Nicotinamide N-methyltransferase (NNMT) is overexpressed in various human tumors and involved in the development and progression of several carcinomas. In breast cancer, NNMT was found to be overexpressed in several cell lines. However, the clinical relevance of NNMT in breast cancer is not yet clear.

Intrarenal calcium oxalate (CaOx) crystals induce inflammation and kidney tubular cell injury, which are processes that involve TLR4/NF-κB signalling. A recent genome-wide gene expression profile analysis of Randall's plaques in CaOx stone patients revealed that the expression of the long noncoding RNA H19 was significantly upregulated. However, to date, its role in kidney CaOx stones has not been reported.

To observe the characteristics of binocular integration and stereopsis in children with television torticollis.

This study aimed to develop a machine learning (ML)-assisted model capable of accurately predicting the probability of biopsy Gleason grade group upgrading before making treatment decisions.

Ferroptosis, implicated in several diseases, is a new form of programmed and nonapoptotic cell death triggered by iron-dependent lipid peroxidation after inactivation of the cystine/glutamate antiporter system xc-, which is composed of solute carrier family 7 membrane 11 (SLC7A11) and solute carrier family 3 membrane 2 (SLC3A2). Therefore, inducing ferroptosis through inhibiting the cystine/glutamate antiporter system xc- may be an effective way to treat cancer. In previous screening tests, we found that the benzopyran derivative 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) significantly inhibited the viability of colorectal cancer cells. However, the impact of IMCA on ferroptosis remains unknown. Hence, this study investigated the effect of IMCA on ferroptosis and elucidated the underlying molecular mechanism. Results showed that IMCA significantly inhibited the cell viability of colorectal cancer cells in vitro and inhibited tumor growth with negligible organ toxicity in vivo. Further studies showed that IMCA significantly induced the ferroptosis of colorectal cancer cells. Mechanistically, IMCA downregulated the expression of SLC7A11 and decreased the contents of cysteine and glutathione, which resulted in reactive oxygen species accumulation and ferroptosis. Furthermore, overexpression of SLC7A11 significantly attenuated the ferroptosis caused by IMCA. In addition, IMCA regulated the activity of the AMPK/mTOR/p70S6k signaling pathway, which is related to the activity of SLC7A11 and ferroptosis. Collectively, our research provided experimental evidences on the activity and mechanism of ferroptosis induced by IMCA and revealed that IMCA might be a promising therapeutic drug for colorectal cancer.

Aberrant alternative splicing events play critical roles in carcinogenesis and progression of many cancers, while sparse studies regarding to alternative splicing are available for clear cell renal cell carcinoma (ccRCC). We identified that alternative splicing of coiled-coil domain containing 50 (CCDC50) was dysregulated in ccRCC, whereas the clinical significance of this splicing event and its splicing regulation mechanisms were still elusive.

Few studies have characterized the microbial community and metabolite profile of solid food waste fermented products from centralized treatment facilities, which could potentially be processed into safe animal feeds. In this study, 16S rRNA gene sequencing and liquid/gas chromatography-mass spectrometry were conducted to investigate the bacterial community structure and metabolite profile of food waste samples inoculated with or without 0.18% of a commercial bacterial agent consisting of multiple unknown strains and 2% of a laboratory-made bacterial agent consisting of Enterococcus faecalis, Bacillus subtilis and Candida utilis. Our findings indicated that microbial inoculation increased the crude protein content of food waste while reducing the pH value, increasing lactic acid production, and enhancing aerobic stability. Microbial inoculation affected the community richness, community diversity, and the microbiota structure (the genera with abundances above 1.5% in the fermentation products included Lactobacillus (82.28%) and Leuconostoc (1.88%) in the uninoculated group, Lactobacillus (91.85%) and Acetobacter (2.01%) in the group inoculated with commercial bacterial agents, and Lactobacillus (37.11%) and Enterococcus (53.81%) in the group inoculated with homemade laboratory agents). Microbial inoculation reduced the abundance of potentially pathogenic bacteria. In the metabolome, a total of 929 substances were detected, 853 by LC-MS and 76 by GC-MS. Our results indicated that inoculation increased the abundance of many beneficial metabolites and aroma-conferring substances but also increased the abundance of undesirable odors and some harmful compounds such as phenol. Correlation analyses suggested that Leuconostoc, Lactococcus, and Weissella would be promising candidates to improve the quality of fermentation products. Taken together, these results indicated that inoculation could improve food waste quality to some extent; however, additional studies are required to optimize the selection of inoculation agents.

Chemoresistance is the main cause of poor prognosis in colorectal cancer (CRC). Nicotinamide N‑methyltransferase (NNMT) is a metabolic enzyme that is upregulated in various tumor types. It has been reported that NNMT inhibits apoptosis and enhances resistance to 5‑fluorouracil (5‑Fu) via inhibition of the apoptosis signal regulating kinase 1 (ASK1)‑p38 MAPK pathway in CRC cells. A natural product library was screened, and it was found that vanillin, also known as 4‑hydroxy‑3‑methoxybenzaldehyde, a plant secondary metabolite found in several essential plant oils, mainly Vanilla planifolia, Vanilla tahitensis, and Vanilla pompon, may be a promising anticancer compound targeted to NNMT. The aim of the present study was to explore the effect of vanillin on promoting apoptosis and attenuating NNMT‑induced resistance to 5‑Fu in CRC. Lentiviral vectors of short hairpin RNA and small interfering RNA were transfected into HT‑29 cells to construct NNMT‑knockdown HT‑29 cell lines. Vectors containing an open reading frame of NNMT were stably transfected into SW480 cells to induce NNMT overexpression in SW480 cell lines. Vanillin was found to inhibit the mRNA and protein expression levels of NNMT following the inhibition of NNMT activity in HT‑29 cell lines. Vanillin was able to reverse NNMT‑induced increased cell proliferation, decreased cell apoptosis and resistance to 5‑Fu by inhibiting NNMT expression. Furthermore, it increased cell apoptosis by activating the ASK1‑p38 MAPK pathway, which could be inhibited by NNMT. In addition, vanillin increased cell apoptosis by promoting mitochondrial damage and reactive oxygen species. In vivo, the combination of vanillin with 5‑Fu yielded a notable synergy in inhibiting tumor growth and inducing apoptosis. Considering that vanillin is an important flavor and aromatic component used in foods worldwide, vanillin is deemed to be a promising anticancer candidate by inhibiting NNMT and may attenuate NNMT‑induced resistance to 5‑Fu in human CRC therapy with few side effects.

Renal tubular cell injury induced by calcium oxalate (CaOx) is a critical initial stage of kidney stone formation. Theaflavin (TF) has been known for its strong antioxidative capacity; however, the effect and molecular mechanism of TF against oxidative stress and injury caused by CaOx crystal exposure in kidneys remains unknown. To explore the potential function of TF on renal crystal deposition and its underlying mechanisms, experiments were conducted using a CaOx nephrocalcinosis mouse model established by glyoxylate intraperitoneal injection, and HK-2 cells were subjected to calcium oxalate monohydrate (COM) crystals, with or without the treatment of TF. We discovered that TF treatment remarkably protected against CaOx-induced kidney oxidative stress injury and reduced crystal deposition. Additionally, miR-128-3p expression was decreased and negatively correlated with SIRT1 level in mouse CaOx nephrocalcinosis model following TF treatment. Moreover, TF suppressed miR-128-3p expression and further abolished its inhibition on SIRT1 to attenuate oxidative stress in vitro. Mechanistically, TF interacted with miR-128-3p and suppressed its expression. In addition, miR-128-3p inhibited SIRT1 expression by directly binding its 3'-untranslated region (UTR). Furthermore, miR-128-3p activation partially reversed the acceerative effect of TF on SIRT1 expression. Taken together, TF exhibits a strong nephroprotective ability to suppress CaOx-induced kidney damage through the recovery of the antioxidant defense system regulated by miR-128-3p/SIRT1 axis. These findings provide novel insights for the prevention and treatment of renal calculus.

Background: Historically, idiopathic pulmonary fibrosis (IPF) was considered a chronic inflammation disorder, but this conception was reassessed in the past decades. Our understanding of the role of inflammation in IPF and its association with clinical significance remained incomplete. Methods: We downloaded mRNA expression data of peripheral blood mononuclear cells (PBMCs) from the Gene Expression Omnibus (GEO) repository. Inflammation-related genes (IRGs) expressed differently between IPF and control (CTRL) were determined. In this study, we systemically analyzed the expression of differently expressed IRGs by comprehensive bioinformatic analysis, and then investigated their potential prognostic values. The related prognostic gene expressions were verified in our cohort. Results: 110 differently expressed IRGs were identified in this study, including 64 upregulated and 46 downregulated IRGs. Three IRGs (S100A12, CCR7, and TNFSF4) were identified as potential hub genes for prognosis. Those genes were subsequently subjected to the construction of the prognostic models. In the results, IPF patients categorized as high risk demonstrated a poor overall survival rate compared to patients categorized as low risk. Based on this prognostic model, the area under the curve (AUC) of the survival-dependent receiver operator characteristic (ROC) for 1-year, 2-year, and 3-year survival rates was 0.611, 0.695, and 0.681, respectively, in the GSE28042 cohort. These observations were validated in the GSE27957 cohort, confirming the good prognostic effect of this model. The expression of the three genes was validated in our cohort. We also conducted a nomogram based on the three IRGs' mRNA for quantitative IPF prognosis. Conclusion: Three IRGs (S100A12, CCR7, and TNFSF4) were identified as potential markers for the prognosis of IPF.

Epithelial cystatin SN (CST1), a type 2 cysteine protease inhibitor, was significantly upregulated in asthma. In this study, we aimed to investigate the potential role and mechanism of CST1 in eosinophilic inflammation in asthma.

Cyclic GMP-AMP synthase (cGAS) binds pathogenic and other cytoplasmic double-stranded DNA (dsDNA) to catalyze the synthesis of cyclic GMP-AMP (cGAMP), which serves as the secondary messenger to activate the STING pathway and innate immune responses. Emerging evidence suggests that activation of the cGAS pathway is crucial for anti-tumor immunity; however, no effective intervention method targeting cGAS is currently available. Here we report that cGAS is palmitoylated by ZDHHC9 at cysteines 404/405, which promotes the dimerization and activation of cGAS. We further identified that lysophospholipase-like 1 (LYPLAL1) depalmitoylates cGAS to compromise its normal function. As such, inhibition of LYPLAL1 significantly enhances cGAS-mediated innate immune response, elevates PD-L1 expression, and enhances anti-tumor response to PD-1 blockade. Our results therefore reveal that targeting LYPLAL1-mediated cGAS depalmitoylation contributes to cGAS activation, providing a potential strategy to augment the efficacy of anti-tumor immunotherapy.

The Background: Stroke is one of the leading causes of morbidity and mortality, and the inflammatory mechanism plays a crucial role in stroke-related brain injury and post-ischemic tissue damage. Xiaoxuming decoction (XXMD) is the first prescription for the treatment of "zhongfeng" (a broad concept referring to stroke) in the Tang and Song Dynasties of China and has a significant position in the history of stroke treatment. Through the study of ancient medical records and modern clinical evidence, it is evident that XXMD has significant efficacy in the treatment of stroke and its sequelae, and its pharmacological mechanism may be related to post-stroke inflammation. However, XXMD contains 12 medicinal herbs with complex composition, and therefore, a simplified version of XXMD, called Xiaoxuming decoction cutting (XXMD-C), was derived based on the anti-inflammatory effects of the individual herbs. Therefore, it is necessary to explore and confirm the anti-inflammatory mechanism of XXMD-C. Aim of the study: Based on the previous experiments of our research group, it was found that both XXMD and XXMD-C have anti-inflammatory effects on LPS-induced microglia, and XXMD-C has a better anti-inflammatory effect. Since miRNAs in exosomes also participate in the occurrence and development of cardiovascular diseases, and traditional Chinese medicine can regulate exosomal miRNAs through intervention, this study aims to explore the anti-inflammatory mechanism of XXMD-C in the treatment of post-stroke inflammation through transcriptome sequencing, providing a basis for the application of XXMD-C. Materials and methods: XXMD-C was extracted using water and filtered through a 0.22 μm membrane filter. The main chemical components of the medicinal herbs in XXMD-C were rapidly qualitatively analyzed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Cell viability was determined using the CCK-8 assay, and an LPS-induced BV-2 cell inflammation model was established. The expression of inflammatory cytokines was detected using ELISA and Western blot (WB). Extracellular vesicles were extracted using ultracentrifugation, and identified using transmission electron microscopy (TEM), nanoparticle tracking analysis, and WB. Differential miRNAs were screened using smallRNA-seq sequencing, and validated using RT-PCR and Western blot. Results: The UPLC-Q-TOF-MS analysis revealed that representative components including ephedrine, pseudoephedrine, cinnamaldehyde, baicalin, baicalein, wogonin, and ginsenoside Rg1 were detected in XXMD-C. The results of ELISA and WB assays showed that XXMD-C had a therapeutic effect on LPS-induced inflammation in BV-2 cells. TEM, nanoparticle tracking analysis, and WB results demonstrated the successful extraction of extracellular vesicles using high-speed centrifugation. Differential miRNA analysis by smallRNA-seq identified miR-9-5p, which was validated by RT-PCR and WB. Inhibition of miR-9-5p was found to downregulate the expression of inflammatory factors including IL-1β, IL-6, iNOS, and TNF-α. Conclusion: The study found that XXMD-C has anti-neuroinflammatory effects. Through smallRNA-seq sequencing of extracellular vesicles, miR-9-5p was identified as a key miRNA in the mechanism of XXMD-C for treating neuroinflammation, and its in vivo anti-inflammatory mechanism deserves further investigation.

Noncoding RNAs (ncRNAs) such as microRNAs (miRNAs) and long ncRNAs (lncRNAs) have been shown to function as pivotal regulators in the carcinogenesis of renal cell carcinoma (RCC). However, the functions and underlying mechanisms of most ncRNAs in RCC are still elusive, and the crosstalks of different layers of ncRNAs are seldom reported. Here we showed that miR-124 and maternally expressed gene 3 (MEG3) were both significantly reduced in RCC, and combined expression of miR-124 and MEG3 emerged as an independent prognostic factor in our RCC cohort. Overexpression of miR-124 or MEG3 inhibited cell proliferation, migration, and invasion in vitro, and restrained tumor growth in vivo. EZH2 knockdown induced the epigenetic silencing of miR-124 and MEG3 expression by H3K27me3. Besides, miR-124 directly targeted the TET1 transcript, and then the interaction resulted in the upregulation of MEG3. Furthermore, we demonstrated that MEG3 induced p53 protein accumulation, whereas p53 was a positive transcriptional regulator of the miR-124. In addition, tumor-suppressive PTPN11 was identified as a direct target of miR-124, as well as the MEG3- and p53-regulated gene. Our study identifies three crosstalks between miR-124 and MEG3, which provide a plausible link for these two ncRNAs in RCC. Both ncRNAs exert important antitumor effects in RCC pathogenesis and might serve as prognostic biomarkers and molecular therapeutic targets.

Apoptosis of alveolar macrophages following Mycobacterium tuberculosis infection have been demonstrated to play a central role in the pathogenesis of tuberculosis. In the present study, we found that Wnt/β-catenin signaling possesses the potential to promote macrophage apoptosis in response to mycobacterial infection. In agreement with other findings, an activation Wnt/β-catenin signaling was observed in murine macrophage RAW264.7 cells upon Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection at a multiple-of-infection of 10, which was accompanied with up-regulation of pro-inflammatory cytokines TNF-α and IL-6 production. However, the BCG-induced TNF-α and IL-6 secretion could be significantly reduced when the cells were exposed to a canonical Wnt signaling ligand, Wnt3a. Importantly, the activation of Wnt/β-catenin signaling was able to further promote apoptosis in BCG-infected RAW264.7 cells in part by a mitochondria-dependent apoptosis pathway. Immunoblotting analysis further demonstrated that Wnt/β-catenin signaling-induced cell apoptosis partly through a caspase-dependent apoptosis mechanism by down-regulation of anti-apoptotic protein Mcl-1, and up-regulation of pro-apoptotic proteins Bax and cleaved-caspase-3, as well as enhancement of caspase-3 activity in BCG-infected RAW264.7 cells. These data may imply an underlying mechanism of alveolar macrophages in response to mycobacterial infection, by which the pathogen induces Wnt/β-catenin signaling activation, which in turn represses mycobacterium-trigged inflammatory responses and promotes mycobacteria-infected cell apoptosis.

Mycobacterium tuberculosis (Mtb)-induced autophagy of alveolar macrophages has been confirmed to play a central role in the pathogenesis of tuberculosis. Growing evidence indicates that excessive or uncontrolled autophagic activity, which results in type II programmed cell death, can be regulated by many factors, including Wnt/β-catenin signalling. Wnt/β-catenin signalling has been demonstrated to be involved in multiple diseases through the regulation of autophagy; however, its exact role in regulating autophagy induced by Mtb remains unclear. Accordingly, this study examined the function of the Wnt/β-catenin signalling pathway in regulating Mycobacterium bovis Bacillus Calmette-Guerin (BCG)-induced autophagy in RAW264.7 macrophage cell line. In the present study, we found that BCG induced the autophagy of RAW264.7 cells in a time- and dose-dependent manner along with an accumulation of LC3 (Microtubule-associated protein 1 light chain 3) protein. Intriguingly, Wnt3a, a Wnt/β-catenin signalling ligand, significantly inhibited autophagy, with decreased autophagy rates and autophagic flux. An immunoblot analysis further revealed that Wnt/β-catenin signalling was capable of inhibiting the expression of the LC3 and autophagy-associated gene (Atg) cascade proteins in BCG-infected cells. Mechanistically, Wnt/β-catenin signalling may inhibit autophagy in BCG-infected macrophages by activating mTOR-dependent pathways. Our findings reveal the mechanisms of Wnt/β-catenin signalling regulates cellular autophagy induced by Mtb and provide novel insights into physiological and immune control of tuberculosis by modulating autophagy processes.

To investigate the effects of total flavonoids of propolis (TFP) on apoptosis of myocardial cells of chronic heart failure and its possible mechanism in rats.

Dysregulated micro-RNAs have been reported in many human cancers, including renal cell carcinoma. Recent studies indicated that miR-490 is involved in tumour development and progression. However, the expression profile and function in renal cell carcinoma remains unknown.

Silibinin, a dietary cancer chemopreventive flavonoid from the seeds of milk thistle, has been reported to exhibit anti-metastatic effects on renal cell carcinoma (RCC), but the mechanism underlying this phenomenon is not fully understood. The present study aimed at examining the potential role of autophagy in regulating silibinin-induced anti-metastatic effects on RCC cells. Using RCC ACHN and 786-O cells as a model system in vitro, we found that silibinin treatment increased the expression of LC3-II, resulted in the formation of autophagolysosome vacuoles, and caused a punctate fluorescence pattern with the monomeric red fluorescence protein-enhanced green fluorescence protein-LC3 (mRFP-EGFP-LC3) protein, which all are markers for cellular autophagy. Autophagy flux was induced by silibinin in RCC cells, as determined by LC3 turnover assay. Mechanically, the adenosine 5'-monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was identified as involved in regulation of silibinin-induced autophagy. Furthermore, autophagy induction was demonstrated to positively contribute to silibinin-induced anti-metastatic effects on RCC cells in vitro. Activation of autophagy enhanced silibinin-induced inhibition of migration and invasion of RCC cells, while inhibition of autophagy attenuated it. These findings thus provide new information about the potential link between autophagy and metastasis inhibition induced by silibinin, and the induction of autophagy may shed some light into future treatment strategies for metastatic RCC.

MicroRNAs (miRNA) that are strongly implicated in carcinogenesis have recently reshaped our understanding of the role of noncoding RNAs. Here, we focused on the function and molecular mechanism of miR-1 and its potential clinical application in clear cell renal cell carcinoma (ccRCC). First, miR-1 was significantly downregulated in 87.8% renal cancer samples compared with corresponding noncancerous tissues (NCT), which was significantly associated with clinical stage, T classification and poor overall survival. Functional study demonstrated that enforced overexpression of miR-1 in renal cancer cells inhibited proliferation and metastasis in vitro and in vivo. Conversely, miR-1 inhibitor silencing miR-1 expression promoted cell proliferation and metastasis in ccRCC. CDK4, CDK6, Caprin1 and Slug were each directly targeted for inhibition by miR-1 and restoring their expression reversed miR-1-mediated inhibition of cell cycle progression and metastasis. Taken together, our findings established a tumor suppressive role for miR-1 in the progression of ccRCC by targeting CDK4, CDK6, Caprin1 and Slug and suggested miR-1 can be served as a novel potential therapeutic target for ccRCC.