IL-33 Accelerates Chronic Atrophic Gastritis through AMPK-ULK1 Axis Mediated Autolysosomal Degradation of GKN1.

Chronic atrophic gastritis (CAG) is a complex disease characterized by atrophy and inflammation in gastric mucosal tissue, especially with high expression of interleukins. However, the interaction and mechanisms between interleukins and gastric mucosal epithelial cells in CAG remain largely elusive. Here, we elucidate that IL-33 stands out as the predominant inflammatory factor in CAG, and its expression is induced by H. pylori and MNNG through the ROS-STAT3 signaling pathway. Furthermore, our findings reveal that the IL-33/ST2 axis is intricately involved in the progression of CAG. Utilizing phosphoproteomics mass spectrometry, we demonstrate that IL-33 enhances autophagy in gastric epithelial cells through the phosphorylation of AMPK-ULK1 axis. Notably, inhibiting autophagy alleviates CAG severity, while augmentation of autophagy exacerbates the disease. Additionally, ROS scavenging emerges as a promising strategy to ameliorate CAG by reducing IL-33 expression and inhibiting autophagy. Intriguingly, IL-33 stimulation promotes GKN1 degradation through the autolysosomal pathway. Clinically, the combined measurement of IL-33 and GKN1 in serum shows potential as diagnostic markers. Our findings unveil an IL-33-AMPK-ULK1 regulatory mechanism governing GKN1 protein stability in CAG, presenting potential therapeutic targets for its treatment.

The Herbal Combination Shu Gan Jie Yu Regulates the SNCG/ER-a/AKT-ERK Pathway in DMBA-Induced Breast Cancer and Breast Cancer Cell Lines Based on RNA-Seq and IPA Analysis.

BACKGROUND: Soothing the liver (called Shu Gan Jie Yu in Chinese, SGJY) is a significant therapeutic method for breast cancer in TCM. In this study, 3 liver-soothing herbs, including Cyperus rotundus L., Citrus medica L. var. sarcodactylis Swingle and Rosa rugosa Thunb. were selected and combined to form a SGJY herbal combinatory. THE AIM OF THE STUDY: To investigate the inhibiting effect of SGJY on breast cancer in vivo and vitro, and to explore the potential mechanisms. MATERIALS AND METHODS: SGJY herbal combination was extracted using water. A breast cancer rat model was developed by chemical DMBA by gavage, then treated with SGJY for 11 weeks. The tumor tissue was preserved for RNA sequencing and analyzed by IPA software. The inhibition effects of SGJY on MCF-7 and T47D breast cancer cells were investigated by SRB assay and cell apoptosis analysis, and the protein expression levels of SNCG, ER-α, p-AKT and p-ERK were measured by western blotting. RESULTS: SGJY significantly reduced the tumor weight and volume, and the level of estradiol in serum. The results of IPA analysis reveal SGJY upregulated 7 canonical pathways and downregulated 16 canonical pathways. Estrogen receptor signaling was the key canonical pathway with 9 genes downregulated. The results of upstream regulator analysis reveal beta-estradiol was the central target; the upstream regulator network scheme showed that 86 genes could affect the expression of the beta-estradiol, including SNCG, CCL21 and MB. Additionally, SGJY was verified to significantly alter the expression of SNCG mRNA, CCL21 mRNA and MB mRNA which was consistent with the data of RNA-Seq. The inhibition effects of SGJY exhibited a dose-dependent response. The apoptosis rates of MCF7 and T47D cells were upregulated. The protein expression of SNCG, ER-α, p-AKT and p-ERK were all significantly decreased by SGJY on MCF-7 and T47D cells. CONCLUSION: The results demonstrate that SGJY may inhibit the growth of breast cancer. The mechanism might involve downregulating the level of serum estradiol, and suppressing the protein expression in the SNCG/ER-α/AKT-ERK pathway.

Dendrobium officinale polysaccharide Converts M2 into M1 Subtype Macrophage Polarization via the STAT6/PPAR-r and JAGGED1/NOTCH1 Signaling Pathways to Inhibit Gastric Cancer.

Dendrobium officinale polysaccharide (DOP) has shown various biological activities. However, the ability of DOP to participate in immune regulation during anti-gastric cancer treatment has remained unclear. In this study, the in vitro results showed that DOP has the potential to polarize THP-1 macrophages from the M2 to the M1 phenotype, downregulate the STAT6/PPAR-r signaling pathway and the protein expression of their down-targeted ARG1 and TGM2, and further decrease the main protein and mRNA expression in the JAGGED1/NOTCH1 signaling pathway. DOP suppressed the migration of gastric cancer cells by decreasing the protein expression of N-cadherin and Vimentin and increasing E-cadherin. In addition, CM-DOP promoted the apoptosis of gastric cancer cells by upregulating Caspase-3 and increasing the ratio of Bax/Bcl-2. In vivo, DOP effectively inhibited the growth of tumors and the expression of Ki-67. In summary, these findings demonstrated that DOP converted the polarization of M2 subtype macrophages into M1 subtypes via the STAT6/PPAR-r and JAGGED1/NOTCH1 signaling pathways in order to reduce apoptosis and prevent migration, thus indicating the potential of DOP as an adjuvant tumor therapy in preclinical and clinical trials.

Quality monitoring of Shenmai injection by HPLC pharmacodynamic fingerprinting.

A probable problem of disconnection between chemical fingerprints and drug effects for TCMs would be contrary to the original intention of fingerprint research, and limits the development and application of fingerprints. In this study, Shenmai injection, as a treatment dosage form of coronary heart disease, shock, and viral myocarditis clinically, was applied as the research object. The fingerprint of Shenmai injection was constructed, and the pharmacodynamic test of antioxidant effect was carried out to obtain quantitative characteristics and pharmacodynamic data. On this basis, a monitoring model based on the HPLC pharmacodynamic fingerprint was established to evaluate the quality of Shenmai injections from different batches and different manufacturers. Results showed that the optimized HPLC method had good repeatability, precision, and stability. A total of 28 characteristic peaks were identified to provide more chemical information. Furthermore, 13 ginsenosides and notoginsenoside have been selected as characteristic components of LC/MS fingerprint method. 8 peaks closely related to antioxidant properties by multiple linear regression method, which were identified as Rg1, Re, Rf, Rb1, and some other ginsenosides using MS analysis. The monitoring model based on HPLC pharmacodynamic fingerprint could successfully identify quality differences for Shenmai injections. Based on the case study of Shenmai injection, the novel and practical fingerprint analytical strategy could be further applied to monitor or predict the quality of TCMs.

Venous sinus thrombosis in a case of immunoglobulin A vasculitis and a systemic review of literature.

OBJECTIVES: To describe venous sinus thrombosis involved in immunoglobulin A (IgA) vasculitis and identify the clinical features and imaging findings of this rare disease. METHODS: We describe a case with venous sinus thrombosis related to IgA vasculitis, and a systematic review of previously reported cases in the literature. RESULTS: A 10-year-old boy presented with recurrent petechiae of the lower extremities with abdominal pain, and was diagnosed as having IgA vasculitis. He had a sudden headache during the treatment of steroids, and venous sinus thrombosis was diagnosed according to magnetic resonance imaging. Venous sinus thrombosis is a rare complication of IgA vasculitis. Based on the systematic review, most of these reported cases who developed venous sinus thrombosis had multi-system involvement, which included skin, joints, gastrointestinal tract or kidneys. Sudden headache was the most common symptom of central venous sinus thrombosis. Some cases may also manifest as seizures and blindness. The sagittal sinus was the most common site of thrombosis. Magnetic resonance image, magnetic resonance venography, or computed tomography angiography were helpful for early diagnosis of this disease. Combination therapy of steroids and anticoagulation medication was effective in rapidly reliving clinical symptoms. CONCLUSIONS: Sudden headache in patients with IgA vasculitis requires vigilance for the possibility of central venous sinus thrombosis. Anti-inflammatories combined with anticoagulant therapy were needed for these patients.

RNA-Seq Analysis Reveals Dendrobium officinale Polysaccharides Inhibit Precancerous Lesions of Gastric Cancer through PER3 and AQP4.

PURPOSE: There has been mounting evidence that Dendrobium officinale polysaccharides (DOP), a traditional Chinese medicine, are a potential candidate treatment for N-methyl-N'-nitro-N-nitrosoguanidine- (MNNG-) induced precancerous lesions of gastric cancer (PLGC). However, the underlying mechanisms have not been adequately addressed. METHOD: We utilized RNA-Seq analysis to investigate possible molecular targets and then used Venn software to identify the differentially expressed genes (DEGs). Further, we analyzed these DEGs with core analysis, upstream analysis, and interaction network analysis by IPA software and validated the DEGs by real-time PCR and Western blot. RESULT: 78 DEGs were identified from the normal control group (CON), the PLGC model group (MOD), and the DOP-treated group (DOP) by the Venn software. Further analysis of these DEGs, including core analysis, upstream analysis, and interaction network analysis, was performed by Ingenuity Pathway Analysis (IPA). The main canonical pathways involved were SPINK1 Pancreatic Cancer Pathway (-log (P value) = 4.45, ratio = 0.0667) and Circadian Rhythm Signaling (-log (P value) = 2.33, ratio = 0.0606). Circadian Rhythm Signaling was strongly upregulated in the model group versus the DOP group. CLOCK was predicted to be strongly activated (z-score = 2.236) in upstream analysis and induced the downstream PER3. In addition, the relative mRNA expression levels of seven DEGs (CD2AP, ECM1, AQP4, PER3, CMTM4, ESRRG, and KCNJ15) from RT-PCR agreed with RNA-Seq data from MOD versus CON and MOD versus DOP groups. The gene and protein expression levels of PER3 and AQP4 were significantly downregulated in the PLGC model and significantly increased by DOP treatment (9.6 g/kg). CONCLUSIONS: These findings not only showed DOP inhibits PLGC development by upregulating the PER3 and AQP4 gene and protein expression but also suggested that its mechanism of action involved modulating the Circadian Rhythm Signaling pathway.

Enhanced degradation of tetracycline in water over Cu-doped hematite nanoplates by peroxymonosulfate activation under visible light irradiation.

Herein, Cu-doped hematite nanoplates (named as CuHNPs) with abundant oxygen-vacancies were prepared through a facile one-pot solvothermal method and used for efficient peroxymonosulfate (PMS) activation to degrade tetracycline (TC) in water. The catalytic activity of optimal CuHNPs-7.5 catalyst to activate PMS for the degradation of TC in water under visible light irradiation is 7.74 and 2.93 times higher than that of pure one without and with visible light irradiation. CuHNPs-7.5 exhibited excellent degradation for TC in the broad pH range from 2.14 to 10.75, and the removal of TC was barely inhibited by co-anions. The combination of free radicals and non-radical pathway, including sulfate radicals (SO4·-), hydroxide radicals (·OH), superoxide radical (·O2-) and single oxygen (1O2), contributed to TC oxidation. The introduction of Cu2+ not only accelerated the transformation of Fe(III)/Fe(II) redox cycle but also induced rich oxygen defects in the structure of hematite, boosting more generation of reactive oxygen species (ROSs) for TC degradation. Density functional theory (DFT) calculation and electrochemical impedance spectroscopy (EIS) tests confirmed the accelerated electrons transfer of CuHNPs-7.5 in PMS activation. This study provides a strategy to construct effective catalysts of PMS activation combining radicals and non-radical pathways for environmental remediation.

RAB27A-dependent release of exosomes by liver cancer stem cells induces Nanog expression in their differentiated progenies and confers regorafenib resistance.

BACKGROUND AND AIM: Regorafenib is a potent multikinase inhibitor for the second-line targeted therapy against hepatocellular carcinoma (HCC); however, drug resistance is emerging in clinical settings. Although cancer stem cells (CSCs) are considered as key determinate of drug sensitivity, it remains unclear how CSCs may communicate with the differentiated counterparts (non-CSC) to dictate therapeutic efficacy. Therefore, we sought to investigate the regorafenib resistance mechanism of CSCs in HCC. METHODS: We used sphere formation and soft agar colony formation assays to evaluate the stemness capacity of cancer cells. Cell viability assay was performed to detect the sensitivity of cancer cells to regorafenib. Real-time quantitative polymerase chain reaction and western blot were used to analyze gene expression. Mouse xenograft tumor model was performed to assess Regorafenib sensitivity in vivo. RESULTS: Exosomes are highly enriched in CSC supernatant compared with that of non-CSC, and RAB27A mediates exosome secretion from CSCs to maintain stem-like phenotype and regorafenib insensitivity. Moreover, exosomes released by CSCs upregulate the expression of Nanog in non-CSC, while depleting Nanog sensitizes non-CSC to regorafenib in the presence of CSC exosomes. Consistently, analysis of TCGA datasets reveals that RAB27A expression tightly correlates with Nanog in HCC tissues. More importantly, depletion of RAB27A downregulates Nanog expression and sensitizes cancer cells to regorafenib in nude mice. CONCLUSIONS: Our findings suggest that CSCs release exosomes in a RAB27A-dependent manner to induce Nanog expression and regorafenib resistance in differentiated cells, targeting this exosome signaling between distinct cellular subsets may be a potential therapeutic strategy for HCC patients.

Efficient activation of persulfate by a magnetic recyclable rape straw biochar catalyst for the degradation of tetracycline hydrochloride in water.

A recyclable magnetic rape straw biochar (MRSB) catalyst was synthesized by a high value-added and energy-saving method using abandoned rape straw as the raw material. The MRSB catalyst showed high catalytic activity and recyclability for activating persulfate (PS) to degrade tetracycline hydrochloride (TC) in water. The Fe3O4 in the MRSB greatly promoted the activation of PS. More importantly, the MRSB catalyst exhibited high catalytic performance over a wide pH range (2.99-11.01) for activating PS to degrade TC in water. Moreover, MRSB still had good catalytic activity for TC degradation after 8 recycling cycles and was easily separated by an external magnetic field for reuse. The electron spin resonance (ESR) analysis indicated that the generation of the sulfate radicals (SO4-), hydroxyl radicals (OH) and superoxide radicals (O2-) was greatly promoted in the MRSB/PS system. As a result, MRSB exhibited 13.24-fold higher reaction rate for activating PS than those of rape straw biochar (RSB). Both radical mechanism and non-radical mechanism existed in the MRSB/PS system, and SO4- and singlet oxygen (1O2) played a determinative role. This study might give a new way to reuse abandoned rape straw and synthesize new recyclable catalysts for activating PS to degrade organic pollutants in water.

TTK regulates proliferation and apoptosis of gastric cancer cells through the Akt-mTOR pathway.

TTK (also known as Mps1) is the core component of the spindle assembly checkpoint, which ensures proper distribution of chromosomes to daughter cells to maintain genome integrity and to balance growth and division. However, the function of TTK in tumorigenesis has not been extensively studied, especially in relation to the development of gastric cancer. In this study, survival and tumor recurrence data related to TTK expression level in gastric cancer patients were collected and analyzed. We observed that TTK expression was negatively correlated with survival and tumor recurrence in vivo. TTK was also upregulated in gastric cancer cells and was observed to be essential for the proliferation and survival of gastric cancer cells. Knockdown of TTK inhibited proliferation and increased apoptosis. Furthermore, we report that TTK regulates the proliferation and apoptosis of tumor cells through the Akt-mTOR pathway. Knockdown of TTK inhibited activation of Akt-mTOR signaling. In summary, our data indicate that TTK is involved in the regulation of gastric cancer proliferation and apoptosis.

Sequence and Structural Analysis of AA9 and AA10 LPMOs: An Insight into the Basis of Substrate Specificity and Regioselectivity.

Lytic polysaccharide monooxygenases (LPMOs) are key enzymes in both the natural carbon cycle and the biorefinery industry. Understanding the molecular basis of LPMOs acting on polysaccharide substrates is helpful for improving industrial cellulase cocktails. Here we analyzed the sequences, structures, and substrate binding modes of LPMOs to uncover the factors that influence substrate specificity and regioselectivity. Our results showed that the different compositions of a motif located on L2 affect the electrostatic potentials of substrate binding surfaces, which in turn affect substrate specificities of AA10 LPMOs. A conserved Asn at a distance of 7 Å from the active center Cu might, together with the conserved Ser immediately before the second catalytic His, determine the localization of LPMOs on substrate, and thus contribute to C4-oxidizing regioselectivity. The findings in this work provide an insight into the molecular basis of substrate specificity and regioselectivity of LPMOs.

One-Dimensional/Two-Dimensional Core-Shell-Structured Bi2O4/BiO2- x Heterojunction for Highly Efficient Broad Spectrum Light-Driven Photocatalysis: Faster Interfacial Charge Transfer and Enhanced Molecular Oxygen Activation Mechanism.

Deliberate tuning of nanoparticles encapsulated with nanosheet shells can bring about fascinating photocatalytic properties because of the fast charge-transfer characteristics of a nanosized core-shell structure. Herein, a novel core-shell-structured Bi2O4/BiO2- x composite was fabricated through a one-step hydrothermal method. The core-shell Bi2O4/BiO2- x composite presented distinct optical absorption property, including UV, visible, and near-infrared (NIR) light regions. Compared to Bi2O4 and BiO2- x, the Bi2O4/BiO2- x composite revealed improved broad spectrum light-responsive molecular oxygen activation into •O2-, especially achieving •O2- generation under NIR light irradiation. The achievement that enhanced broad spectrum light-activated molecular oxygen activation could be ascribed to the faster electron transfer confirmed by the electron spin resonance (ESR) spectra, photoluminescence (PL) spectra, photoelectrochemical test, and quantitative analysis of •O2-. The strong interface effect of the Bi2O4/BiO2- x composite was confirmed by X-ray photoelectron spectroscopy analysis. Density functional theory calculated results suggested that the Bi2O4/BiO2- x composite revealed increased density of states near the Fermi level, suggesting that it possessed higher carrier mobility as compared to Bi2O4 and BiO2- x, contributing to the faster separation of photoinduced carriers and the generation of •O2-. Benefiting to the heterojunction, the Bi2O4/BiO2- x composite showed improved photocatalytic activity and anti-photocorrosion activity during rhodamine B (RhB) and ciprofloxacin (CIP) degradation with the irradiation of UV, visible, and NIR lights. Besides, the possible photocatalytic mechanism and transformation pathway of RhB and CIP degradation by the Bi2O4/BiO2- x composite were proposed by the analyses of the liquid chromatography-mass spectrometry. This study furnishes a new strategy for fabricating high-efficient and broad spectrum light-driven heterojunction photocatalysts for environment purification.

[Implementation of extraction process trajectory for in-line quality control of danhong injection].

Extraction process trajectory of Danhong injection by near-infrared (NIR) spectroscopy in conjunction with multivariate data analysis techniques was developed for in-line monitoring of extraction process. To capture the variation of batch process, the use of score, Hotelling T2 and DModX control charts was investigated for real-time monitoring of extraction process. Various abnormal behaviors of the test batches were detected in time by comparing the extraction process trajectory. It was concluded that the process trajectory for in-line quality control based on NIR spectroscopy was a feasible technology tool of the total process quality control during traditional Chinese medicine (TCM) manufacturing process.

Enhanced visible-light-driven photocatalytic inactivation of Escherichia coli by Bi2O2CO3/Bi3NbO7 composites.

The Bi2O2CO3/Bi3NbO7 (BiCO/BiNbO) composite was successfully fabricated by a simple hydrothermal method and found to be an effective visible-light-driven photocatalyst for inactivation of Escherichia coli (E. coli). The BiCO/BiNbO composite was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), UV-vis diffuse reflectance spectrum (UV-vis DRS), and Fourier transform infrared (FT-IR) spectroscopy. The BiCO/BiNbO composite exhibited largely enhanced photocatalytic inactivation of E. coli as compared to the pure Bi3NbO7 under visible light irradiation. The enhanced photocatalytic performance can be attributed to the improved separation efficiency of the photogenerated holes and electrons. In addition, the possible bactericidal mechanism of the BiCO/BiNbO composite under visible light irradiation was discussed.

In-line monitoring of alcohol precipitation by near-infrared spectroscopy in conjunction with multivariate batch modeling.

Alcohol precipitation is a critical unit operation during the manufacture of Chinese herbal injections. To facilitate enhanced process understanding and develop control strategy, the use of near-infrared spectroscopy (NIRS) combined with multivariate statistical process control (MSPC) methodology was investigated for in-line monitoring of alcohol precipitation. The effectiveness of the proposed approach was evaluated through an experimental campaign. Six batches were run under normal operating conditions to study batch-to-batch variation or batch reproducibility and establish MSPC control limits, while artificial process variations were purposefully introduced into the four test batches to assess the capability of the model for real-time fault detection. Several MSPC tools were compared and assessed. NIRS, in conjunction with MSPC, has proven to be a feasible process analytical technology (PAT) tool for monitoring batch evolution and potentially facilitating model-based advanced process control of the alcohol precipitation during the manufacture of Chinese herbal injections.

Stromal transforming growth factor-beta signaling mediates prostatic response to androgen ablation by paracrine Wnt activity.

Mechanisms of androgen dependence of the prostate are critical to understanding prostate cancer progression to androgen independence associated with disease mortality. Transient elevation of transforming growth factor-beta (TGF-beta) occurs after androgen ablation. To determine the role of TGF-beta on prostate response to androgen ablation, conditional TGF-beta type II receptor knockout mouse models of the epithelia (Tgfbr2(NKX3.1KO)) and stromal fibroblasts (Tgfbr2(fspKO)) were used. After castration, the prostates of Tgfbr2(NKX3.1KO) mice had apoptosis levels similar to those expected for control Tgfbr2(floxE2/floxE2) mice. Prostates of Tgfbr2(fspKO) mice, however, had reduced regression and high levels of proliferation associated with canonical Wnt activity throughout the glandular epithelia regardless of androgen status. In contrast, Tgfbr2(floxE2/floxE2) prostates had epithelial canonical Wnt activity only in the surviving proximal ducts after castration. In vitro studies showed that androgen antagonist, bicalutamide, transiently elevated both Tgfbr2(floxE2/floxE2) and Tgfbr2(fspKO) stromal expression of Wnt-2, Wnt-3a, and Wnt-5a. The neutralization of Wnt signaling by the expression of secreted frizzled related protein-2 (SFRP-2) resulted in decreased LNCaP prostate epithelial cell proliferation in stromal conditioned media transfer experiments. In vivo tissue recombination studies using Tgfbr2(fspKO) prostatic stromal cells in combination with wild-type or SV40 large T antigen expressing epithelia resulted in prostates that were refractile to androgen ablation. The expression of SFRP-2 restored the Tgfbr2(fspKO)-associated prostate responsiveness to androgen ablation. These studies reveal a novel TGF-beta, androgen, and Wnt paracrine signaling axis that enables prostatic regression of the distal ducts after androgen ablation while supporting proximal duct survival.

Effect of rhodoxanthin from Potamogeton crispus L. on cell apoptosis in Hela cells.

Carotenoid, a natural functional pigment, is known to have anti-carcinogenic activity. To verify the anti-cancer effects of rhodoxanthin which is a kind of carotenoids, we investigated the effects of rhodoxanthin from Potamogeton crispus L. on the proliferation rate, cell cycle distribution, apoptosis and the change in mitochondrial membrane potential in Hela cell line. The effects of rhodoxanthin were also tested on the concentration of Ca(2+) in cells. Rhodoxanthin inhibited cell proliferation in Hela cells in a dose and time-dependent manner. Rhodoxanthin induced an accumulation of cells in the S phase of the cell cycle, reduced the mitochondria transmembrane potential and increased the concentration of intracellular Ca(2+). In summary, our results suggested that rhodoxanthin-induced apoptosis in Hela cells occurred via these pathways.