Endothelial aging is an independent risk factor of cardiovascular diseases, and this study aims to explore the mechanism of endothelial aging. We first applied two animal aging models and two cellular aging models to observe the characteristics of senescent endothelium at the morphological, functional, and molecular levels. It was confirmed that the aging of endothelial cells was accompanied by activation of Nod like receptor protein 3 (NLRP3) inflammasome pathway, reduced levels of hydrogen sulfide (H2S) and sirtuin2 (SIRT2) activity. Endothelial specific knockout of cystathionine-γ-lyase (CSE) led to premature aging of blood vessels, and excessive activation of the SIRT2/NLRP3 inflammasome. Finally, H2S supplementation improved vascular and endothelial cell function, normalized inflammatory cytokine levels, and thereby reversed endothelial aging through SIRT2/NLRP3 mediated pathway. In this study, we found that the decrease in SIRT2 activity in aging endothelial cells increased the level of NLRP3 inflammasome and H2S inhibited inflammation to improve endothelial aging through the SIRT2/NLRP3 pathway. This provided H2S could be a new target for improving endothelial aging, and offered new strategies for defending human aging.

Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a liver disease accompanied by inflammatory cell infiltration. There is growing evidence that insufficient mitophagy can exacerbate inflammation and liver fibrosis (LF). TJ0113 is a novel mitophagy inducer. The study aimed to explore the role of TJ0113 in ameliorating fibrosis in MASH and its mechanisms.

A high-fat diet (HFD)-induced MASH mice model and a transforming growth factor (TGF)-β1-induced LX-2 cells model were used, and then they were treated with TJ0113. Changes in hepatocyte damage were observed using electron microscopy. Expression of key molecules related to mitophagy, mitochondrial damage and inflammation in liver was detected by immunofluorescence staining (IF), immunohistochemistry (IHC) and western blotting (WB).

TJ0113 induces mitophagy through parkin/PINK1 and ATG5 signaling pathways and reduces lipid accumulation, inflammation and fibrosis in the liver of MASH mice. TJ0113 attenuated hepatic injury and lowered serum ALT, AST, TC and TG levels. TJ0113 reduced pro-inflammatory factors (IL-1β, IL-6, TNF-α), TGF-β1/Smad pathway activation and typical fibrosis-related molecules (α-SMA, Collagen-1) expression. In addition, NF-κB/NLRP3 signaling pathway activation after MASH was significantly attenuated by enhanced Mitophagy. We found that TJ0113 was able to effectively and safely induce mitophagy in vitro and reduce TGF-β1/Smad signaling and downstream pro-fibrotic responses in TGF-β1-treated LX-2 cells.

TJ0113 enhances mitophagy to inhibit lipid accumulation, inflammation and fibrosis formation in MASH, and is a candidate for MASH treatment.

Inflammation is a complex, tightly regulated process involving biochemical and cellular reactions to harmful stimuli. Often termed "the internal fire", it is crucial for protecting the body and facilitating tissue healing. While inflammation is essential for survival, chronic inflammation can be detrimental, leading to tissue damage and reduced survival. The innate immune system triggers inflammation, closely linked to the development of heart diseases, with significant consequences for individuals. Inflammation in arterial walls or the body substantially contributes to atherosclerotic disease progression, affecting the cardiovascular system. Altered lipoproteins increase the risk of excessive blood clotting, a hallmark of atherosclerotic cardiovascular disease and its complications. Integrating inflammatory biomarkers with established risk assessment techniques can enhance our ability to identify at-risk individuals, assess their risk severity, and recommend appropriate CVD prevention strategies. Exosomes, a type of extracellular vesicle, are released by various cells and mediate cell communication locally and systemically. In the past decade, exosomes have been increasingly studied for their vital roles in health maintenance and disease processes. They can transport substances like non-coding RNAs, lipids, and proteins between cells, influencing immune responses and inflammation to elicit harmful or healing effects. This study focuses on the critical role of inflammation in heart disease progression and how non-coding RNAs in exosomes modulate the inflammatory process, either exacerbating or alleviating inflammation-related damage in the cardiovascular system.

Funding Pyroptosis is a type of programmed cell death (PCD) pathway distinguished by inflammation. It is activated by specific inflammasomes. Once activated, it causes the physical breakdown of the cell, along with the discharge of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). Abundant evidence has demonstrated the existence of pyroptotic cell death within atherosclerotic plaques, which has significance for the development of atherosclerosis (AS). As a result, pyroptosis has become a new and important topic in cardiovascular disease (CVD) research. Cholesterol, it is recognized to have a connection with inflammation, exerts a crucial function in the development process of AS, and has been linked to the initiation of pyroptosis. This review aims to briefly summarize the fundamental aspects of pyroptosis and the influence of cholesterol-related inflammation in AS. Additionally, this review will explore potential therapeutic approaches based on pyroptosis that could be utilized for the prevention and treatment of AS.

Inflammatory bowel disease (IBD) is an inflammatory disease of the intestine whose primary pathological presentation is the destruction of the intestinal epithelium. The intestinal epithelium, located between the lumen and lamina propria, transmits luminal microbial signals to the immune cells in the lamina propria, which also modulate the intestinal epithelium. In IBD patients, intestinal epithelial cells (IECs) die dysfunction and the mucosal barrier is disrupted, leading to the recruitment of immune cells and the release of cytokines. In this review, we describe the structure and functions of the intestinal epithelium and mucosal barrier in the physiological state and under IBD conditions, as well as the patterns of epithelial cell death and how immune cells modulate the intestinal epithelium providing a reference for clinical research and drug development of IBD. In addition, according to the targeting of epithelial apoptosis and necroptotic pathways and the regulation of immune cells, we summarized some new methods for the treatment of IBD, such as necroptosis inhibitors, microbiome regulation, which provide potential ideas for the treatment of IBD. This review also describes the potential for integrating AI-driven approaches into innovation in IBD treatments.

The blue light from the digital screens endangers the visual system among which the corneas at the outmost of eyes are vulnerable to the irradiation. Therein, the human corneal endothelial (HCE) cells are crucial to maintain corneal transparency and their damage leads to HCE decompensation resulting in blindness ultimately. Thus, understanding the phototoxic effects of the blue light on the HCE cells and the underlying mechanisms is important for taking measures to protect the vision clarity from the blue-light hazard.

We pulse-irradiated the HCE cell line cells at logarithmic phase for 3 passages using 440 nm blue light and examined the levels of reactive oxygen species (ROS), ATP, nicotinamide adenine dinucleotide (NAD+) and autophagy using cytochemistry assay to investigate the alterations of energy metabolism. Moreover, we examined the γH2AX+ cells using immunofluorescence and expression of poly(ADP-Ribose)polymerase1 (PARP1) using western blotting to investigate the degrees of DNA damage and repair. We also monitored the levels of inflammasome using western blotting and senescence associated secretory phenotypes (SASPs) of interleukin (IL)-8, IL-1β and IL-6 using qPCR and ELISA to investigate the inflammasome assembly and secretion of SASPs. We detected the senescent features with senescence-associated-β-galactosidase assay, p16 levels by western blotting, Lamin B1 localization by immunofluorescence observation, cell growth by EdU incorporation assay and confluence forming time and alterations of the cell morphology and relative areas by microscopy observation.

The HCE cells exhibited senescent features after blue-light-pulse-irradiation. The blue light provokes overproduction of ROS to decrease the levels of ATP, NAD+ and autophagy leading to energy crisis. Moreover, the excess ROS injure DNA and downregulate PARP1 resulting in stable cell-cycle arrest. The excess ROS also facilitate inflammasome assembly leading to hypersecretion of SASPs.

The blue light elicits HCE cell senescence via inducing energy crisis, stable cell-cycle arrest and SASP hypersecretion.

Irisin is a hormone-like peptide secreted by muscle tissues and generated by hydrolysis of type III fibronectin domain-containing protein 5 by proteolytic hydrolases. Whether Irisin has a potential protective role in traumatic brain injury (TBI). In this study, we will investigate the relevant research progress of Irisin's protective role in traumatic brain injury (TBI) in recent years in terms of attenuating oxidative stress, inhibiting pyroptosis, suppressing inflammatory response, and improving autophagy, with the aim of providing valuable references for the diagnosis and treatment of traumatic brain injury (TBI). Utilize bioinformatics analysis to study the interactions between genes in TBI (Traumatic Brain Injury). Construct a TBI mouse model to observe the effects of Irisin on TBI. The Morris water maze test is used to assess the learning and spatial memory abilities of mice, TUNEL fluorescence is used to detect cell apoptosis, Nissl staining is employed to observe the survival of hippocampal neurons in mice, and HE staining is used to observe the extent of brain injury in mice. Western blot is used to detect protein expression in both in vivo and in vitro experiments. Q-PCR is employed to detect the levels of proteins related to autophagy/pyroptosis/inflammation. Irisin promotes MerTK overexpression by enhancing AMPK activation. Irisin can increase the expression of LC3I and Beclin-1 proteins, indicating the promotion of autophagic response. Additionally, Irisin reduces ROS levels and decreases SYK expression, thereby inhibiting the inflammatory response. Irisin improves the learning and spatial memory abilities of TBI mice and reduces cell apoptosis, as well as decreases hippocampal neuron death. HE staining shows that the brain injury in mice treated with Irisin is significantly alleviated. Irisin can enhance the expression of phosphorylated AMPK and phosphorylated MerTK proteins, promote autophagic response, and inhibit pyroptosis/inflammatory response. Correction experiments confirmed that after stimulation with an AMPK agonist, the expression of phosphorylated MerTK protein is significantly increased, autophagic response is enhanced, and pyroptosis/inflammatory response is weakened. When treated with a MerTK inhibitor during AMPK agonist stimulation, the autophagic response is weakened while pyroptosis/inflammatory response is enhanced. Irisin can inhibit the progression of traumatic brain injury by regulating AMPK/MerTK/autophagy and SYK/ROS/inflammatory signaling.

Macrophages are innate immune cells distributed throughout the body that play vital roles in organ development, tissue homeostasis, and immune surveillance. Macrophages acquire a binary M1/M2 polarized phenotype through signaling cascades upon sensing different signaling molecules in the environment, thereby playing a core role in a series of immune tasks, rendering precise regulation essential. M1/M2 macrophage phenotypes regulate inflammatory responses, while controlled activation of inflammatory signaling pathways is involved in regulating macrophage polarization. Among the relevant signaling pathways, we focus on the six well-characterized NF-κB, MAPK, JAK-STAT, PI3K/AKT, inflammasome, and cGAS-STING inflammatory pathways, and elucidate their roles and crosstalk in macrophage polarization. Furthermore, the effects of many environmental signals that influence macrophage polarization are investigated by modulating these pathways in vivo and in vitro. We thus detail the physiological and pathophysiological status of these six inflammatory signaling pathways and involvement in regulating macrophage polarization in cancer and beyond, as well as describe potential therapeutic approaches targeting these signaling pathways. In this review, the latest research advances in inflammatory signaling pathways regulating macrophage polarization are reviewed, as targeting these inflammatory signaling pathways provides suitable strategies to intervene in macrophage polarization and various tumor and non-tumor diseases.

Renal ischemia-reperfusion injury (RIRI) is a condition characterized by inflammation and cell damage in the kidneys following a period of ischemia and subsequent reperfusion, which lacks effective treating method in the clinic. Exploring molecular mechanisms holds profound significance in guiding the clinical prevention and treatment of RIRI. Herein, the potential function of Forkhead box C1 (FOXC1), a protein belongs to FOX family, in I/R-induced injury in renal tubular epithelial cells (RTECs) was studied to explore potential targets for RIRI. FOXC1 was upregulated in RIRI rats, expressions of which were elevated as time prolonged. FOXC1-overexpressed or knockdown HK-2 cells were constructed, followed by I/R stimulation. FOXC1 was found markedly upregulated in I/R-stimulated HK-2 cells. Notably repressed cell viability, enhanced apoptosis, increased release of inflammatory cytokines, boosted reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and inactivated superoxide dismutase (SOD) enzyme were observed in I/R-stimulated HK-2 cells, which were sharply reversed by silencing FOXC1 and aggravated by overexpression FOXC1. Furthermore, largely increased levels of NLRP3, caspase-1, GSDMD-N, IL-18, IL-1β, and p-p65/p65 were observed in I/R-stimulated HK-2 cells, which were notably suppressed by silencing FOXC1 and further elevated by overexpression FOXC1. Additionally, FOXC1-overexpressed HK-2 cells were stimulated by I/R with or without 10 μM MCC950, an inhibitor of NLRP3. The enhanced apoptosis, triggered inflammation, and facilitated ROS by FOXC1 overexpression in I/R-stimulated HK-2 cells were remarkably abolished by the coculture of MCC950, accompanied by an inhibition on the NF-κB/NLRP3 signaling. Collectively, FOXC1 aggravated the I/R induced injury in RTECs by activating NF-κB/NLRP3 signaling.

Gentiana scabra Bunge (Gentian) is a traditional medicinal plant valued for its anti-inflammatory and analgesic effects, with historical use in treating atopic dermatitis. Despite its therapeutic reputation, a comprehensive scientific analysis of its constituents is lacking. This study systematically evaluates the anti-inflammatory effects of Gentian extract and explores its molecular mechanisms. We characterized the chemical profile of Gentian extracts using HPLC and assessed their anti-inflammatory activity in zebrafish and cellular models. Gentian extract significantly reduced inflammation, as shown by decreased neutrophil migration in response to sodium lauryl sulfate (SLS), reduced tail wagging in zebrafish embryos, and alleviated lipopolysaccharide (LPS)-induced edema. It also lowered reactive oxygen species (ROS) and malondialdehyde (MDA) levels, indicating antioxidant properties, and downregulated pro-inflammatory cytokines and genes. In LPS-stimulated RAW264.7 cells, the extract upregulated IκBα and reduced p65 and STAT3 phosphorylation, inhibiting NF-κB and JAK-STAT pathways. This study is the first to systematically evaluate the anti-inflammatory mechanisms of Gentian extract in zebrafish and RAW264.7 cell models, enhancing its understanding and providing a scientific basis for its application in anti-inflammatory products.

An imbalance in microglial polarization plays an important role in the pathogenesis of neuropathic pain. PPARγ coactivator-1α (PGC-1α), a master coregulator of gene expression in mitochondrial biogenesis, is related to microglial polarization. However, the underlying mechanism involved is poorly understood.The aim of the present study was to explore the role of PGC-1α in regulating microglial polarization through a feedback loop between reactive oxygen species (ROS)-mediated mitochondrial dysfunction and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model of chronic constriction injury (CCI).

we quantified pain behaviour after CCI; analysed the localization of PGC-1α and the changes in the expression of CD68 (an M1 microglial marker)/IBA1 and ARG1 (an M2 microglial marker)/IBA1 in the dorsal horn (DH) via immunofluorescence. Western blotting and immunofluorescence were used to examine the expression of target proteins. Quantitative real-time PCR (qPCR) was used to investigate the mitochondrial DNA copy number (mtDNA). ROS production was measured via dihydroethidium (DHE). SOD activity and the MDA content were measured via SOD and MDA assay kits, respectively. In addition, tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and IL-10 levels were measured via enzyme-linked immunosorbent assay (ELISA).

The results revealed ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome activation, microglia phenotype from the M2 to the M1 phenotype in the CCI rats.Interesting, ROS-mediated mitochondrial dysfunction is one of the critical mediators of NLRP3 inflammasome activation.NLRP3 inflammasome in turn cause ROS production and mitochondrial dysfunction, suggesting for the first time a feedback loop between ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome in the neuropathic pain.The activation of PGC-1α shifts the microglial phenotype via the modulation of a feedback loop between ROS-mediated mitochondrial dysfunction and the NLRP3 inflammasome.

These findings indicate that activation of PGC-1α could be a potential therapeutic approach to ameliorate neuropathic pain.

The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis, but its role in self-DNA-mediated inflammation in acute kidney injury (AKI) is not well understood. Here, our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients. This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome. While inhibition of the STING pathway only slightly attenuates AKI progression, suppression of NLRP3 inflammasome-mediated pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice. Subsequently, we found that Tnfaip3 (encoding A20) is significantly upregulated following oxidized self-DNA treatment. A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated pyroptosis. Moreover, A20-derived peptide (P-II) also significantly alleviates ox-dsDNA-induced pyroptosis and improves the survival and renal injury of AKI mice. Mechanistically, A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome. A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7. Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex. Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models. This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.

Recent investigations into the mechanisms underlying inflammation have highlighted the pivotal role of immune cells in regulating cardiac pathophysiology. Notably, these immune cells modulate cardiac processes through alternations in intracellular metabolism, including glycolysis and oxidative phosphorylation, whereas the extracellular metabolic environment is changed during cardiovascular disease, influencing function of immune cells. This dynamic interaction between immune cells and their metabolic environment has given rise to the novel concept of "immune metabolism". Consequently, both the extracellular and intracellular metabolic environment modulate the equilibrium between anti- and pro-inflammatory responses. This regulatory mechanism subsequently influences the processes of myocardial ischemia, cardiac fibrosis, and cardiac remodeling, ultimately leading to a series of cardiovascular events. This review examines how local microenvironmental and systemic environmental changes induce metabolic reprogramming in immune cells and explores the subsequent effects of aberrant activation or polarization of immune cells in the progression of cardiovascular disease. Finally, we discuss potential therapeutic strategies targeting metabolism to counteract abnormal immune activation.

Nuclear factor-κB (NF-κB) constitutes a family of transcription factors that serve as a critical regulatory hub, dynamically orchestrating inflammatory and immune responses to maintain homeostasis and protect against pathogenic threats. Persistent activation of NF-κB has been implicated in the pathogenesis of various inflammatory diseases and cancer. A critical mechanism to prevent excessive inflammation and its harmful effects is the timely termination of NF-κB's transcriptional activity on target genes. This termination can be facilitated through the ubiquitination and subsequent proteasomal degradation of chromatin-bound RelA, the most active subunit of NF-κB. Several multi-subunit cullin-RING E3 ubiquitin ligases, composed of elongin B/C, cullin2/5, and SOCS-box proteins, have been identified to target RelA for degradation. These E3s, known as ECS complexes, use SOCS-box proteins as substrate-recognizing subunits to engage RelA. SOCS1 is the first identified SOCS-box member that functions in ECSSOCS1 to target chromatin-bound RelA for ubiquitination. Specifically, SOCS1 collaborates with accessory proteins COMMD1 and GCN5 to preferentially recognize Ser468-phosphorylated RelA. Our recent work demonstrates that WSB1 and WSB2 (WSB1/2), two additional SOCS-box proteins with structurally similar WD40 repeat domains, function as substrate-recognizing subunits of ECSWSB1/2 to specifically mediate the ubiquitination and degradation of chromatin-associated RelA methylated at Lys314/315. In this review, we summarize the discovery and functional importance of ECSSOCS1 and ECSWSB1/2 in terminating NF-κB activity, highlight the distinct molecular mechanisms by which they ubiquitinate chromatin-associated RelA in a modification- and gene-specific manner, and discuss their potential as therapeutic targets for inflammatory diseases and cancer.

The high-sensitivity C-reactive protein to albumin (CAR) ratio is a comprehensive measure of inflammation in vivo. Hepatic steatosis and fibrosis are significantly correlated with inflammation. The present study aimed to explore the possible associations between CAR and hepatic steatosis and fibrosis in the American population.

The study population involved the National Health and Nutrition Examination Survey (NHANES) participants from 2017 to 2020. The natural logarithm of CAR, calculated as Ln(CAR) with base "e," was used for further analyses. The relationships between Ln(CAR) and the controlled attenuation parameter (CAP) and between Ln(CAR) and liver stiffness measurement (LSM) were investigated through multivariate linear regression analysis. Interaction and subgroup analysis identified factors affecting these variables. Nonlinear relationships were elucidated by smoothing curves and threshold effect analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance of the CAR for non-alcoholic fatty liver disease (NAFLD). The results were adjusted for U.S. population estimates.

The study included a total of 7,404 individuals. Ln(CAR) was positively correlated with CAP in the fully adjusted model, with an effect value of β = 1.827 (95% CI, 0.611, 3.042). A more pronounced positive association was observed among participants with a BMI ≥ 25 kg/m2 in the subgroup analysis. An inverted U-shaped association was shown between Ln(CAR) and CAP through smooth curve fitting and a two-segment linear regression model, with an inflection point of (-9.594). ROC curve analysis showed that CAR had a moderate predictive value for NAFLD (AUC = 0.6895), with a sensitivity of 0.7276 and a specificity of 0.6092. No significant association was detected between Ln(CAR) and the LSM.

We demonstrate an inverted U-shaped relationship between Ln(CAR) and CAP risk within the U.S. demographic. Our results suggest that CAR may serve as a valuable diagnostic tool for NAFLD. Further prospective research is necessary to validate this conclusion.

The vascular aging process accelerated by type 2 diabetes mellitus (T2DM) is responsible for the elevated risk of associated cardiovascular diseases. Metabolic disorder-induced immune senescence has been implicated in multi-organ/tissue damage. Herein, we sought to determine the role of immunosenescence in diabetic vascular aging and to investigate the underlying mechanisms.

Aging hallmarks of the immune system appear prior to the vasculature in streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM mice or db/db mice. Transplantation of aged splenocytes or diabetic splenocytes into young mice triggered vascular senescence and injury compared with normal control splenocyte transfer. RNA sequencing profile and validation in immune tissues revealed that the toll-like receptor 4-nuclear factor-kappa B-NLRP3 axis might be the mediator of diabetic premature immunosenescence. The absence of Nlrp3 attenuated immune senescence and vascular aging during T2DM. Importantly, senescent immune cells, particularly T cells, provoked perivascular adipose tissue (PVAT) dysfunction and alternations in its secretome, which in turn impair vascular biology. In addition, senescent immune cells may uniquely affect vasoconstriction via influencing PVAT. Lastly, rapamycin alleviated diabetic immune senescence and vascular aging, which may be partly due to NLRP3 signalling inhibition.

These results indicated that NLRP3 inflammasome-mediated immunosenescence precedes and drives diabetic vascular aging. The contribution of senescent immune cells to vascular aging is a combined effect of their direct effects and induction of PVAT dysfunction, the latter of which can uniquely affect vasoconstriction. We further demonstrated that infiltration of senescent T cells in PVAT was increased and associated with PVAT secretome alterations. Our findings suggest that blocking the NLRP3 pathway may prevent early immunosenescence and thus mitigate diabetic vascular aging and damage, and targeting senescent T cells or PVAT might also be the potential therapeutic approach.

Chronic neuroinflammation is a consequence of disease pathogenesis underlying neurological disorders at large. While the immune response that triggers inflammatory signaling cascades is unresolved, its progression could cause functional damage to neurons and glial cells, including astrocytes, microglia, and oligodendrocytes. Controlling neuroinflammatory signaling at the early stage of disease pathogenesis is critical to prevent irreversible tissue necrosis. While the application of anti-inflammatory drugs is standard practice, their protracted use is known to cause gastrointestinal injuries, further enhancing the risk of cardiovascular, renal, liver, and lung diseases. Several medicinal herbs and herbal products with anti-inflammatory potential could be effective substitutes. This review aims to identify the preclinical data from important dietary herbal products that have demonstrated anti-neuroinflammatory efficacy in several animal models. The reviewed dietary herbal products are sourced from Bacopa monnieri, Centella asiatica, Emblica officinalis, Piper nigrum, Zingiber officinale, Punica granatum, Mucuna pruriens, Clitoria ternatea, Moringa oleifera, Phoenix dactylifera and Curcuma longa. This review is based on emphatic data from these products demonstrating the significant anti-neuro-inflammatory potential that could probably reduce neuroinflammatory signaling in a neurological disorder and promote brain health and well-being. Abundant scientific evidence shows that critical proinflammatory cytokines in the brain, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-six (IL-6), could be controlled through regular consumption of such dietary herbal products without debilitating side effects for their disease-modifying impacts.

Osteoporosis (OP) is a common systemic metabolic bone disease characterized by the decrease in bone mass and hyperactivity of osteoclasts. ACT001 is approved as an orphan drug by FDA and has shown multiple protective effects against tissue injury. However, its role in prevention of osteoclast differentiation and the underlying mechanisms have not been elucidated. Herein, we show that ACT001 inhibited RANKL-induced osteoclast differentiation and F-actin ring formation through suppressing the expression of Nfatc1, TRAP, Ctsk, Dc-stamp without obvious cytotoxicity in vitro. ACT001 restrained the phosphorylation of NF-κB and the activation of NLRP3 inflammasome, thereby decreased the expression of pyroptosis-related protein. (GSDMD, caspase-1, IL-1β, IL-18). Consistent with ACT001, the NLRP3 inflammasome inhibitor MCC950 treatment also suppressed the osteoclastogenesis through inhibiting the transcriptional activation of Nfatc1. Furthermore, ACT001 protected ovariectomy-induced bone loss in mice, reduced the number of osteoclasts, downregulated the expression of NLRP3 and IL-1β. These data indicate that ACT001 can reduce RANKL-induced osteoclast differentiation through suppressing the NF-κB/NLRP3 pathway, and attenuate the bone loss induced by estrogen-deficiency, suggesting its therapeutic potential for bone homeostasis maintenance and osteoporosis treatment.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The etiology of UC is multifaceted, and the underlying pathogenesis remains incompletely understood. Pyroptosis, programmed cell death mediated by the gasdermins, is a pivotal driver of UC pathology due to its dual role in epithelial barrier disruption and inflammatory amplification. We previously showed that phenethyl isothiocyanate (PEITC), an isothiocyanate derived from cruciferous vegetables, alleviated acute liver injury in mice by suppressing hepatocyte pyroptosis. In this study we evaluated the therapeutic potential of PEITC in the treatment of UC and the underlying mechanisms. UC mouse models were established by administration of 2.5% (w/v) dextran sulfate sodium (DSS) daily for 7 days. PEITC (5, 10, or 20 mg·kg-1·d-1, i.g.) was given 2 days before the start of modeling, and the dosing lasted for a total of 10 days. We showed that during the progression of DSS-induced UC, the pyroptosis pathway was activated accompanied by elevated expression levels of thioredoxin-interacting protein (TXNIP) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), as well as the activation of caspase-1, gasdermin D (GSDMD) and interleukin-1β (IL-1β). Treatment with PEITC dose-dependently reduced TXNIP and NLRP3 expression while inhibiting the cleavage of proteins associated with the pyroptosis pathway such as caspase-1, GSDMD, and IL-1β. We confirmed the inhibitory effect of PEITC on colonocyte pyroptosis in an in vitro model established in HT29 cells, where PEITC (0.2, 1, 5 µM) dose-dependently inhibited TXNIP and NLRP3 expression and the activation of pro-caspase-1, GSDMD and pro-IL-1β. We revealed that PEITC is directly bound to TXNIP and disrupted the interaction between TXNIP and NLRP3, leading to diminished cellular inflammation and oxidative stress levels. In conclusion, this study demonstrates that PEITC disrupts the interaction of TXNIP and NLRP3 by binding to TXNIP, inhibits NLRP3 activation and colonocyte pyroptosis, and thus effectively alleviates UC symptoms in mice. This study offers novel drug targets along with potential therapeutic candidates for the clinical prevention and treatment of UC.

Mounting evidence suggests that neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Amyloid β peptide (Aβ) could recruit and activate microglia, leading to the generation of pro-inflammatory factors, and ultimately neuroinflammation. Chitooligosaccharide (COS) is widely recognized as anti-inflammation bioactive substance, though whether it exerts beneficial effect on AD is unclear. In this study, we explored the effect of COS on AD prevention and treatment. We found that COS ameliorated cognitive deficiency, increased the expression of Nrf2 but decreased Aβ levels and the activation of NF-κB in APP/PS1 mice. In vitro, COS decreased the secretions of IL-6, IL-1β and TNF-α in Aβ25-35 + lipopolysaccharides (LPS) -exposed BV2 microglia. Meanwhile, COS down-regulated the expressions of iNOS, COX-2, NLRP3, caspase 1 and the nuclear translocation of NF-κB p65, while upregulated the expressions of Nrf2 and HO-1. Further, COS improved the viability of SK-N-SH cells that exposed to Aβ25-35 + LPS-stimulated microglial conditioned media, and the repressive effect of COS on NLRP3, iNOS, and phospho-NF-κB p65 expressions were markedly compromised upon Nrf2-siRNA transfection. Collectively, COS improved cognitive decline and suppressed neuroinflammation via the Nrf2/NF-κB signaling axis, suggesting COS might be a promising candidate in down-regulating inflammatory responses during AD progression.

Terpenoids are important components that exert pharmacological effects in Rubiaceae plants. In this study, two Rubiaceae plants, Nauclea officinalis and Paederia scandens, which are widely distributed in Hainan, China, were collected. The extracts of these two plants were obtained through boiling water extraction and analyzed using UHPLC-ESI-QE-Orbitrap-MS. By comparing with the mzCloud database, terpenoids with a matching rate of 85 % were identified. The results revealed that the aqueous extracts of N. officinalis mainly contain six pentacyclic triterpenoids, one diterpenoid, and one iridoid. The aqueous extracts of P. scandens contains one monoterpenoid, one diterpenoid, two pentacyclic triterpenes, and 4 iridoids. To verify the anti-inflammatory efficacy of the two extracts, in this study, they were added to the lipopolysaccharide (LPS)-induced RAW264.7 macrophages inflammation model. The results showed that the two extracts can reduce the secretion of proinflammatory cytokines IL-1β, IL-6, and TNF-α (p < 0.05) and the mortality rate of cell inflammation (p < 0.05) by inhibiting the activation of the NF-κB/NLRP3 pathway (p < 0.05). The study identified the terpenoids in N. officinalis and P. scandens and verified their anti-inflammatory effects in the RAW264.7 macrophages inflammation model.

More than 300 genomic loci have been associated with increased susceptibility to inflammatory bowel disease (IBD) through genome-wide association studies. A major challenge in the translation of genome-wide association studies to mechanistic insights lies in connecting noncoding variants to function. For example, single-nucleotide variants (SNVs) in the vicinity of the gene encoding the transcription factor ETS2 on human chromosome 21 are associated with the risk of developing IBD in Europeans. The peak of SNV association lies within a distal enhancer that may regulate ETS2 transcription. The interpretation of this and many other SNV associations with IBD depends on a model linking variation in transcriptional regulation to the likelihood of developing chronic intestinal inflammation. One model for the ETS2 locus is that overexpression in monocytes is causally associated with the risk allele, which in turn leads to a hyperinflammatory state. Here we summarize evidence for an alternative mechanism focused on negative regulators of monocyte-macrophage activation. We argue that IBD susceptibility arises from dysregulation of monocyte adaptation in the intestinal milieu to form resident intestinal macrophages that are anergic to inflammatory stimuli. This process depends on signals initiated by macrophage colony-stimulating factor (CSF1) binding to its receptor (CSF1R). Within this framework, ETS2 is a myeloid-specific transcription factor, expressed in pluripotent and committed progenitors and monocytes, and is down-regulated by CSF1, in common with many genes associated with IBD susceptibility, including NOD2. ETS2 is also both a downstream target and a mediator of the CSF1/CSF1R signaling pathway. Therapeutic targeting of ETS2 and its upstream regulators has the potential to prevent CSF1-dependent monocyte differentiation toward a prorepair resident macrophage phenotype and consequently exacerbate intestinal inflammation.

Exposure to metals can trigger a series of diseases by dysregulating the human immune system, but there is still a lack of systematic studies assessing the independent and combined effects of exposure to metals on immune function in the general population, particularly concerning inflammation markers. This cross-sectional study was designed to mainly examine the associations between urinary metal mixtures and inflammatory markers, including white blood cell (WBC), platelet count (PLT), mean platelet volume (MPV), MPV/PLT ratio (MPR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). A total of 3451 participants aged ≥20 years were selected from the 2013-2016 National Health and Nutrition Examination Survey. Generalized linear models were used to investigate the relationships of exposure to single metals on inflammatory markers. Associations between coexposure to multiple metals and inflammatory markers were determined using weighted quantile sum regression and quantile g-computation. Barium, cadmium, lead, thallium, and cobalt showed significant associations with MPV, PLR, and NLR. Metal mixtures showed a negative association with MPV, while they had positive associations with PLR and NLR. Overall, our study highlights the significant effects of multiple metals exposure on inflammation markers, including MPV, PLR, and NLR, among U.S. adults. Thereinto, uranium, cadmium, and cobalt were identified as major contributors. Further prospective studies representative of other countries are warranted to either validate or refute our findings.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by diverse clinical manifestations, including joint symptoms. Arthritis represents one of the earliest manifestations of SLE, profoundly affecting the quality of life for affected individuals, yet the underlying mechanisms of SLE-associated arthritis remain insufficiently investigated. The study aimed to investigate the impact of SLE exacerbation on arthritis using the MRL/lpr mouse model, which closely mimics human SLE manifestations.

In the present study, we evaluated the impact of SLE onset on knee joint degeneration by comparing arthritic phenotype and complex molecular alterations between 6 female 14-week-old MRL/lpr mice, which manifest SLE, and MRL/MpJ mice, which remain unaffected.

Our results demonstrated that MRL/lpr mice exhibited a more severe arthritic phenotype compared to MRL/MpJ mice, characterized by elevated Osteoarthritis Research Society International (OARSI) scores (P < 0.01), disrupted extracellular matrix metabolism, impaired chondrocyte proliferation and increased apoptosis. Notably, inflammatory cytokines proteins such as IL-1β and TNF-α (both P < 0.01), IL-18 and IL-6 (both P < 0.05), were significantly increased in articular cartilage of MRL/lpr mice, accompanied by increased expression of calcitonin gene-related peptide (CGRP) (P < 0.05), NETRIN-1, and NESTIN (both P < 0.01), indicating that SLE promotes inflammation response and sensory nerve ingrowth in the knee joint, contributing to the progression of arthritis. Mechanistic analysis revealed that SLE exacerbation intensified chondrocyte pyroptosis by upregulating pyroptotic-related proteins, including NLRP3, CASPASE-1, and gasdermin D (all P < 0.01), through the regulation of the nuclear factor erythroid 2-related factor (NRF-2)/KEAP-1 and nuclear factor kappa-B (NF-κB) pathway.

Collectively, our findings underscore the mechanistic connection between chondrocyte pyroptosis and arthritis exacerbation in SLE, suggesting potential therapeutic targets for mitigating arthritis progression in the context of SLE.

The activation of inflammasomes (NLRP3 and NLRP1) is central to the pathogenesis of inflammatory bowel disease (IBD). Here we examined the protective effects of a thioredoxin-mimetic peptide CB13 (TXM-CB13), known for its antioxidative stress and anti-inflammatory properties. We examined the effects of TXM-CB13 on dextran sulfate sodium (DSS)-induced colitis and lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation in RAW264.7 macrophages. TXM-CB13 appeared to alleviate symptoms of DSS-induced colitis and to significantly suppress the protein and mRNA levels of NLRP3, Mlck, and IL-1β in colonic tissues. Additionally, TXM-CB13 treatment increased the levels of the intestinal barrier proteins Occludin, ZO-1, and NLRP1, as shown through immunohistochemistry and Western blot analysis. In vitro, TXM-CB13 inhibited LPS-induced TLR4 signaling, reducing MyD88 levels and consequently attenuating the activation of the NF-κB pathways, including p-IκB-α/IκB-α and p-NF-κB-p65/NF-κB-p65. This inhibition further reduced the activation of the NLRP3 inflammasome components, NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. In addition, TXM-CB13 prevented the ROS-mediated dissociation of TXNIP from TRX, inhibiting NLRP3 activation. These findings suggest that TXM-CB13 is a potential therapeutic candidate for IBD through its modulation of the TLR4/MyD88/NF-κB/NLRP3 and ROS/TXNIP/TRX/NLRP3 pathways.

Recurrent oral ulcers (ROUs) of oral mucosa disease are difficult to cure and relapse easily, and immune imLbalance or dysfunction is considered an essential factor in their occurrence and recurrence. Periplaneta americana extract (PAD), a raw material used in Kangfuxin Liquid and Yunnan Baiyao toothpaste, contains a variety of growth factors such as polypeptides and sticky sugar amino acids that promote tissue repair; this can encourage the growth of the granulation tissue and reduce inflammation on the wound surface. This study aimed to investigate the interventional potential of PAD on recurrent oral ulcers in rats and to elucidate the underlying mechanism of action involving the TLR4/NF-κB and Nrf2/HO-1 signaling pathways. A rat model of recurrent oral ulcer (ROU) was established using an oral antigen emulsifier. Rats in the ROU group were administered PAD by gavage for 7 days. To observe the effect of PDA on ROU mice. HE staining revealed that PAD restored the structure of the oral mucosal tissue and reduced inflammatory infiltration. FCM revealed that PAD upregulated CD3 + and CD4 + levels and the CD4 + /CD8 + ratio in peripheral blood T lymphocytes. ELISA revealed that PAD increased the content of IgA, IgG, IgM, VEGF, IL-2, and IL-10, while decreasing IL-6 and TNF-α content. Microplate analysis revealed that PAD significantly increased CAT content in the serum of ROU rats and reduced GSH, NO, SOD, and MDA levels. IHC staining, RT-qPCR, and Western blotting revealed that PAD downregulated Keap1 and IκBα expression, inhibited the TLR4/NF-κB signaling pathway, upregulated Nrf2 and HO-1 expression, and activated the Nrf2/HO-1 signaling pathway. These fndings suggest that PAD improved immune imbalance and oxidative stress in ROU rats by activating the Nrf2/HO-1 pathway and inhibiting the TLR4/NF-κB signaling pathway, thereby promoting the healing of oral ulcer wounds.

P. multocida is notorious for inducing excessive inflammation with high lethality in multiple animals, such as cattle, pigs, and chickens. Our previous study revealed that L-serine was decreased in the lungs of mice infected with P. multocida capsular type A strain CQ2 (PmCQ2), and 2 mg/kg of L-serine could alleviate PmCQ2-induced lung inflammation in vivo, which may largely depend on macrophages. However, the underlying intrinsic alterations remain unknown. Here, we demonstrated that 10 mM of L-serine significantly inhibited the release of inflammatory cytokines (e.g., IL-1β and TNF-α) by blocking inflammasome activation (including NALP1, NLRP3, NLRC4, AIM2, and Caspase-1) in PmCQ2-infected macrophages. Furthermore, the results of RNA-seq and metabonomics revealed that exogenous L-serine supplementation substantially reprogrammed macrophage transcription and metabolism. Mechanically, L-serine reduced inflammatory responses via the inhibition of glycolysis in macrophages based on a seahorse assay. Together, these findings characterize the intrinsic molecular alterations in activated macrophages and provide new targets for modulating P. multocida infection-induced macrophage inflammation.

Parasitic roundworms are remarkable for their ability to manipulate host immune systems and ameliorate inflammatory diseases. Although much is known about the nature of nematode effectors in immune modulation, little is known about the action mode of these molecules. Here, we report that a serine protease inhibitor SPI-I8 in the extracellular vesicles of blood-feeding nematodes like Ancylostoma ceylanicum, Haemonchus contortus and Nippostrongylus brasiliensis, effectively halts excessive inflammatory responses in vitro and in vivo. We demonstrate that H. contortus SPI-I8 promotes the role of a negative regulator of RACK1 and enhances the effects of RACK1 on tumor necrosis factor (TNF)-α-IκB kinases (IKKs)-nuclear factor kappa beta (NF-κB) axis in mammalian cells, by hijacking E3 ubiquitin protein ligase MKRN1-mediated polyubiquitination of RACK1. Administration of recombinant N. brasiliensis SPI-I8 effectively protects mice from dextran sulfate sodium (DSS)-induced colitis and lipopolysaccharide (LPS)-induced sepsis. Considering the structural and functional conservation of SPI-I8s among Strongylida nematodes and the conservation of interactive mediators (i.e., MKRN1 and RACK1) among mammals, our findings provide insights into the host-parasite interface where parasitic roundworms secret molecules to suppress host inflammatory responses. Harnessing these findings should underpin the exploitation of nematode's immunomodulators to relief excessive inflammation associated diseases in animals and humans.

Our study explored the novel mechanisms implicated in the anti-rheumatic potential of fisetin and/or nicorandil (NIC) intervention.

Fifty male rats were categorized into; control, rheumatoid arthritis (RA), fisetin-treated RA, NIC-treated RA, and co-treated RA groups. We assessed paw thickness, arthritis indices, serum CRP, RF, OPG, RANKL, and gene expressions of synovial TLR4, NLRP3, caspase-1, GSDMD, Nrf-2, and HO, along with synovial histopathology and NF-κB immunoreactivity.

The combined therapy demonstrated significantly better anti-rheumatic potential, suppressing oxidative stress and NF-κB, downregulating synovial TLR4, NLRP3, caspase-1, GSDMD, and increasing serum OPG while decreasing RANKL, confirmed by histopathological findings.

Our investigation uncovered the TLR4/NF-κB pyroptotic signaling, Nrf-2/HO-1, and OPG/RANKL pathways as novel mechanistic insights into the anti-rheumatoid potential of fisetin and/or NIC, with superiority of combination approach, providing a beacon of hope for RA patients in terms of optimizing treatment protocol effectiveness and patient outcomes.

Microvascular ischemia, especially in the heart and kidneys, is associated with inflammation and metabolic perturbation, resulting in cellular dysfunction and end-organ failure. Heightened production of adenosine from extracellular nucleotides released in response to inflammation results in protective effects, inclusive of adaptations to hypoxia, endothelial cell nitric oxide release with the regulation of vascular tone, and inhibition of platelet aggregation. Purinergic signaling is modulated by ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39, which is the dominant factor dictating vascular metabolism of extracellular ATP to adenosine throughout the cardiovascular tissues. Excess levels of extracellular purine metabolites, however, have been associated with metabolic and cardiovascular diseases. Physiological estrogen signaling is anti-inflammatory with vascular protective effects, but pharmacological replacement use in transgender and postmenopausal individuals is associated with thrombosis and other side effects. Crucially, the loss of this important sex hormone following menopause or with gender reassignment is associated with worsened pro-inflammatory states linked to increased oxidative stress, myocardial fibrosis, and, ultimately, diastolic dysfunction, also known as Yentl syndrome. While there is a growing body of knowledge on distinctive purinergic or estrogen signaling and endothelial health, much less is known about the relationships between the two signaling pathways. Continued studies of the interactions between these pathways will allow further insight into future therapeutic targets to improve the cardiovascular health of aging women without imparting deleterious side effects.

Neuroinflammation plays an indispensable role in neural damages after ICH, responsible for the induced high mortality and poor prognosis. NLRP3 inflammasome, which is known mediated by ROS, has been widely documented to aggravate brain injuries. Therefore, suppressing neural injuries by ROS/NLRP3 pathway may be beneficial in treating ICH. As the major catechin found in green tea, epigallocatechin-3-gallate (EGCG) shows excellent anti-oxidative and anti-inflammatory effects. In this study, EGCG-carbon quantum dots (EGCG-CQDs) were successfully fabricated based on EGCG by hydrothermal synthesis method. EGCG-CQDs exhibited an excellent aqueous solubility, and emerged more abundant phenolic oxygens as well as oxygen-rich functional groups. Importantly, EGCG-CQDs showed superior free radical scavenging activity by DPPH and ABTS assays in vitro than EGCG. In vivo, a significant antioxidative activity was presented by EGCG-CQDs rather than EGCG. Furthermore, the upregulated NLRP3 and the induced inflammatory cascades (NF-κB, Caspase-1 and GSDMD) in ICH were attenuated by EGCG-CQDs. Inflammatory factor productions were also decreased by EGCG-CQDs, such as IL-1β, IL-18, IL-6 and TNF-α. Finally, the disturbed neural viability, disordered cytomorphology, and neurological deficits were significantly improved by EGCG-CQDs rather than EGCG. Therefore, CQDs might be an effective form to amplify the efficacy and bioavailability of EGCG, exerting considerable effects on treating ICH by suppressing ROS/NLRP3.

Excessive inflammation in cells are a common cause of inflammation-related diseases such as cardiometabolic diseases. The cellular multiprotein complex nucleotide-binding domain and leucine-rich repeat pyrin domain 3 (NLRP3) inflammasome is a cellular key modulator of inflammatory processes. In addition to classic medications, phytochemicals are known for their anti-inflammatory potential. In African folk medicine the seeds of Garcinia kola are used to support the treatment of inflammatory diseases. Of particular interest is the phytochemical garcinoic acid (GA, trans-13'-carboxy-δ-tocotrienol), which is isolated from the Garcinia kola seeds. This derivative and potential metabolite of the vitamin E congener δ-tocotrienol (T3) shows anti-inflammatory properties in vitro. However, the underlying mechanisms are largely unknown. To get better insights into the molecular mode of action, murine J774A.1 macrophages were stimulated with lipopolysaccharides (LPS) only or in combination with adenosine triphosphate (ATP), which led to canonical activation of the NLRP3 inflammasome and subsequent pyroptosis. A combined treatment with GA resulted in significantly reduced stimulation of the transcription factor nuclear factor 'ĸ-light-chain-enhancer' of activated B-cells (NF-ĸB), decreased expression of inflammasome-related genes and marked downregulation of autoproteolytic cleavage of caspase-1 (Casp-1). Consequently, GA had an inhibitory effect on pyroptosis. The results have been validated using the well-known NLRP3 inflammasome inhibitor MCC950. In conclusion, GA was shown to have relevant effects on the regulation of the NLRP3 inflammasome and pyroptosis in vitro. Our study provides new mechanistic insights into the anti-inflammatory mode of action of GA and highlights its relevance as a potential phytochemical drug for the treatment of inflammation.

The NLRP3 inflammasome and NF-κB signaling pathways play crucial roles in orchestrating inflammation and immune defense.​ This review explores the intricate relationship between these pathways and epigenetic regulation, a field of growing importance in understanding immune responses. Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), significantly influence the activity of genes involved in these pathways, thereby modulating inflammatory responses. The review provides a comprehensive overview of current research on how epigenetic mechanisms interact with and regulate the NLRP3 inflammasome and NF-κB signaling pathways. It delves into advanced epigenetic concepts such as RNA modifications and 3D genome organization, and their impact on immune regulation. Furthermore, the implications of these findings for developing novel therapeutic strategies targeting epigenetic regulators in inflammatory diseases are discussed. By synthesizing recent advancements in this rapidly evolving field, this review underscores the critical role of epigenetic regulation in immune signaling and highlights the potential for epigenetic-based therapies in treating a wide range of inflammatory conditions, including autoimmune disorders and cancer.

Bone-related diseases impact a large portion of the global population and, due to their high disability rates and limited treatment options, pose significant medical and economic challenges. Mesenchymal stem cells (MSCs) can differentiate into multiple cell types and offer strong regenerative potential, making them promising for treating various diseases. However, issues with the immune response and cell survival limit the effectiveness of cell transplantation. This has led to increased interest in cell-free stem cell therapy, particularly the use of exosomes, which is the most studied form of this approach. Exosomes are extracellular vesicles that contain proteins, lipids, and nucleic acids and play a key role in cell communication and material exchange. Pyroptosis, a form of cell death involved in innate immunity, is also associated with many diseases. Studies have shown that MSC-derived exosomes have therapeutic potential for treating a range of conditions by regulating inflammation and pyroptosis. This study explored the role of MSC-derived exosomes in modulating pyroptosis to improve the treatment of bone-related diseases.

Sequelae of pelvic inflammatory disease (SPID) occurs in female internal genitalia and surrounding connective tissue. Recent clinical studies have shown that the traditional Chinese medicine Fuke Qianjin capsule (FKQ) can shorten the course of this disease, but its pharmacological effects and potential mechanism have not been fully elucidated.

This study aimed to investigate the efficacy and underlying mechanisms of FKQ in the treatment of SPID.

In this study, we first established a mixed infection model to explore the protective effect of FKQ on common pathogens of SPID. Afterwards, mixed bacterial infection and mechanical injury were used in a SPID rat model to explore the protective mechanism of FKQ on SPID rats. Inflammation, repair and immune cells were tested.

FKQ has a protective effect against infections caused by SPID pathogenic bacterial and may reduce mortality from mixed infections. In the SPID model, FKQ improved pathological damage to the uterus, reduced the area of uterine fibrosis, and inhibited the levels of cytokines (TNF-α, IL-6, IL-1β, IL-18, TGF-β1 and VEGF) caused by pathogenic bacteria. Moreover, FKQ treatment reduced the accumulation of NLRP3, Caspase-1, GSDMD Vimentin, and Cytokeratin 18 in the uterus and suppressed the expression of TGF-β1 and VEGF in the fallopian tubes, thereby reducing inflammation and promoting mucosal repair. In addition, FKQ can restore the immune function balance of SPID rats by increasing the proportion of Treg cells in the spleen and thymus in a rat model of SPID, reducing the proportion of Th17 lymphocytes, and promoting an immunological balance of Treg/Th17 cells, thereby regulating the immune system of the body.

In summary, FKQ treatment for SPID is the result of a fourfold combination of antibacterial, anti-inflammatory, reparative and immune-enhancing activities.

For centuries, the aerial parts of Sideritis species have been known for their medicinal properties as herbal teas. Although the antioxidant and anti-inflammatory properties of the genus have been widely documented, the underlying mechanisms are yet to be sufficiently clarified.

We investigated the anti-inflammatory and anticancer activities of phytochemicals of the Sideritis genus.

Through literature mining, a chemical library containing 657 components of the Sideritis genus was formed. We studied these compounds for binding to NLRP3 and NF-κB proteins in silico by virtual drug screening and molecular docking, and in vitro by microscale thermophoresis (MST). Liquid chromatography-high-resolution mass spectrometry analysis (LC-HRMS) was performed in the Sideritis extracts. One of the identified compounds, verbascoside, was investigated for its cytotoxic activity by mining a panel of 49 tumor cell lines in the data repository of the National Cancer Institute (NCI, USA).

Virtual screening and molecular docking results highlighted two compounds targeting both proteins of interest, i.e., verbascoside (acteoside) and apigenin 7,4'-bis(trans-p-coumarate), as both had lowest binding energies of less than -10 kcal/mol. Using MST, we then verified that both compounds bound to the target proteins. Verbascoside bound to NLRP3 and NF-κB with Kd values of 0.67 ± 0.18 μM and 0.01 ± 0.08 μM, while apigenin 7,4'-bis(trans-p-coumarate) had Kd values of 4.60 ± 1.66 μM and 0.27 ± 0.75 μM, respectively. Verbascoside was abundant in the Sideritis extracts, according to LC-HRMS analysis. Since inflammation is strongly related to carcinogenesis, we investigated the anticancer activity of verbascoside in the second part of this study. We investigated the activity of verbascoside in 49 tumor cell lines of the NCI. Comparing its activity with 81 standard anticancer drugs revealed numerous interactions with DNA-damaging agents (alkylators, topoisomerase I/II inhibitors, antimetabolites), indicating that verbascoside may also affect the DNA of tumor cells. We further investigated the involvement of verbascoside in several main drug resistance mechanisms, i.e., ABC transporters, oncogenes, tumor suppressors, cellular proliferation rates, and other parameters. Except for the correlation to the mutational status of NRAS, no other significant relationships were found, indicating that verbascoside is not involved in most of the common drug resistance mechanisms. Two-dimensional cluster analysis-based heatmap generation of a proteomic profile from 40 out of 3171 proteins revealed a significant correlation between the expression of these proteins in 49 tumor cell lines, and the cellular response to verbascoside. This indicates that the presence of these proteins is a determinant for sensitivity or resistance to this natural product.

The database established here represents a valuable resource for the screening of bioactivites of the Sideritis genus. The experimental validation of the anti-inflammatory and cytotoxic activities of selected compounds proved that virtual drug screening and molecular docking are suitable tools for the identification of putative drug candidates. Verbascoside was among the top 10 compounds binding to two key anti-inflammatory proteins, NLRP3 and NF-kB. Additionally, data from the NCI indicate that verbascoside is not linked to main drug resistance mechanisms.

Ganoderma lucidum (G. lucidum), a traditional Chinese medicinal herb, is commonly recommended for its potential to promote mental relaxation and alleviate memory impairment. Recently, there have been reports suggesting that it exhibits anti-neuroinflammatory activity through the gut-brain axis. Cognitive dysfunction is among the most prevalent neurodegenerative diseases.

This study aimed to investigate the efficacy of polysaccharides extracted from G. lucidum in alleviating cognitive dysfunction.

A polysaccharide was extracted through the process of alkali extraction followed by alcohol precipitation. Comprehensive analysis was conducted to characterize the total sugar content, amino acid composition, and sugar chain structure. The levels of inflammatory related factors were assessed using griess reagent, qPCR and western blotting assay in vitro. The efficacy of alleviating cognitive dysfunction was evaluated through a series of behavioral studies in mice model induced by the high-fat high-sugar diet combined with chronic unpredictable mild stress (HFFD/CUMS) in vivo. The mechanism was investigated by 16S rRNA sequence, immunohistochemistry, flow cytometry and short-chain fatty acid detection.

Ganoderma lucidum polysaccharide (GLP) is a polysaccharide identified as β-glucan. Bioactivity experiments have demonstrated that GLP possesses the potential to ameliorate cognitive dysfunction. The mechanism study revealed that GLP can modulate the composition of gut microbiota and suppress the activation of inflammasomes via NLRP3/NF-κB signaling pathway, thereby attenuating neuroinflammatory. Furthermore, GLP may enhance the peripheral immunity response of the body, leading to a comprehensive regulatory effect.

A polysaccharide alleviates cognitive dysfunction via inhibiting neuroinflammation.

Artemisia ordosica Krasch. represents a medicinal species traditionally and extensively employed in traditional medicine for treating ailments such as rheumatic arthritis, sore throat, and inflammation. This study initially focuses on the extraction, purification, and characterization of Artemisia ordosica Krasch. polysaccharides (AOP). The purified AOP exhibits a molecular mass corresponding to 9.00 kDa and consists of multiple monosaccharide units, with glucose (54.08%) as the predominant component, followed by arabinose (13.75%), mannose (13.43%), galactose (12.79%), xylose (3.15%), glucuronic acid (0.93%), galacturonic acid (0.67%), ribose (0.63%), and fucose (0.56%), respectively. Furthermore, to explore the immune-regulatory mechanisms of AOP, peripheral blood lymphocytes (PBLs) were cultured and exposed to inhibitors targeting receptors and signaling molecules. The results indicated that TLR4 serves as a potential target through which AOP exerts its immunomodulatory functions. AOP mitigates immune stress in PBLs triggered by LPS by disrupting the interaction between LPS and TLR and downregulating the over-activation of the nuclear factor kappa B (NF-κB) signaling pathway. In summary, AOP shows promise as a feed additive to protect animals from immune stress.