Classification of congenital cataracts based on multidimensional phenotypes and its association with visual outcomes.

AIM: To establish a classification for congenital cataracts that can facilitate individualized treatment and help identify individuals with a high likelihood of different visual outcomes. METHODS: Consecutive patients diagnosed with congenital cataracts and undergoing surgery between January 2005 and November 2021 were recruited. Data on visual outcomes and the phenotypic characteristics of ocular biometry and the anterior and posterior segments were extracted from the patients' medical records. A hierarchical cluster analysis was performed. The main outcome measure was the identification of distinct clusters of eyes with congenital cataracts. RESULTS: A total of 164 children (299 eyes) were divided into two clusters based on their ocular features. Cluster 1 (96 eyes) had a shorter axial length (mean±SD, 19.44±1.68 mm), a low prevalence of macular abnormalities (1.04%), and no retinal abnormalities or posterior cataracts. Cluster 2 (203 eyes) had a greater axial length (mean±SD, 20.42±2.10 mm) and a higher prevalence of macular abnormalities (8.37%), retinal abnormalities (98.52%), and posterior cataracts (4.93%). Compared with the eyes in Cluster 2 (57.14%), those in Cluster 1 (71.88%) had a 2.2 times higher chance of good best-corrected visual acuity [<0.7 logMAR; OR (95%CI), 2.20 (1.25-3.81); P=0.006]. CONCLUSION: This retrospective study categorizes congenital cataracts into two distinct clusters, each associated with a different likelihood of visual outcomes. This innovative classification may enable the personalization and prioritization of early interventions for patients who may gain the greatest benefit, thereby making strides toward precision medicine in the field of congenital cataracts.

NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors.

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.

FOXP4-AS1 promotes CD8+ T cell exhaustion and esophageal cancer immune escape through USP10-stabilized PD-L1.

Esophageal cancer (EC) is the 9th most frequently diagnosed malignancy globally with unfavorable prognosis. Immune escape is one of the principal factors leading to poor survival, however, the mechanism underlying immune escape remains largely uninvestigated. The xenograft mouse model and EC cell-CD8+ cytotoxic T lymphocytes (CTLs) co-culture system were established. Immunohistochemistry, qRT-PCR or western blot were employed to detect the levels of long non-coding RNA (lncRNA) FOXP4-AS1, PD-L1, USP10 and other molecules. The abundance of T cells, cytokine production and cell apoptosis were monitored by flow cytometry. The viability of CTLs was assessed by Trypan blue staining. The binding between FOXP4-AS1 and USP10 was validated by RNA pull-down assay, and the interaction between USP10 and PD-L1, as well as the ubiquitination of PD-L1, were detected by co-immunoprecipitation. The elevation of FOXP4-AS1 in EC was associated with decreased CTL abundance, and upregulated PD-L1 facilitated CTL apoptosis in EC. FOXP4-AS1 accelerated EC tumor growth by decreasing the abundance of tumor infiltrating CTLs in vivo. FOXP4-AS1 inhibited the viability of CTLs and facilitated the cytotoxicity and exhaustion of CTLs. In Kyse 450 cell-CTL co-culture system, FOXP4-AS1 suppressed the viability and abundance of CTLs, and inhibited EC cell apoptosis via PD-L1. Mechanistically, FOXP4-AS1 regulated the ubiquitination of PD-L1 through deubiquitinating enzyme USP10. FOXP4-AS1 promoted CTL exhaustion and EC immune escape through USP10-stabilized PD-L1. HIGHLIGHTS: PD-L1 facilitated CD8+ T cell apoptosis in EC. Upregulated FOXP4-AS1 promoted EC tumor growth by inhibiting the viability and facilitating the cytotoxicity and exhaustion of tumor infiltrating CD8+ T cells. FOXP4-AS1 suppressed the viability and abundance of CD8+ T cells through USP10-mediated deubiquitination of PD-L1.

VentX promotes tumor specific immunity and efficacy of immune checkpoint inhibitors.

Immune suppression within tumor microenvironments (TME) have been implicated in limited efficacy of immune check point inhibitors (ICIs) against solid tumors. Down-regulated VentX expression in tumor associated macrophages (TAMs) underlies phagocytotic anergic phenotype of TAMs, which govern immunological state of TME. In this study, using a tumor immune microenvironment enabling model system (TIME-EMS) of non-small cell lung cancer (NSCLC), we found that PD-1 antibody modestly activates cytotoxic T lymphocytes (CTLs) within the NSCLC-TME but not the status of TIME. We showed that the restoration of VentX expression in TAMs reignites the phagocytotic function of TAMs, which in turn, transforms TIME, activates CTLs in a tumor-specific manner and promotes efficacy of PD-1 antibody against NSCLC but not toxicity on normal lung epithelial cells. Supported by in vivo data on NSG-PDX models of primary human NSCLC, our study revealed potential venues to promote the efficacy of ICI against solid tumors through VentX-based mechanisms.

Design, synthesis and antitumor activity of 4-arylamine substituted pyrimidine derivatives as noncovalent EGFR inhibitors overcoming C797S mutation.

Clinical researches have shown that epidermal growth factor receptor (EGFR) is a key target for treatment of non-small cell lung cancer (NSCLC). Many EGFR inhibitors were successfully developed as ani-tumor drugs to treat NSCLC patients. Unfortunately, drug resistances were found in clinic. To overcome C797S mutation in EGFR, a novel series of 4-arylamine substituted pyrimidine derivatives were designed and synthesized under the principle of structure-based drug design. Interestingly, compounds 6e and 9i demonstrated the best anti-proliferative activity against A549, NCI-H1975, and HCC827 cells. In particular, the IC50 values against HCC827 cells reached to 24.6 nM and 31.6 nM, which were much lower than human normal cells 2BS and LO2. Furthermore, compounds 6e and 9i showed extraordinary activity against EGFR19del/T790M/C797S (IC50 = 16.06 nM and 37.95 nM) and EGFRL858R/T790M/C797S (IC50 = 11.81 nM and 26.68 nM), which were potent than Osimertinib (IC50 = 52.28 nM and 157.60 nM). Further studies have shown that compounds 6e and 9i could pertain inhibition of HCC827 colony formation, and arrest HCC827 cells at G2/M phase. Moreover, the most promising compound 6e could inhibit the migration of HCC827 cells, induce HCC827 cells apoptosis, and significantly inhibit the phosphorylation of EGFR, AKT and Erk1/2. In vivo xenograft mouse model with HCC827 cells, compound 6e resulted in remarkable tumor regression without obvious toxicity. In addition, molecular docking studies suggested that compound 6e could firmly combine with T790M-mutant, T790 M/C797S-mutant, and L858R/T790 M/C797S-mutant EGFR kinases as ATP-competitive inhibitor.

A comprehensive analysis of the expression, immune infiltration, prognosis and partial experimental validation of CHST family genes in gastric cancer.

Previous studies have demonstrated that carbohydrate sulfotransferase family proteins (CHSTs) play a crucial role in the extracellular matrix structural constituent and cancer progression, however, the effect of CHSTs on gastric cancer is still superficial. To investigate these, our study seeks to provide a comprehensive understanding of CHSTs' expression, immune infiltration, and prognostic implications in gastric cancer, utilizing data from the TCGA, GEO and GTEx databases. Furthermore, we conducted experimental validation to elucidate the role of CHST14 specifically in gastric cancer. Our findings suggest that most CHSTs were highly expressed in gastric cancer. Gene copy number variations further indicated prevalent CHSTs amplification in gastric cancer, pointing to its potential relevance in disease progression. Intriguingly, we noted strong positive correlations between most CHSTs and immune cell infiltration. Importantly, most members of CHSTs were related to OS and PFI with gastric cancer, with particular emphasis on CHST14 and CHST9. Multifactorial regression analysis indicates that CHST14 is an independent prognostic factor influencing the overall survival of gastric cancer patients. In further experimental validation, our results demonstrate elevated expression of CHST14 in gastric cancer, and knocking down CHST14 inhibits gastric cancer cell proliferation, invasion, migration and EMT. Additionally, CHST14 may exert its function through the regulation of the Wnt pathway. In summary, our study comprehensively analyzes the hitherto undescribed role of CHSTs in gastric cancer through the analysis of multi-omics data. Importantly, we identify CHST14 as a pivotal promoter in the malignant progression of gastric cancer, offering potential targets for gastric cancer therapy.

The Research Progress in Transforming Growth Factor-ß2.

Transforming growth factor-beta 2 (TGF-ß2), an important member of the TGF-ß family, is a secreted protein that is involved in many biological processes, such as cell growth, proliferation, migration, and differentiation. TGF-ß2 had been thought to be functionally identical to TGF-ß1; however, an increasing number of recent studies uncovered the distinctive features of TGF-ß2 in terms of its expression, activation, and biological functions. Mice deficient in TGF-ß2 showed remarkable developmental abnormalities in multiple organs, especially the cardiovascular system. Dysregulation of TGF-ß2 signalling was associated with tumorigenesis, eye diseases, cardiovascular diseases, immune disorders, as well as motor system diseases. Here, we provide a comprehensive review of the research progress in TGF-ß2 to support further research on TGF-ß2.

P2 purinergic receptors regulate the progression of colorectal cancer.

More and more studies have revealed that P2 purinergic receptors play a key role in the progression of colorectal cancer (CRC). P2X and P2Y purinergic receptors can be used as promoters and regulators of CRC and play a dual role in the progression of CRC. CRC microenvironment is rich in ATP and its cleavage products (ADP, AMP, Ado), which act as activators of P2X and P2Y purinergic receptors. The activation of P2X and P2Y purinergic receptors regulates the progression of CRC mainly by regulating the function of immune cells and mediating different signal pathways. In this paper, we focus on the specific mechanisms and functional roles of P2X7, P2Y12, and P2Y2 receptors in the growth and progression of CRC. The antagonistic effects of these selective antagonists of P2X purinergic receptors on the growth, invasion, and metastasis of CRC were further discussed. Moreover, different studies have reported that P2X7 receptor can be used as an effective predictor of patients with CRC. All these indicate that P2 purinergic receptors are a key regulator of CRC. Therefore, antagonizing P2 purinergic receptors may be an innovative treatment for CRC.

Misdiagnosed periappendiceal and intestinal tuberculosis during the COVID-19 pandemic.

Introduction and importance: The coronavirus disease 2019 (COVID-19) was first reported in Wuhan, Hubei Province, China. It mainly involves the respiratory system, causing fever, cough, chest tightness, and other symptoms. However, when combined with other common or rare diseases, such as appendicitis and intestinal tuberculosis (TB), it can cause other systemic lesions, thus making the original disease lose its specific clinical manifestations. This case highlights the importance of early identification and clinical precision medicine diagnosis and treatment. Case presentation: A young woman presented with intermittent pain and discomfort in the right lower quadrant. Ultrasonography suggested appendicitis with a peripheral abscess. The nucleic acid test of COVID-19 was positive, and the chest computed tomography scan showed pulmonary involvement. She was sent for surgery. Postoperative body temperature increased regularly, and the TB T-cell test was positive. Clinical discussion: Multiple infections caused by common bacteria, pandemic virus, and specific mycobacterium TB cause a series of nonspecific clinical manifestations, which brings challenges to clinical diagnosis and treatment. Therefore, when facing a complex infection case, the authors should consider the possibility of multiple infections and give targeted treatment for the pathogens. Conclusions: During the epidemic of COVID-19, the incidence of intestinal TB is relatively low, which is easy to be overlooked and misdiagnosed, especially in the case of appendicitis. Therefore, clinicians must be highly vigilant in the diagnosis process to avoid missed diagnosis or misdiagnosis, so as to provide the best diagnosis and treatment plan.

Ghost cell odontogenic carcinoma: A rare case report and review of literature.

RATIONALE: Ghost cell odontogenic carcinoma is a rare malignant odontogenic carcinoma characterized by the presence of ghost cells. It has a nonspecific clinical and radiographic presentation and can be locally destructive and invasive, sometimes with distant metastases. However, no effective systemic therapy is currently recommended for such patients. PATIENT CONCERNS: The patient has been unable to undergo surgery or radiotherapy again. Therefore, he was referred to our department for a more aggressive, multimodal systematic treatment program. DIAGNOSES: The histopathological examination was morphologically suggestive of ghost cell odontogenic carcinomas. INTERVENTIONS: We report a case of locally invasive primary inoperable odontogenic shadow cell carcinoma in a 31-year-old Chinese man who achieved treatment with Toripalimab and chemotherapy, followed by Toripalimab maintenance therapy after 6 cycles. OUTCOMES: He achieved partial remission after treatment. The quality of life significantly improved after treatment. There were no grade 3/4 treatment-related adverse events during treatment. LESSONS: This case presented that Toripalimab and chemotherapy may be a safe and effective systemic therapy for ghost cell odontogenic carcinoma.

Design, synthesis and biological evaluation of 4-arylamino-pyrimidine derivatives as focal adhesion kinase inhibitors.

A novel series of 4-arylamino-pyrimidine derivatives were designed and synthesized as focal adhesion kinase (FAK) inhibitors under the strategy of structure-based drug design. Most compounds performed excellent anti-proliferative activity against U87-MG cells. Especially, compounds 8d and 9b revealed the highest activity with IC50 values of 0.975 µM and 1.033 µM, which was much potent than the positive control TAE-226 (IC50 = 2.659 µM). On the other hand, the total 27 compounds exhibited low inhibition against human normal 2BS cells. Moreover, compounds 8d and 9b showed outstanding activity against FAK with IC50 values of 0.2438 nM and 0.2691 nM, which was very close to TAE-226 (IC50 = 0.1390 nM). Further studies proved that compounds 8d and 9b could induce U87-MG cell early apoptosis and arrest the cell at G2/M phase. The action mechanism indicated that they could significantly inhibit U87-MG cell clone formation, cell migration, and FAK phosphorylation. Molecular docking and molecular dynamics simulation investigations suggested that compounds 8d and 9b could firmly occupy the ATP binding site of FAK. These findings supported the further researches of compounds 8d and 9b as FAK inhibitors for antitumor drug discovery.

miR-3133 inhibits gastrointestinal cancer progression through activation of Hippo and p53 signalling pathways via multi-targets.

BACKGROUND: Malignant cell growth and chemoresistance, the main obstacles in treating gastrointestinal cancer (GIC), rely on the Hippo and p53 signalling pathways. However, the upstream regulatory mechanisms of these pathways remain complex and poorly understood. METHODS: Immunohistochemistry (IHC), western blot and RT-qPCR were used to analyse the expression of RNF146, miR-3133 and key components of Hippo and p53 pathway. CCK-8, colony formation, drug sensitivity assays and murine xenograft models were used to investigate the effect of RNF146 and miR-3133 in GIC. Further exploration of the upstream regulatory mechanism was performed using bioinformatics analysis, dual-luciferase reporter gene, immunoprecipitation assays and bisulfite sequencing PCR (BSP). RESULTS: Clinical samples, in vitro and in vivo experiments demonstrated that RNF146 exerts oncogenic effects in GIC by regulating the Hippo pathway. Bioinformatics analysis identified a novel miRNA, miR-3133, as an upstream regulatory factor of RNF146. fluorescence in situ hybridization and RT-qPCR assays revealed that miR-3133 was less expressed in gastrointestinal tumour tissues and was associated with adverse pathological features. Functional assays and animal models showed that miR-3133 promoted the proliferation and chemotherapy sensitivity of GIC cells. miR-3133 affected YAP1 protein expression by targeting RNF146, AGK and CUL4A, thus activating the Hippo pathway. miR-3133 inhibited p53 protein degradation and extended p53's half-life by targeting USP15, SPIN1. BSP experiments confirmed that miR-3133 promoter methylation is an important reason for its low expression. CONCLUSION: miR-3133 inhibits GIC progression by activating the Hippo and p53 signalling pathways via multi-targets, including RNF146, thereby providing prognostic factors and valuable potential therapeutic targets for GIC.

Bioactive Aspergteroids G-J from Soft-Coral-Associated Symbiotic and Epiphytic Fungus Aspergillus terreus EGF7-0-1.

Two new disubstituted maleimides, aspergteroids G-H (1-2), and two trisubstituted butenolides aspergteroids I-J (3-4), along with four known analogs, were isolated and structurally identified from the fermentation extract of soft-coral-associated symbiotic and epiphytic fungus Aspergillus terreus EGF7-0-1. The structures of the new compounds were established mainly via spectroscopic data analyses, and their absolute configurations were determined via X-ray diffraction analysis and comparison of the calculated and experimental electronic circular dichroism. Myocardial protection assays showed that compounds 1, 2, 5, and 6 possess protective effects against tert-butyl hydroperoxide (TBHP)-induced H9c2 (rat myocardial cells) apoptosis at low concentrations. Based on the analyses of the protein-protein interaction (PPI) network and Western blotting, compound 1 may inhibit the apoptosis and inflammatory response of cardiomyocytes after TBHP induction and improve the antioxidant capacity of cardiomyocytes. We speculate that the anti-inflammatory response of compound 1 is suppressed by the glycogen synthase kinase-3 beta (GSK-3ß), downregulated by the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation, and suppressed by the expression of cysteinyl aspartate specific proteinase-3 (caspase-3) and B-cell lymphoma-2 associated X protein (Bax).

Isolation and identification of 3,4-seco-labdane diterpenoids from Callicarpa nudiflora and investigation of their cytotoxicity against HepG2 cells.

Twenty-one previously undescribed compounds, including nineteen 3,4-seco-labdanes (nudiflopenes P-W, Y, AI-JI), one 3,4-seco-pimarane (nudiflopene X), and one labdane (nudiflopene Z), along with nine known compounds (one 3,4-seco-pimarane and eight 3,4-seco-labdanes) were isolated from the leaves of Callicarpa nudiflora Hook. Et Arn. The structures of these compounds were elucidated by high-resolution electrospray ionization mass spectrometry and one- and two-dimensional nuclear magnetic resonance spectroscopy. In addition, configurations of the isolated compounds were determined by electronic circular dichroism, DP4+ probability analysis, and single-crystal X-ray diffraction experiments. All undescribed compounds were evaluated for their cytotoxicity against HepG2 cells in vitro, among which compound 12 exhibited a moderate activity with an IC50 value of 27.8 µM.

Dosimetric Impact of Source Displacement in GammaTile Surgically Targeted Radiation Therapy for Gliomas.

Background This study aims to evaluate dosimetric changes that happened during the first month after GammaTile surgically targeted radiation therapy (STaRT) for gliomas due to Cesium-131 (Cs-131) seed displacement caused by cavity shrinkage in brain brachytherapy. Methodology In this study, 10 glioma patients had 4-11 GammaTiles placed along the resection bed after maximal safe resection during craniotomy. Each GammaTile is composed of four Cs-131 seeds embedded in a biodegradable collagen sponge to minimize seed movement and maintain seed-to-cavity surface distance. The Cs-131 seed positions were identified using VariSeed on day one. On day 30, post-implant computed tomography (CT) images and dosimetry parameters were calculated. An iterative closest point (ICP) algorithm was used to compute rigid transformation between the day one and day 30 seed clouds. The seed displacement was calculated after registration. The volume receiving 100% of the prescription dose (V100), the dose received by 90% of the planning target volume (D90_PTV), the planning target volume receiving 100% of the prescription dose (V100_PTV), and the dose to organs at risk (OARs) were calculated for both CT images to determine the dosimetric changes from any seed displacement. Results The mean seed displacement of 1.8 ± 1.0 mm for all patients was observed between day one and day 30. The maximum seed displacement for each patient ranged from 2.3 mm to 7.3 mm. The mean V100 difference between day one and day 30 was 2.5 cc (range = 0.5-6.5 cc). The mean D90_PTVs were 95.5% (range = 69.0%-131.0%) and 98.1% (range = 19.9%-149.0%) on day one and day 30, respectively. The mean V100_PTVs were 88.4% (range = 81.3%-99.1%) and 87.9% (range = 47.0%-99.7%) on day one and day 30, respectively. On day one, the brainstem dose was 63.5 Gy for one case and 28.1 Gy for another case; while on day 30, the brainstem dose was 55.8 Gy and 20.6 Gy for the same patients, contributing to 7.7 Gy (12.8%) and 7.5 Gy (12.5%) dose reductions to brainstem for these patients, respectively. Only two patients received a dose to the optic nerves (34.1 Gy and 5.2 Gy). There were small changes (1.8 Gy and 0.5 Gy, respectively) in the dose to optic nerves when comparing the dose calculated on day one and the dose calculated on day 30 CT images. The same two patients received 30.4 Gy and 6.8 Gy to the chiasm, respectively. Small changes in the dose to the chiasm (≤1.1 Gy) were noted between day one and day 30. Conclusions A maximum seed displacement of up to 7.3 mm and a mean seed displacement of 1.8 mm caused by cavity shrinkage were observed during the first month after GammaTile STaRT for gliomas. There were noticeable changes in dosimetry parameters. Changes in the doses to OARs, particularly the brainstem, were large (up to 12.8% of the prescription dose). These changes in dosimetry should be considered when evaluating treatment outcomes and planning future GammaTile treatments.

New Indole Diketopiperazine Alkaloids from Soft Coral-Associated Epiphytic Fungus Aspergillus versicolor CGF 9-1-2.

Two new indole diketopiperazine alkaloids (IDAs), (+)19-epi-sclerotiamide (1) and (-)19-epi-sclerotiamide (2), along with 13 known analogs (3-15), were isolated from a soft coral-associated epiphytic fungus Aspergillus versicolor CGF 9-1-2. The structures of two new compounds were established based on the combination of HR-ESI-MS, 1D and 2D NMR spectroscopy, optical rotation measurements and quantum chemical 13 C-NMR, the absolute configurations were determined by experimental and electronic circular dichroism (ECD) calculations. The results of molecular docking showed that all the compounds had a good binding with TDP1, TDP2, TOP1, TOP2, Ache, NLRP3, EGFR, EGFR L858R, EGFR T790M and EGFR T790/L858. Biological evaluation of compounds 3, 6, 8, 11 showed that 3 exerted a strong inhibitory effect on TDP2 with a rate of 81.72 %.

Association between urinary nickel with obesity status in adults: A cross-sectional study.

Objectives: The prevalence of obesity is on the rise and is connected to numerous factors. However, the relationship between obesity and nickel has never been investigated. Our study aimed to explore the association between urinary nickel and obesity Status in adults. Methods: From the 2017-2018 National Health and Nutrition Examination Surveys (NHANES), 1,705 participants ≥18 years of age were enrolled. To explore further the relationship among urinary nickel, body mass index (BMI), and waist circumference(WC), Weighted multivariate linear regression analyses and further subgroup analyzes were conducted. Results: Urinary nickel does not correlate with BMI level but positively correlates with WC. In the subgroup analyzed according to sex, Urinary nickel has a positive correlation with BMI and WC in males but has a negative correlation in females. Secondary stratification analysis according to sex and race, Urinary nickel positively correlates with BMI in White males. It also positively correlates with WC in both White and Black males. Conclusions: A correlation was found between urinary nickel levels and BMI and WC in adult males. Adult men, especially those already obese, may need to reduce nickel exposure.

WWP2 drives the progression of gastric cancer by facilitating the ubiquitination and degradation of LATS1 protein.

BACKGROUND: Large tumor suppressor kinase 1 (LATS1), one of the predominant components of the Hippo pathway, has been characterized as a key player controlling the proliferation and invasion of cancer cells, including gastric cancer (GC) cells. However, the mechanism by which the functional stability of LATS1 is modulated has yet to be elucidated. METHODS: Online prediction tools, immunohistochemistry and western blotting assays were used to explore the expression of WW domain-containing E3 ubiquitin ligase 2 (WWP2) in GC cells and tissues. Gain- and loss-of-function assays, as well as rescue experiments were performed to determine the role of the WWP2-LATS1 axis in cell proliferation and invasion. Additionally, the mechanisms involving WWP2 and LATS1 were assessed by coimmunoprecipitation (Co-IP), immunofluorescence, cycloheximide and in vivo ubiquitination assays. RESULTS: Our results demonstrate a specific interaction between LATS1 and WWP2. WWP2 was markedly upregulated and correlated with disease progression and a poor prognosis in GC patients. Moreover, ectopic WWP2 expression facilitated the proliferation, migration and invasion of GC cells. Mechanistically, WWP2 interacts with LATS1, resulting in its ubiquitination and subsequent degradation, leading to increased transcriptional activity of YAP1. Importantly, LATS1 depletion abolished the suppressive effects of WWP2 knockdown on GC cells. Furthermore, WWP2 silencing attenuated tumor growth by regulating the Hippo-YAP1 pathway in vivo. CONCLUSIONS: Our results define the WWP2-LATS1 axis as a critical regulatory mechanism of the Hippo-YAP1 pathway that promotes GC development and progression. Video Abstract.

Anti-Inflammatory Activities of Monoterpene and Sesquiterpene Glycosides from the Aqueous Extract of Artemisia annua L.

Artemisia annua L. is a Chinese medicinal herb, but the origin of its pharmacological properties, including its anti-inflammatory activity, remain unknown. In this study, five new monoterpene glycosides (1-5) and two new sesquiterpene glycosides (6 and 7) were isolated from the aqueous extract of the aerial parts of A. annua. The structures of these glycosides were determined using high-resolution electrospray ionization mass spectrometry, nuclear magnetic resonance spectroscopy, electronic circular dichroism calculations, and chemical hydrolysis methods. The anti-inflammatory activities of the isolated compounds were evaluated by down-regulating interleukin-6 (IL-6) in lipopolysaccharide-stimulated RAW 264.7 macrophages. Notably, all the new compounds significantly inhibited the expression of IL-6 in a dose-dependent manner.