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We examined 3962 people aged 20 to 49 years who had information on spirometry testing and underwent a 24 h dietary recall interview from the 2007-2012 National Health and Nutrition Examination Survey (NHANES) and used multivariable logistic regression to evaluate associations between Dietary Inflammatory Index (DII, a pro-inflammatory diet) and early COPD and lung function. The overall prevalence of early COPD was 5.05%. Higher DII was associated with increased odds of early COPD (quartile 4 vs. 1, the OR = 1.657, 95% CI = 1.100-2.496, p = 0.0156). In a full-adjusted model, each unit of increase in DII score was associated with a 90.3% increase in the risk of early COPD. Higher DII is significantly associated with lower FEV 1 and FVC among individuals with early COPD, each unit increment in the DII was significantly associated with 0.43 L-0.58 L decrements in FEV 1 (β = -0.43, 95% CI = -0.74, -0.12) and FVC (β = -0.58, 95% CI = -1.01, -0.16). These findings demonstrate that higher consumption of a pro-inflammatory diet may contribute to an increased risk of early COPD and lower lung function, and further support dietary interventions as part of a healthy lifestyle in order to preserve lung function and prevent or improve COPD.

At present, an increasing number of individuals are affected by osteoarthritis (OA), resulting in a heavy socioeconomic burden. OA in knee joints is caused by the release of inflammatory cytokines and subsequent biomechanical and structural deterioration. To determine its anti‑inflammatory function, the current study investigated the use of the plant‑derived medicine, curcumenol, in OA treatment. Curcumenol was not cytotoxic to ATDC5 chondrocytes and primary chondrocytes, as determined using a cell viability test. When these cells were treated with TNF‑α and IL‑1β to induce inflammation, curcumenol treatment inhibited the progression of inflammation by inactivating the NF‑κB and MAPK signaling pathways, as well as decreasing the expression levels of MMP3 (as indicated by reverse transcription‑quantitative PCR and western blotting). Moreover, to analyze metabolic and catabolic status in high‑density and pellet culture, catalytic changes and the degradation of the extracellular matrix induced by TNF‑α and IL‑1β, were evaluated by alcian blue staining. These catalytic deteriorations were ameliorated by curcumenol. Using curcumenol in disease management, the mechanical and metabolic disruption of cartilage caused in the destabilization of medial meniscus (DMM) model was prevented in vivo . Thus, curcumenol mitigated inflammation in ATDC5 chondrocytes and primary mice chondrocytes, and also ameliorated OA in a DMM‑induced mouse model.

The Chinese herbal medicine, Huzhen Tongfeng Formula (HZTF), derived from traditional Chinese medicine (TCM) practice, has recognized therapeutic benefits for gouty arthritis (GA). HZTF is currently in the late stage of approval process as a new anti-GA drug application. However, the underlying mechanism of HZTF as an antigout medication is unclear. In this study, we combined network pharmacology and experimental validation approaches to elucidate the mechanism of action of HZTF. First, the relative drug-disease target networks were constructed and analyzed for pathway enrichment. Potential pathways were then validated by in vitro and in vivo experiments. We found that 34 compounds from HZTF matched 181 potential drug targets. Topology analysis revealed 77 core targets of HZTF, which were highly related to gout, following screening of KEGG pathway enrichment. Further analysis demonstrated that the arachidonic acid metabolic pathway was the most relevant pathway involved in the mechanism of HZTF. Validation experiments showed that HZTF significantly inhibited the inflammatory cell infiltration into gouty joints, improved the swelling of affected joints, and increased the pain threshold. HZTF significantly reduced the transcription and production of various cytokines and inflammatory mediators in vitro . In particular, cyclooxygenase (COX)-1, COX-2, and 5-lipoxygenase were simultaneously downregulated. In conclusion, our study suggests that the antigout mechanism of HZTF is associated with the inhibition of the arachidonic acid pathway, resulting in the suppression of inflammatory cytokines and mediators. These findings extend our understanding of the pharmacological action of HZTF, rationalizing the application HZTF as an effective herbal therapy for GA., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Jianping Deng et al.)

Obesity induces accumulation of adipose tissue macrophages (ATMs) and ATM-driven inflammatory responses that promote the development of glucose and lipid metabolism disorders. ClC-3 chloride channel/antiporter, encoded by the Clcn3, is critical for some basic cellular functions. Our previous work has shown significant alleviation of type 2 diabetes in Clcn3 knockout (Clcn3 -/- ) mice. In the present study we investigated the role of Clcn3 in high-fat diet (HFD)-induced obesity and ATM inflammation. To establish the mouse obesity model, both Clcn3 -/- mice and wild-type mice were fed a HFD for 4 or 16 weeks. The metabolic parameters were assessed and the abdominal total adipose tissue was scanned using computed tomography. Their epididymal fat pad tissue and adipose tissue stromal vascular fraction (SVF) cells were isolated for analyses. We found that the HFD-fed Clcn3 -/- mice displayed a significant decrease in obesity-induced body weight gain and abdominal visceral fat accumulation as well as an improvement of glucose and lipid metabolism as compared with HFD-fed wild-type mice. Furthermore, the Clcn3 deficiency significantly attenuated HFD-induced ATM accumulation, HFD-increased F4/80 + CD11c + CD206 - SVF cells as well as HFD-activated TLR-4/NF-κB signaling in epididymal fat tissue. In cultured human THP-1 macrophages, adenovirus-mediated transfer of Clcn3 specific shRNA inhibited, whereas adenovirus-mediated cDNA overexpression of Clcn3 enhanced lipopolysaccharide-induced activation of NF-κB and TLR-4. These results demonstrate a novel role for Clcn3 in HFD-induced obesity and ATM inflammation.

Acute lung injury (ALI) is a severe health issue with significant morbidity and mortality. Artemisinin is used for the treatment of fever and malaria in clinical practice. Dihydroartemisinin (DHA), the major active metabolite of artemisinin, plays a role in anti‑organizational fibrosis and anti‑neuronal cell death. However, whether DHA can attenuate ALI remains unclear. The current study thus examined the effects of DHA on ALI and primary macrophages. The results revealed that DHA attenuated lipopolysaccharide (LPS)‑induced pulmonary pathological damage. DHA suppressed the LPS‑induced infiltration of inflammatory cells, the elevation of myeloperoxidase activity, oxidative stress and the production of pro‑inflammatory cytokines, including interleukin (IL)‑1β, tumor necrosis factor‑α, and IL‑6. Furthermore, DHA reduced the LPS‑induced inflammatory response by suppressing the degradation of I‑κB and the nuclear translocation of nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB)/p65 in vivo and in vitro. DHA activated the nuclear factor‑erythroid 2 related factor 2 (Nrf2) pathway, which was suppressed by LPS treatment. The Nrf2 inhibitor, ML385, diminished the protective effects of DHA against LPS‑induced inflammation in macrophages. On the whole, the findings of this study demonstrate that DHA exerts therapeutic effects against LPS‑induced ALI by inhibiting the Nrf2‑mediated NF‑κB activation in macrophages. The present study also confirmed the therapeutic effects of DHA in mice with LPS‑induced ALI. Thus, these findings demonstrate that DHA exhibits anti‑inflammatory activities and may be a therapeutic candidate for the treatment of ALI.

(1) Background: Chemokine-like factor 1 (CKLF1) is a chemokine with potential to be a target for stroke therapy. Compound IMM-H004 is a novel coumarin derivative screened from a CKLF1/C-C chemokine receptor type 4 (CCR4) system and has been reported to improve cerebral ischemia/reperfusion injury. This study aims to investigate the protective effects of IMM-H004 on cerebral ischemia injury and its infectious cardiopulmonary complications in adult and aged rats from the CKLF1 perspective. (2) Methods: The effects of IMM-H004 on the protection was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavior tests, magnetic resonance imaging (MRI) scans, enzyme-linked immunosorbent assay (ELISA), Nissl staining, histo-pathological examination, and cardiopulmonary function detection. Immunohistological staining, immunofluorescence staining, quantitative real-time PCR (qPCR), and western blotting were used to elucidate the underlying mechanisms. (3) Results: IMM-H004 protects against cerebral ischemia induced brain injury and its cardiopulmonary complications, inhibiting injury, and inflammation through CKLF1-dependent anti-inflammation pathway in adult and aged rats. IMM-H004 downregulates the amount of CKLF1, suppressing the followed inflammatory response, and further protects the damaged organs from ischemic injury. (4) Conclusions: The present study suggested that the protective mechanism of IMM-H004 is dependent on CKLF1, which will lead to excessive inflammatory response in cerebral ischemia. IMM-H004 could also be a therapeutic agent in therapy for ischemic stroke and cardiopulmonary complications in the aged population.

Aims/hypothesis: Müller glia (MG) are major sources of retinal cytokines, and their activation is closely linked to retinal inflammation and vascular leakage in diabetic retinopathy. Previously, we demonstrated that X-box binding protein 1 (XBP1), a transcription factor activated by endoplasmic reticulum (ER) stress in diabetic retinopathy, is involved in regulation of inflammation in retinal endothelial cells. Now, we have explored the role of XBP1 and ER stress in the regulation of MG-derived proinflammatory factors, and their influence on vascular permeability in diabetic retinopathy., Methods: MG-specific conditional Xbp1 knockout (Xbp1 Müller-/- ) mice were generated by crossing Xbp1 flox/flox mice with Müller-Cre transgenic mice. Diabetes was modelled by induction with streptozotocin, and retinal vascular permeability was measured with FITC-conjugated dextran 2 months after induction. Primary Müller cells were isolated from Xbp1 Müller-/- and Xbp1 Müller+/+ mice and exposed to hypoxia and high levels of glucose. Levels of ER-stress and inflammatory factors were examined by real-time PCR, western blotting or immunohistochemistry., Results: Xbp1 Müller-/- mice exhibited normal retinal development and retinal function and expressed similar levels of ER-stress and inflammatory genes to Xbp1 Müller+/+ littermates. In diabetes-inducing conditions, compared with Xbp1 Müller+/+ mice, Xbp1 Müller-/- mice had higher mRNA levels of retinal Vegf (also known as Vegfa) and Tnf-α (also known as Tnf) and ER-stress marker genes Grp78 (also known as Hspa5), Atf4, Chop (also known as Ddit3) and Atf6 and higher protein levels of vascular endothelial growth factor (VEGF), TNF-α, phospho-c-Jun N-terminal kinase (JNK), 78 kDa glucose-regulated protein (GRP78), phospho-eukaryotic translation initiation factor (eIF)2α and activating transcription factor (ATF)6. Retinal vascular permeability was significantly higher in diabetic Xbp1 Müller-/- mice than in diabetic Xbp1 Müller+/+ mice (p < 0.01). Results obtained in vitro with primary Müller cells isolated from Xbp1 Müller-/- mice confirmed higher expression levels of inflammatory and ER-stress markers (but not GRP78) than in cells from Xbp1 Müller+/+ mice. Moreover, XBP1-deficient Müller cells were more susceptible to high-glucose- or hypoxia-induced ER stress and inflammation than cells from Xbp1 Müller+/+ mice. Inhibition of ER stress with chemical chaperones suppressed hypoxia-induced VEGF and TNF-α production in XBP1-deficient Müller cells., Conclusions/interpretation: Our results have revealed an important role of XBP1 and ER stress in MG-driven retinal inflammation, and suggest that targeting ER stress may represent a promising approach for the prevention and treatment of diabetic retinopathy.

Inflammation and lipid disorders play crucial roles in synergistically accelerating the progression of diabetic nephropathy (DN). In this study we investigated how inflammation and lipid disorders caused tubulointerstitial injury in DN in vivo and in vitro. Diabetic db/db mice were injected with 10% casein (0.5 mL, sc) every other day for 8 weeks to cause chronic inflammation. Compared with db/db mice, casein-injected db/db mice showed exacerbated tubulointerstitial injury, evidenced by increased secretion of extracellular matrix (ECM) and cholesterol accumulation in tubulointerstitium, which was accompanied by activation of the CXC chemokine ligand 16 (CXCL16) pathway. In the in vitro study, we treated HK-2 cells with IL-1β (5 ng/mL) and high glucose (30 mmol/L). IL-1β treatment increased cholesterol accumulation in HK-2 cells, leading to greatly increased ROS production, ECM protein expression levels, which was accompanied by the upregulated expression levels of proteins in the CXCL16 pathway. In contrast, after CXCL16 in HK-2 cells was knocked down by siRNA, the IL-1β-deteriorated changes were attenuated. In conclusion, inflammation accelerates renal tubulointerstitial lesions in mouse DN via increasing the activity of CXCL16 pathway.

Inflammation plays a critical role in adverse cardiac remodeling and heart failure. The P2y12 receptor is one of the predominant activating receptors for platelets, thus initiating inflammatory responses under various diseases. In this study, we investigated the functional significance of P2y12-mediated platelet activation in pressure overload-induced cardiac remodeling. Notably, P2y12 knockout (P2y12 -/- ) mice exhibited suppressed transverse aortic constriction-induced changes in cardiac hypertrophy, collagen synthesis, inflammatory cell recruitment, and cardiac dysfunction. Activated platelets and platelet-leukocyte aggregates were markedly downregulated in P2y12 knockout mice compared with wild-type counterparts after transverse aortic constriction. Moreover, bone marrow chimera experiments revealed that wild-type recipients of P2y12 knockout bone marrow markedly improved cardiac function and attenuated cardiac remodeling, reversed by wild-type platelets reinjection. Platelet depletion and P-selectin inhibition mimicked these protective effects by limiting the interaction between activated platelets and leukocytes. Furthermore, activated wild-type platelets directly induced cardiomyocyte hypertrophy and collagen synthesis via α-granule exocytosis, vanished in P2y12 knockout platelets or those administered anti-NSF (N-ethlymalimide-sensitive factor) antibodies. The results suggest that P2y12-mediated platelet activation promotes cardiac remodeling by triggering a series of inflammatory changes and interacting with leukocytes and endotheliocytes., (© 2017 American Heart Association, Inc.)

Reactions of peroxynitrite (ONOO - ) with biomolecules can lead to cytotoxic and cytoprotective events. Due to the difficulty of directly and unambiguously measuring its levels, most of the beneficial effects associated with ONOO - in vivo remain controversial or poorly characterized. Recently, optical imaging has served as a powerful noninvasive approach to studying ONOO - in living systems. However, ratiometric probes for ONOO - are currently lacking. Herein, we report the design, synthesis, and biological evaluation of F 482 , a novel fluorescence indicator that relies on ONOO - -induced diene oxidation. The remarkable sensitivity, selectivity, and photostability of F 482 enabled us to visualize basal ONOO - in immune-stimulated phagocyte cells and quantify its generation in phagosomes by high-throughput flow cytometry analysis. With the aid of in vivo ONOO - imaging in a mouse inflammation model assisted by F 482 , we envision that F 482 will find widespread applications in the study of the ONOO - biology associated with physiological and pathological processes in vitro and in vivo., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects., Competing Interests: The authors declare no conflict of interest.

Unmethylated CpG DNA, as a stimulatory molecule, has potent pro-inflammatory effects in the central nervous system (CNS). Dexmedetomidine (DEX) has been confirmed to exert anti-inflammatory effects in CNS. Our study was aimed to explore the effects of DEX on tumor necrosis factor-α (TNF-α) expression in unmethylated CpG DNA-challenged microglia. In vivo, after 3 d intracisternal injection of ODN1668, we evaluated the severity of meningitis with or without DEX via pathobiology method and detected the expression of TNF-α from molecular and protein levels. In vitro, we explored whether the ODN1668 could activate microglia to express TNF-α and the inhibition mechanism of DEX. Our results demonstrated that DEX could alleviate the severity of ODN1668-induced meningitis. And while BV2 microglia was stimulated by ODN1668 for different time, TNF-α was increased in mRNA and protein levels but the effect was attenuated by DEX via decreasing phosphorylated AKT and ERK.

Inflammation and oxidative stress have been implicated in various pathological processes including skin tumorigenesis. Skin cancer is the most common form of cancer responsible for considerable morbidity and mortality, the treatment progress of which remains slow though. Therefore, chemoprevention and other strategies are being considered. Menthol has shown high anticancer activity against various human cancers, but its effect on skin cancer has never been evaluated. We herein investigated the chemopreventive potential of menthol against 9,10-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation, oxidative stress and skin carcinogenesis in female ICR mice. Pretreatment with menthol at various doses significantly suppressed tumor formation and growth, and markedly reduced tumor incidence and volume. Moreover, menthol inhibited TPA-induced skin hyperplasia and inflammation, and significantly suppressed the expression of cyclooxygenase-2 (COX-2). Furthermore, pretreatment with menthol inhibited the formation of reactive oxygen species and affected the activities of a battery of antioxidant enzymes in the skin. The expressions of NF-κB, Erk and p38 were down-regulated by menthol administration. Thus, inflammation and oxidative stress collectively played a crucial role in the chemopreventive efficacy of menthol on the murine skin tumorigenesis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Aortic valve (AV) calcification occurs via a pathophysiological process that includes lipoprotein deposition, inflammation, and osteoblastic differentiation of valvular interstitial cells. Here, we investigated the association between endoplasmic reticulum (ER) stress and AV calcification., Approach and Results: We identified ER stress activation in AV of patients with calcified AV stenosis. We generated an AV calcification model in hypercholesterolemic rabbits and mice, respectively, and found marked AV ER stress induction. Classical ER stress inhibitor, tauroursodeoxycholic acid, administration markedly prevented AV calcification, and attenuated AV osteoblastic differentiation and inflammation in both rabbit and mouse models of AV calcification via inhibition of ER stress. In cultured valvular interstitial cells (VICs), we found that oxidized low density lipoprotein (oxLDL) caused ER stress in a cytosolic [Ca](2+)i-dependent manner. OxLDL promoted osteoblastic differentiation via ER stress-mediated protein kinase-like ER kinase/activating transcription factor 4/osteocalcin and inositol-requiring transmembrane kinase and endonuclease-1α (IRE1α)/spliced X-box-binding protein 1/Runx2 pathway, and induced inflammatory responses through IRE1α/c-Jun N-terminal kinase and IRE1α/nuclear factor kappa-light-chain-enhancer of activated B cells signaling in VICs. Inhibition of ER stress by either tauroursodeoxycholic acid or 4-phenyl butyric acid could both suppress oxLDL-induced osteoblastic differentiation and inflammatory responses in VICs., Conclusions: These data provide novel evidence that ER stress participates in AV calcification development, and suggest that ER stress may be a novel target for AV calcification prevention and treatment.

The number of people with asthma has dramatically increased over the past few decades and the cost of care is more than $11·3 billion per year. The use of steroids is the major treatment to control asthma symptoms, but the side effects are often devastating. Seeking new drugs or new strategies to reduce the dose of steroid taken has always been an important task. A bovine whey protein extract (WPE), which is enriched in transforming growth factor-β (TGF-β), has been demonstrated to have the potential for reducing symptoms associated with mild-to-moderate T-helper cell type 1-mediated psoriasis in human subjects. However, whether WPE also has potential for inhibiting T-helper cell type 2 (Th2)-mediated disease remains unclear. In the present study, using a murine asthma model, we found that sensitised mice fed WPE daily, before they were challenged, resulted in reducing airway inflammation, serum ovalbumin-specific IgE, Th2-related cytokine production and airway hyperresponsiveness. Increase in the regulatory T cell (Treg) population in vitro and in vivo was observed when treated with WPE. According to the results from the TGF-β-blocking antibody study, we suggest that TGF-β is the main component that endows WPE with the potential to reduce the generation of Treg. Thus, the present data suggest that WPE has the potential to alleviate the symptoms of asthma by inducing the generation of Treg. Therefore, regular administration of WPE might be potentially beneficial for patients with asthma.

There is a current view that myosin light chain kinase (MLCK) plays a critical role in endothelial permeability. To investigate the functions of MLCK in endothelial cells in vivo, we generated a mouse model in which MLCK was selectively deleted by crossing Mylk1 floxed mice with Tie2/cre transgenic mice. Knocking out Mylk1 from endothelial cells had no effect on the global phenotype of the mice, including body weight and blood pressure. Lipopolysaccharide (LPS)-mediated septic death was also not altered in the knockout (KO) mice. Consistently, LPS-induced inflammatory injury and the increase in microvascular permeability in the main organs, including the lung and the kidney, was not significantly attenuated in KO mice as compared with wild-type mice. However, the LPS-induced microvascular hyperpermeability of the esophagus and the eyeballs was attenuated in KO mice. We also found that the LPS-mediated increase in the number of caveolae in the endothelial cells of the esophagus was significantly reduced in KO mice. Our results do not support a role for endothelial cell MLCK in the pathogenesis of inflammatory diseases., (© 2012 The Authors Journal compilation © 2012 FEBS.)

Background: Pulmonary hypertension (PH) represents a progressive condition characterized by the remodeling of pulmonary arteries, ultimately culminating in right heart failure and increased mortality rates. Substantial evidence has elucidated the pivotal role of perivascular inflammatory factors and immune dysregulation in the pathogenesis of PH. Chemokines, a class of small secreted proteins, exert precise control over immune cell recruitment and functionality, particularly with respect to their migration to sites of inflammation. Consequently, chemokines emerge as critical drivers facilitating immune cell infiltration into the pulmonary tissue during inflammatory responses. This review comprehensively examines the significant contributions of CC chemokines in the maintenance of immune cell homeostasis and their pivotal role in regulating inflammatory responses. The central focus of this discussion is directed towards elucidating the precise immunoregulatory actions of CC chemokines concerning various immune cell types, including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, mast cells, eosinophils, and basophils, particularly in the context of pH processes. Furthermore, this paper delves into an exploration of the underlying pathogenic mechanisms that underpin the development of PH. Specifically, it investigates processes such as cellular pyroptosis, examines the intricate crosstalk between bone morphogenetic protein receptor type 2 (BMPR2) mutations and the immune response, and sheds light on key signaling pathways involved in the inflammatory response. These aspects are deemed critical in enhancing our understanding of the complex pathophysiology of PH. Moreover, this review provides a comprehensive synthesis of findings from experimental investigations targeting immune cells and CC chemokines. Aim of review: In summary, the inquiry into the inflammatory responses mediated by CC chemokines and their corresponding receptors, and their potential in modulating immune reactions, holds promise as a prospective avenue for addressing PH. The potential inhibition of CC chemokines and their receptors stands as a viable strategy to attenuate the inflammatory cascade and ameliorate the pathological manifestations of PH. Nonetheless, it is essential to acknowledge the current state of clinical trials and the ensuing progress, which regrettably appears to be less than encouraging. Substantial hurdles exist in the successful translation of research findings into clinical applications. The intention is that such emphasis could potentially foster the advancement of potent therapeutic agents presently in the process of clinical evaluation. This, in turn, may further bolster the potential for effective management of PH.

Background: Using machine learning methods based on neurocognitive deficits and neuroimmune biomarkers, two distinct classes were discovered within schizophrenia patient samples. Increased frequency of psychomotor retardation, formal thought disorders, mannerisms, psychosis, hostility, excitation, and negative symptoms defined the first subgroup, major neurocognitive psychosis (MNP). Cognitive deficits in executive functions and memory and diverse neuroimmune aberrations were other MNP features. Simple neurocognitive psychosis (SNP) was the less severe phenotype. Aims: The study comprised a sample of 40 healthy controls and 90 individuals diagnosed with schizophrenia, divided into MNP and SNP based on previously determined criteria. Soft Independent Modelling of Class Analogy (SIMCA) was performed using neurocognitive test results and measurements of serum M1 macrophage and T helper-17 cytokines as discriminatory/modelling variables. The model-to-model distances between controls and MNP + SNP and between MNP and SNP were computed, and the top discriminatory variables were established. Results: A notable SIMCA distance of 146.1682 was observed between MNP + SNP and the control group. The top-3 discriminatory variables were lowered motor speed, an activated T helper-17 axis, and lowered working memory. This study successfully differentiated MNP from SNP yielding a SIMCA distance of 19.3. M1 macrophage activation, lowered verbal fluency, and executive functions were the prominent features of MNP versus SNP. Discussion: Based on neurocognitive assessments and the immune-linked neurotoxic M1 and T helper-17 profiles, we found that MNP and SNP are qualitatively distinct classes. Future biomarker research should focus on examining biomarkers specifically in the MNP and SNP subgroups, rather than in the schizophrenia group.

Abstract Gypenoside XIII is isolated from Gynostemma pentaphyllum (Thunb.) Makino. In mice, G. pentaphyllum extract and gypenoside LXXV have been shown to improve non‐alcoholic steatohepatitis (NASH). This study investigated whether gypenoside XIII can regulate lipid accumulation in fatty liver cells or attenuate NASH in mice. We used HepG2 hepatocytes to establish a fatty liver cell model using 0.5 mM oleic acid. Fatty liver cells were treated with different concentrations of gypenoside XIII to evaluate the molecular mechanisms of lipid metabolism. In addition, a methionine/choline‐deficient diet induced NASH in C57BL/6 mice, which were given 10 mg/kg gypenoside XIII by intraperitoneal injection. In fatty liver cells, gypenoside XIII effectively suppressed lipid accumulation and lipid peroxidation. Furthermore, gypenoside XIII significantly increased SIRT1 and AMPK phosphorylation to decrease acetyl‐CoA carboxylase phosphorylation, reducing fatty acid synthesis activity. Gypenoside XIII also decreased lipogenesis by suppressing sterol regulatory element‐binding protein 1c and fatty acid synthase production. Gypenoside XIII also increased lipolysis and fatty acid β‐oxidation by promoting adipose triglyceride lipase and carnitine palmitoyltransferase 1, respectively. In an animal model of NASH, gypenoside XIII effectively decreased the lipid vacuole size and number and reduced liver fibrosis and inflammation. These findings suggest that gypenoside XIII can regulate lipid metabolism in fatty liver cells and improve liver fibrosis in NASH mice. Therefore, gypenoside XIII has potential as a novel agent for the treatment of NASH.

Abstract Ulcerative colitis (UC) is a complicated and recurrent intestinal disease. Currently available drugs for UC treatment are scarce, therefore, novel therapeutic drugs for the UC are urgently to be developed. Gingerenone A (GA) is a phenolic compound known for its anti‐inflammatory effect, but its effect on UC remains unknown. Here, it is shown that GA protects mice against UC, which is closely associated with inhibiting intestinal mucosal inflammation and enhancing intestinal barrier integrity in vivo and in vitro. Of note, RNA sequencing analysis demonstrates an evident correlation with IL‐17 signaling pathway after GA treatment, and this effect is further corroborated by Western blot. Mechanistically, GA directly interacts with IL‐17RA protein through pull‐down, surface plasmon resonance analysis and molecular dynamics simulation. Importantly, lentivirus‐mediated IL‐17RA/Act1 knock‐down or GA co‐treatment with brodalumab/ixekizumab significantly impairs the protective effects of GA against DSS‐induced inflammation and barrier dysfunction, suggesting a critical role of IL‐17RA signaling for GA‐mediated protection against UC. Overall, these results indicate that GA is an effective agent against UC mainly through the direct binding of IL‐17RA to inhibit inflammatory signaling activation.

Taxus cuspidata S. et Z. is a precious species of frigid zone plant belonging to the Taxaceae family, which possesses anticancer, anti-inflammatory, hypoglycemic, and antibacterial pharmacological properties. While taxane extracted from Taxus chinensis has been reported to elicit antioxidant activities, whether Taxus cuspidata S. et Z. has skin-protective actions against injuries remained unknown. This study aims to explore the pharmacological effects of three Taxus extracts on skin melanin deposition, oxidation, inflammation, and allergy so as to provide new ideas for the prevention and treatment of various diseases related to skin damage.

Microplastics (MPs) may pollute drinking water, accumulate in the food chain, and release toxic chemicals that may cause a variety of diseases. The detrimental effects of MPs on kidney injury and fibrosis under long-term accumulation have not been fully documented. In this study, mice were exposed to MPs with three different diameters (80 nm, 0.5 µm, and 5 µm) to investigate the detrimental influences of MPs on the kidney. The results showed that MPs of different diameters caused varying degrees of injury to the murine kidney. MPs exposure can induce an inflammatory response, oxidative stress, and cell apoptosis in the kidney and induce kidney injury, which ultimately promotes kidney fibrosis. Furthermore, transcriptome data revealed that chronic exposure to MPs could alter the expressions of multiple genes related to immune response (80 nm) and circadian rhythm (0.5 µm, and 5 µm). Overall, our data provide new evidence and potential research for investigating the harm of MPs to kidney of mammals and even humans.

PurposeBladder cancer (BLCA) is one of the most frequently diagnosed urological malignancies and is the 4th most common cancer in men worldwide. Molecular targets expressed in bladder cancer (BLCA) are usually used for developing targeted drug treatments. However, poor prognosis and poor immunotherapy efficacy remain major challenges for BLCA. Numerous studies have shown that long non-coding RNAs (LncRNAs) play an important role in the development of cancer. However, the role of lncRNAs related to inflammation in BLCA and their prognostic value remain unclear. Therefore, this study is aimed to explore new potential biomarkers that can predict cancer prognosis.MethodsWe downloaded BLCA-related RNA sequencing data from The Cancer Genome Atlas (TCGA) and searched for inflammation-related prognostic long non-coding RNAs (lncRNAs) by univariate Cox (uniCox) regression and co-expression analysis. We used the least absolute shrinkage and selection operator (LASSO) analysis to construct an inflammation-related lncRNA prognosis risk model. Samples were divided into high-risk score (HRS) group and low-risk score (LRS) group based on the median value of risk scores. The independent variable factors were identified by univariate Cox (uni-Cox) and multivariate Cox (multi-Cox) regression analyses, and receiver operating characteristic (ROC) curves were used to compare the role of different factors in predicting outcomes. Nomogram and Calibration Plot were generated by the R package rms to analyze whether the prediction results are correct and show good consistency. Correlation coefficients were calculated by Pearson analysis. The Kaplan-Meier method was used to assess the prognostic value. The expression of 7 lncRNAs related with inflammation was also confirmed by qRT-PCR in BLCA cell lines. Kyoto Encyclopedia of Gene and Genome (KEGG) pathways that were significantly enriched (P < 0.05) in each risk group were identified by the GSEA software. The R package pRRophetic was used to predict the IC50 of common chemotherapeutic agents. TIMER, XCELL, QUANTISEQ, MCPCOUNTER, EPIC and CIBERSORT were applied to quantify the relative proportions of infiltrating immune cells. We also used package ggpubr to evaluate TME scores and immune checkpoint activation in LRS and HRS populations. R package GSEABase was used to analyze the activity of immune cells or immune function. Different clusters of principal component analysis (PCA), t-distribution random neighborhood embedding (t-SNE), and Kaplan-Meier survival were analyzed using R package Rtsne’s. The R package ConsensesClusterPlus was used to class the inflammation-related lncRNAs.ResultsIn this study, a model containing 7 inflammation-related lncRNAs was constructed. The calibration plot of the model was consistent with the prognosis prediction outcomes. The 1-, 3-, and 5-year ROC curve (AUC) were 0.699, 0.689, and 0.699, respectively. High-risk patients were enriched in lncRNAs related with tumor invasion and immunity, and had higher levels of immune cell infiltration and immune checkpoint activation. Hot tumors and cold tumors were effectively distinguished by clusters 2 and 3 and cluster 1, respectively, which indicated that hot tumors are more susceptible to immunotherapy.ConclusionOur study showed that inflammation-related LncRNAs are closely related with BLCA, and inflammation-related lncRNA can accurately predict patient prognosis and effectively differentiate between hot and cold tumors, thus improving individualized immunotherapy for BLCA patients. Therefore, this study provides an effective predictive model and a new therapeutic target for the prognosis and clinical treatment of BLCA, thus facilitating the development of individualized tumor therapy.

[Display omitted] • The immune response and inflammation in pulmonary hypertension (PH) have been systematically summarized based on recent studies. • The relationship between CC chemokines and the pathogenesis of pH is summarized in clinical and animal models. • We found that although the immune response serves as an important potential factor in the pathogenesis of PH, less attention has been paid to CC chemokines and their receptors. • We believe that a greater understanding of the relationship between PH and CC chemokines and their receptors is a pressing issue. • We believe that we need to further clarify the pathogenesis of pH and provide basis for the clinical treatment of PH. Pulmonary hypertension (PH) represents a progressive condition characterized by the remodeling of pulmonary arteries, ultimately culminating in right heart failure and increased mortality rates. Substantial evidence has elucidated the pivotal role of perivascular inflammatory factors and immune dysregulation in the pathogenesis of PH. Chemokines, a class of small secreted proteins, exert precise control over immune cell recruitment and functionality, particularly with respect to their migration to sites of inflammation. Consequently, chemokines emerge as critical drivers facilitating immune cell infiltration into the pulmonary tissue during inflammatory responses. This review comprehensively examines the significant contributions of CC chemokines in the maintenance of immune cell homeostasis and their pivotal role in regulating inflammatory responses. The central focus of this discussion is directed towards elucidating the precise immunoregulatory actions of CC chemokines concerning various immune cell types, including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, mast cells, eosinophils, and basophils, particularly in the context of pH processes. Furthermore, this paper delves into an exploration of the underlying pathogenic mechanisms that underpin the development of PH. Specifically, it investigates processes such as cellular pyroptosis, examines the intricate crosstalk between bone morphogenetic protein receptor type 2 (BMPR2) mutations and the immune response, and sheds light on key signaling pathways involved in the inflammatory response. These aspects are deemed critical in enhancing our understanding of the complex pathophysiology of PH. Moreover, this review provides a comprehensive synthesis of findings from experimental investigations targeting immune cells and CC chemokines. Aim of review : In summary, the inquiry into the inflammatory responses mediated by CC chemokines and their corresponding receptors, and their potential in modulating immune reactions, holds promise as a prospective avenue for addressing PH. The potential inhibition of CC chemokines and their receptors stands as a viable strategy to attenuate the inflammatory cascade and ameliorate the pathological manifestations of PH. Nonetheless, it is essential to acknowledge the current state of clinical trials and the ensuing progress, which regrettably appears to be less than encouraging. Substantial hurdles exist in the successful translation of research findings into clinical applications. The intention is that such emphasis could potentially foster the advancement of potent therapeutic agents presently in the process of clinical evaluation. This, in turn, may further bolster the potential for effective management of PH. [ABSTRACT FROM AUTHOR]

Increased medical attention is needed as the prevalence of autism spectrum disorder (ASD) rises. Both cardiovascular disorder (CVD) and hyperlipidemia are closely associated with adult ASD. Shank3 plays a key genetic role in ASD. We hypothesized that Shank3 contributes to CVD development in young adults with ASD. In this study, we investigated whether Shank3 facilitates the development of atherosclerosis. Using Gene Set Enrichment Analysis software (Version No.: GSEA-4.0.3), we analyzed the data obtained from Shank3 knockout mice (Gene Expression Omnibus database), a human population-based study cohort (from Taiwan’s National Health Insurance Research Database), and a Shank3 knockdown cellular model. Shank3 knockout upregulated the expression of genes of cholesterol homeostasis and fatty acid metabolism but downregulated the expression of genes associated with inflammatory responses. Individuals with autism had higher risks of hyperlipidemia (adjusted hazard ratio (aHR): 1.39; p < 0.001), major adverse cardiac events (aHR: 2.67; p < 0.001), and stroke (aHR: 3.55; p < 0.001) than age- and sex-matched individuals without autism did. Shank3 downregulation suppressed tumor necrosis factor-α-induced fatty acid synthase expression; vascular cell adhesion molecule 1 expression; and downstream signaling pathways involving p38, Jun N-terminal kinase, and nuclear factor-κB. Thus, Shank3 may influence the development of early-onset atherosclerosis and CVD in ASD. Furthermore, regulating Shank3 expression may reduce inflammation-related disorders, such as atherosclerosis, by inhibiting tumor necrosis factor-alpha-mediated inflammatory cascades.

Pulmonary fibrosis (PF) is a chronic lung disorder characterized by the presence of scarred and thickened lung tissues. Although the Food and Drug Administration approved two antifibrotic drugs, pirfenidone, and nintedanib, that are currently utilized for treating idiopathic PF (IPF), the clinical therapeutic efficacy remains unsatisfactory. It is crucial to develop new drugs or treatment schemes that combine pirfenidone or nintedanib to achieve more effective outcomes for PF patients. Understanding the complex mechanisms underlying PF could potentially facilitate drug discovery. Previous studies have found that the activation of inflammasomes, including nucleotide-binding and oligomerization domain (NOD)-like receptor protein (NLRP)1, NLRP3, NOD-like receptor C4, and absent in melanoma (AIM)2, contributes to lung inflammation and fibrosis. This article aims to summarize the cellular and molecular regulatory cues that contribute to PF with a particular emphasis on the role of AIM2 inflammasome in mediating pathophysiologic events during PF development. The insights gained from this research may pave the way for the development of more effective strategies for the prevention and treatment of PF.

Ulcerative colitis (UC) is a complicated and recurrent intestinal disease. Currently available drugs for UC treatment are scarce, therefore, novel therapeutic drugs for the UC are urgently to be developed. Gingerenone A (GA) is a phenolic compound known for its anti‐inflammatory effect, but its effect on UC remains unknown. Here, it is shown that GA protects mice against UC, which is closely associated with inhibiting intestinal mucosal inflammation and enhancing intestinal barrier integrity in vivo and in vitro. Of note, RNA sequencing analysis demonstrates an evident correlation with IL‐17 signaling pathway after GA treatment, and this effect is further corroborated by Western blot. Mechanistically, GA directly interacts with IL‐17RA protein through pull‐down, surface plasmon resonance analysis and molecular dynamics simulation. Importantly, lentivirus‐mediated IL‐17RA/Act1 knock‐down or GA co‐treatment with brodalumab/ixekizumab significantly impairs the protective effects of GA against DSS‐induced inflammation and barrier dysfunction, suggesting a critical role of IL‐17RA signaling for GA‐mediated protection against UC. Overall, these results indicate that GA is an effective agent against UC mainly through the direct binding of IL‐17RA to inhibit inflammatory signaling activation. [ABSTRACT FROM AUTHOR]

Background: Parotid gland carcinoma (PGC) is a rare malignant tumor. The purpose of this study was to investigate the role of immune-inflammatory-nutrition indicators and age-adjusted Charlson comorbidity index score (ACCI) of PGC and develop the nomogram model for predicting prognosis. Method: All patients diagnosed with PGC in two tertiary hospitals, treated with surgical resection, from March 2012 to June 2018 were obtained. Potential prognostic factors were identified by univariate and multivariate Cox regression analyses. The nomogram models were established based on these identified independent prognostic factors. The performance of the developed prognostic model was estimated by related indexes and plots. Result: The study population consisted of 344 patients with PGC who underwent surgical resection, 285 patients without smoking (82.8%), and 225 patients (65.4%) with mucoepidermoid carcinoma, with a median age of 50.0 years. American Joint Committee on Cancer (AJCC) stage (p < 0.001), pathology (p = 0.019), tumor location (p < 0.001), extranodal extension (ENE) (p < 0.001), systemic immune-inflammation index (SII) (p = 0.004), prognostic nutrition index (PNI) (p = 0.003), ACCI (p < 0.001), and Glasgow prognostic Score (GPS) (p = 0.001) were independent indicators for disease free survival (DFS). Additionally, the independent prognostic factors for overall survival (OS) including AJCC stage (p = 0.015), pathology (p = 0.004), tumor location (p < 0.001), perineural invasion (p = 0.009), ENE (p < 0.001), systemic immune-inflammation index (SII) (p = 0.001), PNI (p = 0.001), ACCI (p = 0.003), and GPS (p = 0.033). The nomogram models for predicting DFS and OS in PGC patients were generated based on these independent risk factors. All nomogram models show good discriminative capability with area under curves (AUCs) over 0.8 (DFS 0.802, and OS 0.825, respectively). Decision curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification index (NRI) show good clinical net benefit of the two nomograms in both training and validation cohorts. Kaplan-Meier survival analyses showed superior discrimination of DFS and OS in the new risk stratification system compared with the AJCC stage system. Finally, postoperative patients with PGC who underwent adjuvant radiotherapy had a better prognosis in the high-, and medium-risk subgroups (p < 0.05), but not for the low-risk subgroup. Conclusion: The immune-inflammatory-nutrition indicators and ACCI played an important role in both DFS and OS of PGC patients. Adjuvant radiotherapy had no benefit in the low-risk subgroup for PGC patients who underwent surgical resection. The newly established nomogram models perform well and can provide an individualized prognostic reference, which may be helpful for patients and surgeons in proper follow-up strategies. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the causal relationship between inflammatory cytokines and the risk of varicose veins. The data were sourced from genome‐wide association studies (GWAS) of European individuals. Multiple Mendelian randomization (MR) methods were used to evaluate the association between inflammatory cytokines and varicose veins. The study found significant associations between elevated levels of certain inflammatory biomarkers (e.g., CASP‐8, Vascular endothelial growth factor A levels (VEGF_A)) and an increased risk of varicose veins, while others (e.g., 4EBP1, MMP‐10) showed a protective effect. The MR‐Egger Intercept and heterogeneity tests indicated no significant pleiotropy or heterogeneity. This comprehensive MR analysis identifies several cytokines as potential contributors to the pathogenesis of varicose veins, offering insights into novel therapeutic targets. Our findings underscore the importance of inflammation in varicose veins and suggest that targeting specific cytokines could be a promising strategy for the treatment and prevention of varicose veins. [ABSTRACT FROM AUTHOR]

The gingival epithelium–capillary interface is a unique feature of periodontal soft tissue, preserving periodontal tissue homeostasis and preventing microorganism and toxic substances from entering the subepithelial tissue. However, the function of the interface is disturbed in periodontitis, and mechanisms of the breakdown of the interface are incompletely understood. To address these limitations, we developed a microfluidic epithelium–capillary barrier with a thin culture membrane (10 μm) that closely mimics the in vivo gingival epithelial barrier with an immune micro-environment. To test the validity of the fabricated gingival epithelial barrier model, epithelium–capillary interface-on-a-chip was cultured with human gingival epithelial cells (HGECs) and human vascular endothelial cells (HUVEC). Their key properties were tested using optical microscope, transepithelial/transendothelial electrical resistance (TEER), and permeability assays. The clear expression of VE-cadherin revealed the tight junctions in endothelial cells. Live/dead assays indicated a high cell viability, and the astrocytic morphology of HGE cells was confirmed by F-actin immunostaining. By the third day of cell culture, TEER levels typically exceeded in co-cultures. The resultant permeability coefficients showed a significant difference between 70 kDa and 40 kDa FITC-dextran. The expression of protein intercellular cell adhesion molecule (ICAM-1) and human beta defensin-2 (HBD2) decreased when exposed to TNF-α and LPS, but recovered with the NF-κB inhibitor treatment- Pyrrolidinedithiocarbamic acid (PDTC), indicating the stability of the fabricated chip. These results demonstrate that the developed epithelium-capillary interface system is a valid model for studying periodontal soft tissue function and drug delivery.

Spinal cord injury is a complex central nervous system disease with an unsatisfactory prognosis, often accompanied by multiple pathological processes. However, the underlying mechanisms of action of this disease are unclear, and there are no suitable targeted therapeutic options. Long non-coding RNA mediates a variety of neurological diseases and regulates various biological processes, including apoptosis and autophagy, inflammatory response, microenvironment, and oxidative stress. It is known that long non-coding RNAs have significant differences in gene expression in spinal cord injury. To further understand the mechanism of long non-coding RNA action in spinal cord injury and develop preventive and therapeutic strategies regarding spinal cord injury, this review outlines the current status of research between long non-coding RNAs and spinal cord injury and potential long non-coding RNAs targeting spinal cord injury. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study aimed to explore the changes of programmed death-ligand 1 (PDL1) and programmed death-1 (PD-1) expression on antigen-presenting cells (APCs) and evaluate their association with organ failure and mortality during early sepsis. METHODS: In total, 40 healthy controls and 198 patients with sepsis were included in this study. Peripheral blood was collected within the first 24 h after the diagnosis of sepsis. The expression of PDL1 and PD-1 was determined on APCs, such as B cells, monocytes, and dendritic cells (DCs), by flow cytometry. Cytokines in plasma, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-6, IL-10, and IL-17A were determined by Luminex assay. RESULTS: PD-1 expression decreased significantly on B cells, monocytes, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs) as the severity of sepsis increased. PD-1 expression was also markedly decreased in non-survivors compared with survivors. In contrast, PD-L1 expression was markedly higher on mDCs, pDCs, and monocytes in patients with sepsis than in healthy controls and in non-survivors than in survivors. The PD-L1 expression on APCs (monocytes and DCs) was weakly related to organ dysfunction and inflammation. The area under the receiver operating characteristic curve (AUC) of the PD-1 percentage of monocytes (monocyte PD-1%)+APACHE II model (0.823) and monocyte PD-1%+SOFA model (0.816) had higher prognostic value than other parameters alone. Monocyte PD-1% was an independent risk factor for 28-day mortality. CONCLUSION: The severity of sepsis was correlated with PD-L1 or PD-1 over-expression on APCs. PD-L1 in monocytes and DCs was weakly correlated with inflammation and organ dysfunction during early sepsis. The combination of SOFA or APACHE II scores with monocyte PD-1% could improve the prediction ability for mortality. [ABSTRACT FROM AUTHOR]

Although cisplatin is a potent chemotherapeutic agent against cancers, its clinical application is seriously limited by its severe side effects of nephrotoxicity. Previous studies reported that saponins isolated from the roots of Platycodon grandiflorum (PGS) exerted protective effects in various animal models of renal injury, with no confirmation on cisplatin-induced injury. This study was designed to investigate the protective effect of PGS (15 and 30 mg/kg) on cisplatin-induced kidney injury in mice. The levels of serum creatinine (CRE) and blood urea nitrogen (BUN), and renal histopathology demonstrated the protective effect of PGS against cisplatin-induced kidney injury. PGS exerted anti-inflammation effects via suppressing nuclear factor-kappa B (NF-κB) activation and alleviating the cisplatin-induced increase in inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in kidney tissues. The expressions of phosphorylation of phosphatidylinositol 3-kinase/protein kinase B and its downstream apoptotic factors, such as Bcl-2 and caspase families were regulated by PGS in a dose-dependent manner. In conclusion, PGS exerted kidney protection effects against cisplatin-induced kidney injury by inhibiting the activation of NF-κB and regulating PI3K/Akt/apoptosis signaling pathways in mice.