Antimony is a common environmental contaminant that causes biological toxicity in exposed populations worldwide. Previous studies have revealed that antimony promotes prostate cancer growth by stabilizing the c-Myc protein and mimicking androgen activity. However, the role of lncRNAs in the regulation of antimony-induced carcinogenesis remains unknown, and the precise mechanisms need to be explored. In the present study, we found that chronic exposure to antimony promoted cell growth and lipid metabolic disequilibrium in prostate cancer. Mechanistically, we identified a long noncoding RNA molecule, PCA3, that was substantially upregulated in LNCaP cells in response to long-term antimony exposure. Functional studies indicated that abnormal PCA3 expression modulated antimony-induced proliferation and cellular triglyceride and cholesterol levels. In addition, PCA3 levels were found to be inversely correlated with MIR-132-3 P levels by acting as a decoy for MIR-132-3P. Besides, SREBP1 directly interacted with MIR-132-3 P to increase cell growth and disrupt lipid metabolism by targeting its 3'UTR regions. Taken together, our results revealed that lncRNA PCA3 promotes antimony-induced lipid metabolic disorder in prostate cancer by targeting MIR-132-3 P/SREBP1 signaling.

Background: Diabetic nephropathy (DN) is one of the major diabetic microvascular complications, and macrophage polarization plays a key role in the development of DN. Endothelial cells regulate macrophage polarization. Peroxisome proliferator-activated receptor (PPAR)-α agonists were demonstrated to prevent DN and improve endothelial function. In this study, we aimed to investigate whether PPAR-α agonists prevented DN through regulating macrophage phenotype via improving endothelial cell function. Methods: Eight-week-old male C57BLKS/J db/m and db/db mice were given fenofibrate or 1% sodium carboxyl methylcellulose by gavage for 12 weeks. Results: Db/db mice presented higher urinary albumin-to-creatinine ratio (UACR) than db/m mice, and fenofibrate decreased UACR in db/db mice. Fibrosis and collagen I were elevated in db/db mouse kidneys compared with db/m mouse kidneys; however, they were decreased after fenofibrate treatment in db/db mouse kidneys. Apoptosis and cleaved caspase-3 were enhanced in db/db mouse kidneys compared to db/m mouse kidneys, while fenofibrate decreased them in db/db mouse kidneys. Db/db mice had a suppression of p-endothelial nitric oxide synthase (eNOS)/t-eNOS and nitric oxide (NO), and an increase of angiopoietin-2 and reactive oxygen species (ROS) in kidneys compared with db/m mice, and fenofibrate increased p-eNOS/t-eNOS and NO, and decreased angiopoietin-2 and ROS in db/db mouse kidneys. Hypoxia-inducible factor (HIF)-1α and Notch1 were promoted in db/db mouse kidneys compared with db/m mouse kidneys, and were reduced after fenofibrate treatment in db/db mouse kidneys. Furthermore, the immunofluorescence staining indicated that M1 macrophage recruitment was enhanced in db/db mouse kidneys compared to db/m mouse kidneys, and this was accompanied by a significant increase of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in kidneys and in serum of db/db mice compared with db/m mice. However, fenofibrate inhibited the renal M1 macrophage recruitment and cytokines associated with M1 macrophages in db/db mice. Conclusions: Our study indicated that M1 macrophage recruitment due to the upregulated HIF-1α/Notch1 pathway induced by endothelial cell dysfunction involved in type 2 diabetic mouse renal injury, and PPAR-α agonist fenofibrate prevented DN by reducing M1 macrophage recruitment via inhibiting HIF-1α/Notch1 pathway regulated by endothelial cell function in type 2 diabetic mouse kidneys.

Clinically, rheumatoid arthritis (RA) is frequently accompanied by multi-system diseases. Among them, the incidence of comorbid tumors in RA is relatively high, resulting in a gradual increase in mortality; this poses a considerable challenge to clinical treatment. To date, no effective treatment plan for simultaneous tumor and RA therapy is available. Accordingly, we reported a sialic acid-modified doxorubicin hydrochloride liposome (DOX-SAL) that targets peripheral blood neutrophils (PBNs), which play an important role in tumors and RA. Furthermore, the prepared liposome induced PBN apoptosis by binding to L-selectin, which is highly expressed on the surface of PBNs activated by inflammation. This liposome, in turn, reduced the accumulation of inflammatory neutrophils at the disease site. In the first successfully established mouse model of RA comorbidity, induced by employing S180 sarcoma cells and collagen, DOX-SAL effectively inhibited tumor growth while simultaneously alleviating systemic RA symptoms without side effects. Additionally, the animals demonstrated adequate growth during the 48 days of treatment. This treatment strategy encompasses the best of both worlds, breaking the deadlock that tumors and RA cannot be effectively treated in parallel, highlighting a new concept and reference for the clinical treatment of comorbid tumors and RA.

No abstract available

Although it is known that unbound bilirubin can enter the brain, there is little evidence of its association with the development of acute bilirubin encephalopathy. Here, we investigated this potential relationship in neonates who had undergone exchange transfusion.

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.

Diabetes mellitus-induced erectile dysfunction (DMED) is a frequent complication of diabetes mellitus (DM), with limited therapy at present. This study aimed to explore the role and mechanism of Ganoderma lucidum polysaccharide (GLP) on DMED.

To investigate the clinical characteristics of cerebral cavernous malformations (CCMs) with MAP3K3 somatic mutation.

A competitive fluorescence immunoassay for the quantitative detection of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) in pan-fried meat patties was developed, using magnetic nanoparticles coupled with coating antigen as the capture probe and anti-IQ antibody coupled with NaYF4: Yb, Er upconversion nanoparticles as the signal probe. Under optimal conditionals, the wide detection range for IQ in phosphate buffer saline is from 0.01 to 100 μg·L-1 (R2 = 0.991) with a detection limit of 0.007 μg·L-1. This proposed method has been applied to detect IQ in two different types of pan-fried meat patties at varying frying times, and the IQ content in chicken patties and fish patties are 2.11-3.47 μg·kg-1 and 1.35-2.85 μg·kg-1, respectively. These results are consistent with that of the ultraperformance liquid chromatography-tandem mass spectrometry. In summary, this method can serve as a sensitive and specific test tool for the determination of IQ in processed meat.

Advanced gastric cancer (AGC) is a disease with poor prognosis due to the current lack of effective therapeutic strategies. Immune checkpoint blockade treatments have shown effective responses in patient subgroups but biomarkers remain challenging. Traditional classification of gastric cancer (GC) is based on genomic profiling and molecular features. Therefore, it is critical to identify the immune-related subtypes and predictive markers by immuno-genomic profiling.

TNF receptor-associated factor 6 (TRAF6) has been reported to be associated with the development of cancer. Nevertheless, the exact role of TRAF6 in cancer remains unclear. The purpose of the present study was to explore the mechanism of 2-benzoyl-3-hydroxy-4-methyl-9H-xanthen-9-one leading to the inhibition of the activation of AKT and TGF-β-activated kinase 1 (TAK1), and to the apoptosis of MCF-7 cells. Using a computational docking program and examination of AKT and TAK1 level changes, a new small molecule was identified, 2-benzoyl-3-hydroxy-4-methyl-9H-xanthen-9-one, which competitively bound to TRAF6. Next, the effect of this new compound on MCF-7 cells' biological behavior was studied in vitro. MTT assays were used to investigate cell viability; flow cytometry and invasion assays were performed to detect early apoptosis and invasion in MCF-7 cells, respectively. Immunoprecipitation, western blotting and caspase-3/9 activity assays were carried out to explore changes in protein expression. Briefly, the present data indicated that 2-benzoyl-3-hydroxy-4-methyl-9H-xanthen-9-one could suppress proliferation, induce early apoptosis and inhibit invasion in MCF-7 cells by suppressing the expression of Bcl-2 and promoting the expression of Bax, caspase-9, and caspase-3. These findings indicated that 2-benzoyl-3-hydroxy-4-methyl-9H-xanthen-9-one could induce apoptosis by inhibiting the activation of AKT and TAK1, and affecting the Bcl-2/Bax-caspase-9-caspase-3 pathway by competitively binding with TRAF6.

Time-restricted feeding (TRF) is an emerging dietary intervention that improves metabolic disorders such as obesity, insulin resistance and dyslipidemia. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder affecting the gastrointestinal tract, where nutrition plays an important role in its pathogenesis. Although numerous strategies of nutritional intervention have been reported, whether TRF can improve IBD has been elusive. In this study, we investigated the effect of two cycles of 7-day TRF intervention in a dextran sulfate sodium-induced IBD mouse model. We found that TRF was able to reduce the disease activity index and ameliorate the IBD-associated symptoms, as well as increase the number of colonic crypts and decrease the histological score in the colon. Furthermore, TRF lowered the percentage of CD4+ T cells in the peripheral blood and mesenteric lymph node, and increased the number of CD4+CD25+ T cells in the mesenteric lymph nodes. Additionally, TRF reduced the infiltration of leukocytes and macrophages around the crypt base in the colon. However, unlike the intermittent caloric restriction with fasting-mimicking diet, TRF was not able to increase the markers of progenitor and cell proliferation in the colon. Collectively, these results demonstrated that TRF is able to improve IBD in mice via reduction in intestinal inflammation.

Innate lymphoid cells (ILC) are abundant in mucosal tissues. They serve critical functions in anti-pathogen response and tissue homeostasis. However, the heterogenous composition of ILCs in mucosal sites and their various maturation trajectories are less well known. In this study, we characterize ILC types and functions from both the lung and the small intestine, and identify their tissue-specific markers. We find that ILC2s residing in the lung express CCR2, whereas intestinal ILC2s express CCR4. Through the use of CCR2 and CCR4 reporter mice, we show that ILC2s undergo translocation via the lung-gut axis upon IL-33 treatment. This trajectory of ILC2s is also observed at the postnatal stage. Allergen-induced activation of lung ILC2s affects the homeostasis of gut ILC2s. Together, our findings implicate that ILCs display tissue-specific features in both the lung and gut, and ILC2s mature along the lung-gut axis in particular homeostatic and inflammatory conditions.

Recent studies have suggested that sodium-glucose co-transporter2 inhibitors go beyond their glycemic advantages to ameliorate the development of NAFLD. However, little research has been done on the underlying mechanisms. Here, we took deep insight into the effect of canagliflozin (CANA), one of the sodium-glucose co-transporter2 inhibitor, on the progression of NAFLD, and explored the molecular mechanisms. Our findings showed that CANA-treated ob/ob and diabetic mice developed improved glucose and insulin tolerance, although their body weights were comparable or even increased compared with the controls. The CANA treatment ameliorated hepatic steatosis and lipid accumulation of free fatty acid-treated AML12 cells, accompanied by decreased lipogenic gene expression and increased fatty acid β oxidation-related gene expression. Furthermore, inflammation and fibrosis genes decreased in the livers of CANA-treated ob/ob and diabetic mice mice. FGF21 and its downstream ERK1/2/AMPK signaling decreased, whereas NLRP3-mediated pyroptosis increased in the livers of the ob/ob and diabetic mice mice, which was reversed by the CANA treatment. In addition, blocking FGF21 or ERK1/2 activity antagonized the effects of CANA on NLRP3-mediated pyroptosis in lipopolysaccharide plus nigericin-treated J774A.1 cells. We conclude that CANA treatment alleviated insulin resistance and the progression of NAFLD in ob/ob and diabetic mice mice independent of the body weight change. CANA protected against the progression of NAFLD by inhibiting NLRP3-mediated pyroptosis and enhancing FGF21-ERK1/2 pathway activity in the liver. These findings suggest the therapeutic potential of sodium-glucose co-transporter2 inhibitors in the treatment of NAFLD.

Background: Prostate cancer (PCa) is one of the most common cancers in males around the globe, and about one-third of patients with localized PCa will experience biochemical recurrence (BCR) after radical prostatectomy or radiation therapy. Reportedly, a proportion of patients with BCR had a poor prognosis. Cumulative studies have shown that RNA modifications participate in the cancer-related transcriptome, but the role of pseudouridylation occurring in lncRNAs in PCa remains opaque. Methods: Spearman correlation analysis and univariate Cox regression were utilized to determine pseudouridylation-related lncRNAs with prognostic value in PCa. Prognostic pseudouridylation-related lncRNAs were included in the LASSO (least absolute shrinkage and selection operator) regression algorithm to develop a predictive model. KM (Kaplan-Meier) survival analysis and ROC (receiver operating characteristic) curves were applied to validate the constructed model. A battery of biological cell assays was conducted to confirm the cancer-promoting effects of RP11-468E2.5 in the model. Results: A classifier containing five pseudouridine-related lncRNAs was developed to stratify PCa patients on BCR and named the "ψ-lnc score." KM survival analysis showed patients in the high ψ-lnc score group experienced BCR more than those in the low ψ-lnc score group. ROC curves demonstrated that ψ-lnc score outperformed other clinical indicators in BCR prediction. An external dataset, GSE54460, was utilized to validate the predictive model's efficacy and authenticity. A ceRNA (competitive endogenous RNA) network was constructed to explore the model's potential molecular functions and was annotated through GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses. RP11-468E2.5 was picked for further investigation, including pan-cancer analysis and experimental validation. Preliminarily, RP11-468E2.5 was confirmed as a tumor promoter. Conclusion: We provide some evidence that pseudouridylation in lncRNA played a role in the development of PCa and propose a novel prognostic classifier for clinical practice.

Faces are salient social stimuli that attract a stereotypical pattern of eye movement. The human amygdala and hippocampus are involved in various aspects of face processing; however, it remains unclear how they encode the content of fixations when viewing faces. To answer this question, we employed single-neuron recordings with simultaneous eye tracking when participants viewed natural face stimuli. We found a class of neurons in the human amygdala and hippocampus that encoded salient facial features such as the eyes and mouth. With a control experiment using non-face stimuli, we further showed that feature selectivity was specific to faces. We also found another population of neurons that differentiated saccades to the eyes vs. the mouth. Population decoding confirmed our results and further revealed the temporal dynamics of face feature coding. Interestingly, we found that the amygdala and hippocampus played different roles in encoding facial features. Lastly, we revealed two functional roles of feature-selective neurons: 1) they encoded the salient region for face recognition, and 2) they were related to perceived social trait judgments. Together, our results link eye movement with neural face processing and provide important mechanistic insights for human face perception.

Evidence on the relationship between the low-/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) and carotid plaques remains limited. This study aimed to examine the association between LDL-C/HDL-C and carotid plaques in participants with coronary heart disease (CHD) and to further explore the extent to which a healthy lifestyle reduces the risk of LDL-C/HDL-C-related carotid plaques.

Brain arteriovenous malformation (AVM), a presumed congenital lesion, may involve traditional language areas but usually does not lead to language dysfunction unless it ruptures. The objective of this research was to study right-hemispheric language reorganization patterns in patients with brain AVMs using functional magnetic resonance imaging (fMRI). We prospectively enrolled 30 AVM patients with lesions involving language areas and 32 age- and sex-matched healthy controls. Each subject underwent fMRI during three language tasks: visual synonym judgment, oral word reading, and auditory sentence comprehension. The activation differences between the AVM and control groups were investigated by voxelwise analysis. Lateralization indices (LIs) for the frontal lobe, temporal lobe, and cerebellum were compared between the two groups, respectively. Results suggested that the language functions of AVM patients and controls were all normal. Voxelwise analysis showed no significantly different activations between the two groups in visual synonym judgment and oral word reading tasks. In auditory sentence comprehension task, AVM patients had significantly more activations in the right precentral gyrus (BA 6) and right cerebellar lobule VI (AAL 9042). According to the LI results, the frontal lobe in oral word reading task and the temporal lobe in auditory sentence comprehension task were significantly more right-lateralized in the AVM group. These findings suggest that for patients with AVMs involving language cortex, different language reorganization patterns may develop for different language functions. The recruitment of brain areas in the right cerebral and cerebellar hemispheres may play a compensatory role in the reorganized language network of AVM patients.

Radiation pneumonitis is a common dose-limiting factor in radiotherapy for thoracic malignancies, and its treatment encounters a bottleneck. As an essential adjuvant treatment method, Chinese herbal injections (CHIs) have been used to treat radiation pneumonitis (RP), and clinical studies have appeared potentially beneficial and nontoxic. However, the efficacy and safety of CHIs for RP have not been evaluated comprehensively.

Breast microcalcifications is a characteristic feature in diagnostic imaging and a prognostic factor of breast cancer. However, the underlying mechanisms of breast microcalcifications formation are not fully understood. Previous studies have shown that upregulation of bone morphogenetic protein 2 (BMP-2) is associated with the occurrence of microcalcifications and tumor-associated macrophages (TAMs) in the tumor microenvironment can secrete BMP-2. The aim of this study is to elucidate the role of secretion of BMP-2 by TAMs in promoting microcalcifications of breast cancer through immunohistochemical staining and co-culturing of breast cancer cells with TAMs.