TMEM252 inhibits epithelial-mesenchymal transition and progression in papillary thyroid carcinoma by regulating Notch1 expression.

BACKGROUND: Papillary thyroid carcinoma (PTC) accounts for about 85% of thyroid cancer cases. Transmembrane protein 252 (TMEM252) is a gene encoding a transmembrane protein that has only been reported to be associated with triple-negative breast cancer. Herein, we first elucidated the physiological roles and possible regulatory proteins of TMEM252 in PTC pathogenesis. METHODS: Quantitative real-time polymerase chain reaction, western blot, and immunohistochemical analyses were utilized to ascertain the relative TMEM252 expression in PTC and surrounding normal tissues. Functional investigations involved CCK-8 viability assay, EdU incorporation assay for proliferation, transwell assays for migration and invasion, and an in vivo tumor development assessment to evaluate the TMEM252-mediated regulation of tumor formation. RESULTS: Our results first revealed diminished TMEM252 transcript and protein expressions in PTC tissues and cell lines. TMEM252 overexpression suppressed cell proliferation through reducing p53, p21, and p16 expression. Conversely, TMEM252 depletion has opposite effects in PTC cells both in vivo. Additionally, the upregulation of TMEM252 demonstrated cell migration and invasion suppression by impeding the epithelial-mesenchymal transition (EMT) process via inhibition of the Notch pathway. Furthermore, overexpression of TMEM252 suppressed tumor growth in vivo. CONCLUSION: Our study elucidates that TMEM252 suppresses PTC progression by modulating the Notch pathway. These findings underscore TMEM252 is a potential therapeutic target in managing PTC.

Combined therapy of dabrafenib and an anti-HER2 antibody-drug conjugate for advanced BRAF-mutant melanoma.

BACKGROUND: Melanoma is the most lethal skin cancer characterized by its high metastatic potential. In the past decade, targeted and immunotherapy have brought revolutionary survival benefits to patients with advanced and metastatic melanoma, but these treatment responses are also heterogeneous and/or do not achieve durable responses. Therefore, novel therapeutic strategies for improving outcomes remain an unmet clinical need. The aim of this study was to evaluate the therapeutic potential and underlying molecular mechanisms of RC48, a novel HER2-target antibody drug conjugate, either alone or in combination with dabrafenib, a V600-mutant BRAF inhibitor, for the treatment of advanced BRAF-mutant cutaneous melanoma. METHODS: We evaluated the therapeutic efficacy of RC48, alone or in combination with dabrafenib, in BRAF-mutant cutaneous melanoma cell lines and cell-derived xenograft (CDX) models. We also conducted signaling pathways analysis and global mRNA sequencing to explore mechanisms underlying the synergistic effect of the combination therapy. RESULTS: Our results revealed the expression of membrane-localized HER2 in melanoma cells. RC48 effectively targeted and inhibited the growth of HER2-positive human melanoma cell lines and corresponding CDX models. When used RC48 and dabrafenib synergically induced tumor regression together in human BRAF-mutant melanoma cell lines and CDX models. Mechanically, our results demonstrated that the combination therapy induced apoptosis and cell cycle arrest while suppressing cell motility in vitro. Furthermore, global RNA sequencing analysis demonstrated that the combination treatment led to the downregulation of several key signaling pathways, including the PI3K-AKT pathway, MAPK pathway, AMPK pathway, and FOXO pathway. CONCLUSION: These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.

Potential molecular mechanism of photosynthesis regulation by PeMPK7 in poplar under para-hydroxybenzoic acid stress.

Due to continuous plantation of poplar, its growth and biomass accumulation may be negatively affected by the accumulation of allelochemicals such as para-hydroxybenzoic acid (pHBA) in soil. As photosynthesis is the most fundamental process in plants, it can be negatively impacted by pHBA stress. Therefore, it is crucial to improve photosynthetic capacity under pHBA stress to facilitate poplar plant growth. The mitogen-activated protein kinase (MAPK) cascade pathway is widely involved in environmental stress responses in plants. However, the regulation mechanisms of photosynthesis-related pathways by MAPK pathway genes under pHBA stress are still unclear. In this study, through transcriptome analysis and weighted gene co-expression network analysis, we observed that PeMPK7 overexpression in poplar can regulate the expression of photosynthesis-related genes and transcription factor genes, namely, WRKY1, WRKY33, and ERF3, during the early stage of pHBA stress. In addition, PeMPK7 can improve photosynthesis in poplar under long-term pHBA stress. Moreover, yeast two-hybrid and pull-down assays confirmed the interaction between PeMPK7 and PeMKK7/10. Based on these results, a schematic diagram of the pathways involved in the regulation of photosynthesis by PeMPK7 was constructed. This study provided novel insights into the molecular mechanisms of regulation of pHBA stress via MAPK cascade pathway.

Synergistic antitumor activity between HER2 antibody-drug conjugate and chemotherapy for treating advanced colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer associated with a poor prognosis. Effective targeted therapy alone or in combination for treating advanced CRC remains to be a major clinical challenge. Here, we propose the therapeutic efficacy and molecular mechanism underlying RC48, a FDA-approved anti-HER2 antibody conjugate via a cleavable linker to the microtubule inhibitor monomethyl auristatin E (MMAE), either alone or in combination with gemcitabine (GEM) in various models of HER2-positive advanced CRC. Our findings demonstrated that HER2 was widely expressed and located on the plasma membrane of CRC patient specimens, PDX xenograft tumors and cell lines. It confirmed that RC48 alone significantly targeted and eradicated HER2 positive CRC tumor in these models. Moreover, we screened a panel of FDA-approved first-line chemotherapy drugs in vitro. We found that GEM exhibited stronger antiproliferative activity compared to the other first-line anti-cancer agents. Furthermore, combination therapy of RC48 and GEM significantly showed synergetic antitumor activity in vitro and in vivo. To gain further mechanistic insights into the combination therapy, we performed RNA-seq analysis. The results revealed that combination treatment of RC48 and GEM regulated multiple signaling pathways, such as PI3K-AKT, MAPK, p53, Foxo, apoptosis, cell cycle and cell senescence, etc., to exert its antitumor activity in CRC cells. Collectively, these preclinical findings demonstrated that RC48 alone or combinational therapy exerted promising antitumor activity, and meriting the preclinical framework for combinational therapy of anti-HER2 drug conjugate drug and chemotherapy drugs for HER2-positive patients with advanced CRC.

Visualization of Ice Crystal Behavior in Mouse Oocytes During High-Speed Quench Cooling and Ice Inhibition by Antifreezing Hydrogels.

Oocyte vitrification has become a widely adopted method in clinical practice. However, the solidification behavior and its impact on oocytes during the ultrarapid cooling process remain poorly understood. In this study, we established a system and methodology to observe crystallization behavior in oocytes during quench cooling and warming. Subsequently, the threshold concentration of cryoprotective agents (CPAs) required for oocyte vitrification was determined through a visualization method. The results demonstrated that the ice front could not be observed in the image sequence when using 16.5% DMSO +16.5% EG during high-speed quench cooling (2821.58°C/min). Finally, oocytes were encapsulated with an antifreezing hydrogel (7.5% EG +7.5% DMSO +0.5% alginate) and subjected to high-speed quench cooling. No ice crystals appeared in the antifreezing hydrogel-encapsulated oocytes at a low concentration of osmotic CPA (2.4 M). This research opens up new possibilities for oocyte vitrification with a reduced concentration of CPA.

Combined inhibition of HER2 and VEGFR synergistically improves therapeutic efficacy via PI3K-AKT pathway in advanced ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is a prevalent malignancy in the female reproductive system, and developing effective targeted therapies for this disease remains challenging. The aim of this study was to use clinically-relevant OC models to evaluate the therapeutic effectiveness of RC48, an antibody-drug conjugate (ADC) targeting HER2, either alone or in combination with the VEGFR inhibitor Cediranib Maleate (CM), for the treatment of advanced OC. METHODS: OC tumor specimens and cell lines were analyzed to determine HER2 and VEGFR expression by Western blot, immunocytochemistry and immunofluorescence. Moreover, the OC cell lines, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were treated with RC48 and/or CM and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for OC both in vitro and in vivo. Additionally, RNA-Seq was performed to investigate the critical mechanism underlying the combination therapy of RC48 and CM. RESULTS: Our results demonstrated that RC48 alone effectively targeted and inhibited the growth of HER2-positive OC tumors in both cell lines and PDX models. Furthermore, the combination of RC48 and CM synergistically induced tumor regression in human OC cell lines, as well as CDX and PDX models. Mechanistically, we observed that the combination treatment inhibited the growth of OC cells involved inducing apoptosis and suppressing cell motility. RNA-seq analysis provided further mechanistic insights and revealed that co-administration of RC48 and CM downregulated multiple cancer-related pathways, including the AKT/mTOR pathway, cell cycle, and cell proliferation. Notably, our data further confirmed that the PI3K-AKT pathway played a key role in the inhibition of proliferation triggered by combinational treatment of RC48 and CM in OC cells. CONCLUSIONS: These findings provide a preclinical framework supporting the potential of dual targeting HER2 and VEGFR as a promising therapeutic strategy to improve outcomes in patients with OC.

The P286R mutation of DNA polymerase ε activates cancer-cell-intrinsic immunity and suppresses endometrial tumorigenesis via the cGAS-STING pathway.

Endometrial carcinoma (EC) is a prevalent gynecological tumor in women, and its treatment and prevention are significant global health concerns. The mutations in DNA polymerase ε (POLE) are recognized as key features of EC and may confer survival benefits in endometrial cancer patients undergoing anti-PD-1/PD-L1 therapy. However, the anti-tumor mechanism of POLE mutations remains largely elusive. This study demonstrates that the hot POLE P286R mutation impedes endometrial tumorigenesis by inducing DNA breakage and activating the cGAS-STING signaling pathway. The POLE mutations were found to inhibit the proliferation and stemness of primary human EC cells. Mechanistically, the POLE mutants enhance DNA damage and suppress its repair through the interaction with DNA repair proteins, leading to genomic instability and the upregulation of cytoplasmic DNA. Additionally, the POLE P286R mutant also increases cGAS level, promotes TBK1 phosphorylation, and stimulates inflammatory gene expression and anti-tumor immune response. Furthermore, the POLE P286R mutation inhibits tumor growth and facilitates the infiltration of cytotoxic T cells in human endometrial cancers. These findings uncover a novel mechanism of POLE mutations in antagonizing tumorigenesis and provide a promising direction for effective cancer therapy.

Effect of silencing CITED1 gene to regulate PI3K/AKT pathway on the biological function of PTC cells and its mechanism.

This study aims to investigate the effect of silencing the CITED1 gene to regulate the PI3K/AKT pathway on the biological function of papillary thyroid carcinoma (PTC) cells and its mechanism of action. Human PTC cells SW1736 were divided into 4 groups: control group, siCITED1 group, LY294002 group and siCITED1+LY294002 group. CITED1 was silenced by transfection with siCITED1 plasmid. The PI3K/AKT pathway was inhibited by LY294002 (5 µmmol/L). Each group was determined for cell proliferation, apoptosis and invasion capabilities, as well as PI3K/AKT transcription and protein expression levels. CITED1 mRNA and protein levels in the siCITED1 group and the siCITED1+LY294002 group were significantly lower than those in the control group (P < 0.05), and the two levels were not significantly different between the LY294002 group and the control group (P > 0.05). Compared with the control group, the siCITED1 group showed remarkably lower proliferation and invasion capabilities, and remarkably higher apoptosis rate (P < 0.05). There was no significant difference in proliferation, apoptosis and invasion capabilities between the LY294002 group and the siCITED1+LY294002 group (P > 0.05), both of which had significantly lower proliferation and invasion capabilities but significantly higher apoptosis rate than the siCITED1 group (P < 0.05). PI3K and AKT protein levels in the siCITED1 group were significantly lower than those in the control group (P < 0.05). The PI3K and AKT protein levels in the LY294002 group and the siCITED1+LY294002 group were not significantly different (P > 0.05), and were significantly lower than those in the siCITED1 group (P < 0.05). In conclusion: CITED1 silence may inhibit the progression of PTC cells by inhibiting the PI3K/AKT pathway.

Haplotype analysis and marker development of five salt-tolerant-related genes in rice (Oryza sativa L.).

Salinity stress is a great threat to the growth and productivity of crops, and development of salt-tolerant crops is of great necessity to ensure food security. Although a few genes with natural variations that confer salt tolerance at germination and seedling stage in rice have been cloned, effective intragenic markers for these genes are awaited to be developed, which hinder the use of these genes in genetic improvement of salt tolerance in rice. In this study, we first performed haplotype analysis of five rice salt-tolerant-related genes using 38 rice accessions with reference genome and 4,726 rice germplasm accessions with imputed genotypes and classified main haplotype groups and haplotypes. Subsequently, we identified unique variations for elite haplotypes reported in previous studies and developed 11 effective intragenic makers. Finally, we conducted genotyping of 533 of the 4,726 rice accessions from worldwide and 70 approved temperate geng/japonica cultivars in China using the developed markers. These results could provide effective donors and markers of salt-tolerant-related genes and thus could be of great use in genetic improvement of salt tolerance in rice.

Clinical efficacy of gasless submental-transoral endoscopic thyroidectomy with Kirschner wire suspension for papillary thyroid carcinoma.

PURPOSE: To analyze the clinical efficacy of gasless submental-transoral endoscopic thyroidectomy (ETE) with Kirschner wire suspension in patients with papillary thyroid carcinoma (PTC). METHODS: Retrospectively, we enrolled 112 patients with PTC who received treatment in The Second Affiliated Hospital of Nanchang University between December 2020 and December 2021. Among them, 60 cases (laparoscopic group) received gasless submental-transoral ETE with Kirschner wire suspension, and the other 52 cases (open group) were treated by traditional thyroidectomy. Surgical indicators (operative time (OT), intraoperative blood loss (IBL), and postoperative drainage volume (DV)), number of central lymph node (CLN) dissected, length of hospital stay (LOS), Visual Analogue Scale (VAS) score, aesthetic satisfaction score, and complications were observed and compared between the two groups. RESULTS: There was no significant difference between the two groups in OT (55.73±5.49 min vs. 55.00±7.79 min), IBL (20.67±7.75 mL vs. 23.08±6.24 mL), postoperative DV (33.17±15.09 mL vs. 39.52±19.22 mL), number of CLN dissected (5.54±2.75 vs. 5.43±3.15), LOS (3.63±0.69 d vs. 3.68±0.57 d), postoperative VAS score (3.19±1.07 points vs. 3.38±1.09 points), and total complication rate (3.85% vs. 8.33%; all P>0.05). However, the laparoscopic group exhibited a significantly higher aesthetic satisfaction score than the open group (7.10±1.46 points vs. 6.42±1.46 points; P<0.05). In addition, patients in both groups were followed up for at least 3 months, and no recurrence or metastasis was observed. CONCLUSIONS: Gasless submental-transoral ETE with Kirschner wire suspension offers comparable curative effect as traditional thyroidectomy and safety, but it provides superior esthetic results, making it a viable treatment option for patients with PTC.

The quality of group interactions in medical problem-based learning in China: the roles of intercultural sensitivity and group ethnic composition.

BACKGROUND: Chinese universities are increasingly recruiting foreign students, and problem-based learning (PBL) is an effective approach to integrating those students. This study focuses on the role of intercultural sensitivity and group ethnic composition on the quality of group interaction in medical problem-based learning in China. METHODS: This paper reports an investigation of the differences in three types of group interaction (exploratory questions, cumulative reasoning, and handling conflict) among 139 s-year medical undergraduates from two backgrounds (Chinese and foreign) in a PBL setting. The roles of intercultural sensitivity, group ethnic composition, and students' personal characteristics including age, gender and ethnicity on students' perceptions of the three types of interaction were quantitatively analyzed. A 35-item questionnaire and demographic survey were administered to second year medical undergraduates. RESULTS: The results indicated that group ethnic composition was a significant negative predictor while intercultural sensitivity was a strong positive predictor of group interactions involving exploratory questions and cumulative reasoning. In addition, group heterogeneity in terms of age and ethnicity were significant predictors of group interaction. CONCLUSIONS: The findings of this study provide insights for strategically designing effective multiethnic group learning environments that encourage interaction and collaboration.

PeMPK17 interacts with PeMKK7 and participates in para-hydroxybenzoic acid stress resistance by removing reactive oxygen species.

Mitogen-activated protein kinase (MAPK) plays a crucial role in plant stress response. Poplar is one of the most important afforestation and timber species and inevitably encounters allelopathy effects during continuous cropping. para-hydroxybenzoic acid (pHBA) is a primary soil allelochemical, which can restrict the growth and biomass of poplar. However, the involvement of MAPKs in the underlying physiological and molecular regulatory mechanisms in response to pHBA stress remains unclear. In this study, PeMPK17, a gene encoding a group D MAPK, was cloned from Populus × euramericana. PeMPK17 protein was localized in both nucleus and plasma membrane. Quantitative real-time polymerase chain reaction analysis demonstrated that PeMPK17 expression in poplar increased when treated with pHBA, PEG, and H2O2. Exogenous pHBA and H2O2 induced PeMPK17 expression mediated by reactive oxygen species (ROS). The transgenic poplar plants overexpressing PeMPK17 demonstrated attenuated phenotypic injury, higher relative water content in leaves, and lower ion leakage under pHBA stress. In transgenic poplar, the activity and expression of antioxidant enzymes including superoxide dismutase, peroxidase, and catalase increased, while the content of H2O2, O2·-, and malondialdehyde decreased. These results suggested that PeMPK17 protects cell membranes from oxidative damage by removing excess ROS. In addition, overexpression of PeMPK17 promoted osmoprotectant accumulation including soluble sugar and free proline, which may aid in the regulation of ROS balance under pHBA treatment. Furthermore, the interaction between PeMPK17 and PeMKK7 was confirmed. Collectively, these data identify the molecular mechanisms and signal pathways associated with PeMPK17 that regulate pHBA response in poplar.

IodoTMT-labeled redox proteomics reveals the involvement of oxidative post-translational modification in response to para-hydroxybenzoic acid and hydrogen peroxide stresses in poplar.

Poplar is widely planted as an economic and ecological tree species. However, accumulation of the phenolic acid allelochemical para-hydroxybenzoic acid (pHBA) in soil is a severe threat to the growth and productivity of poplar. pHBA stress leads to excessive production of reactive oxygen species (ROS). However, it is unclear which redox-sensitive proteins are involved in the pHBA-induced cellular homeostasis regulatory mechanism. We here identified reversible redox-modified proteins and modified cysteine (Cys) sites in exogenous pHBA- and hydrogen peroxide (H2O2)-treated poplar seedling leaves by using the iodoacetyl tandem mass tag-labeled redox proteomics method. In total, 4786 redox modification sites were identified in 3176 proteins, with 104 and 91 proteins being differentially modified at 118 and 101 Cys sites in response to pHBA and H2O2 stresses, respectively. The differentially modified proteins (DMPs) were predicted to be mainly localized in the chloroplast and cytoplasm, with most proteins being enzymes with catalytic activities. The KEGG enrichment analysis of these DMPs revealed that proteins related to the MAPK signaling pathway, soluble sugar metabolism, amino acid metabolism, photosynthesis, and phagosome pathways were extensively regulated by redox modifications. Moreover, combined with our previous quantitative proteomics data, 8 proteins were upregulated and oxidized under both pHBA and H2O2 stresses. Reversible oxidation of Cys sites in these proteins might be actively responsible for the regulation of tolerance to pHBA-induced oxidative stress. Based on the aforementioned results, a redox regulatory model activated by pHBA- and H2O2-induced oxidative stress was proposed. This study conducts the first redox proteomics analysis of poplar in response to pHBA stress and provides a new insight into the mechanistic framework of reversible oxidative post-translational modifications to gain a better understanding of pHBA-induced chemosensory effects on poplar.

Therapeutic efficacy of a MMAE-based anti-DR5 drug conjugate Oba01 in preclinical models of pancreatic cancer.

Pancreatic cancer (PC) is among the most aggressive malignancies associated with a 5-year survival rate of <9%, and the treatment options remain limited. Antibody-drug conjugates (ADCs) are a new class of anticancer agents with superior efficacy and safety profiles. We studied the antitumor activity of Oba01 ADC and the mechanism underlying the targeting of death receptor 5 (DR5) in preclinical PC models. Our data revealed that DR5 was highly expressed on the plasma membrane of PC cells and Oba01 showed potent in vitro antitumor activity in a panel of human DR5-positive PC cell lines. DR5 was readily cleaved by lysosomal proteases after receptor-mediated internalization. Monomethyl auristatin E (MMAE) was then released into the cytosol to induce G2/M-phase growth arrest, cell death via apoptosis induction, and the bystander effect. Furthermore, Oba01 mediated cell death via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. For improved potency, we investigated the synergetic effect of Oba01 in combination with approved drugs. Oba01 combined with gemcitabine showed better antiproliferative activity than either standalone treatment. In cell- and patient-derived xenografts, Oba01 showed excellent tumoricidal activity in mono- or combinational therapy. Thus, Oba01 may provide a novel biotherapeutic approach and a scientific basis for clinical trials in DR5-expressing patients with PC.

Comparative Analysis of Antioxidant System and Salt-Stress Tolerance in Two Hibiscus Cultivars Exposed to NaCl Toxicity.

Hibiscus (Hibiscus syriacus L.) is known as a horticultural plant of great ornamental and medicinal value. However, the effect of NaCl stress on hibiscus seedlings is unclear. Little is known about H. syriacus 'Duede Brabaul' (DB) and H. syriacus 'Blueberry Smoothie' (BS). Here, the effects of solutions with different concentrations of NaCl on the organic osmolytes, ion accumulation, and antioxidant enzyme activity of hibiscus seedling leaves were determined. The results showed that the Na+/K+ ratio was imbalanced with increasing NaCl concentration, especially in BS (range 34% to 121%), which was more sensitive than DB (range 32% to 187%) under NaCl concentrations of 50 to 200 mM. To cope with the osmotic stress, the content of organic osmolytes increased significantly. Additionally, NaCl stress caused a large increase in O2·- and H2O2, and other reactive oxygen species (ROS), and antioxidant enzyme activity was significantly increased to remove excess ROS. The expression level of genes related to salt tolerance was significantly higher in DB than that in BS under different NaCl concentrations. Taken together, DB possessed a stronger tolerance to salt stress and the results suggest membrane stability, Na+/K+, H2O2, catalase and ascorbate peroxidase as salt tolerance biomarkers that can be used for gene transformation and breeding in future hibiscus research.

Overexpressed ZC3H13 suppresses papillary thyroid carcinoma growth through m6A modification-mediated IQGAP1 degradation.

PURPOSE: The purpose of this study was to clarify the effect of ZC3H13 on the growth of papillary thyroid carcinoma (PTC). METHODS: Firstly, we used qRT-PCR and Western blot to compare the difference in the expression of ZC3H13 between normal thyroid epithelial cells and PTC cell lines. Then, ZC3H13 overexpression/knockout thyroid cancer cells were constructed by lentivirus transfection, and the effects of overexpression of ZC3H13 on the proliferation, migration and invasion of PTC cells were detected by CCK8 and transwell experiments. Lastly, MeRIP-qPCR, RIP and o Actinomycin D were used to verify that ZC3H13 regulated the expression of downstream target gene IQGAP1 through m6A modification. RESULTS: ZC3H13 expression was decreased in PTC cell lines BCPAP, KTC-1, k1, HTH83, and TPC-1. Proliferation, invasion, and migration of PTC cells were inhibited by overexpressed ZC3H13 but increased by knockdown of ZC3H13. IQGAP1 expression was suppressed by ZC3H13 overexpression but enhanced by ZC3H13 knockdown. In ZC3H13-overexpressed PTC cells, the m6A level of IQGAP1 mRNA was increased, and the IQGAP1 mRNA expression was decreased with the increasing time of Actinomycin D treatment. YTHDF2 enriched more IQGAP1 mRNA than IgG and knockdown of YTHDF2 reversed the effect of ZC3H13 overexpression on IQGAP1 mRNA stability. The xenograft tumor experiment in nude mice confirmed that the overexpression of ZC3H13 inhibited tumor growth, while overexpression of IQGAP1 could reverse the inhibitory effect of ZC3H13 overexpression on tumor growth. CONCLUSION: ZC3H13 mediates IQGAP1 mRNA degradation by promoting m6A modification of IQGAP1 mRNA, this provides a prospective therapeutic target for PTC.

LGALS2 suppresses the progression of papillary thyroid carcinoma by regulating the PI3K/AKT pathway.

Background: The galectin 2 (LGALS2) protein has been shown to be associated with the pathogenic progression of a range of cancer types, yet its role in papillary thyroid carcinoma (PTC) remains poorly defined. Accordingly, the present study was conducted to address this gap in the literature. Methods: Eighty pairs of tumor and paracancerous tissues from PTC patients were collected. Western immunoblotting and real-time quantitative polymerase chain reaction (qPCR) were used to compare LGALS2 expression levels in tumor and paracancerous tissues from PTC patients. An LGALS2 overexpression construct was produced by inserting the coding sequence for this gene into a pcDNA4.0 vector, and LGALS2-specific and control siRNA constructs were obtained. CCK-8, EdU uptake, and apoptotic assays were used to gauge the role of LGALS2 as a regulator of in vitro PTC cell growth and apoptosis, while its in vivo role was assessed using a murine xenograft model. Results: LGALS2 mRNA and protein levels were reduced in both PTC tumors and cell lines, and the expression of this gene was related to PTC patient prognosis and clinicopathological features. LGALS2 knockdown enhanced PTC cell proliferative activity while decreasing the sensitivity of these cells to apoptotic death. In contrast, the opposite effect was evident following LGALS2 overexpression in vitro and in vivo. LGALS2 also suppressed the progression of PTC by its ability to induce phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway activation. Conclusions: These data indicate that LGALS2 suppresses PTC progression via PI3K/AKT pathway activation, suggesting that LGALS2 offers value as a treatment target for patients with this cancer type.

Clinical and Molecular Analysis of ST11-K47 Carbapenem-Resistant Hypervirulent Klebsiella pneumoniae: A Strain Causing Liver Abscess.

Klebsiella pneumoniae has been the predominant pathogen of liver abscess, but ST11-K47 carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) has rarely been studied as the causative organism. We identified an ST11-K47 CR-hvKP (HvKp-su1) from the drainage fluid of a liver abscess in a Chinese man who was diagnosed with liver abscess combined with diabetes, pneumonia, pleural infection, abdominal abscess, and splenic abscess. HvKp-su1 was non-hypermucoviscous and lacked the magA and rmpA genes and pLVPK plasmid but exhibited high virulence, with a high mortality rate (90%) to wax moth larvae (G. mellonella), similar to the hypervirulent Klebsiella pneumoniae ATCC43816 (91.67%). Whole-genome sequencing and bioinformatics analysis indicated that HvKp-su1 possesses a plasmid similar to a type of pLVPK-like plasmid (JX-CR-hvKP-2-P2), which is an uncommon plasmid in CR-hvKP. HvKp-su1 carried multiple resistance genes, including blaKPC-2. blaTEM-1, blaSHV-55, and blaCTX-M-65; hypervirulence genes such as aerobactin (iutA), salmochelin (iroEN), and yersiniabactin (ybtAEPQSTUX); and the type 3 fimbriae-encoding system (mrkACDF). Moreover, v_5377 and v_5429 (cofT, CFA/III (CS8)) located on plasmid 1 were simultaneously predicted to be virulence genes. After the long-term combination use of antibiotics, the patient successfully recovered. In summary, our study clarified the clinical and molecular characteristics of a rare ST11-K47 CR-hvKP (HvKp-su1), raising great concerns about the emergence of ST11-K47 CR-hvKP with multidrug resistance and hypervirulence, and providing insights into the control and treatment of liver abscess caused by ST11-K47 CR-hvKP.

A comparative analysis of photosynthetic function and reactive oxygen species metabolism responses in two hibiscus cultivars under saline conditions.

Hibiscus (Hibiscus syriacus Linn.) is considered to be an important flowering shrub in Asia, and has high medicinal value. However, there are few studies on its cultivation and application in salinity soils. To understand the photosynthetic adaptive strategies employed by hibiscus to deal with saline conditions, the potential tolerant [H. syriacus 'Duede Brabaul' (DB)] and sensitive [H. syriacus 'Blueberry Smoothie' (BS)] cultivars were grown under 0-200 mM NaCl concentrations followed by a comprehensive assessment of their photosynthetic function and reactive oxygen species (ROS) metabolism. NaCl treatment significantly reduced the chlorophyll content of the two hibiscus cultivars, and the photosynthetic carbon assimilation capacity of the hibiscus leaves decreased, which was a result of stomatal and nonstomatal limiting factors. With the extension of NaCl stress days, nonphotochemical quenching (NPQ) can be significantly increased, which can effectively activate the nonradiant heat energy dissipation mechanism to release excess excitation energy to reduce the damage from the stressful environment and protect itself. Moreover, DB showed high antioxidant activities of reduced glutathione, and lower accumulation of ROS compared to BS. Taken together, this work suggests that the greater oxidative damage of the sensitive cultivar BS leaves is an important reason for its higher degree of photoinhibition to PSII than those of the tolerant cultivar DB leaves under NaCl stress.

Calcitriol ameliorates renal injury with high-salt diet-induced hypertension by upregulating GLIS2 expression and AMPK/mTOR-regulated autophagy.

The goal of the present study was to investigate the protective effect of calcitriol on high-salt diet-induced hypertension. The hypertension rat model was established by a long-term high-salt diet (8% NaCl). Rats were treated with calcitriol, losartan, or their combination. Histological staining was used to confirm renal pathology. Global transcriptome analysis of renal tissues was performed, and the mechanism of the therapeutic effect of calcitriol was analysed by functional annotation and pathway analysis of the differentially expressed genes (DEGs) as well as by Western blotting analysis. The core genes for potential therapeutic regulation were identified through the coexpression gene network. For in vitro HK-2 cell experiments, small interfering RNA (siRNA) was used to knockdown key a transcription factor (TF) Glis2 to validate the therapeutic target of calcitriol. MAPK1 and CXCL12 expression was downregulated and the apoptosis pathway was significantly enriched by calcitriol treatment. The western blotting results showed that calcitriol treatment increased AMPK phosphorylation and decreased downstream mTOR phosphorylation, which was accompanied by a decrease in autophagy protein p62 expression and an increase in LC3-II/I expression. GLIS2 was identified as a specific therapeutic target for calcitriol. GLIS2 expression was upregulated by calcitriol and confirmed by HK-2 cells in vitro. Our omics data show that calcitriol can alleviate oxidative stress and fibrosis. Moreover, calcitriol can regulate the CXCL12/ERK1/2 cascade to inhibit the inflammatory response and renal cell apoptosis and induce renal autophagy through the AMPK/mTOR pathway. Our study partially elucidate the pathogenesis and treatment mechanism underlying hypertension, and provide new insights into the treatment of hypertension.