Monocytes are circulating immune cells that migrate to inflamed tissues and differentiate into macrophages, where they play a dual role in regulating pro-inflammatory and pro-resolving responses through cytokine and lipid mediator secretion. Platelet-derived microvesicles (PMVs), released during platelet activation, infiltrate inflamed areas and interact with monocytes and macrophages, facilitating the transfer of bioactive contents. While these interactions have been observed, their functional consequences on monocyte/macrophage inflammatory profiles remain poorly understood. In this study, PMVs are shown to be internalized by human THP-1 monocytes. The interaction with THP-1 cells occurs rapidly, with 60 % of cells interacting with PMVs within one hour. When cells are differentiated to M0 and M1 macrophages, interactions with PMVs only peak after 24 h. Interaction of cells with PMVs resulted in an increased capacity to synthesize cyclooxygenase- and lipoxygenase-derived lipid mediators of inflammation, especially in M1 cells. Cytokine production was also influenced in a cell-state-dependent manner. PMVs had no impact on undifferentiated THP-1 cells but enhanced the production of several cytokines in M0 cells as well as IL-23 and IL-6 in M1 macrophages. When stimulated with lipopolysaccharides, PMV-treated M0 macrophages demonstrated elevated production of the anti-inflammatory cytokine IL-10, while M1 macrophages exhibited increased secretion of IL-1β, MCP-1, and IL-6, highlighting an effect on pro-inflammatory cytokine production. These findings reveal that PMVs selectively modulate the inflammatory cytokine and lipid mediator profiles of monocytes and macrophages depending on their differentiation state. This study underscores the role of PMVs as key players in intercellular communication and immune regulation, particularly in the context of inflammation.

Covering: up to early 2025Privileged compound classes of anti-inflammatory natural products are those where there are many reported members that possess anti-inflammatory properties. The identification of these classes is of particular relevance to drug discovery, as they could serve as valuable starting points in developing effective and safe anti-inflammatory agents. The privileged compound classes of natural products include the polyphenols, coumarins, labdane diterpenoids, sesquiterpene lactones, isoquinoline and indole alkaloids, each offering a variety of molecular scaffolds and functional groups that enable diverse interactions with biological targets. From a medicinal chemistry point of view, natural products are both a boon and a bane. The multi-targeting nature of natural products is a boon in the treatment of multi-factorial diseases such as inflammation, but promiscuity, poor potency and pharmacokinetic properties are significant hurdles that must be addressed to ensure these compounds can be effectively used as therapeutics. In addition, there are continued controversies regarding the efficacies of some of these natural products that will continue to polarise their use. In this review, examples of natural products of six privileged compound classes will be discussed for their potential use and possible further development as anti-inflammatory drugs.

Epidemiological studies report inconsistent findings regarding the association between dietary polyunsaturated fatty acid (PUFA) intake and cancer risk. Genetic variations-particularly single-nucleotide polymorphisms (SNPs) in the FADS1 and FADS2 genes-affect PUFA metabolism, linking circulating PUFA levels to the risk of several cancers, including breast, colorectal, prostate, and pancreatic cancers. This review aimed to investigate the relationship between FADS1 and FADS2 gene variants and dietary intake, supplementation, or intervention with omega-3 fatty acids, gamma-linolenic acid (GLA), or their combination in cancer patients. A secondary objective was to examine genetically determined fatty acid profiles-shaped by FADS1 and FADS2 polymorphisms-in cancer patients without intervention and their potential association with PUFA-related cancer risk. A systematic search of the Scopus, PubMed, and Web of Science databases (up to 2024) identified 11 eligible studies out of 298 initial records. Analysis of the available literature suggests that specific FADS genotypes influence long-chain PUFA (LC-PUFA) concentrations in blood and tissues and that altered LC-PUFA levels may contribute to cancer development. The most consistent association identified is between the rs174537 variant and altered PUFA metabolism in prostate and breast cancer. However, conclusive evidence is lacking on the impact of dietary patterns on FADS desaturase activity or expression. Only one study has examined omega-3 supplementation in relation to FADS gene variants in prostate cancer patients, while the effects of GLA supplementation remain unexplored. Given the relative novelty of this research area and the limited number of studies, future investigations should integrate dietary PUFA intake, genetic variation in PUFA-metabolizing enzymes, and potential gene-nutrient interactions involving FADS gene polymorphisms and PUFAs to clarify their role in cancer risk.

Genomic instability is an enabling characteristic that allows cancer cells to acquire additional hallmarks of cancer through the accumulation of alterations in driver genes. Furthermore, it creates opportunities to enhance the sensitivity of cancer cells to chemotherapeutic agents targeting DNA, owing to the presence of incomplete DNA damage repair pathways. This study identifies LIN28B as a crucial regulator of colon cancer cells' sensitivity to DNA damage- or repair-related compounds by promoting genomic instability. LIN28B mechanistically reduces glutathione (GSH) synthesis and activity by inhibiting the expression of four GSH metabolic enzymes (GCLC, G6PD, GSTM4, and GSTT2B), thereby reducing the capacity of cells to eliminate reactive oxygen species (ROS). LIN28B enhances the proinflammatory signaling pathway in cancer cells through the upregulation of ARID3A, a transcription factor that transactivates PTGES and PTGES2, resulting in increased production of PGE2, a key inflammatory mediator that can elevate ROS generation. In conclusion, LIN28B altered the equilibrium of ROS production and elimination in colon cancer, resulting in elevated ROS levels and subsequent genomic instability.

EP2 is a G-protein coupled receptor that is activated by prostaglandin E2 (PGE2). Signaling through the EP2 receptor has been shown to play a key role in various processes involved in diseases such as immune disorders or cancer. A new class of selective EP2 antagonists with an attractive in vitro and in vivo profile has been identified. The amide bond in the original screening hit is replaced by various alternatives. The introduction of an aminopyrimidine scaffold results in excellent potency. Improvement of physicochemical and ADME properties is achieved by incorporation of a carboxylic acid moiety, resulting in lead compound 29 exhibiting drug-like properties.

Prostaglandin E2 (PGE2) signaling via receptors prostaglandin E2 receptor 2 (EP2) and prostaglandin E2 receptor 4 (EP4) is involved in various aspects of cancer and has been shown to promote tumor progression, metastasis, and immune evasion. Inhibition of PGE2 signaling by blockade of the EP2 and EP4 receptors has the potential to counteract the tumor-promoting effects of PGE2. Herein, the discovery of compound 30 (ACT-1002-4271), a dual EP2/EP4 antagonist with single-digit nanomolar potency on both receptors, is presented. The medicinal chemistry strategy is based on fine-tuning of the substitution pattern on an EP2 selective starting point to achieve dual EP2/EP4 antagonism. ACT-1002-4271 demonstrated significant antitumor efficacy in an experimental mammary tumour-6 mouse model when administered subcutaneously.

Low molecular weight chondroitin sulfate (CS) has gained considerable attention for its superior bioactivity compared to native CS. In this study, the mechanisms of low molecular weight chondroitin sulfate from hybrid sturgeon cartilage (LMSCS), prepared using the H2O2/Vc system, on the remission of osteoarthritis (OA) were investigated both in in vitro and in vivo. A Caco-2/SW1353 co-culture cell model and a monosodium iodoacetate (MIA)-induced OA mouse model were used to validate its inhibited apoptosis, anti-inflammatory effects, and intestinal flora modulation. LMSCS was found to effectively alleviate inflammation, decrease chondrocyte apoptosis, and reduce MMP-13 levels by inhibiting the activation of NF-κB and MAPK signaling pathways. Notably, in vivo experiments, LMSCS exhibited significant anti-inflammatory effects compared to SCS. This trend, however, was not observed in vitro, which could be largely attributed to LMSCS' ability to regulate intestinal flora. Compared to SCS, LMSCS enhanced the abundance of beneficial bacteria, particularly, the Prevotellaceae_NK3B31_group and Akkermansia, and increased the levels of short-chain fatty acids such as butyrate and propionate. The effectiveness of LMSCS in mitigating inflammatory responses in vivo is thus largely due to its intestinal flora modulation, providing for its development and application.

A library comprising twenty-four isosteric derivatives of celecoxib substituted with carboxylic acid (labeled as 5a-5x), was synthesized and characterized through 1H NMR, 13C NMR, HRMS, and elemental analysis. Molecular docking studies revealed that all compounds successfully docked into the binding pocket of COX-2, and the introduction of carboxyl group enhances the interaction between the derivatives and COX-2. The compounds were further evaluated for cell toxicity, and in vitro anti-inflammatory activity. Notably, compound 5l exhibited significant inhibition of both COX-2 and NO release in vitro in comparison to the standard compound, displaying the highest selectivity towards the COX-2 enzyme (SI = 295.9) in comparison to celecoxib (SI = 261.3). 5l also exhibited the most potent anti-inflammatory activity and safety (ulcer index = 5.2) in vivo comparable to celecoxib at the same concentration. Through the molecular modeling and dynamics analysis, it was observed that compound 5l effectively stabilized within the active binding site of COX-2 through strong hydrogen bond interactions, and through the ADMET studies investigated the physiochemical properties and drug-likeliness behavior of compound 5l. In conclusion, compound 5l demonstrated to be a potential selective COX-2 anti-inflammatory candidate with reduced gastrointestinal risks.

Chronic inflammation of the intestine is a significant risk factor in the development of colorectal cancer. The emergence of colitis and colorectal cancer is a complex, multifactorial process involving chronic inflammation, immune regulation, and tumor microenvironment remodeling. Macrophages represent one of the most prevalent cells in the colorectal cancer microenvironment and play a pivotal role in maintaining intestinal health and the development of colitis-associated colon cancer (CAC). Macrophages are activated mainly in two ways and resulted in three phenotypes: classically activated macrophages (M1), alternatively activated macrophages (M2). The most characteristic of these cells are the pro-inflammatory M1 and anti-inflammatory M2 types, which play different roles at different stages of the disease. During chronic inflammation progresses to cancer, the proportion of M2 macrophages gradually increases. The M2 macrophages secrete cytokines such as IL-10 and TGF-β, which promote angiogenesis and matrix remodeling, and create the favorable conditions for cancer cell proliferation, infiltration, and migration. Therefore, macrophage polarization has a dual effect on the progression of colitis to CAC. The combination of immunotherapy with reprogrammed macrophages and anti-tumor drugs may provide an effective means for enhancing the therapeutic effect. It may represent a promising avenue for developing novel treatments for CAC. In this review, we focus on the process of intestinal macrophage polarization in CAC and the role of intestinal macrophage polarization in the progression of colitis to colon cancer, and review the immunotherapy targets and relevant drugs targeting macrophages in CAC.

Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a reversible stage of liver disease accompanied by inflammatory cell infiltration. Neutrophils extrude a meshwork of chromatin fibers to establish neutrophil extracellular traps (NETs), which play important roles in inflammatory response regulation. Our previous work demonstrated that NETs promote HCC in MASH. However, it is still unknown if NETs play a role in the molecular mechanisms of liver fibrosis.

Following 12 weeks of Western diet/carbon tetrachloride, MASH fibrosis was identified in C57BL/6 mice with increased NET formation. However, NET depletion using DNase I treatment or mice knocked out for peptidyl arginine deaminase type IV significantly attenuated the development of MASH fibrosis. NETs were demonstrated to induce HSCs activation, proliferation, and migration through augmented mitochondrial and aerobic glycolysis to provide additional bioenergetic and biosynthetic supplies. Metabolomic analysis revealed markedly an altered metabolic profile upon NET stimulation of HSCs that were dependent on arachidonic acid metabolism. Mechanistically, NET stimulation of toll-like receptor 3 induced cyclooxygenase-2 activation and prostaglandin E2 production with subsequent HSC activation and liver fibrosis. Inhibiting cyclooxygenase-2 with celecoxib reduced fibrosis in our MASH model.

Our findings implicate NETs playing a critical role in the development of MASH hepatic fibrosis by inducing metabolic reprogramming of HSCs through the toll-like receptor 3/cyclooxygenase-2/cyclooxygenase-2 pathway. Therefore, NET inhibition may represent an attractive treatment target for MASH liver fibrosis.

The induction of apoptosis in tumor cells is a common target for the development of anti-tumor therapies; however, these therapies still leave patients at increased risk of disease recurrence. For example, apoptotic tumor cells can promote tumor growth and immune evasion via the secretion of metabolites, apoptotic extracellular vesicles, and induction of pro-tumorigenic macrophages. This paradox of apoptosis induction and the pro-tumorigenic effects of tumor cell apoptosis has begged the question of whether apoptosis is a suitable cancer therapy, and led to further explorations into other immunogenic cell death-based approaches. However, these strategies still face multiple challenges, the most critical of which is the tumor microenvironment. Contrary to the promotion of immune tolerance mediated by apoptotic tumor cells, apoptotic bodies with enriched tumor-related antigens have demonstrated great immunogenic potential, as evidenced by their ability to initiate systemic T-cell immune responses. These characteristics indicate that apoptotic body-based therapies could be ideal "in situ" extra-tumoral tumor vaccine candidates for the treatment of cancers, and further address the current issues with apoptosis-based or immunotherapy treatments. Although not yet tested clinically, apoptotic body-based vaccines have the potential to better treatment strategies and patient outcomes in the future.

Novel combinations are required to overcome resistance to immune checkpoint inhibitors in proficient mismatch repair (pMMR) or microsatellite-stable (MSS) metastatic colorectal cancer (mCRC). We aimed to determine whether vorbipiprant, a prostaglandin E2 receptor EP4 subtype antagonist, can convert immune-resistant mCRC into a tumor responsive to anti-PD-1 inhibition.

This phase Ib/IIa prospective, open-label, single-arm trial followed a 3 + 3 dose-escalation and dose-optimization design. A total of 28 patients with chemorefractory pMMR/MSS mCRC were given dose-escalated oral vorbipiprant (30, 90, or 180 mg twice daily), along with biweekly intravenous balstilimab (3 mg/kg), an anti-PD-1 antibody. The primary endpoints included safety and the disease control rate (DCR). Secondary endpoints were the overall response rate, duration of response, progression-free survival, and overall survival.

No dose-limiting toxicities were observed. Of the 28 patients, seven (25%) experienced serious adverse events, but only one was attributed to vorbipiprant and one to balstilimab. The trial achieved a DCR of 50% observed across the entire cohort. In the subgroup of patients with liver metastases (n = 12), the DCR was 25%. The overall response rate was 11%, with three patients showing a partial response (median duration of response, 7.4 months). The median progression-free survival was 2.6 months, and the median overall survival was 14.2 months. Translational exploratory analyses suggested that vorbipiprant may boost response to anti-PD-1 in patients with immunogenic tumors.

The combination of vorbipiprant and a PD-1 inhibitor (balstilimab) yielded sufficient activity in refractory pMMR/MSS mCRC, which is worthy of confirmation in future clinical trials in biomarker-enriched populations.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature and limited therapeutic options. Recent research underscores the pivotal role of G protein-coupled receptors (GPCRs) in shaping the tumor immune microenvironment (TIME) within TNBC. This review focuses on four principal GPCRs-chemokine receptors, sphingosine-1-phosphate receptors, prostaglandin E2 receptors, and lactate receptors-that have garnered substantial attention in TNBC studies. GPCRs modulate immune cell recruitment, polarization, and function, thereby fostering an immunosuppressive milieu conducive to tumor progression and metastasis. The review examines how alterations in GPCR expression on immune cells influence the pathogenesis and advancement of TNBC. Further, it discusses emerging therapeutic strategies targeting GPCR signaling pathways to remodel the immunosuppressive TIME in TNBC. These insights into GPCR-mediated immune regulation not only deepen our comprehension of TNBC's pathophysiology but also offer promising avenues for developing novel immunotherapies aimed at enhancing clinical outcomes for TNBC patients.

Schwannomas are tumors that originate from myelinating Schwann cells and can occur in cranial, spinal, and peripheral nerves. Although our understanding of the molecular biology underlying schwannomas remains incomplete, numerous studies have identified various molecular findings and biomarkers associated with schwannomas of the central nervous system (CNS). The development of these tumors is primarily linked to mutations in the NF2 gene. Merlin, the protein encoded by NF2, is integral to several signaling pathways, including Ras/Raf/MEK/ERK, PI3K/Akt/mTORC1, Wnt/β-catenin, and the Hippo pathway.

Recent research has also uncovered novel genetic alterations, such as the SH3PXD2A::HTRA1 fusion gene, VGLL-fusions in intraparenchymal CNS schwannomas, and the SOX10 mutation particularly in non-vestibular cranial nerve schwannomas. In addition to genetic alterations, research is also being conducted on gene expression and epigenetic regulation, with a focus on NF2 methylation and post-transcriptional silencing by micro RNA. Furthermore, the advent of advanced techniques like single-cell sequencing and multi-omics analysis has facilitated rapid discoveries related to the tumor microenvironment and tumor heterogeneity in schwannomas.

A deeper exploration of these molecular findings could clarify the mechanisms of schwannoma tumorigenesis and progression, ultimately guiding the development of new therapeutic targets. This review offers a comprehensive overview of the current molecular understanding of CNS schwannomas, emphasizing the insights gained from previous research, while addressing existing controversies and outlining future research and treatment perspectives.

The lungs are a mucosal organ constantly exposed to potentially harmful compounds and pathogens. Beyond their role in gas exchange, they must perform a well-orchestrated protective response against foreign invaders. The lungs identify these foreign compounds, respond to them by eliciting an inflammatory response, and restore tissue homeostasis after inflammation to ensure the lungs continue to function. In addition, lung function can be affected by genetics, environmental exposures, and age, leading to pulmonary diseases that infringe on quality of life. Recent studies indicate that diet can influence pulmonary health including the incidence and/or severity of lung diseases. Specifically, long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) have gained attention because of their potential to reduce inflammation and promote resolution of inflammation. Docosahexaenoic acid and eicosapentaenoic acid are 2 potentially beneficial n-3 PUFAs primarily acquired through dietary intake. Here we review current literature examining the role of n-3 PUFAs and the biological mechanisms by which these fatty acids alter the incidence and pathologies of chronic lung diseases including asthma, chronic obstructive pulmonary disease, and interstitial lung disease. We also highlight the role of n-3 PUFAs in vulnerable populations such as pre/postnatal children, those with obesity, and the elderly. Lastly, we review the impact of n-3 PUFA intake and supplementation to evaluate if increasing consumption can mitigate mechanisms driving chronic lung diseases.

Cyperus articulatus L., popularly known as priprioca, is a plant used in the Amazon for perfumed baths and homemade perfumes. In traditional medicine, its rhizomes are used to treat diseases related to inflammatory processes.

Due to its promising bioactive properties, this study sought to investigate its phytochemistry and the anti-inflammatory and antinociceptive activity of the essential oil obtained from C. articulatus (CAEO) in in vitro and in vivo tests.

The essential oil was obtained from the rhizomes of C. articulatus and extraction was carried out via hydrodistillation. Then, the oil was analyzed by GC-MS analyses. Initially, culture of RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS) was used to evaluate cytotoxicity and interference in the production of mediators of the inflammatory process (nitrite, IL-1β, TNF-α and PGE2) after exposure to CAEO. The acute toxicity of CAEO was evaluated and the results were used to define doses of 10, 100 and 400 mg kg-1 for evaluation of CAEO in in vivo tests using mice. The carrageenan-induced air pouch models and the Evans test were used to evaluate the anti-inflammatory activity by measuring the number of total leukocytes and vascular permeability. Antinociceptive activity was evaluated via tests of contortions induced by acetic acid, hot plate, and formalin.

Treatment with CAEO reduced the levels of nitrite IL-1β, TNF-α and PGE2 in the macrophage culture, revealing its anti-inflammatory potential. CAEO decreased carrageenan-induced leukocyte migration and vascular permeability, which are important events related to the acute inflammatory response. Nociceptive activity was significantly inhibited by CAEO in the acetic acid-induced contortions model, hot plate, and in both phases of the formalin test. The treatment with naloxane reversed the antinociceptive effect observed in the formalin test, suggesting the participation of opioid receptors in the mechanism of action of CAEO.

The observed results reveal the anti-inflammatory and antinocipeptive activity of C. articulatus essential oil in vivo and support the traditional use of this plant in the treatment of different diseases involving inflammation and pain.

So far, it has been proven that benign prostatic hyperplasia (BPH) is strongly associated with inflammation resulting from, i.a. the presence of infectious agent, autoimmune disease, aging process and lipid disorders associated with metabolic syndrome (MetS). We analyzed the association between serum eicosanoides (HETE, HODE, lipoxins, prostaglandin, and leucotrien) in aging man with benign prostatic hyperplasia (BPH) and healthy controls. The study involved 219 men (with BPH, n = 144; healthy controls, n = 75). We assessed the content arachidonic and linoleic acid derivatives in the serum samples of the study participants using liquid chromatography (HPLC). The levels of: RvE1 (p < 0.001); LXA4 5S,6R,15R (p = 0.001); 10S,17R-DiDHA (p < 0.001); MaR1 (p = 0.002); 9S-HODE (p < 0.05); 15S-HETE (p < 0.05); 12S-HETE (p < 0.001); 5-oxoETE (p < 0.05) and 5-HETE (p < 0.001) were significantly higher in patients with BPH than in the control group. PGE2 (p = 0.007), LTB4 (p < 0.001), and 18RS-HEPE (p < 0.001) were significantly higher in control group. We also analyzed the relationship between LXA4 5S,6R,15R serum levels of oxidative stress markers and concomitance of MetS. We noticed a relationship between levels and MetS (F1216 = 6.114965, p = 0.01). Our research results suggest that pro-inflammatory mediators and suppressors of inflammation are involved in the development of BPH, but their exact contribution has yet to be investigated.

Inhibiting microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme involved in prostaglandin E2 (PGE2) biosynthesis and tumor microenvironment (TME) homeostasis, is a valuable strategy for treating inflammation and cancer. In this work, 5-methylcarboxamidepyrrole-based molecules were designed and synthesized as new compounds targeting mPGES-1. Remarkably, compounds 1f, 2b, 2c, and 2d were able to significantly reduce the activity of the isolated enzyme, showing IC50 values in the low micromolar range. With the aim of further profiling the synthesized molecules, their ability to interfere with the activity of soluble epoxide hydrolase (sEH), whose inhibition blocks the loss of the anti-inflammatory mediators epoxyeicosatrienoic acids (EETs or epoxyicosatrienoic acids), was investigated in silico and by employing specific biological assays. Among the set of tested compounds, 1f, 2b, 2c, and 2d emerged as mPGES-1/sEH dual inhibitors. Moreover, given that overexpression of mPGES-1 has been observed in many human tumors, we finally explored the biological effect of our compounds in an in vitro model of human colorectal cancer (CRC). The obtained outcomes pave the way for future investigation to optimize and further characterize anticancer pharmacological profile of the carboxamidepyrrole-based molecules.

Globally, cardiovascular diseases (CVDs) remain the leading cause of death, and their prevention and treatment continue to face major challenges. Oxylipins, as novel circulating markers of cardiovascular disease, are crucial mediators linking cardiovascular risk factors such as inflammation and platelet activation, and they play an important role in unraveling cardiovascular pathogenesis and therapeutic mechanisms. Chinese herbal medicine plays an important role in the adjuvant treatment of cardiovascular diseases, which has predominantly focused on the key pathways of classic lipids, inflammation, and oxidative stress to elucidate the therapeutic mechanisms of cardiovascular diseases. However,The regulatory effect of traditional Chinese medicine on oxylipins in cardiovascular diseases remains largely unknown. With the increasing number of recent reports on the regulation of oxylipins by Chinese herbal medicine in cardiovascular diseases, it is necessary to comprehensively elucidate the regulatory role of Chinese herbal medicine in cardiovascular diseases from the perspective of oxylipins. This approach not only benefits further research on the therapeutic targets of Chinese herbal medicine, but also brings new perspectives to the treatment of cardiovascular diseases.

In this study, we investigated a novel anti-cancer drug design approach by revisiting diclofenac-based carborane-substituted prodrugs. The redesigned compounds combine the robust carborane scaffold with the oxindole framework, resulting in four carborane-derivatized oxindoles and a unique zwitterionic amidine featuring a nido-cluster. We tested the anti-cancer potential of these prodrugs against murine colon adenocarcinoma (MC38), human colorectal carcinoma (HCT116), and human colorectal adenocarcinoma (HT29). The tests showed that diclofenac and the carborane-substituted oxindoles exhibited no cytotoxicity, the dichlorophenyl-substituted oxindole had moderate anti-cancer activity, while with the amidine this effect was strongly potentiated with activity mapping within low micromolar range. Compound 3 abolished the viability of selected colon cancer cell line MC38 preferentially through strong inhibition of cell division and moderate apoptosis accompanied by ROS/RNS depletion. Our findings suggest that carborane-based prodrugs could be a promising direction for new anti-cancer therapies. Inhibition assays for COX-1 and COX-2 revealed that while diclofenac had strong COX inhibition, the re-engineered carborane compounds demonstrated a varied range of anti-cancer effects, probably owing to both, COX inhibition and COX-independent pathways.

Microsomal prostaglandin E2 synthase 1 (mPGES-1) is a promising target for treating inflammatory diseases and pain. This study introduces a novel series of benzimidazoles, with the most potent analogs exhibiting IC50 values of 0.27-7.0 nM in a cell-free assay for prostaglandin (PG)E2 production. Compound 44 (AGU654) demonstrated remarkable selectivity for mPGES-1 (IC50 = 2.9 nM) over COX-1, COX-2, 5-LOX, and FLAP, along with excellent bioavailability. Metabololipidomics analysis with activated human monocyte-derived macrophages and human whole blood revealed that AGU654 selectively suppresses PGE2 production triggered by bacterial exotoxins while sparing other prostaglandins. Furthermore, in vivo studies showed that AGU654 significantly alleviated fever, inflammation, and inflammatory pain in preclinical guinea pig models, suggesting that it could be an effective strategy for managing inflammatory diseases. In conclusion, these benzimidazole derivatives warrant further exploration into new and alternative analogs, potentially uncovering novel compounds with a favorable pharmacological profile possessing significant anti-inflammatory and analgesic properties.

The establishment and maintenance of pregnancy encompass a series of complex and high-energy-consuming physiological processes, resulting in a significant energy demand. Fatty acids, one of the most essential nutrients, play a crucial role in energy supply via oxidation and perform critical biological functions such as anti-inflammatory and anti-oxidant effects, which substantially impact human health. Disordered fatty acid metabolism can cause anomalies in fetal growth and development, as well as a range of pregnancy problems, which can influence the health of both the mother and the fetus. In this review, we innovatively explore the relationship between fatty acid metabolism abnormalities and pregnancy complications, emphasizing the potential of dietary interventions with polyunsaturated fatty acids in improving pregnancy outcomes. These findings provide important evidence for clinical interventions and enhance the understanding and practical application of health management during pregnancy.

Pinocembrin (PCB), a flavonoid known for its anti-inflammatory properties, has been approved for various clinical trial applications. To evaluate deeper into the anti-inflammatory potential of the specific enantiomer of natural PCB, we conducted the first investigation into the efficacy of the pure enantiomer (2S)-PCB in modulating inflammatory mediators induced by lipopolysaccharide (LPS) in both murine RAW 264.7 and human U937 macrophage cell lines. This particular compound was isolated from Goniothalamus macrophyllus (Annonaceae), a native plant of Indonesia. This plant has been used traditionally as an herbal medicine to alleviate inflammation. (2S)-PCB was isolated from the stem bark of G. macrophyllus by defatting with n-hexane followed by maceration with methanol. Purification was performed using several chromatographic techniques. The absolute configuration was determined using electronic circular dichroism (ECD) spectroscopy. This compound was then tested for its inhibitory activity on prostaglandin E2 (PGE2) and subjected to docking simulations. The results indicated that (2S)-PCB significantly suppressed the production of PGE2 induced by LPS in both RAW 264.7 and U937 cell lines. The docking simulations revealed that (2S)-PCB reduced PGE2 levels by suppressing mitogen-activated protein kinase (MAPK) activation through inhibiting p38 and extracellular signal-regulated kinases (ERK). These findings suggest that the compound may prevent worsening of septic shock caused by bacterial infection.

There is ongoing exploration into herbal treatments to identify adjunct therapies with minimal side effects. One such treatment involves curcumin from turmeric (Curcuma longa). This study aims to review the efficacy of curcumin as an anti-inflammatory agent for periodontitis along with the mechanisms of action involved.

A systematic review of pre-clinical and clinical studies published on Scopus, PubMed, ScienceDirect, and Google Scholar up to May 2024 was employed following the PRISMA guidelines. Three tools were used for risk of bias assessment, namely the QUIN tool for in vitro studies, the SYRCLE's RoB for in vivo studies, and the Cochrane RoB 2 for RCTs. Finally, nineteen studies were included for review.

This study highlights curcumin's efficacy in addressing periodontitis through diverse mechanisms. Curcumin demonstrated efficacy in attenuating inflammation within periodontal tissue by inhibiting several pro-inflammatory cytokines and mediators such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, matrix metalloproteinases (MMPs), prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, while concurrently increasing IL-4 and IL-10. In addition, several transcription factors such as nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 1 (STAT1) were also inhibited by curcumin. Administration of curcumin has additionally been demonstrated to reduce other biomarkers of periodontitis, including C-reactive protein (CRP), alkaline phosphatase (ALP), and procalcitonin (PCT).

Curcumin has been shown to be effective as an adjunct therapeutic agent for periodontitis due to its anti-inflammatory effects by reducing the inflammatory response through a diverse range of mechanisms of action.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common male urological disease characterized by chronic pelvic pain and various discomforts. Astaxanthin (AST) has multiple functions, including anti-inflammatory property, but it is unclear whether AST plays a key role in CP/CPPS and how it works. This study aimed to investigate the protective effect of AST on CP/CPPS in rats and the underlying mechanism.

A CP/CPPS rat model was induced by intraprostatic injection of carrageenan and the blood specimens and prostates were harvested for further research after oral administration of AST for 4 weeks.

Tactile allodynia test showed that AST ameliorated chronic pelvic pain in a dose-depended manner. In addition, histological evaluation indicated that AST alleviated CP/CPPS rat prostate histological inflammation. Meanwhile, AST suppressed the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α). Besides, AST inhibited the activities of prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2). Furthermore, AST decreased the activation of the nuclear factor-κB (NF-κB) signaling pathway.

Our study has shown that AST exerts an anti-inflammatory and protective effect against CP/CPPS and the function is mediated at least through the suppression of NF-κB signaling pathway. These results provide evidence of AST as the potential agents for the treatment of CP/CPPS.

We reported that Ca2+-independent phospholipase A2β (iPLA2β)-derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4+ and CD8+ T cells are critical in promoting β-cell death, we tested the hypothesis that iDL signaling from these cells participates in T1D development.

CD4+ and CD8+ T cells from wild-type non-obese diabetic (NOD) and NOD.iPLA2β+/- (NOD.HET) mice were administered in different combinations to immunodeficient NOD.scid.

In mice receiving only NOD T cells, T1D onset was rapid (5 weeks), incidence 100% by 20 weeks, and islets absent. In contrast, onset was delayed 1 week and incidence reduced 40%-50% in mice receiving combinations that included NOD.HET T cells. Consistently, islets from these non-diabetic mice were devoid of infiltrate and contained insulin-positive β-cells. Reduced iPLA2β led to decreased production of proinflammatory lipids from CD4+ T cells including prostaglandins and dihydroxyeicosatrienoic acids (DHETs), products of soluble epoxide hydrolase (sEH), and inhibition of their signaling decreased (by 82%) IFNγ+CD4+ cells abundance. However, only DHETs production was reduced from CD8+ T cells and was accompanied by decreases in sEH and granzyme B.

These findings suggest that differential select iDL signaling in CD4+ and CD8+ T cells contributes to T1D development, and that therapeutics targeting such signaling might be considered to counter T1D.

Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a-g, 11a-g and 12a-g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e, 9g and 11f are the most effective derivatives against COX-2 with IC50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC50 = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e, 9g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e, 9g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e, 9g and 11f on both isoenzymes.

Eukaryotic cells contain several membrane-separated organelles to compartmentalize distinct metabolic reactions. However, it has remained unclear how these organelle systems are coordinated when cells adapt metabolic pathways to support their development, survival or effector functions. Here we present OrgaPlexing, a multi-spectral organelle imaging approach for the comprehensive mapping of six key metabolic organelles and their interactions. We use this analysis on macrophages, immune cells that undergo rapid metabolic switches upon sensing bacterial and inflammatory stimuli. Our results identify lipid droplets (LDs) as primary inflammatory responder organelle, which forms three- and four-way interactions with other organelles. While clusters with endoplasmic reticulum (ER) and mitochondria (mitochondria-ER-LD unit) help supply fatty acids for LD growth, the additional recruitment of peroxisomes (mitochondria-ER-peroxisome-LD unit) supports fatty acid efflux from LDs. Interference with individual components of these units has direct functional consequences for inflammatory lipid mediator synthesis. Together, we show that macrophages form functional multi-organellar units to support metabolic adaptation and provide an experimental strategy to identify organelle-metabolic signalling hubs.

Chronic atrophic gastritis (CAG) is a prevalent chronic gastritis usually accompanied by precancerous lesions such as intestinal metaplasia and dysplasia. The increasing application of traditional Chinese medicine in CAG treatment has shown promising results with low side effects and significant efficacy.

To investigate the pharmacological effects of Yiqi Jiedu Huayu decoction (YJHD) on precancerous lesions of CAG.

A CAG rat model was established by Helicobacter pylori bacteria solution combined with N-methyl-N'-nitro-N-nitrosoguanidine. Histopathological measurements were conducted by hematoxylin-eosin and alcian blue and periodic acid-Schiff staining. Serum levels of inflammatory factors and gastric mucosal-related factors were examined using enzyme-linked immunosorbent assay. Protein and mRNA levels were quantified via western blot and quantitative real-time polymerase chain reaction analysis, respectively. Molecular interaction was verified by chromatin immunoprecipitation (ChIP) assay.

YJHD greatly attenuated pathological changes in the gastric mucosa and precancerous lesions in CAG rats. Meanwhile, YJHD treatment reduced serum levels of inflammatory factors [interleukin (IL)-6, tumor necrosis factor-α and C-reactive protein] and increased serum levels of gastric mucosal-related factors (gastrin, pepsin, somatostatin and prostaglandin E2) in CAG rats. In addition, YJHD administration suppressed NLRP3 inflammasome-mediated cell pyroptosis, as well as the activation of TLR4/NF-κB and IL-6/STAT3 signaling pathways. Mechanically, ChIP experiments confirmed that NLRP3 transcription was regulated by TLR4/NF-κB and IL-6/STAT3 signaling.

Taken together, YJHD alleviated NLRP3 inflammasome formation and pyroptosis of epithelial cells in CAG, potentially through the inactivation of TLR4/NF-κB and IL-6/STAT3 pathways.

Elevated levels of prostaglandin E2 have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of cyclooxygenase enzymatic activity, thereby leading to the suppression of prostaglandin E2, are often associated with several side effects due to their non-specific inhibition of cyclooxygenase enzymes. Consequently, the targeted suppression of prostaglandin E2 production with innovative molecules and/or mechanisms emerges as a compelling therapeutic strategy for the treatment of inflammatory-related diseases. Therefore, in this study, a systematic analysis of 28 pyrazole derivatives was conducted to explore their potential mechanisms for reducing prostaglandin E2 levels. In this context, the evaluation of these derivatives extended to examining their capacity to reduce prostaglandin E2in vitro in human whole blood, inhibit cyclooxygenase-1 and cyclooxygenase-2 enzymes, modulate cyclooxygenase-2 expression, and suppress oxidative burst in human leukocytes. The results enabled the establishment of significant structure-activity relationships, elucidating key determinants for their activities. In particular, the 4-styryl group on the pyrazole moiety and the presence of chloro substitutions were identified as key determinants. Pyrazole 8 demonstrated the capacity to reduce prostaglandin E2 levels by downregulating cyclooxygenase-2 expression, and pyrazole-1,2,3-triazole 18 emerged as a dual-acting agent, inhibiting human leukocytes' oxidative burst and cyclooxygenase-2 activity. Furthermore, pyrazole 26 demonstrated effective reduction of prostaglandin E2 levels through selective cyclooxygenase-1 inhibition. These results underscore the multifaceted anti-inflammatory potential of pyrazoles, providing new insights into the substitutions and structural frameworks that are beneficial for the studied activity.

Decreased levels of β-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.

Immunotherapy has been an advanced and effective approach to treating various types of solid tumors in recent years, and the most successful strategy is immune checkpoint inhibitors (ICIs), which have shown beneficial effects in patients with colorectal cancer (CRC). Drug resistance to ICIs is usually associated with CD8+ T-cells targeting tumor antigens; thus, CD8+ T-cells play an important role in immunotherapy. Unfortunately, Under continuous antigen stimulation, tumor microenvironment(TME), hypoxia and other problems it leads to insufficient infiltration of CD8+ T-cells, low efficacy and mechanism exhaustion, which have become obstacles to immunotherapy. Thus, this article describes the relationship between CRC and the immune system, focuses on the process of CD8+ T-cells production, activation, transport, killing, and exhaustion, and expounds on related mechanisms leading to CD8+ T-cells exhaustion. Finally, this article summarizes the latest strategies and methods in recent years, focusing on improving the infiltration, efficacy, and exhaustion of CD8+ T-cells, which may help to overcome the barriers to immunotherapy.

Gain-of-function mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha gene (PIK3CA) is a significant factor in head and neck cancer (HNC). Patients with HNC harboring PIK3CA mutations receive therapeutic benefits from the use of non-steroidal anti-inflammatory drugs (NSAIDs). However, the molecular mechanisms underlying these effects remain unknown. Here, we examined the Detroit562 and FaDu cell lines as HNC models with and without a hyperactive PIK3CA mutation (H1047R), respectively, regarding their possible distinct responses to the NSAIDs celecoxib and sulindac sulfide (SUS). Detroit562 cells exhibited relatively high PI3K/Akt pathway-dependent cyclooxygenase-2 (COX-2) expression, associated with cell proliferation. Celecoxib treatment restricted cell proliferation and upregulated endoplasmic reticulum (ER) stress-related markers, including GRP78, C/EBP-homologous protein, activating transcription factor 4, death receptor 5, and reactive oxygen species (ROS). These effects were much stronger in Detroit562 cells than in FaDu cells and were largely COX-2-independent. SUS treatment yielded similar results. Salubrinal (an ER stress inhibitor) and N-acetyl-L-cysteine (a ROS scavenger) prevented NSAID-induced ROS generation and ER stress, respectively, indicating crosstalk between ER and oxidative stress. In addition, celecoxib and/or SUS elevated cleaved caspase-3 levels, Bcl-2-associated X protein/Bcl-2-interacting mediator of cell death expression, and mitochondrial damage, which was more pronounced in Detroit562 than in FaDu cells. Salubrinal and N-acetyl-L-cysteine attenuated celecoxib-induced mitochondrial dysfunction. Collectively, our results suggest that celecoxib and SUS efficiently suppress activating PIK3CA mutation-harboring HNC progression by inducing ER and oxidative stress and mitochondrial dysfunction, leading to apoptotic cell death, further supporting NSAID treatment as a useful strategy for oncogenic PIK3CA-mutated HNC therapy.

The prostaglandin transporter (PGT, SLCO2A1) mediates transport of prostanoids (a.o. prostaglandin E2 (PGE2)) into cells and thereby promotes their degradation. Overexpression of PGT leads to low extracellular PGE2 levels and has been linked to impaired wound healing of diabetic foot ulcers. Inhibition of PGT could thus be beneficial, however, no PGT inhibitors are currently on the market and drug discovery efforts are hampered by lack of high-through screening assays for this transporter. Here we report on a label-free impedance-based assay for PGT that measures transport activity through receptor activation (TRACT) utilizing prostaglandin E2 receptor subtype EP3 and EP4 that are activated by PGE2. We found that induction of PGT expression on HEK293-JumpIn-SLCO2A1 cells that also express EP3 and EP4 leads to an over 10-fold reduction in agonistic potency of PGE2. PGE2 potency could be recovered upon inhibition of PGT-mediated PGE2 uptake with PGT inhibitors olmesartan and T26A, the potency of which could be established as well. Moreover, the TRACT assay enabled the assessment of transport function of PGT natural variants. Lastly, HUVEC cells endogenously expressing prostanoid receptors and PGT were exploited to study wound healing properties of PGE2 and T26A in real-time using a novel impedance-based scratch-induced wound healing assay. These novel impedance-based assays will advance PGT drug discovery efforts and pave the way for the development of PGT-based therapies.