing J. mollissima extract, which could be a strong candidate for the development of herbal products that can be used to complement the current antivenom therapy against snake venom local toxicity.

Physalin H ameliorates LPS-induced acute lung injury via KEAP1/NRF2 axis.

Physalin H (PH), a withanolide isolated from Physalisangulata L. has been reported to have anti-inflammatory effect. However, its impact on acute lung injury (ALI) remains unexplored. In this study, we observed that PH significantly alleviated inflammation in LPS-stimulated macrophages by suppressing the release of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) and down-regulating the expression of the inflammation-related genes. RNA sequencing analysis revealed a significant up-regulation of the NRF2 pathway by PH. Further investigation elucidated that PH attenuated the ubiquitination of NRF2 by impeding the interaction between NRF2 and KEAP1, thereby facilitating NRF2 nuclear translocation and up-regulating the expression of target genes. Consequently, it regulated redox system and exerted anti-inflammatory effect. Consistently, PH also significantly alleviated pathological damage and inflammation in LPS-induced ALI mice model, which could be reversed by administration of an NRF2 inhibitor. Collectively, these results suggest that PH ameliorates ALI by activating the KEAP1/NRF2 pathway. These findings provide a foundation for further development of pH as a new anti-inflammatory agent for ALI therapy.

Caffeic acid ethanolamide induces antifibrosis, anti-inflammatory, and antioxidant effects protects against bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease; its cause is unknown, and it leads to notable health problems. Currently, only two drugs are recommended for IPF treatment. Although these drugs can mitigate lung function decline, neither can improve nor stabilize IPF or the symptoms perceived by patients. Therefore, the development of novel treatment options for pulmonary fibrosis is required. The present study investigated the effects of a novel compound, caffeic acid ethanolamide (CAEA), on human pulmonary fibroblasts and evaluated its potential to mitigate bleomycin-induced pulmonary fibrosis in mice. CAEA inhibited TGF-ß-induced α-SMA and collagen expression in human pulmonary fibroblasts, indicating that CAEA prevents fibroblasts from differentiating into myofibroblasts following TGF-ß exposure. In animal studies, CAEA treatment efficiently suppressed immune cell infiltration and the elevation of TNF-α and IL-6 in bronchoalveolar lavage fluid in mice with bleomycin-induced pulmonary fibrosis. Additionally, CAEA exerted antioxidant effects by recovering the enzymatic activities of oxidant scavengers. CAEA directly inhibited activation of TGF-ß receptors and protected against bleomycin-induced pulmonary fibrosis through inhibition of the TGF-ß/SMAD/CTGF signaling pathway. The protective effect of CAEA was comparable to that of pirfenidone, a clinically available drug. Our findings support the potential of CAEA as a viable method for preventing the progression of pulmonary fibrosis.

Study on the ameliorative effect of honeysuckle on DSS-induced ulcerative colitis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Honeysuckle, first documented in the Miscellaneous Records of Famous Physicians, is known for its ability to expel toxin and cool blood to stop diarrhea. Modern pharmacological research has shown that honeysuckle has anti-inflammatory, antibacterial, antioxidant, and immune-regulating effects and is widely used in clinical practice. However, the effect of honeysuckle on ulcerative colitis (UC) is still not fully understood, which presents challenges for quality control, research and development. AIM OF THE STUDY: This study aimed to determine the anti-inflammatory properties and mechanism of action of aqueous extracts of honeysuckle in the treatment of ulcerative colitis. MATERIALS AND METHODS: The dextran sodium sulfate (DSS) induced-ulcerative colitis mouse model was established, and the mice were divided into five groups: the control group, the model group, and the low, medium, and high dose honeysuckle treatment groups. RESULTS: All dose groups of honeysuckle were found to significantly reduce IL-6 and TNF-α levels and regulate DSS-induced mRNA levels of CLDN4, COX-2, IL-6, INOS, MUC-2, occludin and NLRP3. The high-dose group displayed the most effective inhibition, and a differentially expressed mRNA detection indicated abnormal mRNA expression. The 16sRNA sequencing revealed that the honeysuckle was able to significantly upregulate the abundance of beneficial bacteria and downregulate the abundance of harmful bacteria. The study of short-chain fatty acids revealed that the levels of acetic, propionic, isobutyric, valeric and isovaleric acids were significantly increased after administering honeysuckle at medium and high doses. CONCLUSION: Honeysuckle reduces the production of pro-inflammatory cytokines, increases the content of short-chain fatty acids and restores the intestinal ecological balance, resulting in better therapeutic effects.

Rosavin Alleviates LPS-Induced Acute Lung Injure by Modulating the TLR-4/NF-κB/MAPK Singnaling Pathways.

Acute lung injury (ALI) is a serious inflammatory disease with high morbidity and mortality. Rosavin is an anti-inflammatory and antioxidant phenylpropanoid and glucoside, which is isolated from Rhodiola rosea L. However, its potential molecular mechanisms and whether it has protective effects against lipopolysaccharide (LPS)-induced ALI remain to be elucidated. To assess the in vitro anti-inflammatory effects and anti-lung injury activity of rosavin, RAW264.7 and A549 cells were stimulated using 1 µg/mL LPS. Rosavin attenuated LPS-induced activation of the TLR-4/NF-κB signaling pathway in RAW264.7 cells and inhibited LPS-induced release of inflammatory factors in A549 cells. A mouse model of acute lung injury was constructed by intraperitoneal injection of 5 mg/kg LPS to observe the therapeutic effect of rosavin. Transcriptomics analysis and Western blot assays were utilized to verify the molecular mechanism, rosavin (20, 40, and 80 mg/kg) dose-dependently ameliorated histopathological alterations, reduced the levels of inflammatory factors, and inhibited the TLR-4/NF-κB/MAPK signaling pathway and apoptosis activation. Rosavin is a promising therapeutic candidate for acute lung injury by inhibiting the TLR-4/NF-κB/MAPK pathway.

Discovery of novel osthole derivatives exerting anti-inflammatory effect on DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice.

The modification based on natural products is a practical way to find anti-inflammatory drugs. In this study, 26 osthole derivatives were synthesized, and their anti-inflammatory properties were evaluated. The preliminary activity study revealed that most osthole derivatives could effectively inhibit inflammatory cytokines IL-6 secretion in LPS stimulated mouse macrophages J774A.1. Compound 7m exhibited the most effective anti-inflammatory activity (RAW264.7 IL-6 IC50: 4.57 µM, 32 times more active than osthole) in vitro with no significant influence on cell proliferation. Additionally, the mechanistic analysis demonstrated that compound 7m could block MAPK signal transduction by inhibiting the phosphorylation of JNK and p38, thereby inhibiting the release of inflammatory cytokines. Moreover, in vivo functional investigations revealed that 7m could substantially reduce DSS-induced ulcerative colitis and LPS-induced acute lung injury, with good therapeutic effects. The pharmacokinetics and acute toxicity experiments proved the safety and reliability of 7min vivo. Overall, Compound 7m could further be studied as potential anti-inflammatory candidate.

Calycosin enhances Treg differentiation for alleviating skin inflammation in atopic dermatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disorder that poses a significant global health challenge. There is a lack of safe and effective medications to treat AD. Astragalus membranaceous is a traditional Chinese medicine widely used in clinical treatment of skin diseases. Calycosin (CA), derived from the root of Astragalus membranaceous, exhibits dual attributes of anti-inflammatory and antioxidant properties, suggesting its promise for addressing cutaneous inflammation. Nonetheless, the precise mechanisms underlying CA's therapeutic actions in AD remain elusive. AIM OF THE STUDY: This study aimed to evaluate the efficacy and safety of CA in treating AD while also delving into the mechanistic underpinnings of CA's action in AD. MATERIALS AND METHODS: The cell viability and anti-inflammatory impacts of CA in vitro were first gauged using CCK-8 and RT-qPCR. The potential mechanisms of CA were then probed using modular pharmacology. Flow cytometry was employed to ascertain the differentiation of Treg and Th17 cells derived from naïve T cells, as well as the proportions and mean fluorescence intensity (MFI) of human iTreg cells. The expressions of IL-10 and TGF-ß1 were measured and Treg suppression assay was performed. The in vivo therapeutic efficacy of topical CA application was assessed using a calcipotriol (MC903)-induced AD mouse model. The expression metrics of inflammatory cytokines, IL-17A, FOXP3, and RORγt were authenticated via immunohistochemistry, RT-qPCR, Western blot, and ELISA. RESULTS: CA exhibited a favorable safety profile and reduced the mRNA expressions of Th2 inflammatory cytokines in HaCaT cells. Modular pharmacology analysis pinpointed Th17 differentiation as the pivotal mechanism behind CA's therapeutic effect on AD. In vitro, CA fostered the differentiation of naïve T cells into Tregs while inhibiting their differentiation into Th17 cells. Furthermore, CA augmented the proliferation of human iTregs. In vivo, CA alleviated skin manifestations and decreased the levels of inflammatory mediators (IL-4, IL-5, IL-13, TSLP, and NF-κB related cytokines) in AD-like mouse models. Simultaneously, it regulated Treg/Th17 balance through suppressing IL-17A and RORγt expressions and bolstering FOXP3 expression. CONCLUSIONS: The study provides insights into the mechanistic pathways through which CA exerts its anti-inflammatory effects, particularly through promoting Treg cell differentiation and inhibiting Th17 cell differentiation. Furthermore, CA emerges as an alternative or adjunctive treatment strategy for managing AD.

Structural modification of natural axinelline A: Achieving reduced colitis side effects through balanced COX inhibition.

Marine natural products continue to hold great promise as potential candidates for the discovery of anti-inflammatory drug. In our previous investigation, we successfully synthesized axinelline A, a naturally occurring cyclooxygenase-2 (COX-2) inhibitor, as a promising anti-inflammatory lead compound. This study was to discover novel COX inhibitors with balanced inhibition, aiming to mitigate the severe adverse effects through further structural modification of axinelline A. Of the synthetic derivatives, compound 5e showed highest COX-2 inhibitory activity and balanced COX inhibition (IC50 = 1.74 µM; selectivity ((IC50 (COX-1)/IC50(COX-2) = 16.32). The in vitro anti-inflammatory results indicated that 5e effectively suppressed the expression of pro-inflammatory mediators via the NF-κB signaling pathway rather than the MAPK signaling pathway. The in vivo ulcerative colitis assay demonstrated 5e significantly ameliorated the histological damages and showed strong protection against DSS-induced acute colitis. Therefore, our findings suggest that compound 5e exhibits potential as a promising anti-inflammatory agent with attenuated colitis-related adverse effects.

Unconjugated bilirubin and its derivative ameliorate IMQ-induced psoriasis-like skin inflammation in mice by inhibiting MMP9 and MAPK pathway.

Psoriasis is a chronic immune-mediated inflammatory skin disease that involves dysregulated proliferation of keratinocytes. Psoriatic skin lesions are characterized by redness, thickness, and scaling. The interleukin axis of IL-23/IL-17 is critically involved in the development of human psoriasis. Imiquimod (IMQ), an agonist of TLR7 is known to induce psoriatic-like skin inflammation in mice. The topical application of IMQ induces systemic inflammation with increased proinflammatory cytokines in serum and secondary lymphoid organs. Further, matrix metalloproteases (MMPs) have been implicated in the pathophysiology of psoriatic-like skin inflammation. The increased MMP9 activity and gene expression of proinflammatory cytokines in IMQ-induced psoriatic skin is mediated by the activation of the MAPK pathway. Moreover, the increased expression of neutrophil-specific chemokines confirmed the infiltration of neutrophils at the site of psoriatic skin inflammation. In contrast, expression of IL-10, an anti-inflammatory cytokine gene expression is reduced in IMQ-treated mice skin. Topical application of unconjugated bilirubin (UCB) and its derivative dimethyl ester of bilirubin (BD1) on IMQ-induced psoriatic mice skin significantly mitigated the symptoms of psoriasis by inhibiting the activity of MMP9. Further, UCB and BD1 reduced neutrophil infiltration as evidenced by decreased myeloperoxidase (MPO) activity and reduced gene expression of proinflammatory cytokines, and neutrophil-specific chemokines. Apart from these modulations UCB and BD1 reduced MAPK phosphorylation and upregulated anti-inflammatory cytokines. To conclude, UCB and BD1 immunomodulated the psoriatic skin inflammation induced by IMQ in mice by inhibiting neutrophil mediated MMP9, decreased proinflammatory cytokines gene expression and modulating the MAPK pathway.

Baicalin-2-ethoxyethyl ester alleviates gentamicin-induced acute kidney injury via NF-κB signaling pathway.

Drug nephrotoxicity has high fatality rates and complications. To study this conditional, traditionally, Gentamicin (GM) is used to induce acute injury and establish a nephrotic syndrome model. Baicalin, a flavonoid derived from baicalin with potent anti-inflammatory and antioxidant activity, has been used to treat various inflammatory diseases. This study aims to investigate the process of baicalin-2-ethoxyethyl ester (BAE) synthesis and its therapeutic effect on GM-induced acute kidney injury (AKI). Briefly, baicalin was processed by various reactions to yield BAE. A GM-induced AKI model was established for in vivo evaluation of the protective effect and mechanism of BAE. The results indicated that BAE reduced serum creatinine and urea nitrogen levels and improved pathological alterations, inflammatory responses, and oxidative stress in renal tissues. Furthermore, it was revealed that BAE might exert anti-inflammatory and anti-oxidative responses during AKI via the NF-κB signaling pathway regulation. The findings imply that BAE has a protective impact on the kidneys and might serve as a potent medicine for treating renal damage.