Integrated physiological, transcriptomic and metabolomic analyses provide insights into phosphorus-mediated cadmium detoxification in Salix caprea roots.

Phosphorus (P) plays a crucial role in facilitating plant adaptation to cadmium (Cd) stress. However, the molecular mechanisms underlying P-mediated responses to Cd stress in roots remain elusive. This study investigates the effects of P on the growth, physiology, transcriptome, and metabolome of Salix caprea under Cd stress. The results indicate that Cd significantly inhibits plant growth, while sufficient P alleviates this inhibition. Under Cd exposure, P sufficiency resulted in increased Cd accumulation in roots, along with reduced oxidative stress levels (superoxide anion and hydrogen peroxide contents were reduced by 16.8% and 30.1%, respectively). This phenomenon can be attributed to the enhanced activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), as well as increased levels of antioxidants including ascorbic acid (AsA) and flavonoids under sufficient P conditions. A total of 4208 differentially expressed genes (DEGs) and 552 differentially accumulated metabolites (DAMs) were identified in the transcriptomic and metabolomic analyses, with 2596 DEGs and 113 DAMs identified among treatments with different P levels under Cd stress, respectively. Further combined analyses reveal the potential roles of several pathways in P-mediated Cd detoxification, including flavonoid biosynthesis, ascorbate biosynthesis, and plant hormone signal transduction pathways. Notably, sufficient P upregulates the expression of genes including HMA, ZIP, NRAMP and CAX, all predicted to localize to the cell membrane. This may elucidate the heightened Cd accumulation under sufficient P conditions. These findings provide insights into the roles of P in enhancing plant resistance to Cd stress and improving of phytoremediation.

Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer.

Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that SAM and SH3 domain containing protein 1 (SASH1) expression is negatively correlated with mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) expression in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1 and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

Development and validation of a model for predicting the risk of prostate cancer.

BACKGROUND: Abnormal hematologic parameters before patients undergoing prostate biopsy play a pivotal role in guiding the surgical management of prostate cancer (PCa) incidence. This study aims to establish the first nomogram for predicting PCa risk for better surgical management. METHODS: We retrospectively reviewed and analyzed the data including basic information, preoperative hematologic parameters, and imaging examination of 540 consecutive patients who underwent transrectal ultrasound (TRUS)-guided prostate biopsy for elevated prostate-specific antigen (PSA) in our medical center between 2017 and 2021. Logistic regression analysis was used to determine the risk factors for PCa occurrence, and the nomogram was constructed to predict PCa occurrence. Finally, the data including 121 consecutive patients in 2022 were prospectively collected to further verify the results. RESULTS: In retrospective analyses, univariate and multivariate logistic analyses identified that three variables including age, diabetes, and De Ritis ratio (aspartate transaminase/alanine transaminase, AST/ALT) were determined to be significantly associated with PCa occurrence. A nomogram was constructed based on these variables for predicting the risk of PCa, and a satisfied predictive accuracy of the model was determined with a C-index of 0.765, supported by a prospective validation group with a C-index of 0.736. The Decision curve analysis showed promising clinical application. In addition, our results also showed that the De Ritis ratio was significantly correlated with the clinical stage of PCa patients, including T, N, and M stages, but insignificantly related to the Gleason score. CONCLUSIONS: The increased De Ritis ratio was significantly associated with the risk and clinical stage of PCa and this nomogram with good discrimination could effectively improve individualized surgical management for patient underdoing prostate biopsy.

ZNF217-activated Notch signaling mediates sulforaphane-suppressed stem cell properties in colorectal cancer.

Cancer stem cells (CSCs) are known to contribute to the progression of colorectal cancer (CRC). However, understanding of the molecular mechanisms and key factors involved in CRC is still insufficient to identify therapeutic targets against colorectal CSCs. In an effort to identify such mechanisms, we conducted bioinformatics analyses to evaluate the expression patterns in tumor and normal colorectal tissues, leading us to focus on the role of the ZNF217/Notch1 axis in mediating stem cell properties in CRC. Our findings revealed that ZNF217 overexpression activated self-renewal ability, expression of colorectal CSC markers, and Notch signaling in CRC. Dual-luciferase reporter assay suggested a role for ZNF217 in targeting Notch1 to activate Notch signaling. We observed that the promotional effects of Notch signaling, as well as CSC markers, under ZNF217 overexpression were attenuated after Notch1 knockdown. In addition to in vitro data, our in vivo results confirmed the inhibitory effect of sulforaphane on the tumorigenicity of CSCs, depicted the suppressive role of sulforaphane on colorectal CSCs mediated by the ZNF217/Notch1 axis, thereby providing new targetable vulnerabilities and therapeutic strategies for CRC.

Diatomic iron nanozyme with lipoxidase-like activity for efficient inactivation of enveloped virus.

Enveloped viruses encased within a lipid bilayer membrane are highly contagious and can cause many infectious diseases like influenza and COVID-19, thus calling for effective prevention and inactivation strategies. Here, we develop a diatomic iron nanozyme with lipoxidase-like (LOX-like) activity for the inactivation of enveloped virus. The diatomic iron sites can destruct the viral envelope via lipid peroxidation, thus displaying non-specific virucidal property. In contrast, natural LOX exhibits low antiviral performance, manifesting the advantage of nanozyme over the natural enzyme. Theoretical studies suggest that the Fe-O-Fe motif can match well the energy levels of Fe2 minority ß-spin d orbitals and pentadiene moiety π* orbitals, and thus significantly lower the activation barrier of cis,cis-1,4-pentadiene moiety in the vesicle membrane. We showcase that the diatomic iron nanozyme can be incorporated into air purifier to disinfect airborne flu virus. The present strategy promises a future application in comprehensive biosecurity control.

[Expression and prognostic value of IL-6 and ß-catenin in oral squamous cell carcinoma].

PURPOSE: To investigate the expression of interleukin-6 (IL-6) and ß-catenin in oral squamous cell carcinoma (OSCC) and its clinicopathological significance. METHODS: The serum IL-6 concentration in 110 OSCC patients and 109 healthy controls were determined by chemiluminescence analysis. IL-6 and ß-catenin expression levels in 68 tumor specimens of OSCC patients undergoing surgical treatment and 6 normal mucosal tissues were determined by immunohistochemistry method. The correlation between IL-6 and ß-catenin and clinicopathological parameters and their prognostic value were analyzed. SPSS 22.0 software package was used for data analysis. RESULTS: Chemiluminescence method showed that the serum IL-6 content of OSCC patients was significantly increased (P＜0.001). Immunohistochemical results demonstrated that high expression of IL-6 in OSCC tissues was remarkably associated with cervical lymph node metastasis(P=0.017), pathological differentiation(P=0.014), recurrence and distant metastasis (P=0.048). OSCC patients with high IL-6 expression showed a poor prognosis by Kaplan-Meier survival analysis. Multivariate Cox regression analysis showed that high expression of IL-6 was an independent risk factor affecting the prognosis of patients with OSCC(P＜0.05). ß-catenin hyperexpression was associated with pathological differentiation(P=0.006) and overall poor survival in OSCC patients. Spearman correlation analysis showed a positive correlation between IL-6 and ß-catenin expression in OSCC (P＜0.001). CONCLUSIONS: Serum IL-6 is expected to be a biomarker for detection of OSCC, and IL-6 and ß-catenin expression in tumour tissues can be used as markers to evaluate the poor prognosis of OSCC.

Long non-coding RNA X-Inactive Specific Transcript (XIST) interacting with USF2 promotes osteogenic differentiation of periodontal ligament stem cells through regulation of WDR72 transcription.

BACKGROUND: Periodontal ligament stem cells (PDLSCs) are the most potential cells in periodontal tissue regeneration and bone tissue regeneration. Our prior work had revealed that WD repeat-containing protein 72 (WDR72) was crucial for osteogenic differentiation of PDLSCs. Here, we further elucidated its underlying mechanism in PDLSC osteogenic differentiation. METHODS: Human PDLSCs, isolated and identified by flow cytometry, were prepared for osteogenic differentiation induction. Levels of WDR72, long non-coding RNA X-Inactive Specific Transcript (XIST), upstream stimulatory factor 2 (USF2), and osteogenic marker genes (Runx2, Osteocalcin, and Collagen I) in human PDLSCs and clinical specimens were detected by RT-qPCR. Protein expressions of WDR72, Runx2, Osteocalcin, and Colla1 were tested by Western blot. The interactions among the molecules were verified by RIP, RNA pull-down, ChIP, and luciferase reporter assays. Osteogenic differentiation was evaluated by alkaline phosphatase (ALP) and alizarin red staining (ARS). RESULTS: WDR72 was decreased in periodontal tissues of periodontitis patients, and overexpression reversed TNF-α-mediated suppressive effects on PDLSC osteogenic differentiation. Mechanically, XIST recruited the enrichment of USF2 to the WDR72 promoter region, thereby positively regulating WDR72. WDR72 silencing overturned XIST-mediated biological effects in PDLSCs. CONCLUSION: WDR72, regulated by the XIST/USF2 axis, enhances osteogenic differentiation of PDLSCs, implying a novel strategy for alleviating periodontitis.

Pan-cancer analysis identifies SPEN mutation as a predictive biomarker with the efficacy of immunotherapy.

The association between specific genetic mutations and immunotherapy benefits has been widely known, while such studies in pan-cancer are still limited. SPEN, mainly involved in X chromosome inactivation (XCI), plays an essential in tumorigenesis and sex differences in cancer. Thus, we firstly analyzed the potential role of SPEN in the TCGA pan-cancer cohort and clinical samples. Bioinformatics analysis and immunohistochemistry (IHC) staining confirm that the expression of SPEN is significantly different in various cancers and may involve RNA splicing and processing via enrichment analysis. Then, our data further revealed that those patients with SPEN mutation could predict a better prognosis in pan-cancer and had distinct immune signatures, higher tumor mutation burden (TMB), and microsatellite instability (MSI) in common cancer types. Finally, the cancer patients from 9 studies treated with immune checkpoint inhibitors were included to investigate the efficacy of immunotherapy. The results further showed that SPEN mutation was associated with better clinical outcomes (HR, 0.74; 95%CI, 0.59-0.93, P = 0.01), and this association remained existed in female patients (HR, 0.60; 95%CI, 0.38-0.94 P = 0.024), but not in male patients (HR, 0.82; 95%CI, 0.62-1.08 P = 0.150). Our findings demonstrated that SPEN mutation might strongly predict immunotherapy efficacy in pan-cancer.

Potential functions of engineered nanomaterials in cadmium remediation in soil-plant system: A review.

Soil cadmium (Cd) contamination is a global environmental issue facing agriculture. Under certain conditions, the stable Cd that bound to soil particles tend to be remobilized and absorbed into plants, which is seriously toxic to plant growth and threat food safety. Engineering nanomaterials (ENMs) has attracted increasing attentions in the remediation of Cd pollution in soil-plant system due to their excellent properties with nano-scale size. Herein, this article firstly systematically summarized Cd transformation in soil, transport in soil-plant system, and the toxic effects in plants, following which the functions of ENMs in these processes to remediate Cd pollution are comprehensively reviewed, including immobilization of Cd in soil, inhibition in Cd uptake, transport, and accumulation, as well as physiological detoxication to Cd stress. Finally, some issues to be further studied were raised to promote nano-remediation technology in the environment. This review provides a significant reference for the practical application of ENMs in remediation of Cd pollution in soil, and contributes to sustainable development of agriculture.

Relationship between testosterone and male bladder cancer.

Researches had proven that the occurrence of bladder cancer (BC) is much higher in men than those in women, which induced us to explore whether androgen plays a role in BC. A total of 147 patients who were diagnosed with primary BC by histopathological biopsy were included. Meanwhile 154 non-tumor patients were matched as the control group. The continuous variables were expressed as median (interquartile range, IQR) and compared by Mann-Whitney U test, for the reason that the data were not matched the requirementsthe of normal test. A Chi-square test was used to compare the categorical variables, which were expressed as frequency (percentage). Meanwhile univariate and multivariate logistic regression was done to further evaluating the potential independent factor of BC. P < 0.05 was considered statistically significant. Univariate multivariate analyse showed significant difference between two groups in hemoglobin (OR 0.979, 95% CI 0.968-0.991, P < 0.001), hypertension (OR 3.026, 95% CI 1.731-5.288, P < 0.001), diabetes (OR 4.294, 95% CI 1.887-9.771, P = 0.001) and smoking (OR 1.729, 95% CI 1.096-2.729, P = 0.019). Furthermore, multivariate logistic regression analysis was conducted to eliminate the interference of confounding factors, which showed that testosterone seems to be great correlated with the BC (OR 1.002, 95% CI 1.000-1.003, P = 0.017). Similar results were also found in hemoglobin (OR 0.981, 95% CI 0.968-0.993, P = 0.002), hypertension (OR 2.780, 95% CI 1.509-5.120, P = 0.001), diabetes (OR 3.313 95% CI 1.373-7.991, P = 0.008) and smoking (OR 1.938, 95% CI 1.184-3.174, P = 0.009). As a conclusion, our study showed that there was significant correlation between serum total testosterone levels and the occurrence of BC, similar results were shown in hemoglobin, hypertension, diabetes and smoking.

Tandem mass tag (TMT) labeling-based quantitative proteomic analysis reveals the cellular protein characteristics of 16HBE cells infected with coxsackievirus A10 and the potential effect of HMGB1 on viral replication.

Coxsackievirus A10 (CV-A10) is recognized as one of the most important pathogens associated with hand, foot, and mouth disease (HFMD) in young children under 5 years of age worldwide, and it can lead to fatal neurological complications. However, available commercial vaccines fail to protect against CV-A10. Therefore, there is an urgent need to study new protein targets of CV-A10 and develop novel vaccine-based therapeutic strategies. Advances in proteomics in recent years have enabled a comprehensive understanding of host pathogen interactions. Here, to study CV-A10-host interactions, a global quantitative proteomic analysis was conducted to investigate the molecular characteristics of host cell proteins and identify key host proteins involved in CV-A10 infection. Using tandem mass tagging (TMT)-based mass spectrometry, a total of 6615 host proteins were quantified, with 293 proteins being differentially regulated. To ensure the validity and reliability of the proteomics data, three randomly selected proteins were verified by Western blot analysis, and the results were consistent with the TMT results. Further functional analysis showed that the upregulated and downregulated proteins were associated with diverse biological activities and signaling pathways, such as metabolic processes, biosynthetic processes, the AMPK signaling pathway, the neurotrophin signaling pathway, the MAPK signaling pathway, and the GABAergic synaptic signaling. Moreover, subsequent bioinformatics analysis demonstrated that these differentially expressed proteins contained distinct domains, were localized in different subcellular components, and generated a complex network. Finally, high-mobility group box 1 (HMGB1) might be a key host factor involved in CV-A10 replication. In summary, our findings provide comprehensive insights into the proteomic profile during CV-A10 infection, deepen our understanding of the relationship between CV-A10 and host cells, and establish a proteomic signature for this viral infection. Moreover, the observed effect of HMGB1 on CV-A10 replication suggests that it might be a potential therapeutic target treatment of CV-A10 infection.

Molecular Characterization of Two Wamide Neuropeptide Signaling Systems in Mollusk Aplysia.

Neuropeptides with the C-terminal Wamide (Trp-NH2) are one of the last common ancestors of peptide families of eumetazoans and play various physiological roles. In this study, we sought to characterize the ancient Wamide peptides signaling systems in the marine mollusk Aplysia californica, i.e., APGWamide (APGWa) and myoinhibitory peptide (MIP)/Allatostatin B (AST-B) signaling systems. A common feature of protostome APGWa and MIP/AST-B peptides is the presence of a conserved Wamide motif in the C-terminus. Although orthologs of the APGWa and MIP signaling systems have been studied to various extents in annelids or other protostomes, no complete signaling systems have yet been characterized in mollusks. Here, through bioinformatics, molecular and cellular biology, we identified three receptors for APGWa, namely, APGWa-R1, APGWa-R2, and APGWa-R3. The EC50 values for APGWa-R1, APGWa-R2, and APGWa-R3 are 45, 2100, and 2600 nM, respectively. For the MIP signaling system, we predicted 13 forms of peptides, i.e., MIP1-13 that could be generated from the precursor identified in our study, with MIP5 (WKQMAVWa) having the largest number of copies (4 copies). Then, a complete MIP receptor (MIPR) was identified and the MIP1-13 peptides activated the MIPR in a dose-dependent manner, with EC50 values ranging from 40 to 3000 nM. Peptide analogs with alanine substitution experiments demonstrated that the Wamide motif at the C-terminus is necessary for receptor activity in both the APGWa and MIP systems. Moreover, cross-activity between the two signaling systems showed that MIP1, 4, 7, and 8 ligands could activate APGWa-R1 with a low potency (EC50 values: 2800-22,000 nM), which further supported that the APGWa and MIP signaling systems are somewhat related. In summary, our successful characterization of Aplysia APGWa and MIP signaling systems represents the first example in mollusks and provides an important basis for further functional studies in this and other protostome species. Moreover, this study may be useful for elucidating and clarifying the evolutionary relationship between the two Wamide signaling systems (i.e., APGWa and MIP systems) and their other extended neuropeptide signaling systems.

A biphasic calcium phosphate/acylated methacrylate gelatin composite hydrogel promotes osteogenesis and bone repair.

PURPOSE/AIM: Bone defects caused by trauma, tumors, congenital malformation, or inflammation are very common in orthopedics. In recent years, mimicking the composition and structure of natural bone tissue has become a hot topic in biomaterial research, with the aim of developing an ideal biomaterial for bone defect transplantation. Here, the feasibility of a biphasic calcium phosphate (BCP)/acylated methacrylate gelatin (GelMA) composite hydrogel to repair bone defects was evaluated in vitro and in rats. MATERIALS AND METHODS: The biocompatibility of a biphasic calcium phosphate (BCP)/acylated methacrylate gelatin (GelMA) composite hydrogel was evaluated by cytoskeleton staining, live/dead cell staining and cell proliferation assays. The in vitro osteogenic activities of the composite hydrogel were evaluated by alkaline phosphatase and alizarin red staining, as well as osteogenic gene expression analysis at both transcript and protein levels. The in vivo bone repair activities were evaluated using the rat skull defect model. RESULTS: The BCP/GelMA composite hydrogel displayed excellent biocompatibility and promoted osteogenesis of bone marrow mesenchymal stem cells in vitro. In addition, the BCP/GelMA composite hydrogel markedly promoted new bone formation in the rat skull-defect model. CONCLUSIONS: BCP/GelMA composite hydrogel may be an effective artificial material for bone tissue engineering.

Metabolic-associated fatty liver disease and risk of esophagogastric cancer: a systematic review and meta-analysis.

INTRODUCTION: Metabolic-associated fatty liver disease (MAFLD) has been found to be strongly linked to several diseases. Although previous studies have explored the association between MAFLD and extrahepatic cancers, research on the relationship between MAFLD and gastric carcinoma (GC) and esophageal carcinoma (EC) is relatively scarce and requires updating. Therefore, the objective of this study is to conduct a comprehensive investigation into the association between MAFLD and GC or EC. MATERIAL AND METHODS: We conducted a comprehensive search for relevant studies published up to 5 August 2022, using the PubMed, Embase and Web of Science databases. To estimate the risk ratio (RR) and the 95% confidence interval (CI), we employed a random-effects model. We also conducted subgroup analyses based on study characteristics. The protocol for this systematic review is registered in the Prospero database under the registration number CRD42022351574. RESULTS: Our analysis included eight eligible studies, comprising a total of 8 629 525 participants. We found that the pooled RR values for the risk of GC in patients with MAFLD were 1.49 (95%CI: 1.17-1.91), whereas the pooled RR values for the risk of EC in patients with MAFLD were 1.76 (95%CI: 1.34-2.32). CONCLUSIONS: Based on our meta-analysis, we conclude that there is a significant association between the presence of MAFLD and the development of GC and EC.

STK24 Promotes Progression of LUAD and Modulates the Immune Microenvironment.

Objective: Recent studies have shown that serine/threonine-protein kinase 24 (STK24) plays an important role in cancer development. However, the significance of STK24 in lung adenocarcinoma (LUAD) remains to be determined. This study is aimed at investigating the significance of STK24 in LUAD. Methods: STK24 was silenced and overexpressed by siRNAs and lentivirus, respectively. Cellular function was assessed by CCK8, colony formation, transwell, apoptosis, and cell cycle. mRNA and protein abundance was checked by qRT-PCR and WB assay, respectively. Luciferase reporter activity was evaluated to examine the regulation of KLF5 on STK24. Various public databases and tools were applied to investigate the immune function and clinical significance of STK24 in LUAD. Results: We found that STK24 was overexpressed in lung adenocarcinoma (LUAD) tissues. High expression of STK24 predicted poor survival of LUAD patients. In vitro, STK24 enhanced the proliferation and colony growth ability of A549 and H1299 cells. STK24 knockdown induced apoptosis and cell cycle arrest at G0/G1 phase. Furthermore, Krüppel-like factor 5 (KLF5) activated STK24 in lung cancer cells and tissues. Enhanced lung cancer cell growth and migration triggered by KLF5 could be reversed by silencing of STK24. Finally, the bioinformatics results showed that STK24 may be involved in the regulation of the immunoregulatory process of LUAD. Conclusion: KLF5 upregulation of STK24 contributes to cell proliferation and migration in LUAD. Moreover, STK24 may participate in the immunomodulatory process of LUAD. Targeting KLF5/STK24 axis may be a potential therapeutic strategy for LUAD.

Adrenal Tuberculosis: A Case Report and Literature Review.

Adrenal tuberculosis (TB) is a rare disease, which is difficult to diagnose because of its atypical symptoms. We reported a 41-year-old female who was admitted to hospital due to a left adrenal tumor, which was found in health examination without any symptoms. Abdominal CT showed a mass in her left adrenal. The results of blood test were normal. A retroperitoneal laparoscopic adrenalectomy was carried out, and adrenal TB was finally pathologically diagnosed. Following this, examinations focusing on TB were conducted which revealed negative results except for T-cell enzyme-linked immunospot. After the operation, the hormone level was normal. However, a wound infection occurred, which was recovered after antituberculosis treatment. In conclusion, even if there is no evidence of TB, we should be alert when diagnosing adrenal masses. Examinations of pathology, radiography, and hormone play important roles in determining the definite diagnosis of adrenal TB.

Research of targeted therapy for renal cancer from 2006 to 2022: a bibliometric and visualized analysis.

Background: This review aimed to analyze the research progress and development trends in targeted therapy (TT) for renal cancer (RC) from 2006 to 2022. Methods: The Web of Science Core Collection database was searched using the search terms "renal cancer", "kidney neoplasms", "kidney cancer", and "targeted therapy", and all publications were extracted. VOSviewer version 1.6.18 was used to complete the visual analysis based on the information of publications, including author, journal, subject, year, and institution. Results: A total of 1,136 studies related to TT for RC were found. The top journals in this field were the Journal of Clinical Oncology, Annals of Oncology, and European Urology. Among them, the Journal of Clinical Oncology had the highest number of publications (n=35). In terms of country, the United States had the highest number of publications (n=366). The main document type was article, which accounted for 64.26% of the total publications. Conclusions: To the best of our knowledge, this is the first bibliometric analysis related to TT for RC. The annual number of publications has exhibited a steady growth trend, with the United States having the greatest contribution in this field. Through an analysis of a keyword time density map, we identified that hypoxia-inducing factor-1, drug resistance and therapeutic targets are the research hotspots and trends in this field.

Characterization of an Aplysia vasotocin signaling system and actions of posttranslational modifications and individual residues of the ligand on receptor activity.

The vasopressin/oxytocin signaling system is present in both protostomes and deuterostomes and plays various physiological roles. Although there were reports for both vasopressin-like peptides and receptors in mollusc Lymnaea and Octopus, no precursor or receptors have been described in mollusc Aplysia. Here, through bioinformatics, molecular and cellular biology, we identified both the precursor and two receptors for Aplysia vasopressin-like peptide, which we named Aplysia vasotocin (apVT). The precursor provides evidence for the exact sequence of apVT, which is identical to conopressin G from cone snail venom, and contains 9 amino acids, with two cysteines at position 1 and 6, similar to nearly all vasopressin-like peptides. Through inositol monophosphate (IP1) accumulation assay, we demonstrated that two of the three putative receptors we cloned from Aplysia cDNA are true receptors for apVT. We named the two receptors as apVTR1 and apVTR2. We then determined the roles of post-translational modifications (PTMs) of apVT, i.e., the disulfide bond between two cysteines and the C-terminal amidation on receptor activity. Both the disulfide bond and amidation were critical for the activation of the two receptors. Cross-activity with conopressin S, annetocin from an annelid, and vertebrate oxytocin showed that although all three ligands can activate both receptors, the potency of these peptides differed depending on their residue variations from apVT. We, therefore, tested the roles of each residue through alanine substitution and found that each substitution could reduce the potency of the peptide analog, and substitution of the residues within the disulfide bond tended to have a larger impact on receptor activity than the substitution of those outside the bond. Moreover, the two receptors had different sensitivities to the PTMs and single residue substitutions. Thus, we have characterized the Aplysia vasotocin signaling system and showed how the PTMs and individual residues in the ligand contributed to receptor activity.

Radiosensitization of Nasopharyngeal Carcinoma by Graphene Oxide Nanosheets to Reduce Bcl-2 Level.

There are many treatments for nasopharyngeal carcinoma (NPC), but none of them are very effective. Radiotherapy is used extensively in NPC treatment, but radioresistance is a major problem. Graphene oxide (GO) has been previously studied in cancer treatment, and this study is aimed to explore its role in radiosensitization of NPC. Therefore, graphene oxide nanosheets were prepared, and the relationship between GO and radioresistance was explored. The GO nanosheets were synthesized by a modified Hummers' method. The morphologies of the GO nanosheets were characterized by field-emission environmental scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The morphological changes and radiosensitivity of C666-1 and HK-1 cells with or without the GO nanosheets were observed by an inverted fluorescence microscopy and laser scanning confocal microscopy (LSCM). Colony formation assay and Western Blot were applied for analysis of NPC radiosensitivity. The as-synthesized GO nanosheets have lateral dimensions (sizes ∼1 µm) and exhibit a thin wrinkled two-dimensional lamellar structure with slight folds and crimped edges (thickness values ∼1 nm). C666-1 cells with the GO was significantly changed the morphology of cells postirradiation. The full field of view visualized by a microscope showed the shadow of dead cells or cell debris. The synthesized graphene oxide nanosheets inhibited cell proliferation, promoted cell apoptosis, and inhibited the expression of Bcl-2 in C666-1 and HK-1 cells but increased the level of Bax. The GO nanosheets could affect the cell apoptosis and reduce the pro-survival protein Bcl-2 related to the intrinsic mitochondrial pathway. The GO nanosheets could enhance radiosensitivity, which might be a radioactive material in NPC cells.

Dual-Atom Support Boosts Nickel-Catalyzed Urea Electrooxidation.

Nickel-based catalysts have been regarded as one of the most promising electrocatalysts for urea oxidation reaction (UOR), however, their activity is largely limited by the inevitable self-oxidation reaction of Ni species (NSOR) during the UOR. Here, we proposed an interface chemistry modulation strategy to trigger the occurrence of UOR before the NSOR via constructing a 2D/2D heterostructure that consists of ultrathin NiO anchored Ru-Co dual-atom support (Ru-Co DAS/NiO). Operando spectroscopic characterizations confirm this unique triggering mechanism on the surface of Ru-Co DAS/NiO. Consequently, the fabricated catalyst exhibits outstanding UOR activity with a low potential of 1.288 V at 10 mA cm-2 and remarkable long-term durability for more than 330 h operation. DFT calculations and spectroscopic characterizations demonstrate that the favorable electronic structure induced by this unique heterointerface endows the catalyst energetically more favorable for the UOR than the NSOR.