The therapeutic effects of traditional Chinese medicine on insulin resistance in obese mice by modulating intestinal functions.

Introduction: Obesity, mainly caused by excessive accumulation of visceral fat, excessive fat metabolism will cause hormone secretion imbalance and inflammation and other diseases. is extremely detrimental to human health. Although many treatments are available for obesity, most treatments fail to exert a radical effect or are associated with several side effects. Traditional Chinese medicine (TCM) for regulating the intestinal flora, lipid content and inflammation is considered effective. Based on previous studies, Artemisia capillaris, Astragalus propinquus, Phellodendron amurense, Salvia miltiorrhiza, Poria cocos, and Anemarrhena asphodeloides were selected to prepare an innovative herbal formula. Methods: TCM was characterized by UHPLC-Q-Orbitrap-MS. The anti-inflammatory and lipid-lowering effects of the TCM formula prepared were evaluated in a high-fat diet-fed obese mouse model. The effects of the TCM formula on the intestinal flora were also investigated. Results: Weights and insulin resistance, as well as inflammation, decreased in the mice after treatment. At the same time, lipid metabolism increased after the mice were gavaged with the TCM formula for 2 weeks. The intestinal motility of the drug administration group was enhanced, with partial restoration of the intestinal flora. Conclusion: In summary, our innovative Chinese herbal formula significantly reduced weight, reduced intestinal inflammation, improved intestinal motility, and improved lipid metabolism in obese mice. Furthermore, the innovative formula effectively prevented relevant obesity-induced metastatic diseases in the mice.

The crucial prognostic signaling pathways of pancreatic ductal adenocarcinoma were identified by single-cell and bulk RNA sequencing data.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis and high mortality. Although a large number of studies have explored its potential prognostic markers using traditional RNA sequencing (RNA-Seq) data, they have not achieved good prediction effect. In order to explore the possible prognostic signaling pathways leading to the difference in prognosis, we identified differentially expressed genes from one scRNA-seq cohort and four GEO cohorts, respectively. Then Cox and Lasso regression analysis showed that 12 genes were independent prognostic factors for PDAC. AUC and calibration curve analysis showed that the prognostic model had good discrimination and calibration. Compared with the low-risk group, the high-risk group had a higher proportion of gene mutations than the low-risk group. Immune infiltration analysis revealed differences in macrophages and monocytes between the two groups. Prognosis related genes were mainly distributed in fibroblasts, macrophages and type 2 ducts. The results of cell communication analysis showed that there was a strong communication between cancer-associated fibroblasts (CAF) and type 2 ductal cells, and collagen formation was the main interaction pathway.

Differences in toxicity induced by the various polymer types of nanoplastics on HepG2 cells.

The problem of microplastics (MPs) contamination in food has gradually come to the fore. MPs can be transmitted through the food chain and accumulate within various organisms, ultimately posing a threat to human health. The concentration of nanoplastics (NPs) exposed to humans may be higher than that of MPs. For the first time, we studied the differences in toxicity, and potential toxic effects of different polymer types of NPs, namely, polyethylene terephthalate (PET), polyvinyl chloride (PVC), and polystyrene (PS) on HepG2 cells. In this study, PET-NPs, PVC-NPs, and PS-NPs, which had similar particle size, surface charge, and shape, were prepared using nanoprecipitation and emulsion polymerization. The results of the CCK-8 assay showed that the PET-NPs and PVC-NPs induced a decrease in cell viability in a concentration-dependent manner, and their lowest concentrations causing significant cytotoxicity were 100 and 150 µg/mL, respectively. Moreover, the major cytotoxic effects of PET-NPs and PVC-NPs at high concentrations may be to induce an increase in intracellular ROS, which in turn induces cellular damage and other toxic effects. Notably, our study suggested that PET-NPs and PVC-NPs may induce apoptosis in HepG2 cells through the mitochondrial apoptotic pathway. However, no relevant cytotoxicity, oxidative damage, and apoptotic toxic effects were detected in HepG2 cells with exposure to PS-NPs. Furthermore, the analysis of transcriptomics data suggested that PET-NPs and PVC-NPs could significantly inhibit the expression of DNA repair-related genes in the p53 signaling pathway. Compared to PS-NPs, the expression levels of lipid metabolism-related genes were down-regulated to a greater extent by PET-NPs and PVC-NPs. In conclusion, PET-NPs and PVC-NPs were able to induce higher cytotoxic effects than PS-NPs, in which the density and chemical structure of NPs of different polymer types may be the key factors causing the differences in toxicity.

The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.

Nonalcoholic steatohepatitis (NASH) is a metabolism-associated fatty liver disease with accumulated mitochondrial stress, and targeting mitochondrial function is a potential therapy. The mitochondrial genome-encoded bioactive peptide MOTS-c plays broad physiological roles, but its effectiveness and direct targets in NASH treatment are still unclear. Here, we show that long-term preventive and short-term therapeutic effects of MOTS-c treatments alleviate NASH-diet-induced liver steatosis, cellular apoptosis, inflammation, and fibrosis. Mitochondrial oxidative capacity and metabolites profiling analysis show that MOTS-c significantly reverses NASH-induced mitochondrial metabolic deficiency. Moreover, we identify that MOTS-c directly interacts with the BH3 domain of antiapoptotic B cell lymphoma-2 (Bcl-2), increases Bcl-2 protein stability, and suppresses Bcl-2 ubiquitination. By using a Bcl-2 inhibitor or adeno-associated virus (AAV)-mediated Bcl-2 knockdown, we further confirm that MOTS-c improves NASH-induced mitochondrial dysfunction, inflammation, and fibrosis, which are dependent on Bcl-2 function. Therefore, our findings show that MOTS-c is a potential therapeutic agent to inhibit the progression of NASH.

The effect of polystyrene nanoplastics on arsenic-induced apoptosis in HepG2 cells.

Microplastics are detrimental to the environment. However, the combined effects of microplastics and arsenic (As) remain unclear. In this study, we investigated the combined effects of polystyrene (PS) microplastics and As on HepG2 cells. The results showed that PS microplastics 20, 50, 200, and 500 nm in size were taken up by HepG2 cells, causing a decrease in cellular mitochondrial membrane potential. The results of lactate dehydrogenase release and flow cytometry showed that PS microplastics, especially those of 50 nm, enhanced As-induced apoptosis. In addition, transcriptome analysis revealed that TP53, AKT1, CASP3, ACTB, BCL2L1, CASP8, XIAP, MCL1, NFKBIA, and CASP7 were the top 10 hub genes for PS that enhanced the role of As in HepG2 cell apoptosis. Our results suggest that nano-PS enhances As-induced apoptosis. Furthermore, this study is important for a better understanding of the role of microplastics in As-induced hepatotoxicity.

Exosomal miRNA analysis provides new insights into exposure to nanoplastics and okadaic acid.

As an emerging environmental pollutant, nanoplastics (NPs) have attracted wide attention in terms of their impact on the ecological environment and human health. Currently, researches on the cytotoxicity of NPs mainly focus on oxidative stress, damage to the cell membrane and organelles, induction of immune response and genotoxicity. Okadaic acid (OA) is the main component of diarrheal shellfish toxin. Based on the previous combined toxicity exploration of polystyrene (PS) NPs and (OA) to human gastric adenocarcinoma (AGS) cells, cell-derived exosomes were extracted and exosomal miRNA profiles were analyzed for the first time in this study. The results showed that the composition of miRNAs varied after the exposure of NPs and OA. Specifically, the expression of miR-1-3p in both PS-Exo and PS-OA-Exo was significantly reduced. And the expression of miR-1248 was upregulated most significantly by comparing the DE miRNAs between PS-Exo and PS-OA-Exo. MiR-1-3p and miR-1248 may be the key genes for the combined toxicity of NPs and OA. After analysis, we found that both the decreased expression of miR-1-3p and the increased expression of miR-1248 can increase the expression of FN1 and affect DNA replication, which was surprisingly consistent with the results of our previous cytotoxicity studies. Since exosomal miRNAs are selectively encapsulated by donor cell, we speculate that the changes of exosomal miRNAs may due to the synchronous changes of intracellular environment and the downregulation of intracellular FN1 may be attributed to decreased expression of miR-1-3p and increased expression of miR-1248 in donor cells. Accordingly, we come to the conclusion that the changes of miRNAs in the exosomes derived from AGS cells after environmental stimulation could reflect the biological effects of donor cells.

RNA-binding Protein QKI Inhibits Osteogenic Differentiation Via Suppressing Wnt Pathway.

BACKGROUND: Dysregulation of MSCs differentiation is associated with many pathophysiological processes. Genetically modified MSCs transplantation helps restore bone loss efficiently. METHODS: BMSCs-specific QKI overexpressing and knockdown mice were built to explore QKI's role in bone formation and fat accumulation. Primary BMSCs with QKI overexpression and knockout were subjected to osteogenic and adipogenic differentiation. ALP staining and oil red O staining were performed to evaluate the differences between the groups. RNA immunoprecipitation was performed to identify the QKI-related pathway. QKI deficient BMSCs were transplanted into mice with glucocorticoid-induced osteoporosis to evaluate its therapeutic potential. RESULTS: Mice harboring BMSC-specific transgenic QKI exhibited reduced bone mass, while BMSC-specific QKI-deficient mice showed an increase in bone mass. Osteogenic differentiation of QKI deficient BMSCs was promoted and adipogenic differentiation was inhibited, while QKI overexpression in BMSCs displayed the opposite effects. To define the underlying mechanisms, RIP sequencing was performed. Wnt pathway-related genes were the putative direct target mRNAs of QKI, Canonical Wnt pathway activation was involved in QKI's effects on osteogenic differentiation. RNA immunoprecipitation quantitative real-time Polymerase Chain Reaction (PCR) and RNA fluorescence in situ hybridization experiments further validated that QKI repressed the expressions of Wnt5b, Fzd7, Dvl3 and ß-catenin via direct binding to their putative mRNA specific sites. Glucocorticoid-induced osteoporotic mice transplanted with QKI deficient BMSCs exhibited less bone loss compared with mice transplanted with control BMSCs. CONCLUSIONS: QKI suppressed BMSCs osteogenic differentiation by downregulating the expressions of Wnt5b, Fzd7, Dvl3 and ß-catenin. Loss of QKI in BMSCs transplantation may provide a new strategy for the treatment of orthopedic diseases such as osteoporosis.

Exosome-like Nanovesicles Derived from the Mucilage of Pinctada Martensii Exhibit Antitumor Activity against 143B Osteosarcoma Cells.

Osteosarcoma is prone to metastasis and has a low long-term survival rate. The drug treatment of osteosarcoma, side effects of treatment drugs, and prognosis of patients with lung metastasis continue to present significant challenges, and the efficacy of drugs used in the treatment of osteosarcoma remains low. The development of new therapeutic drugs is urgently needed. In this study, we successfully isolated Pinctada martensii mucilage exosome-like nanovesicles (PMMENs). Our findings demonstrated that PMMENs inhibited the viability and proliferation of 143B cells, induced apoptosis, and inhibited cell proliferation by suppressing the activation of the ERK1/2 and Wnt signaling pathways. Furthermore, PMMENs inhibited cell migration and invasion by downregulating N-cadherin, vimentin, and matrix metalloprotease-2 protein expression levels. Transcriptomic and metabolomic analyses revealed that differential genes were co-enriched with differential metabolites in cancer signaling pathways. These results suggest that PMMENs may exert anti-tumor activity by targeting the ERK1/2 and Wnt signaling pathways. Moreover, tumor xenograft model experiments showed that PMMENs can inhibit the growth of osteosarcoma in mice. Thus, PMMENs may be a potential anti-osteosarcoma drug.

Extracellular vesicles derived from Pinctada martensii mucus regulate skin inflammation via the NF-κB/NLRP3/MAPK pathway.

Extracellular vesicles (EVs) and their exosome subsets are vesicle-like nanoparticles (EVs) that are secreted by cells and contain various factors that treat various diseases. However, studies on extracting EVs from marine shellfish are still relatively lacking. In this study, EVs were isolated from Pinctada martensii mucus and the efficacy of EVs in modulating the inflammatory environment was demonstrated. A human skin inflammatory cell model was established to investigate the effect of Pinctada martensii mucus-derived EVs on inflammation. The results showed that EVs could restore the viability of inflammatory HaCaT cells and decrease the level of reactive oxygen species (ROS), as well as the mRNA expression of IL-6, IL-8 and TNF-α. The inflammation of HaCaT cells was treated by inhibiting the activation of the MAPK, NF-κB and NLRP3 inflammasome signaling pathways, which prevented the phosphorylation of related inflammatory proteins and the entry of P65 protein into the nucleus. This study provides novel EVs from marine shellfish-derived bioactive materials.

Cyanidin Chloride Improves LPS-Induced Depression-Like Behavior in Mice by Ameliorating Hippocampal Inflammation and Excitotoxicity.

Depression is a global disease that places a significant burden on human health. Neuroinflammation and disturbance of glutamate metabolism in brain regions, such as the hippocampus, play vital roles in the development of depression. Previous studies have shown that cyanidin chloride (Cycl) has anti-inflammatory and antioxidant properties with neuroprotective effects in peripheral tissues. However, the effects of Cycl on depression and the possible mechanism by which this compound targets brain regions remain less elucidated. We investigated the role of Cycl in lipopolysaccharide (LPS)-induced depression and examined the influence of the drug on central inflammation and the expression of excitatory amino acid transporters in the hippocampus. We found that prophylactic i.p. application of Cycl at 20 or 40 mg/kg for 5 days significantly reduced the immobility time assessed by the tail suspension test (TST) and forced swim test (FST) in LPS-challenged mice, suggesting an effective antidepressant activity of the drug. Western blotting and immunofluorescence staining in the hippocampus revealed that Cycl inhibited the upregulation of proinflammatory cytokines, including TNF-α and IL-6, and suppressed the hyperactivity of microglia induced by LPS, indicating an anti-inflammatory role in the hippocampus. Moreover, treatment with Cycl also recovered the downregulated expression of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), and glutamate-aspartate transporter (GLAST) and excitatory amino acid transporter 2 (EAAT2), two members in the excitatory amino acid transporter family. The role of Cycl was also verified in cultured BV2 and U251 cells. In conclusion, the present in vivo and in vitro studies demonstrate that Cycl exerts potent antidepressant action in an LPS-induced depression model and the underlying mechanism is associated with reduced hippocampal inflammation, improved neurotrophic function, and attenuated excitotoxicity induced by glutamate.

Identification and validation of ferroptosis-related lncRNA signature as a prognostic model for skin cutaneous melanoma.

Background: Melanoma is a type of skin cancer, which originates from the malignant transformation of epidermal melanocytes, with extremely high lethality. Ferroptosis has been documented to be highly related to cancer pathogenesis and the effect of immunotherapy. In addition, the dysregulation of lncRNAs is greatly implicated in melanoma progression and ferroptosis regulation. However, the significance of ferroptosis-related lncRNA in melanoma treatment and the prognosis of melanoma patients remains elusive. Methods: Via Least Absolute Shrinkage Selection Operator (LASSO) regression analysis in the TCGA SKCM database, a cutaneous melanoma risk model was established based on differentially-expressed ferroptosis-related lncRNAs (DEfrlncRNAs). The nomogram, receiver operating characteristic (ROC) curves, and calibration plots were conducted to examine the predictive performance of this model. Sequentially, we continued to analyze the differences between the high- and low-risk groups, in terms of clinical characteristics, immune cell infiltration, immune-related functions, and chemotherapy drug sensitivity. Moreover, the expressions of DEfrlncRNAs, PD-L1, and CD8 were also examined by qRT-PCR and immunohistochemical staining in melanoma tissues to further confirm the potential clinical implication of DEfrlncRNAs in melanoma immunotherapy. Results: 16 DEfrlncRNAs were identified, and a representative risk score for patient survival was constructed based on these 16 genes. The risk score was found to be an independent prognostic factor for the survival of melanoma patients. In addition, the low-risk group of patients had higher immune cell infiltration in the melanoma lesions, higher sensitivity to chemotherapeutic agents, and a better survival prognosis. Besides, the high expression of the identified 5 DEfrlncRNA in the low-risk group might suggest a higher possibility to benefit from immune checkpoint blockade therapy in the treatment of melanoma. Conclusion: The DEfrlncRNA risk prediction model related to ferroptosis genes can independently predict the prognosis of patients with melanoma and provide a basis for evaluating the response of clinical treatment in melanoma.

QKI degradation in macrophage by RNF6 protects mice from MRSA infection via enhancing PI3K p110ß dependent autophagy.

BACKGROUND: Sepsis is a fatal condition commonly caused by Methicillin-resistant Staphylococcus aureus (MRSA) with a high death rate. Macrophages can protect the host from various microbial pathogens by recognizing and eliminating them. Earlier we found that Quaking (QKI), an RNA binding protein (RBP), was involved in differentiation and polarization of macrophages. However, the role of QKI in sepsis caused by pathogenic microbes, specifically MRSA, is unclear. This study aimed to investigate the role of QKI in regulation of host-pathogen interaction in MRSA-induced sepsis and explored the underlying mechanisms. METHODS: Transmission electron microscope and immunofluorescence were used to observe the autophagy level in macrophages. Real-time PCR and western blot were used to analyzed the expression of mRNA and protein respectively. The potential protein interaction was analyzed by iTRAQ mass spectrometry and Immunoprecipitation. RNA fluorescence in situ hybridization, dual-luciferase reporter assay and RNA immunoprecipitation were used to explore the mechanism of QKI regulating mRNA of PI3K-p110ß. RESULTS: The mRNA level of QKI was aberrantly decreased in monocytes and PBMCs of septic patients with the increasing level of plasma procalcitonin (PCT). Then the mice with myeloid specific knockout of QKI was challenged with MRSA or Cecal Ligation and Puncture (CLP). Mice in these two models displayed higher survival rates and lower bacterial loads. Mechanistically, QKI deletion promoted phagocytosis and autophagic degradation of MRSA via activating p110ß (a member of Class IA phosphoinositide 3-kinases) mediated autophagic response. QKI expression in macrophages led to the sequestration of p110ß in mRNA processing (P) bodies and translational repression. Upon infection, the direct interaction of RNF6, a RING-type E3 ligase, mediated QKI ubiquitination degradation and facilitated PI3K-p110ß related autophagic removal of pathogen. The administration of nanoparticles with QKI specific siRNA significantly protected mice from MRSA infection. CONCLUSIONS: This study disclosed the novel function of QKI in the P body mRNA regulation during infection. QKI degradation in macrophage by RNF6 protects mice from MRSA infection via enhancing PI3K-p110ß dependent autophagy. It suggested that QKI may serve as a potential theranostic marker in MRSA-induced sepsis.

Separation of false-positive microplastics and analysis of microplastics via a two-phase system combined with confocal Raman spectroscopy.

In the field of microplastics research, more accurate standardised methods and analytical techniques still need to be explored. In this study, a new method for the microplastics quantitatively and qualitatively analysis by two-phase (ethyl acetate-water) system combined with confocal Raman spectroscopy was developed. Microplastics can be separated from false-positive microplastics in beach sand and marine sediment, attributing to the hydrophobic-lipophilic interaction (HLI) of the two-phase system. Results show that the recovery rates of complex environment microplastics (polypropylene (PP), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polyamide 66 (PA 66), polycarbonate (PC) and polyethylene (PE)) are higher than 92.98%. Moreover, the new technique can also be used to detect hydrophobic and lipophilic antibiotics, such as sulfamethoxazole (SMX), erythromycin (EM), madimycin (MD), and josamycin (JOS), which adsorbed on microplastics and are extracted based on the dissolving-precipitating mechanism. This innovative research strategy provides a new scope for further detection of marine environment microplastics and toxic compounds adsorbed on its surface.

QKI deficiency in macrophages protects mice against JEV infection by regulating cell migration and antiviral response.

Japanese encephalitis (JE) is a major reason to cause viral encephalitis, with 50% patients suffering from severe neuro-inflammation and permanent neural injury. Effective anti-viral treatment is urgently needed. Here, we found RNA binding protein quaking (QKI) was involved in the progression of JE by regulating migration and anti-viral response of macrophages. After JE virus (JEV) infection, QKI-deficient mice had lower viral loads in the brain and fewer neurological symptoms. In comparison with control mice, proinflammatory cytokines in the brain of QKI-deficient animals revealed distinct patterns, with lower levels of IL-6 (interleukin-6) and IFN-ß (interferon-ß) at the early stage but higher levels at the end of JE. Then we found infiltration of CCR2 positive ((C-C motif) receptor 2) peripheral macrophages and CCR2 expression on macrophages were inhibited in QKI-deficient mice, while the expression of CCR2 ligands was not changed. Bioinformatical analysis showed that a QRE (quaking response element) located on 3'UTR (untranslated region) of Ccr2. We further verified that QKI was able to interact with Ccr2 mRNA and regulate its degradation in vitro. Additionally, since the IFN-ß production was increased in QKI-ablation mice after JEV infection, the anti-viral response was analyzed. Results in QKI-silenced N9 cells showed that the expression of RIG-I (retinoic acid-inducible gene-I) and TBK1 (TANK binding kinase 1) was increased, thus further inducing IRF3 (interferon regulatory factor 3) phosphorylation and interferon activation. Overall, these results revealed QKI mediated the anti-viral process via interfering migration of macrophages to CNS (central nervous system) and enhancing RIG-I/IRF3/IFN-ß pathway to restrict virus dissemination.

Rapid and Sensitive Assay of Helicobacter pylori With One-Tube RPA-CRISPR/Cas12 by Portable Array Detector for Visible Analysis of Thermostatic Nucleic Acid Amplification.

Helicobacter pylori (H. pylori) has infected more than half of the world's population and is still a threat to human health. The urea breath test, despite being widely used in clinical diagnosis, still faces huge challenges in the immediate detection of H. pylori. Thus, a rapid, sensitive, and highly specific point of care diagnosis is particularly important for preventing the further transmission of H. pylori and for real-time monitoring of the disease in a given population. Recently, the clustered regularly interspaced short palindromic repeats (CRISPR)-based diagnostics have been applied to various types of nucleic acid testing; however, there are often shortcomings of complex operation and high signal transmission background. In this study, we proposed a new platform for the assay of H. pylori using one-tube-based CRISPR/Cas12a diagnostic methods and designed a detector for this platform, which is a portable array detector for visible analysis of thermostatic nucleic acid amplification (Pad-VATA). By incorporating isothermal recombinase polymerase amplification, our platform could detect the conserved gene fragments of H. pylori with a constant low as 2 copies/µl. The assay process can be performed at a single temperature in about 30 min and integrated into the reactor in the palm-sized Pad-VATA to facilitate rapid diagnosis of H. pylori. We also verified the accuracy of our platform using 10 clinical samples and found that the platform can quickly detect H. pylori infection in a given population. We believe that this fast, convenient, efficient, and inexpensive screening and diagnostic platform can be widely used in various settings, including homes and clinics.

AQP5 Is a Novel Prognostic Biomarker in Pancreatic Adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor with a poor prognosis. The identification of effective molecular markers is of great significance for diagnosis and treatment. Aquaporins (AQPs) are a family of water channel proteins that exhibit several properties and play regulatory roles in human carcinogenesis. However, the association between Aquaporin-5 (AQP5) expression and prognosis and tumor-infiltrating lymphocytes in PAAD has not been reported. Methods: AQP5 mRNA expression, methylation, and protein expression data in PAAD were analyzed using GEPIA, UALCAN, HAP, METHSURV, and UCSC databases. AQP5 expression in PAAD patients and cell lines from our cohort was examined using immunohistochemistry and Western blotting. The LinkedOmics database was used to study signaling pathways related to AQP5 expression. TIMER and TISIDB were used to analyze correlations among AQP5, tumor-infiltrating immune cells, and immunomodulators. Survival was analyzed using TCGA and Kaplan-Meier Plotter databases. Results: In this study, we investigated AQP5 expression in PAAD and determined whether the expression of AQP5 is a strong prognostic biomarker for PAAD. We searched and analyzed public cancer databases (GEO, TCGA, HAP, UALCAN, GEPIA, etc.) to conclude that AQP5 expression levels were upregulated in PAAD. Kaplan-Meier curve analysis showed that high AQP5 expression positively correlated with poor prognosis. Using TIMER and TISIDB, we found that the expression of AQP5 was associated with different tumor-infiltrating immune cells, especially macrophages. We found that hypomethylation of the AQP5 promoter region was responsible for its high expression in PAAD. Conclusions: AQP5 can serve as a novel biomarker to predict prognosis and immune infiltration in PAAD.

Adipocyte-Derived CTRP3 Exhibits Anti-Inflammatory Effects via LAMP1-STAT3 Axis in Psoriasis.

Psoriasis is a systemic disease that is associated with metabolic disorders, which may contribute to abnormal adipokine levels. However, the underlying mechanism is largely unknown. Here, we investigated the role of the adipokine CTRP3 in the pathogenesis of psoriasis and comorbidities. The circulating CTRP3 level in patients with psoriasis was significantly lower than that in healthy controls and negatively correlated with metabolic risk factors. Rescuing CTRP3 levels with the GLP-1 receptor agonist exendin-4 in diet-induced obese mice could alleviate its more severe psoriatic symptoms in an imiquimod-induced mouse model. Topical application of CTRP3 also exerted a protective effect on imiquimod-induced normal diet mice. Moreover, CTRP3 could directly inhibit the inflammatory responses of psoriatic keratinocytes by blocking phosphorylation of signal transducer and activator of transcription 3 via LAMP1 in vitro. We identified the critical psoriatic cytokines, including IL-17A and TNF-α, that impaired adipocyte differentiation and sufficient CTRP3 secretion. In sum, our study reveals that adipocyte dysfunction and low level of CTRP3 caused by IL-17A exacerbates psoriasis progression and related metabolic syndrome, implying a mechanism underlying the vicious cycle between psoriasis and metabolic disorders. Pharmacological agents that improve CTRP3 level in obese patients with psoriasis may be considered as a potential strategy for psoriasis treatment.

Nanoplastics aggravate the toxicity of arsenic to AGS cells by disrupting ABC transporter and cytoskeleton.

The coexistence of nanoplastics (NPs) and pollutants such as arsenic (As) has become an unignorable environmental problem. However, there is still a considerable knowledge gap about the impact of NPs and pollutants on human health risks. In this study, the human gastric adenocarcinoma (AGS) cells were used as a model to investigate the toxicity of NPs with different particle sizes and As by MTT assay, western blotting, immunofluorescence and so on. The results showed that 20 nm (8 µg/mL), 50 nm (128 µg/mL), 200 nm (128 µg/mL), 500 nm (128 µg/mL), 1000 nm (128 µg/mL) polystyrene (PS) did not affect cell viability, ROS, intracellular calcium and activate apoptosis pathway in AGS cells. However, noncytotoxic concentration of NPs enhanced the cytotoxicity and intracellular accumulation of As. NPs destroys the fluidity of cell membrane and cytoskeleton, inhibits the activity of ABC transporter, and leads to the accumulation of As in cells. This work highlights that the damage caused by NPs, especially at the level of noncytotoxicity, joint with As cannot be ignored and provides a specific toxicological mechanism of NPs accompanied by exposure to As.

Loss of QKI in macrophage aggravates inflammatory bowel disease through amplified ROS signaling and microbiota disproportion.

Inflammatory bowel disease (IBD) is a refractory chronic inflammatory illness of the gastrointestinal (GI) tract. Macrophage exerts an important role in IBD development. QKI, as an RNA binding protein, was related with inflammatory responses in bacterial infections by regulating the polarization of macrophages. Therefore, we suspected that QKI-regulated macrophages have the potential to play a certain role in IBD and the underlying mechanism. Our results demonstrated that the mice with macrophage-specific deletion of QKI induced with dextran sodium sulfate (DSS) are more susceptible to IBD development, exhibited a severe leaky gut barrier phenotype and higher intense oxidative stress, which are rescued by treating with butylated hydroxyanisole (BHA), an agonist of NRF2. Mechanically, we observed that Keap1 mRNA in the nucleus was exported to the cytoplasm after LPS stimuli in parallel with QKI reductions, and the removal of QKI by shRNA facilitated Keap1 mRNA nuclear exporting and expression in cytoplasm, consequently NRF2 activation in nucleus was weakened, and led to the impaired antioxidant abilities. In addition, mice models of fecal microbiota transplant (FMT) and the co-culturing of mice epithelia cells with feces derived from the DSS-treated QKI-deficit mice revealed consistently aggravated colitis along with a severe oxidative stress; 16S sequencing analysis substantiated the altered compositions of commensal bacteria too. Overall, the current study represents the first effort to explore the anti-oxidant role of QKI in the intestinal macrophage via post-transcriptional regulation of Keap1 mRNA localization and the relevant NRF2 antioxidant signaling, and the disproportional changes in the microbiota were attributable to the mediation of pathogenic damage in the IBD development of QKI-deficit mice.