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Surgery is unanimously regarded as the primary strategy to cure solid tumors in the early stages but is not always used in advanced cases. However, tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure. Tumor surgery may result in a deep wound, which induces many biological responses favoring tumor metastasis. In particular, NETosis, which is the process of forming neutrophil extracellular traps (NETs), has received attention as a risk factor for surgery-induced metastasis. To reduce cancer mortality, researchers have made efforts to prevent secondary metastasis after resection of the primary tumor. From this point of view, a better understanding of surgery-induced metastasis might provide new strategies for more effective and safer surgical approaches. In this paper, recent insights into the surgical effects on metastasis will be reviewed. Moreover, in-depth opinions about the effects of NETs on metastasis will be discussed.Cancer treatment: Understanding risk of spread after surgeryTherapies that limit the formation of web-like structures formed by white cells known as neutrophils may lower the risk of cancer spread (metastasis) following surgical tumor removal. Removing solid tumors remains a key cancer treatment, but in some cases surgery itself increases the risk of metastasis. Jong-Wan Park at Seoul National University, South Korea, and co-workers reviewed current understanding of metastasis following surgery. Surgical removal destroys the architecture supporting cancer cells but this can release tumor cells into blood vessels. The stress of deep wounds also affects immune responses, most notably neutrophil extracellular traps (NETs), web-like structures formed by neutrophils to trap and kill pathogens. NETs have previously been implicated in metastasis. In a post-surgical environment enriched in neutrophils and pro-inflammatory cytokines, NET formation may help cancer cells thrive, promoting metastasis.

Diabetes might be associated with increased cancer risk, with several studies reporting hyperglycemia as a primary oncogenic stimulant. Since glucose metabolism is linked to numerous metabolic pathways, it is difficult to specify the mechanisms underlying hyperglycemia-induced cancer progression. Here, we focused on the polyol pathway, which is dramatically activated under hyperglycemia and causes diabetic complications. We investigated whether polyol pathway-derived fructose facilitates hyperglycemia-induced gastric cancer metastasis. We performed bioinformatics analysis of gastric cancer datasets and immunohistochemical analyses of gastric cancer specimens, followed by transcriptomic and proteomic analyses to evaluate phenotypic changes in gastric cancer cells. Consequently, we found a clinical association between the polyol pathway and gastric cancer progression. In gastric cancer cell lines, hyperglycemia enhanced cell migration and invasion, cytoskeletal rearrangement, and epithelial-mesenchymal transition (EMT). The hyperglycemia-induced acquisition of metastatic potential was mediated by increased fructose derived from the polyol pathway, which stimulated the nuclear ketohexokinase-A (KHK-A) signaling pathway, thereby inducing EMT by repressing the CDH1 gene. In two different xenograft models of cancer metastasis, gastric cancers overexpressing AKR1B1 were found to be highly metastatic in diabetic mice, but these effects of AKR1B1 were attenuated by KHK-A knockdown. In conclusion, hyperglycemia induces fructose formation through the polyol pathway, which in turn stimulates the KHK-A signaling pathway, driving gastric cancer metastasis by inducing EMT. Thus, the polyol and KHK-A signaling pathways could be potential therapeutic targets to decrease the metastatic risk in gastric cancer patients with diabetes. Gastric cancer’s deadly dance with diabetes: the role of fructose in metastasis Diabetes and cancer, two major worldwide health concerns, often coexist in patients. Recent research suggests diabetes can heighten the risk of various cancers. However, the precise reasons behind this link remain unknown. In this study, researchers discovered that high glucose levels (sugar in the blood), a diabetes hallmark, can enhance cancer cell aggression. This occurs via the polyol pathway (a process where glucose transforms into a substance named fructose). The fructose then triggers a specific signaling pathway (a series of chemical reactions) in the cancer cells, leading to their increased movement and invasion, signs of more aggressive cancers. This study offers a potential reason for the diabetes-cancer connection and implies that managing blood sugar levels in cancer patients with diabetes could be vital in preventing cancer progression. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Artemisia princeps var. orientalis (Asteraceae, A. princeps) is a well-known traditional medicinal herb used for treating various inflammatory disorders in Korea, Japan, China, and other Asian countries. In the present study, we investigated the effects of A. princeps extract (APO) on interleukin- (IL-) 1β regulation and inflammasome activation in bone marrow-derived macrophages (BMDMs) and monosodium urate- (MSU-) induced peritonitis mouse model in vivo. The APO treatment to BMDMs primed with lipopolysaccharide (LPS) attenuated the NLRP3 and AIM2 inflammasome activation induced by danger signals, such as ATP, nigericin, silica crystals, and poly (dA:dT), respectively. Mechanistic study revealed that APO suppressed the ASC oligomerization and speck formation, which are required for inflammasome activation. APO treatment also reduced the ASC phosphorylation induced by the combination of LPS and a tyrosine phosphatase inhibitor. In vivo evaluation revealed that intraperitoneal administration of APO reduced IL-1β levels, significantly (p<0.05) and dose dependently, in the MSU-induced peritonitis mouse model. In conclusion, our study is the first to report that the extract of A. princeps inhibits inflammasome activation through the modulation of ASC phosphorylation. Therefore, APO might be developed as therapeutic potential in the treatment of inflammasome-mediated inflammatory disorders, such as gouty arthritis.

Arctium lappa (A. lappa), Compositae, is considered a potential source of nutrition and is used as a traditional medicine in East Asian countries for centuries. Although several studies have shown its biological activities as an anti-inflammatory agent, there have been no reports on A. lappa with regard to regulatory role in inflammasome activation. The purpose of this study was to investigate the inhibitory effects of A. lappa extract (ALE) on NLRP3 inflammasome activation and explore the underlying mechanisms. We found that ALE inhibited IL-1β secretion from NLRP3 inflammasome activated bone marrow derived macrophages but not that secreted by NLRC4 and AIM2 inflammasomes activation. Mechanistic studies revealed that ALE suppressed the ATPase activity of purified NLRP3 and reduced mitochondrial reactive oxygen species (mROS) generated during NLRP3 activation. Therefore, the inhibitory effect of ALE on NLRP3 inflammasome might be attributed to its ability to inhibit the NLRP3 ATPase function and attenuated the mROS during inflammasome activation. In addition, ALE significantly reduced the LPS-induced increase of plasma IL-1β in mouse peritonitis model. These results provide evidence of novel anti-inflammatory mechanisms of A. lappa, which might be used for therapeutic applications in the treatment of NLRP3 inflammasome-associated inflammatory disorders.

Emodin, an active constituent of oriental herbs, is widely used to treat allergy, inflammation, and other symptoms. This study provides the scientific basis for the anti-inflammasome effects of emodin on both in vitro and in vivo experimental models. Bone marrow-derived macrophages were used to study the effects of emodin on inflammasome activation by using inflammasome inducers such as ATP, nigericin, and silica crystals. The lipopolysaccharide (LPS)-induced endotoxin shock model was employed to study the effect of emodin on in vivo efficacy. Emodin treatment attenuated interleukin (IL)-1β secretion via the inhibition of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation induced by ATP, nigericin, and silica crystals. Further, emodin ameliorated the severity of NLRP3 inflammasome-mediated symptoms in LPS-induced endotoxin mouse models. This study is the first to reveal mechanism-based evidence, especially with respect to regulation of inflammasome activation, substantiating traditional claims of emodin in the treatment of inflammation-related disorders.

Neutrophilic chronic rhinosinusitis (CRS) is characterized by persistent inflammation and often responds poorly to corticosteroid therapy. In this disease, neutrophil extracellular traps (NETs) are increasingly recognized as key mediators of mucosal damage and polypogenesis. The removal of NETs by deoxyribonuclease 1 could be a potential therapeutic approach to overcome steroid resistance in neutrophilic CRS. In this study, we established a mouse model of neutrophilic CRS and evaluated the effect of a genetically engineered deoxyribonuclease 1 'AR-CR8 Dnase1' on NETs and polyp formation in the mice. Human neutrophils were isolated and treated with LPS to induce NET formation. An animal model for neutrophilic CRS and polyps was developed by intranasal administration of LPS and Staphylococcal toxin. H&E staining and immunofluorescence were performed to identify polyps, NETs, and immune cells in nasal cavities. AR-CR8 Dnase1 effectively degraded NET-like structures in LPS-stimulated human neutrophils. In the mouse CRS model, the intranasal administration of AR-CR8 Dnase1 noticeably reduced the burden of nasal polyps. The intranasal treatment of Dnase1 was effective as much as an injection of dexamethasone in reducing polyp number and NET accumulation in this model. These results suggest that an engineered deoxyribonuclease 1 like AR-CR8 Dnase1 be an emerging bio-drug to inhibit inflammatory reaction and polyp formation in patients with neutrophilic CRS. AR-CR8 Dnase1 may be an alternative therapeutic for patients with CRS who are not suitable for steroid therapy, and further studies comparing dosing, durability, and safety are needed before considering clinical use. Not applicable.

Emodin, an active constituent of oriental herbs, is widely used to treat allergy, inflammation, and other symptoms. This study provides the scientific basis for the anti-inflammasome effects of emodin on both in vitro and in vivo experimental models. Bone marrow-derived macrophages were used to study the effects of emodin on inflammasome activation by using inflammasome inducers such as ATP, nigericin, and silica crystals. The lipopolysaccharide (LPS)-induced endotoxin shock model was employed to study the effect of emodin on in vivo efficacy. Emodin treatment attenuated interleukin (IL)-1β secretion via the inhibition of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation induced by ATP, nigericin, and silica crystals. Further, emodin ameliorated the severity of NLRP3 inflammasome-mediated symptoms in LPS-induced endotoxin mouse models. This study is the first to reveal mechanism-based evidence, especially with respect to regulation of inflammasome activation, substantiating traditional claims of emodin in the treatment of inflammation-related disorders.

Acute pancreatitis (AP) is a complicated disease without specific drug therapy. The cofactor nicotinamide adenine dinucleotide (NAD + ) is an important regulator of cellular metabolism and homeostasis. However, it remains unclear whether modulation of NAD + levels has an impact on caerulein-induced AP. Therefore, in this study, we investigated the effect of increased cellular NAD + levels on caerulein-induced AP. We demonstrated for the first time that the activities and expression of SIRT1 were suppressed by reduction of intracellular NAD + levels and the p53-microRNA-34a pathway in caerulein-induced AP. Moreover, we confirmed that the increase of cellular NAD + by NQO1 enzymatic action using the substrate β-Lapachone suppressed caerulein-induced AP with down-regulating TLR4-mediated inflammasome signalling, and thereby reducing the inflammatory responses and pancreatic cell death. These results suggest that pharmacological stimulation of NQO1 could be a promising therapeutic strategy to protect against pathological tissue damage in AP.

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD+) levels by accelerating the oxidation of NADH to NAD+, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD+ levels on cancer-associated thrombosis. In this study, we show that dunnione (a strong substrate of NQO1) attenuates the prothrombotic state and lung thrombosis in tumor-bearing mice by inhibiting the expression of tissue factor and formation of neutrophil extracellular traps (NETs). Dunnione increases the cellular NAD+ levels in lung tissues of tumor-bearing mice to restore the declining sirtuin 1 (SIRT1) activity, thus deacetylating nuclear factor-kappa B (NF-κB) and preventing the overexpression of tissue factor in bronchial epithelial and vascular endothelial cells. In addition, we demonstrated that dunnione abolishes the ability of neutrophils to generate NETs by suppressing histone acetylation and NADPH oxidase (NOX) activity. Overall, our results reveal that the regulation of cellular NAD+ levels by pharmacological agents may inhibit pulmonary embolism in tumor-bearing mice, which may potentially be used as a viable therapeutic approach for the treatment of cancer-associated thrombosis.