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Pain and inflammation contribute immeasurably to reduced quality of life, yet modern analgesic and anti-inflammatory therapeutics can cause dependence and side effects. Here, we screened 1444 plant extracts, prepared primarily from native species in California and the United States Virgin Islands, against two voltage-gated K+ channels - T-cell expressed Kv1.3 and nociceptive-neuron expressed Kv7.2/7.3. A subset of extracts both inhibits Kv1.3 and activates Kv7.2/7.3 at hyperpolarized potentials, effects predicted to be anti-inflammatory and analgesic, respectively. Among the top dual hits are witch hazel and fireweed; polymodal modulation of multiple K+ channel types by hydrolysable tannins contributes to their dual anti-inflammatory, analgesic actions. In silico docking and mutagenesis data suggest pore-proximal extracellular linker sequence divergence underlies opposite effects of hydrolysable tannins on different Kv1 isoforms. The findings provide molecular insights into the enduring, widespread medicinal use of witch hazel and fireweed and demonstrate a screening strategy for discovering dual anti-inflammatory, analgesic small molecules.

Background: Inflammatory bowel disease (IBD) is a chronic, systemic condition affecting the gastrointestinal tract. IBD can be severe and are associated with impairment in growth, school absences, abdominal pain, and fatigue. Physical activity (PA) could have an anti-inflammatory effect in addition to other benefits. It is important to address the possible risks, physiological effects of PA, and potential barriers, and facilitators for PA participation in pediatric IBD. However, potential barriers and facilitators to PA have yet to be adequately described. Methods: We conducted a scoping review to map and describe the current literature on PA in pediatric IBD populations between 1980 and April 2022 using Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines for Scoping reviews. Results: Nineteen articles were identified including 10 descriptive, 6 interventional, and 3 physiological responses to PA studies. Patients and healthy controls demonstrated similar responses to exercise. Barriers to participation were low self-esteem, body image, and active IBD symptoms. Facilitators included personal interest, activity with friends, and support from family. Conclusion: This review highlighted that PA participation may reduce in children with IBD-related symptoms. Short- and medium-term impacts of PA on immune modulation require further study; it is possible that regular PA does not negatively affect biomarkers of disease activity. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Treatments for atopic dermatitis (AD) often fail to achieve lasting disease control. In the CrisADe CONTROL phase III study (ClinicalTrials.gov: NCT04040192), participants aged ≥ 3 months with mild to moderate AD treated with once-daily (QD) crisaborole, following initial treatment success with crisaborole twice daily (BID), had longer periods of flare-free maintenance, a higher number of flare-free days, and a lower number of flares compared with those who received vehicle. The study was an exploratory analysis of data on the maintenance of response per Investigators Static Global Assessment (ISGA; ISGA score of 0 [clear] or 1 [almost clear]) during the CrisADe CONTROL study through week 52. METHODS: Exploratory endpoints were the time to ISGA response during the open-label run-in period, and the maintenance of ISGA response and the severity and duration of flares during the double-blind maintenance period. Outcomes were stratified by age (participants aged 3 months to

BACKGROUND: Due to encouraging pre-clinical data and supportive observational studies, there has been growing interest in applying cardiovascular drugs (including aspirin, angiotensin-converting enzyme [ACE] inhibitors, statins, and metformin) approved to treat diseases such as hypertension, hyperlipidemia, and diabetes mellitus to the field of oncology. Moreover, given growing costs with cancer care, these medications have offered a potentially more affordable avenue to treat or prevent recurrence of cancer. We sought to investigate the anti-cancer effects of drugs repurposed from cardiology or anti-inflammatories to treat cancer. We specifically evaluated the following drug classes: HMG-CoA reductase inhibitors (statins), cyclo-oxygenase inhibitors, aspirin, metformin, and both angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors. We also included non-steroidal anti-inflammatory drugs (NSAIDs) because they exert a similar mechanism to aspirin by blocking prostaglandins and reducing inflammation that is thought to promote the development of cancer. METHODS: We performed a systematic literature review using PubMed and Web of Science with search terms including aspirin, NSAID, statin (including specific statin drug names), metformin, ACE inhibitors, and ARBs (including specific anti-hypertensive drug names) in combination with cancer. Searches were limited to human studies published between 2000 and 2023. MAIN OUTCOMES AND MEASURES: The number and percentage of studies reported positive results and pooled estimates of overall survival, progression-free survival, response, and disease-free survival. RESULTS: We reviewed 3094 titles and included 67 randomized clinical trials. The most common drugs that were tested were metformin (n = 21; 30.9%), celecoxib (n = 20; 29.4%), and simvastatin (n = 8; 11.8%). There was only one study that tested cardiac glycosides and none that studied ACE inhibitors. The most common tumor types were non-small-cell lung cancer (n = 19; 27.9%); breast (n = 8; 20.6%), colorectal (n = 7; 10.3%), and hepatocellular (n = 6; 8.8%). Most studies were conducted in a phase II trial (n = 38; 55.9%). Most studies were tested in metastatic cancers (n = 49; 72.1%) and in the first-line setting (n = 36; 521.9%). Four studies (5.9%) were stopped early because of difficulty with accrual. The majority of studies did not demonstrate an improvement in either progression-free survival (86.1% of studies testing progression-free survival) or in overall survival (94.3% of studies testing overall survival). Progression-free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression-free survival was worse in one study (2.8% of studies testing progression-free survival). CONCLUSIONS AND RELEVANCE: Despite promising pre-clinical and population-based data, cardiovascular drugs and anti-inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology.

Mural cells directly contact macrophages in the dural layer of the meninges to suppress pro-inflammatory phenotypes, including antigen presentation and lymphocyte differentiation. These mechanisms represent new targets for modulating CNS immune surveillance and pathological inflammation (Min et al. 2024. J. Exp. Med.https://doi.org/10.1084/jem.20230326).

We developed a high-content image-based screen that utilizes the pro-inflammatory stimulus lipopolysaccharide (LPS) and murine macrophages (RAW264.7) with the goal of enabling the identification of novel anti-inflammatory lead compounds. We screened 2,259 bioactive compounds with annotated mechanisms of action (MOA) to identify compounds that block the LPS-induced phenotype in macrophages. We utilized a set of seven fluorescence microscopy probes to generate images that were used to train and optimize a deep neural network classifier to distinguish between unstimulated and LPS-stimulated macrophages. The top hits from the deep learning classifier were validated using a linear classifier trained on individual cells and subsequently investigated in a multiplexed cytokine secretion assay. All 12 hits significantly modulated the expression of at least one cytokine upon LPS stimulation. Seven of these were allosteric inhibitors of the mitogen-activated protein kinase kinase (MEK1/2) and showed similar effects on cytokine expression. This deep learning morphological assay identified compounds that modulate the innate immune response to LPS and may aid in identifying new anti-inflammatory drug leads.

Background and aimsWe previously reported that Oxy210, an oxysterol-based drug candidate, exhibits antifibrotic and anti-inflammatory properties. We also showed that, in mice, it ameliorates hepatic hallmarks of non-alcoholic steatohepatitis (NASH), including inflammation and fibrosis, and reduces adipose tissue inflammation. Here, we aim to investigate the effects of Oxy210 on atherosclerosis, an inflammatory disease of the large arteries that is linked to NASH in epidemiologic studies, shares many of the same risk factors, and is the major cause of mortality in people with NASH.MethodsOxy210 was studied in vivo in APOE*3-Leiden.CETP mice, a humanized mouse model for both NASH and atherosclerosis, in which symptoms are induced by consumption of a high fat, high cholesterol "Western" diet (WD). Oxy210 was also studied in vitro using two cell types that are important in atherogenesis: human aortic endothelial cells (HAECs) and macrophages treated with atherogenic and inflammatory agents.ResultsOxy210 reduced atherosclerotic lesion formation by more than 50% in hyperlipidemic mice fed the WD for 16 weeks. This was accompanied by reduced plasma cholesterol levels and reduced macrophages in lesions. In HAECs and macrophages, Oxy210 reduced the expression of key inflammatory markers associated with atherosclerosis, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), vascular cell adhesion molecule-1 (VCAM-1), and E-Selectin. In addition, cholesterol efflux was significantly enhanced in macrophages treated with Oxy210.ConclusionsThese findings suggest that Oxy210 could be a drug candidate for targeting both NASH and atherosclerosis, as well as chronic inflammation associated with the manifestations of metabolic syndrome.

Several inflammatory cytokines bind to the allosteric site (site 2) and allosterically activate integrins. Site 2 is also a binding site for 25-hydroxycholesterol, an inflammatory lipid mediator, and is involved in inflammatory signaling (e.g., TNF and IL-6 secretion) in addition to integrin activation. FGF2 is pro-inflammatory and pro-thrombotic, and FGF1, homologous to FGF2, has anti-inflammatory and anti-thrombotic actions, but the mechanism of these actions is unknown. We hypothesized that FGF2 and FGF1 bind to site 2 of integrins and regulate inflammatory signaling. Here, we describe that FGF2 is bound to site 2 and allosterically activated β3 integrins, suggesting that the pro-inflammatory action of FGF2 is mediated by binding to site 2. In contrast, FGF1 bound to site 2 but did not activate these integrins and instead suppressed integrin activation induced by FGF2, indicating that FGF1 acts as an antagonist of site 2 and that the anti-inflammatory action of FGF1 is mediated by blocking site 2. A non-mitogenic FGF1 mutant (R50E), which is defective in binding to site 1 of αvβ3, suppressed β3 integrin activation by FGF2 as effectively as WT FGF1.

Metal-free radical cascade synthesis of substituted pyrazole derivatives was initiated by PhI(OAc)2 at 23 °C. This protocol features wide functional group tolerance, a simple purification process without column chromatography, and an oxygen migration. Compound 5 demonstrated significant anti-inflammatory activity, indicating potential for therapy. [ABSTRACT FROM AUTHOR]

The n-butanol extract of Stachys arvensis (L.) L. aerial parts (BESA) was analysed by LC-HRMS/MS. 43 Polyphenols, including flavonoids, cinnamic acid derivatives, phenylethaoids, chromones, gallotannins, coumarins and chalcones with hyperoside (13.85%), panasenoside (10.31%), myricitrin (7.89%) and sayaendoside (7.16%), as the major compounds, were identified. High total phenolics (470.21 ± 1.22 mg GAE/g extract) and total flavonoids (189.05 ± 0.72 mg QE/g extract) contents were measured. In addition, the BESA exhibited a higher antioxidant effect in CUPRAC (A0.5:0.45 ± 0.03 μg/mL), DPPH (IC50:4.51 ± 0.16 μg/mL) and ABTS (IC50:7.10 ± 0.18 μg/mL) assays than the standards BHA and α-Tocopherol. Moreover the extract showed a good inhibitory effect against BChE (IC50: 145.02 ± 0.03 μg/mL) and α-amylase (IC50:2.66 ± 0.0024 mg/mL). The BESA exhibited an excellent anti-inflammatory activity (IC50:416 ± 0,056 μg/mL) which was close to that of acetylsalicylic acid, used as a control. The BESA was toxic towards T. molitor larvae and it possessed a good antibacterial activity against gram (+) and gram (-) tested strains. [ABSTRACT FROM AUTHOR]

A series of para -quinone methide derivatives were evaluated their anti-inflammatory activity. Through the screening of the lipopolysaccharide (LPS)-induced inflammatory cell model in Raw264.7 cells, it was found that the inhibitory activity of meta -substituted derivatives on NO production was superior to that of ortho - and para -substituted derivatives. Among them, in the inflammatory cell model, the meta -trifluoromethyl substituted para -quinone methide derivative 1i had the best activity in inhibiting LPS-induced excess generation of NO. And 1i could effectively inhibit the increase of ROS in inflammatory cells, the expression of iNOS related to the production of NO, and the expressions of inflammation related initiating protein TLR4, pro-inflammatory cytokines IL-6 and TNF-α, inflammasome NLRP3 and Caspase1. In the dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model, the active derivative 1i could inhibit DSS-induced colon shortening, and reverse DSS-induced pathological changes in colon tissue, such as inflammatory infiltration, structural destruction and crypt disappearance. 1i could effectively inhibit oxidative stress, inflammation and apoptosis in UC mice. Moreover, through the determination of serum biochemical indicators, tissue pathologies and tissue organ indexes, 1i could effectively reverse the damage to mouse liver and kidney caused by DSS, playing a protective role in liver and kidney of mice. In summary, 1i was an effective anti-inflammatory reagent and could be developed as a potential drug for anti-UC. [ABSTRACT FROM AUTHOR]

AbstractThree new compounds, including two glycosides, named gerbelavinsides E/G (1/2), and a flavone, named gerbelavin G (3), were isolated from 50% ethanol extract of Gerbera delavayi. Their structures were elucidated based on HR-ESI-MS, IR, UV and NMR spectral data, and the absolute configurations of 1 and 3 were determined by ECD spectra. Three compounds were tested for their inhibition effect against LPS-induced NO production in RAW 264.7 cells. They exhibited different degrees of inhibition activities with rates of 40.55 ± 1.65%, 70.13 ± 0.55%, 56.74 ± 1.15%, respectively. [ABSTRACT FROM AUTHOR]

The global public health addiction crisis has been stark, with over 932,400 deaths in the USA and Canada from opioid overdose since 1999–2020, surpassing the mortality rates at the top of the HIV/AIDS epidemic. Both nations exhibit opioid consumption rates significantly above the norm for developed countries. Analgesic type of opioids present both therapeutic benefits and substantial health risks, necessitating balanced drug regulation, careful prescribing, and dedicated opioid stewardship. The role of the cytochrome P450 2D6 (CYP2D6) system (Enzymatic functions) in metabolizing opioids highlights the potential of genotype-guided analgesia. By integrating Pharmacogenomics (PGx), this approach aims to optimize pain management, enhance safety, and reduce addiction risks. This understanding prompted the utilization of multifactor dimensionality reduction (MDR) to explore a range of phenotypes including PGx and gene–gene interactions (GGI) in a healthy cohort, thereby personalizing pain management strategies. The study sampled 100 unrelated healthy Western Iranians and 100 individuals from the 1000 Genome Project. Pre-testing involved searching for PGx annotations (variants associated with drug-gene-diseases) related to pain sensitivity and inflammation using the PharmGKB database, which identified 128 relevant genes. A questionnaire helped select 100 participants who had never used potent opioids but also other psychoactive agents (e.g., nicotine, amphetamines, etc.) and disease-related drugs. Whole-exome sequencing (WES) was then employed to analyze these genes in an Iranian cohort. Further analyses included MDR for identifying synergistic gene annotations and GGI for exploring complex gene interactions through the Visualization of Statistical Epistasis Networks (ViSEN). The study identified a Pain, Anti-Inflammatory, and Immunomodulating agents (PAIma) panel from the 128 genes, resulting in 55,590 annotations across 21 curated pathways. After filtering, 54 significant structural or regulatory variants were identified. This research also highlighted novel gene relationships involving the CYP3A5 gene, hsa-miR-355-5p, Paliperidone, and CYP2D6, which warrant further investigation. This study offers a novel pharmacogenetic framework that could potentially transform opioid prescribing practices to mitigate misuse and enhance personalized pain management. Further validation of these findings from multi countries and ethnic groups could guide clinicians in implementing DNA-based opioid prescribing, aligning treatment more closely with individual genetic profiles. [ABSTRACT FROM AUTHOR]

Background: Green synthesized nanoparticles have recently gained significant medicinal applications and oftentimes outperform their green sources. Selenium is of fundamental importance to human health, stemming from its distinctive physicochemical properties, such as antioxidant activity, inhibition of Lipid peroxidation, stabilization of membrane proteins, maintenance of membrane fluidity and modulation of cell signaling. Though reports have shown some therapeutic potential of Ackee plant parts such as antioxidant, anti-inflammatory, antimicrobial, neuroprotective, very few scientific proofs still exist in support of these effects. Methods: This study synthesized selenium nanoparticles (Se-NPs) from crude methanolic extracts of Ackee leaves (AKL) and Ackee arils (AKA), examined the photo-physical characteristics of the Se-NPs and determined the in-vitro antioxidant, antidiabetic, and anti-inflammatory potentials of AKL, AKA, and their Se-NPs using established protocols. Results: In both leaves and arils Se-NPs: UV spectroscopy revealed a qualitative absorbance at 310 nm; FTIR indicated multiple vibrations around 4000 cm−1- 400 cm−1; SEM images of 5 µm principally showed consistent size distribution of amorphous and granular shape at a magnification of 10,000X; while EDS spectra strongly confirm the presence of atomic Se compound at 30 kV. Various antioxidant activities assays carried out showed a range of approximately 4 to 60 times higher activities of the AKL, AKA, and Se-NPs than Ascorbic acid—the standard drug used. Furthermore, appreciable activities of more than 50% were obtained for alpha-amylase and alpha-glucosidase inhibitory activities, along with highly significant activities of haemoglobin glycosylation, glucose uptake, membrane stabilization, anti-arthritic, anti-haemolysis activities, when AKL, AKA, and Se-NPs were compared with standard drugs. Conclusion: Encouraging the development and utilization of AKL, AKA, and Se-NPs will provide tremendous therapeutic efficacy and bioavailability approaches towards the management of diabetes, inflammation, and other oxidative stress-related diseases. [ABSTRACT FROM AUTHOR]

Introduction: Due to its remarkable anti-inflammatory pharmacological activity, Farfarae Flos has gained extensive usage in the treatment of various inflammatory diseases such as bronchitis, pneumonia, prostatitis and colitis. And Farfarae Flos come in two color types depending on the color of the flowers: yellowish-white (YW), and purplish-red (PR). However, the difference in anti-inflammatory activity and metabolic profiles between the two flower colors remains unexplored. Methods: This study aims to explore the difference in the anti-inflammatory potential between YW and PR variants of Farfarae Flos and unravel the mechanisms responsible for the observed differences in anti-inflammatory activity through an integrated approach encompassing untargeted metabolomics and in vivo / vitro experimental studies. Initially, we verified the contrasting effects of YW and PR on the inhibition of the inflammatory factors interleukin-6 (IL-6) and nitric oxide (NO) by utilizing an in vitro RAW 264.7 cell inflammation model. Subsequently, a comprehensive evaluation of the systemic inhibitory capacity of YW and PR on IL-6, Interleukin-10 (IL-10), and tumor necrosis factor- α (TNF- α) was conducted using a validated whole-body mouse model, followed by the analysis of inflammatory factors and histological examination of collected serum, liver, and spleen after 7 days. Furthermore, non-targeted metabolomics profiling was employed to analyze the metabolite profiles of Farfarae Flos with different colors, and quantitative analysis was conducted to identify differential metabolites between YW and PR. The correlation between the anti-inflammatory activities of differentially accumulated metabolites (DAMs) and Farfarae Flos was investigated, resulting in the identification of 48 compounds exhibiting significant anti-inflammatory activity. Additionally, KEGG pathway enrichment analysis was performed to elucidate the underlying mechanisms. Results: Our findings demonstrate that both YW and PR possess anti-inflammatory abilities, with PR exhibiting significantly superior efficacy. The integration of in vivo / vitro experiments and non-targeted metabolomics confirmed the exceptional anti-inflammatory potential of PR and solidified its classification as the "purplish-red better" of Farfarae Flos. Discussion: This study provides valuable insights into the breeding and medical transformation of Farfarae Flos varieties, along with a scientific basis for the establishment of quality standards and the development of new drugs utilizing Farfarae Flos. [ABSTRACT FROM AUTHOR]

In this paper, triazole derivatives were prepared by a three-step mild reaction using carbon disulfide as starting material. In face of microbial threats, we found that compound 3-cyclopropyl-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole-6-thiol (C2) has good antibacterial activity, inhibition and clearance ability against biofilms, low hemolytic activity and toxicity, good anti-inflammatory activity. At the same time, we found that B and C series compounds have good metal ion scavenging ability, with removal rates of C series ranging from 47% to 67% and B series ranging from 67% to 87%. [ABSTRACT FROM AUTHOR]

Background: Voriconazole (VRZ) is involved in a variety of drug‒drug interactions (DDIs), but few studies have reported adverse events (AEs) associated with the DDIs of VRZ. The primary goal of this study was to analyse the potential risk factors for AEs caused by DDIs between VRZ and other drugs via the OpenVigil FDA platform and to provide a reference for preventing VRZ DDIs and monitoring clinically related adverse drug events. Methods: A retrospective pharmacovigilance study was conducted to investigate the AEs related to DDIs between VRZ and four categories of drugs: proton pump inhibitors (PPIs), non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, and other antibacterial drugs. AE information for the target drugs from the first quarter of 2004 to the third quarter of 2022 was downloaded from the OpenVigil FDA data platform. Four frequency statistical models—the reporting ratio method, Ω shrinkage measure model, combination risk ratio model, and the chi-square statistics model—were used to analyse the AEs related to DDIs and evaluate the correlation and influence of sex and age between the drug(s) and the target AEs detected. Results: A total of 38 drugs were included, with 262 AEs detected by at least one of the four models and 48 AEs detected by all four models. Some 77 detected AEs were significantly positively correlated with DDIs and were related to higher reporting rates of AEs than when used alone. Graft-versus-host disease was the AE that had the strongest correlation with the drug interaction between VRZ and immunosuppressants (tacrolimus, mycophenolate mofetil, cyclophosphamide, and cyclosporine), and multiple organ dysfunction syndrome was correlated with VRZ in combination with other antibacterial drugs (linezolid, meropenem, cefepime, and vancomycin). Significant sex and age differences in the target AEs were detected for five and nine target drugs, respectively. For VRZ in combination with linezolid, aggravated conditions and respiratory failure should be given more attention in male patients, and mycophenolate mofetil and respiratory failure in female patients. When conditions are aggravated, febrile neutropenia and septic shock should be of particular concern in patients over 18 years of age who use VRZ in combination with ceftazidime, ciprofloxacin, or cytarabine. In patients aged under 18, septic shock should be considered when VRZ is used in combination with meropenem and dexamethasone. Conclusion: AEs related to DDIs should receive more attention when VRZ is used in combination with PPIs (renal impairment), NSAIDs (constipation and renal failure), immunosuppressants (graft versus host disease, septic shock) and other antibacterial drugs (multiple organ dysfunction syndrome, febrile neutropenia, and respiratory failure). Considering the influence of sex and age differences in VRZ DDIs, these factors need to be considered when assessing the risk of AEs in patients receiving VRZ and other drugs. [ABSTRACT FROM AUTHOR]

Background/Aims: The effect of proton pump inhibitors (PPIs) on the lower gastrointestinal (GI) tract is uncertain, with potential to worsen damage. This study aimed to find the best method for protecting the entire GI tract from mucosal damage. Methods: A retrospective cohort study at Samsung Medical Center (2002-2019) included 195,817 patients prescribed GI mucosa-damaging agents. The primary goal was to assess the effectiveness of GI protective agents in preventing significant hemoglobin drops (>2 g/dL), indicating overall GI mucosal damage. Self-controlled case series and landmark analysis were used to address biases in real-world data. Results: The incidence rate ratios for rebamipide, PPI, and histamine-2 receptor antagonist (H2RA) were 0.34, 0.33, and 0.52, respectively. Rebamipide showed a significantly lower incidence rate than H2RA and was comparable to PPIs. Landmark analysis revealed significant reductions in hemoglobin drop risk with rebamipide and H2RA, but not with PPI. Conclusions: Rebamipide, like PPIs, was highly effective in preventing blood hemoglobin level decreases, as shown in real-world data. Rebamipide could be a comprehensive strategy for protecting the entire GI tract, especially when considering PPIs' potential side effects on the lower GI tract. [ABSTRACT FROM AUTHOR]

The increasing legalization of Cannabis sativa plant products has sparked growing interest in their therapeutic applications. Prohibition laws established in 1937 hindered formal research on cannabis, a plant with cultural and medicinal roots dating back to 2700 BC in Chinese history. Despite regulatory hurdles, published research on cannabis has emerged; yet elite athletes remain an underrepresented population in these studies. Athletes, known for exploring diverse substances to optimize performance, are drawn to the potential benefits of cannabinoid therapy, with anecdotal reports suggesting positive effects on issues ranging from anxiety to brain injuries. This review aims to evaluate empirical published cannabis research with a specific focus on its potential applications in athletics. The changing legal landscape, especially the removal of cannabis from drug testing programs in leagues such as the National Basketball Association (NBA), and endorsements by Major League Baseball (MLB) for cannabinoid products and the National Football League (NFL) for cannabis research, reflects a shift in the acceptability of such substances in sports. However, stigma, confusion, and a lack of education persist, hindering a cohesive understanding among sports organizations, including business professionals, policymakers, coaches, and medical/training staff, in addition to athletes themselves. Adding to the confusion is the lack of consistency with cannabinoid regulations from sport to sport, within or out of competition, and with cannabis bioactive compounds. The need for this review is underscored by the evolving attitudes toward cannabinoids in professional sports and the potential therapeutic benefits or harms they may offer. By synthesizing current cannabis research, this review aims to provide a comprehensive understanding of the applications and implications of cannabinoid use in the realm of athletics. [ABSTRACT FROM AUTHOR]

• Controversy exists concerning the blood glucose-lowering activity of whole grains. • Whole grains elicit high inter-individual variability in blood glucose tolerance. • Gut microbiota and host metabolism likely influence individuals' responses to whole grains. • Machine learning of multi-omics analyses will help to identify whole grain benefits. • Our planned trial could establish a precision nutrition framework for recommendations. Randomized controlled trials (RCT) demonstrate that whole wheat consumption improves glycemia. However, substantial inter-individual variation is often observed, highlighting that dietary whole grain recommendations may not support the health of all persons. The objective of this report is to describe the rationale and design of a planned RCT aimed at establishing the gut microbiota and metabolome signatures that predict whole wheat-mediated improvements in glucose tolerance in adults with prediabetes. It is hypothesized that a controlled diet containing wheat bread (WHEAT; 160 g/day) compared with refined bread (WHITE) will improve glucose tolerance in a gut microbiota-mediated manner. Biospecimens will be collected before and after each 2-week study arm. Testing for oral glucose tolerance and gastrointestinal permeability will be performed post-intervention. Assessments will include oral glucose tolerance (primary outcome) and secondary outcomes including gut microbiota, targeted and untargeted metabolomics of fecal and plasma samples, intestinal and host inflammatory responses, and intestinal permeability. WHEAT is predicted to alleviate glucose intolerance by shifting microbiota composition to increase short-chain fatty acid-producing bacteria while reducing populations implicated in intestinal inflammation, barrier dysfunction, and systemic endotoxemia. Further, benefits from WHEAT are anticipated to correlate with gut-level and systemic metabolomic responses that can help to explain the expected inter-individual variability in glucose tolerance. Thus, knowledge gained from integrating multi-omic responses associating with glucose tolerance could help to establish a precision nutrition-based framework that can alleviate cardiometabolic risk. This framework could inform novel dietary whole grain recommendations by enhancing our understanding of inter-individual responsiveness to whole grain consumption. This report describes the rationale and design of a planned randomized, controlled trial examining the benefits of WHEAT on glucose tolerance in adults with prediabetes. It is hypothesized that WHEAT will improve glucose tolerance in a gut-mediated manner. Machine learning approaches will identify the metagenomic and metabolomic signatures predicting inter-individual responses to WHEAT. Outcomes are expected to inform a precision nutrition framework for whole wheat to alleviate prediabetes. Abbreviation: WHEAT, whole wheat bread. Created in BioRender. Bruno, R. (2024) BioRender.com/h45v815 [Display omitted] [ABSTRACT FROM AUTHOR]

Paw swelling induced by carrageenan injection serves as a reliable model for assessing acute inflammatory responses in rats. In this study, we synthesized and evaluated a series of quinoxaline derivatives for their anti-inflammatory activity using the carrageenan-induced rat hind paw edema method. The compounds 5a, 5e, 5f, 5g, 5h, 5l, 5q, and 5u were selected based on their inhibitory activity against p38a MAP kinase. Among these, compound 5f, which possesses a 2-chlorophenyl group at position 4 of the triazole ring, demonstrated the highest inhibition of paw edema, with an 84.15% reduction, comparable to the standard drug diclofenac sodium (83.22%). The structure-activity relationship revealed that the presence of a chloro group at the 6th position of the quinoxaline ring led to reduced anti-inflammatory activity. This study highlights the potential of quinoxaline derivatives as effective anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Cholesterol crystal embolism (CCE) is an underrecognized multisystemic disease caused by the displacement of cholesterol crystals from atheromatous aortic plaques to distal vascular beds, leading to ischemic injury of target organs, particularly the kidneys, i.e., atheroembolic renal disease (ARD). According to recent research, cellular necrosis, induced by crystal-induced cytotoxicity, enhances the autoinflammatory cascade of the NLPR3 inflammasome, leading in turn to the so-called "necroinflammation". The purported involvement of the latter in CCE offers a rationale for the therapeutic approach with anti-inflammatory drugs such as glucocorticoids, the use of which has long been a matter of debate in CCE. Diagnostic delay and no consistent evidence regarding efficacious treatment, leading to inconsistency in clinical practice, may worsen the already poor prognosis of ARD. The possible role of glucocorticoids in the treatment of ARD is thereby herein explored in a narrative fashion, analyzing the limited data from case reports and clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Bronchitis obliterans syndrome (BOS) may occur following lung transplantation (LTx) or hematopoietic cell transplantation (HCT). The primary issue is graft-versus-host disease, complicating diagnosis. Treatment is based on empirical evidence and interdisciplinary knowledge. Recent advances emphasize understanding the etiology, clinical features, and pathobiology of BOS, fostering cross-disciplinary knowledge. Treatment algorithms are based on thorough research and expert clinical insights, with new therapies being explored to enhance survival rates and prevent LTx or re-transplantation. Background: Similar in histological characteristics and clinical manifestations, bronchiolitis obliterans syndrome (BOS) can develop following lung transplantation (LTx) or hematopoietic cell transplantation (HCT). In contrast to lung transplantation, where BOS is restricted to the lung allograft, HCT-related systemic graft-versus-host disease (GVHD) is the root cause of BOS. Because lung function declines following HCT, diagnosis becomes more difficult. Given the lack of proven effective medicines, treatment is based on empirical evidence. Methods: Cross-disciplinary learning is crucial, and novel therapies are under investigation to improve survival and avoid LTx. Recent advances have focused on updating the understanding of the etiology, clinical features, and pathobiology of BOS. It emphasizes the significance of learning from experts in other transplant modalities, promoting cross-disciplinary knowledge. Results: Our treatment algorithms are derived from extensive research and expert clinical input. It is important to ensure that immunosuppression is optimized and that any other conditions or contributing factors are addressed, if possible. Clear treatment algorithms are provided for each condition, drawing from the published literature and consensus clinical opinion. There are several novel therapies currently being investigated, such as aerosolized liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies, and B-cell-directed therapies. Conclusions: We urgently need innovative treatments that can greatly increase survival rates and eliminate the need for LTx or re-transplantation. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral cancer represents a main public health issue around the world due to the mortality rates associated with it, the lack of effective and potent drugs, the multitude of side effects and the expensive treatments. Until now, no natural alternative therapeutic methods have been found beneficial enough to replace conventional drugs. Thus, bioactive compounds with anticancer properties can represent a necessary alternative through a targeted molecular approach to the multiple pathways involved in carcinogenesis. This review explores how the therapeutic potential of natural compounds can be harnessed and how they can be used as adjuvant therapies for oral cancer treatment. The collected results focused only on plant extracts and biologically active metabolites known for their antioxidant, anti-inflammatory and antitumor potential, which can be described as future chemopreventive agents against oral cancer, alone or in therapeutic combinations. Background: With a significant increase in both incidence and mortality, oral cancer—particularly oral squamous cell carcinoma (OSCC)—is one of the main causes of death in developing countries. Even though there is evidence of advances in surgery, chemotherapy, and radiotherapy, the overall survival rate for patients with OSCC has improved, but by a small percentage. This may be due, on the one hand, to the fact that the disease is diagnosed when it is at a too-advanced stage, when metastases are already present. Methods: This review explores the therapeutic potential of natural herbal products and their use as adjuvant therapies in the treatment of oral cancer from online sources in databases (PubMed, Web of Science, Google Scholar, Research Gate, Scopus, Elsevier). Results: Even if classic therapies are known to be effective, they often produce many serious side effects and can create resistance. Certain natural plant compounds may offer a complementary approach by inducing apoptosis, suppressing tumor growth, and improving chemotherapy effectiveness. The integration of these compounds with conventional treatments to obtain remarkable synergistic effects represents a major point of interest to many authors. This review highlights the study of molecular mechanisms and their efficiency in in vitro and in vivo models, as well as the strategic ways in which drugs can be administered to optimize their use in real contexts. Conclusions: This review may have a significant impact on the oncology community, creating new inspirations for the development of more effective, safer cancer therapies with less toxic potential. [ABSTRACT FROM AUTHOR]

Our aim in the current study was to determine the in vitro and in vivo synergistic antiinflammatory and antiallergic effect associated with the IL-12 production of guaijaverin and epigallocatechin gallate (EGCG) complex (GEC) and ILS-F-2301 (2:8 extract of Psidium guajava and Camellia sinensis). Compared to EGCG alone, GEC showed synergistic inhibition of nitric oxide (NO), inducible NO synthase, and cyclooxygenase-2 by 3.8, 5.1, and 4.1%, respectively. The downregulation of interleukin-12 (IL-12) by 2,4-dinitrophenyl-human serum albumin conjugate/DNP-immunoglobulin E or ovalbumin (OVA) was synergistically increased by GEC by about 7.5% or 5.4% compared to EGCG alone. The level of downregulation of IL-12 in plasma increased by 100 mg/kg with ILS-F-2301 (28.7%) when compared to the OVA/Alu-treated group. Also, GEC synergistically increased by GEC by about 7.5% or 5.4% compared to EGCG alone. The level of down and cyclooxygenase C synergistically inhibited p-Akt, PI3K, mTOR, p-STAT6, and GATA3 by 4.9%, 4.1%, 19.2%, 23.8%, and 35.3%, respectively, while increasing the expressions of p-STAT1 and T-bet (showing 53.3% and 9.4% activation) when compared to EGCG alone. In an allergenic rhinitis mouse model, 100 mg/kg of ILS-F-2301 was shown to inhibit p-Akt, PI3K, mTOR, p-c-Jun N-terminal kinase (p-JNK), p-extracellular signal-regulated kinase (p-ERK), and p-p38 by 23.3%, 43.8%, 17.2%, 32.2%, 29.1%, and 41.8% when compared to the OVA/Alu-sensitized group. Taken together, our findings suggest that ILS-F-2301 may have potential as a functional food for alleviating antiallergic rhinitis. [ABSTRACT FROM AUTHOR]

Excessive and prolonged alcohol consumption can lead to a serious health condition known as alcohol-related liver disease (ARLD). This ailment represents a significant worldwide health challenge, affecting populations across various demographics. ARLD has a multifactorial pathogenesis involving oxidative stress, inflammation, dysregulated lipid metabolism, and apoptosis. In this study, we investigated the hepatoprotective effects of Laurus nobilis L. leaf water extract (LLE) against ARLD in alcohol-treated hepatocytes and mice. LLE exhibited antioxidant and anti-inflammatory properties by enhancing antioxidant enzyme activities and suppressing proinflammatory cytokines and CYP2E1 expression in ethanol-treated hepatocytes. Moreover, LLE mitigated lipogenesis by modulating the expression of lipogenic factors in ethanol-treated hepatocytes. In vivo, LLE administration attenuated liver injury, oxidative stress, inflammation, and lipid accumulation induced by alcohol consumption in mice. Additionally, LLE suppressed apoptosis signaling pathways implicated in alcohol-induced hepatocyte apoptosis. These findings suggest that LLE functions as a multifaceted therapeutic agent for ARLD by modulating multiple cellular mechanisms, including the reduction of oxidative damage, mitigation of inflammatory responses, alleviation of lipid-mediated toxicity, and regulation of programmed cell death pathways. [ABSTRACT FROM AUTHOR]

Aurantii Fructus (AF) and Aurantii Fructus Immaturus (AFI) are distinct herbs outlined by the Chinese Pharmacopoeia. They are sourced from the same plant but harvested at different times, resulting in differences in efficacy. It is important to avoid mixing them clinically and to distinguish between the two. Furthermore, dissimilar cultivation conditions may cause variability in the quality of herbs, so it is vital to differentiate drugs from dissimilar origins. In this study, two plants, AF and AFI from different provinces, were comparatively analyzed based on High Performance Liquid Chromatography (HPLC) fingerprints and classified using chemometric methods. The results indicate that the two medicines can be clearly distinguished. Also, AF and AFI grown in different locations can be distinguished. Ten chemical markers were screened, and their variations were determined, including eriocitrin, narirutin, naringin, meranzin hydrate, naringenin, hesperidin, nobiletin, tangeretin, neohesperidin, and poncirin. Subsequent network pharmacology correlated the screened chemical components with the biological network of the organism. The material basis of the difference in efficacy of the two homologous herbs was explored from the perspective of changes in chemical composition. This study provides a reference for formulating quality evaluation standards for AF and AFI and lays a foundation for the efficacy-related quality research of the two. [ABSTRACT FROM AUTHOR]

Acrylamide (ACR) is an obligate human neurotoxicant ubiquitously produced and found in foods processed at high temperature. There is an increasing public health concern regarding its probable carcinogenic potential. Its prevailing toxicity mechanism is oxidative inflammation and apoptosis. Herein, we explored whether thymoquinone (TQ), a bioactive quinone in Nigella sativa seed, could mitigate ACR-induced cerebellar toxicity in rats. Our study design featured four rat groups: control, TQ (5 mg/kg bw), ACR (50 mg/kg bw), and TQ + ACR (5 mg/kg + 50 mg/kg). After 14 days of respective treatments, cerebellar homogenate was used to estimate acetylcholinesterase activity (AchE) activity, antioxidant enzymes (catalase [CAT], superoxide dismutase [SOD], and glutathione peroxidase [GPx]), malondialdehyde (MDA), inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α, IL-4, and IL-10), nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), caspase-3, and caspase-9. The level of DNA damage by fragmentation and histopathological lesions was also determined in the cerebellum. The rat exposure to ACR caused significant decreases in the cerebellar activities of AchE, CAT, SOD, and GPx, IL-4, IL-10, and expression of Nrf2, whereas the levels of MDA, IL-6, TNF-α, caspase-3, and caspase-9 were prominently increased compared with the control. ACR induced significant DNA fragments and cerebellar lesions when compared with the control. Contrarily, TQ treatment inhibited the depression of CAT, SOD, and GPx activities and reversed the MDA level and expression of Nrf2/NF-κB, cytokines, and caspases. These effects were confirmed by reduced DNA damage and cerebellar histopathological lesions in comparison with the ACR. TQ afforded neuroprotection via its antioxidant, anti-inflammatory, and antiapoptotic mechanisms in rats. [ABSTRACT FROM AUTHOR]

Objective: To study the impact of tumour necrosis factor-α inhibitor (TNFi) therapy on the use of non-steroidal anti inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) in Iceland. Method: This registry cohort study used data from the nationwide database on biologics in Iceland (ICEBIO) and the Icelandic Prescription Medicines Register on disease activity, and filled prescriptions for NSAIDs, to study the period from 2 years before to 2 years after initiation of a first TNFi. Five randomly selected individuals from the general population matched on age, sex, and calendar time for each patient served as comparators. Results: Data from 940 patients and 4700 comparators were included. Patients with arthritis were prescribed 6.7 times more defined daily doses of NSAIDs than comparators (149 vs 22 per year). After TNFi initiation, NSAID use decreased to a mean of 85 DDD per year, or by 42% in RA, 43% in PsA, and 48% in axSpA. At TNFi initiation, the quintile of axSpA patients who used most NSAIDs reported significantly worse pain (mean ± sd 66 ± 21 vs 60 ± 23 mm), global health (70 ± 20 vs 64 ± 23 mm), and Health Assessment Questionnaire score (1.21 ± 0.66 vs 1.02 ± 0.66) than the other patients, whereas no significant differences were observed in the groups with peripheral arthritis. Conclusion: Patients with inflammatory arthritides requiring TNFi therapy use more NSAIDs than matched comparators, and consumption decreased following TNF initiation. Patient-reported measures are not associated with high NSAID use in patients with peripheral arthritis. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy and safety of iguratimod in adult patients with active axial spondyloarthritis (axSpA). Method: This randomized, double-blind, placebo-controlled clinical trial lasted for 28 weeks. Patients with axSpA were randomized 1:1 to receive iguratimod 25 mg twice daily or a placebo. All patients also took celecoxib 200 mg twice daily for the first 4 weeks and on demand from 4 to 28 weeks. The primary endpoints were ASAS20 at 4 weeks and the non-steroidal anti-inflammatory drug (NSAID) index at 28 weeks. Other assessment variables included ASAS40, ASAS5/6 response rates, Spondyloarthritis Research Consortium of Canada (SPARCC) scores, and adverse events. Results: In total, 35 patients completed the study and were included for analyses. The median (interquartile range) NSAID index was 43.8 (34.9–51.8) in the iguratimod group, which is significantly lower than 68.9 (42.5–86.4) in the placebo group (p = 0.025). ASAS response rates and changes in disease activity scores were similar between the iguratimod and placebo groups. Patients in the iguratimod group had more improvement in median (interquartile range) SPARCC scores for sacroiliac joints than did those in the placebo group [71% (54–100%) vs 40% (0–52%), p = 0.006]. Iguratimod combined with celecoxib was not associated with a greater risk of adverse effects than was monotherapy with celecoxib. No severe adverse events occurred. Conclusions: In the treatment of active axSpA, iguratimod has a potential NSAID-sparing effect, and may also reduce magnetic resonance imaging-assessed bone marrow oedema in sacroiliac joints. Iguratimod provides an additional treatment option for patients with active axSpA.Clinical trial registration numberChiCTR2000029112, Chinese Clinical Trial Registry () [ABSTRACT FROM AUTHOR]

Objectives To assess the impact of baseline RF level on drug concentrations and efficacy of certolizumab pegol [CZP; TNF inhibitor (TNFi) without a crystallizable fragment (Fc)] and adalimumab (ADA; Fc-containing TNFi) in patients with RA. Methods The phase 4 EXXELERATE study (NCT01500278) was a 104-week, randomized, single-blind (double-blind until week 12; investigator-blind thereafter), head-to-head study of CZP vs ADA in patients with RA. In this post hoc analysis, we report drug concentration and efficacy outcomes stratified by baseline RF quartile (≤Q3 or >Q3). Results Baseline data by RF quartiles were available for 453 CZP-randomized and 454 ADA-randomized patients (≤Q3: ≤204 IU/ml; >Q3: >204 IU/ml). From week 12, the area under the curve (AUC) of ADA concentration was lower in patients with RF >204 IU/ml vs patients with RF ≤204 IU/ml; the AUC of CZP concentration was similar in patients with RF ≤204 IU/ml and >204 IU/ml. For patients with RF ≤204 IU/ml, disease activity score (DAS28)-CRP was similar between CZP- and ADA-treated patients through week 104. For patients with RF >204 IU/ml, mean DAS28-CRP was lower in CZP- vs ADA-treated patients at week 104. The proportion of patients with RF >204 IU/ml achieving DAS28-CRP low disease activity at week 104 was greater in CZP- vs ADA-treated patients. Conclusion CZP was associated with maintained drug concentration and efficacy in patients with RA and high RF and may therefore be a more suitable therapeutic option than TNFis with an Fc fragment in these patients. Trial registration Clinicaltrials.gov, http://clinicaltrials.gov , NCT01500278 [ABSTRACT FROM AUTHOR]

Objectives Osteoarticular infection (OAI) is a feared complication of Staphylococcus aureus bacteraemia (SAB) and is associated with poor outcomes. We aimed to explore the risk of OAI and death following SAB in patients with and without rheumatoid arthritis (RA) and to identify risk factors for OAI in patients with RA. Methods Danish nationwide cohort study of all patients with microbiologically verified first-time SAB between 2006–18. We identified RA, SAB, comorbidities, and RA-related characteristics (e.g. orthopaedic implants and antirheumatic treatment) in national registries including the rheumatology registry DANBIO. We estimated the cumulative incidence of OAI and death and adjusted hazard ratios (HRs, multivariate Cox regression). Results We identified 18 274 patients with SAB (n  = 367 with RA). The 90-day cumulative incidence of OAI was 23.1% (95% CI 18.8; 27.6) for patients with RA and 12.5% (12.1; 13.0) for patients without RA (non-RA) [HR 1.93 (1.54; 2.41)]. For RA patients with orthopaedic implants cumulative incidence was 29.4% (22.9; 36.2) [HR 1.75 (1.08; 2.85)], and for current users of tumor necrosis factor inhibitors (TNFi) it was 41.9% (27.0; 56.1) [HR 2.27 (1.29; 3.98) compared with non-users]. All-cause 90-day mortality following SAB was similar in RA [35.4% (30.6; 40.3)] and non-RA [33.9% (33.2; 34.5), HR 1.04 (0.87; 1.24)]. Conclusion Following SAB, almost one in four patients with RA contracted OAI corresponding to a doubled risk compared with non-RA. In RA, orthopaedic implants and current TNFi use were associated with approximately doubled OAI risk. One in three died within 90 days in both RA and non-RA. These findings encourage vigilance in RA patients with SAB to avoid treatment delay of OAI. [ABSTRACT FROM AUTHOR]