OBJECTIVE: To reveal the mechanisms by which miR-513b-5p inhibits metastasis of colon cancer stem cells (CCSCs) through IL-6/STAT3 in HCT116 cells.
METHODS: Sphere formation media and magnetic cell sorting were used to enrich and screen CCSCs. We used a colony formation assay, cell proliferation and viability assays, and a nude mouse transplantation tumor assay to identify CCSCs. ELISA was performed to identify IL-6 in the cell culture medium, and the growth, viability, wound healing, and transwell migration of distinct cell groups were compared to differentiate them. Dual-luciferase reporter assay, RT-PCR, and/or Western Blot analysis were conducted to determine the correlation between them.
RESULTS: CD133+CD44+ HCT116 cells were shown to have higher cloning efficiency, greater proliferation ability and viability, and stronger tumorigenicity. A dual-luciferase reporter assay revealed that miR-513b-5p negatively affected STAT3 expression. RT-PCR and/or Western Blot analysis suggested that miR-513b-5p negatively affected STAT3 and Vimentin, while positively affecting E-cadherin expression. The STAT3 overexpression vector + miR-513b-5p inhibitor cell group had the highest efficiency, greatest proliferation ability and viability, and the highest IL-6 level in the experiments.
CONCLUSIONS: Mir-513b-5p inhibited the epithelial-mesenchymal transition (EMT) of CCSCs through IL-6/STAT3. This potential mechanism may provide a new therapeutic target for colon cancer.

Colorectal cancer (CRC) has emerged as a prevalent malignancy worldwide, exhibiting the high morbidity and mortality rates. Resolvin D1 (RvD1) can exert anti-inflammation and anti-cancer effects on various diseases. This study is aimed to explore the role of RvD1 in CRC cells. HCT15 and SW480 cells were stimulated with IL-6 in our study. A series of assays such as CCK-8, colony formation, wound healing, Transwell, Western blotting, and immunofluorescence staining were designed and conducted to figure out the role of RvD1 in CRC cells. RvD1 suppressed IL-6-induced SW480 and HCT15 cell proliferation. In addition, RvD1 inhibited IL-6-induced SW480 and HCT15 cell migration, invasion, and EMT process. In mechanism, RvD1 inhibited the activation of IL-6/STAT3 signaling in SW480 and HCT15 cells. Angoline strengthened the inhibitive effect of RvD1 on cell malignancy. RvD1 inhibited cell growth, migration, invasion and EMT process by inactivating IL-6/STAT3 signaling in CRC.

BACKGROUND: Primary membranous nephropathy (PMN) is an autoimmune glomerular disease. IL-6 is a potential therapeutic target for PMN. Previous clinical studies have demonstrated the effectiveness of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in treating membranous nephropathy. However, the mechanism of action of MFSD remains unclear.
METHODS: Serum IL-6 levels were measured in patients with PMN and healthy subjects. The passive Heymann nephritis (PHN) rat model was established, and high and low doses of MFSD were used for intervention to observe the repair effect of MFSD on renal pathological changes and podocyte injury. RNA-seq was used to screen the possible targets of MFSD, and the effect of MFSD targeting IL-6/STAT3 was further verified by combining the experimental results. Finally, the efficacy of tocilizumab in PHN rats was observed.
RESULTS: Serum IL-6 levels were significantly higher in PMN patients than in healthy subjects. These levels significantly decreased in patients in remission after MFSD treatment. MFSD treatment improved laboratory indicators in PHN rats, as well as glomerular filtration barrier damage and podocyte marker protein expression. Renal transcriptome changes showed that MFSD-targeted differential genes were enriched in JAK/STAT and cytokine-related pathways. MFSD inhibits the IL6/STAT3 pathway in podocytes. Additionally, MFSD significantly reduced serum levels of IL-6 and other cytokines in PHN rats. However, treatment of PHN with tocilizumab did not achieve the expected effect.
CONCLUSIONS: The IL-6/STAT3 signaling pathway is activated in podocytes of experimental membranous nephropathy. MFSD alleviates podocyte damage by inhibiting the IL-6/STAT3 pathway.

Interleukin-6 (IL-6) is involved in the activation of several oncogenic pathways in prostate cancer. However, its upstream trans-signaling pathway remains largely unknown. This work proposes a mechanistic explanation of IL-6\'s upstream effectors in prostate carcinogenesis.
Samples were harvested to validate the expression of EZH2, miR-26a-5p, and IL-6. Moreover, the protein and its phosphorylation of STAT3 (signal transducer and transcription activator 3) were assessed in prostate cancer cells. We explored the effects of these effectors on malignant phenotypes in vitro and tumor growth in vivo using functional assays. Bioinformatics analysis, dual-luciferase reporter gene assays, and chromatin immunoprecipitation (ChIP) assays were used to determine their binding relationships.
Overexpression of EZH2 and IL-6, and under expression of miR-26a-5p was observed in prostate cancer. Silencing IL-6 repressed STAT3 to suppress the malignant phenotypes of prostate cancer cells. Mechanistically, EZH2 inhibited miR-26a-5p expression by promoting H3K27 histone methylation, and miR-26a-5p restricted the malignant phenotypes of prostate cancer by targeting IL-6. Ectopic EZH2 expression reduced xenograft growth by inhibiting miR-26a-5p and activating the IL-6/STAT3 axis.
EZH2 May potentially be involved in regulating its expression by recruiting H3K27me3 to the miR-26a-5p promoter region, which could further impact the IL6/STAT3 pathway.

UNASSIGNED: To further investigate why curcumin (CUR) can attenuate psoriasis-like dermatitis of mice.
UNASSIGNED: Sixteen mice were randomized into four groups. The control group used carrier cream, and the model and the CUR group were applied with topical 5% imiquimod in the naked mice skin once a day for 6 days (62.5 mg/day/mice). Meanwhile, the control and model mice were given the same dose of saline by oral means, while mice in the CUR groups received oral drug doses of 50 and 100 mg/kg once a day for 6 days, respectively. CUR could largely improve imiquimod-induced lesions of mice. By using the ELISA and qPCR, we found that the protein and mRNA levels of epidermal TNF-α and IL-6 were inhibited by CUR. The phosphorylation levels of STAT3 and its downstream associated protein levels (eg, Cyclin D1, Bcl-2 and Pim1) in skin tissues of different groups were also inhibited by CUR. Furthermore, the results of immunohistochemistry also showed the repressed effect of CUR for the expression of TNF-α, IL-6 and p-STAT3 in psoriasis-like lesions of mice.
UNASSIGNED: CUR can effectively ameliorate the featured lesions of psoriasis mice, which may be closely associated with the involvement of IL-6/STAT3 signaling.

Background: Prostate cancer is the most common malignant tumor in men, accounting for one of the top five cancer incidences worldwide. However, there is no effective pharmacological treatment for advanced prostate cancer (APC). Herein, we aim to investigate the mechanism of Zhoushi Qiling decoction (ZQD), a traditional Chinese medicine compound, in inhibiting prostate cancer cells proliferation and tumor growth. Methods: IC50 was determined in PC3 and DU145 cells. Cell viability was determined using MTT assay after interleukin (IL) 6 stimulation. Cell proliferation ability was evaluated using colony formation assay. IL-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway was analyzed using qRT-PCR and Western blot in PC3 and DU145 cells and xenograft tumor tissues. Results: It was found that ZQD significantly inhibited Il-6-induced cell viability and proliferation in PC3 and DU145 cells. Moreover, ZQD significantly reduced mRNA levels of IL-6, IL-1β, STAT3, Bcl2, and CyclinD1, stimulated by IL-6. The protein levels of p-STAT3, Bcl2 and CyclinD1 were reduced by ZQD treatment at 40 mg/mL both in PC3 and DU145 cells. Additionally, in xenograft tumor tissues, tumor volume, weight and proliferation were significantly reduced by ZQD treatment. In addition, the mRNA and protein levels of IL-6 and pSTAT3 were significantly inhibited by ZQD treatment in vivo. Conclusion: We demonstrate that ZQD can effectively reduce cell proliferation and tumor growth by inhibiting the activation of IL-6/STAT3 signaling pathway.

The association between oral microbiota and cancer development has been a topic of intense research in recent years, with compelling evidence suggesting that the oral microbiome may play a significant role in cancer initiation and progression. However, the causal connections between the two remain a subject of debate, and the underlying mechanisms are not fully understood. In this case-control study, we aimed to identify common oral microbiota associated with several cancer types and investigate the potential mechanisms that may trigger immune responses and initiate cancer upon cytokine secretion. Saliva and blood samples were collected from 309 adult cancer patients and 745 healthy controls to analyze the oral microbiome and the mechanisms involved in cancer initiation. Machine learning techniques revealed that six bacterial genera were associated with cancer. The abundance of Leuconostoc, Streptococcus, Abiotrophia, and Prevotella was reduced in the cancer group, while abundance of Haemophilus and Neisseria enhanced. G protein-coupled receptor kinase, H+-transporting ATPase, and futalosine hydrolase were found significantly enriched in the cancer group. Total short-chain fatty acid (SCFAs) concentrations and free fatty acid receptor 2 (FFAR2) expression levels were greater in the control group when compared with the cancer group, while serum tumor necrosis factor alpha induced protein 8 (TNFAIP8), interleukin-6 (IL6), and signal transducer and activator of transcription 3 (STAT3) levels were higher in the cancer group when compared with the control group. These results suggested that the alterations in the composition of oral microbiota can contribute to a reduction in SCFAs and FFAR2 expression that may initiate an inflammatory response through the upregulation of TNFAIP8 and the IL-6/STAT3 pathway, which could ultimately increase the risk of cancer onset.

The tumor microenvironment is a complex and dynamic ecosystem composed of various physical cues and biochemical signals that facilitate cancer progression, and tumor-associated macrophages are especially of interest as a treatable target due to their diverse pro-tumorigenic functions. Engineered three-dimensional models of tumors more effectively mimic the tumor microenvironment than monolayer cultures and can serve as a platform for investigating specific aspects of tumor biology within a controlled setting. To study the combinatorial effects of tumor-associated macrophages and microenvironment mechanical properties on osteosarcoma, we co-cultured human osteosarcoma cells with macrophages within biomaterials-based bone tumor niches with tunable stiffness. In the first 24 h of direct interaction between the two cell types, macrophages induced an inflammatory environment consisting of high concentrations of tumor necrosis factor alpha (TNFα) and interleukin (IL)-6 within moderately stiff scaffolds. Expression of Yes-associated protein (YAP), but not its homolog, transcriptional activator with PDZ-binding motif (TAZ), in osteosarcoma cells was significantly higher than in macrophages, and co-culture of the two cells slightly upregulated YAP in both cells, although not to a significant degree. Resistance to doxorubicin treatment in osteosarcoma cells was correlated with inflammation in the microenvironment, and signal transducer and activator of transcription 3 (STAT3) inhibition diminished the inflammation-related differences in drug resistance but ultimately did not improve the efficacy of doxorubicin. This work highlights that the biochemical cues conferred by tumor-associated macrophages in osteosarcoma are highly variable, and signals derived from the immune system should be considered in the development and testing of novel drugs for cancer.

The ongoing pandemic of COVID-19 has caused more than 6.7 million tragic deaths, plus, a large percentage of people who survived it present a myriad of chronic symptoms that last for at least 6 months; this has been named as long COVID. Some of the most prevalent are painful symptoms like headache, joint pain, migraine, neuropathic-like pain, fatigue and myalgia. MicroRNAs are small non-coding RNAs that regulate genes, and their involvement in several pathologies has been extensively shown. A deregulation of miRNAs has been observed in patients with COVID-19. The objective of the present systematic review was to show the prevalence of chronic pain-like symptoms of patients with long COVID and based on the expression of miRNAs in patients with COVID-19, and to present a proposal on how they may be involved in the pathogenic mechanisms of chronic pain-like symptoms. A systematic review was carried out in online databases for original articles published between March 2020 to April 2022; the systematic review followed the PRISMA guidelines, and it was registered in PROSPERO with registration number CRD42022318992. A total of 22 articles were included for the evaluation of miRNAs and 20 regarding long COVID; the overall prevalence of pain-like symptoms was around 10 to 87%, plus, the miRNAs that were commonly up and downregulated were miR-21-5p, miR-29a,b,c-3p miR-92a,b-3p, miR-92b-5p, miR-126-3p, miR-150-5p, miR-155-5p, miR-200a, c-3p, miR-320a,b,c,d,e-3p, and miR-451a. The molecular pathways that we hypothesized to be modulated by these miRNAs are the IL-6/STAT3 proinflammatory axis and the compromise of the blood-nerve barrier; these two mechanisms could be associated with the prevalence of fatigue and chronic pain in the long COVID population, plus they could be novel pharmacological targets in order to reduce and prevent these symptoms.

Oxaliplatin (OXA) is easy to cause sinusoidal obstruction syndrome (SOS), leading to liver injury. Isolinderalactone (ILL), one of the main components of Lindera aggregate, has been reported to have a protecting effect on the liver. However, it is unclear whether ILL has a therapeutic effect on liver injury caused by OXA. This study aims to determine the effect of ILL on the prevention and treatment of OXA-induced liver injury and to provide a basis for the chemotherapy of gastrointestinal tumors.
Intraperitoneal injection of folinic acid, 5-fluorouracil, and OXA was administered on the SOS rat model for 7 weeks. The indexes of liver function were measured by biochemical kit. The ratio of liver weight to body weight was calculated. The pathological analysis of the liver was scored with the SOS scoring standard, fibrosis was evaluated with a four-point scale. The expression of inflammation factors was detected by Real-Time PCR, and the related indexes of IL-6/STAT3 were examined by Western blot analysis.
ILL down-regulated the portal vein pressure and alleviated the abnormal liver function of SOS rats and improved the liver lesions. ILL inhibited the SOS by inhibiting IL-6/STAT3.
ILL resistance to liver injury through inhibiting IL-6/STAT3 signal pathway.