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Zi-jun He,1,2,* Jin-tao Wei,1,* Hai-mei Jiang,1 Jin-yong Wang,1 Jiong-yao Lai,1 Shu-qing Li,1 Zhi Chen,1 Qing-lu Luo1– 3 1Department of Rehabilitation Medicine, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan, People’s Republic of China; 2Dongguan Experimental Centre for Sports Rehabilitation Research, Dongguan, People’s Republic of China; 3Dongguan Key Specialty of Traditional Chinese Medicine (Rehabilitation Department), Dongguan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing-lu Luo; Zhi Chen, Department of Rehabilitation Medicine, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s hospital), Wanjiang District, Dongguan, Guangdong, 510280, People’s Republic of China, Email luo_qinglu@126.com; 13686616688@139.comObjective: To identify distinct developmental trajectories of weight-bearing pain (WBP) and non-weight-bearing pain (NWBP) and examine the trajectory predictors in individuals with or at risk of knee osteoarthritis.Methods: We included 971 participants from the Osteoarthritis Initiative whose baseline magnetic resonance imaging data and 9-year follow-up data on pain were available. We applied group-based trajectory modeling to identify WBP and NWBP trajectories over 9 years. Univariate and multivariate multinomial logistic regression analyses were performed to examine the predictors of identified trajectories.Results: Three distinct WBP trajectories were identified: “no pain” (32.4%), “mild pain” (44.6%), and “moderate pain” (23%). Three distinct NWBP trajectories were identified: “no pain” (50.9%), “mild pain” (33.4%), and “moderate pain” (15.7%). In multivariate analyses, high body mass index, depression, multisite pain, radiographic knee OA, and comorbidities were associated with worse development trajectories for WBP and NWBP. Weak quadriceps strength and bone marrow lesion were only associated with worse WBP trajectories, whereas low education level was only associated with worse NWBP trajectories.Conclusion: The developmental course of pain is heterogeneous in WBP or NWBP. Quadriceps strength and bone marrow leisure may be WBP-specific predictors, whereas education level may be a NWBP-specific predictor. The assessment of knee pain should be more accurate, which may help select appropriate therapeutic targets.Keywords: knee osteoarthritis, pain, weight-bearing, trajectories, predictors

Hongmei Jiang,1 Henggui Hu,2 Yali Zhang,1 Ping Yue,3 Lichang Ning,1 Yan Zhou,1 Ping Shi,1 Rui Yuan1 1School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou, 2Department of Clinical Laboratory, The Third Hospital Subsidiary of Bengbu Medical College, Suzhou, Anhui, 3School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China Abstract: Dendritic cells (DCs) play an important role in the initiation of autoimmunity in rheumatoid arthritis (RA); therefore, the use of DCs needs to be explored to develop new therapeutic approaches for RA. Here, we investigated the therapeutic effect of bovine type II collagen (BIIC)-loaded DCs modified with NF-κB decoy oligodeoxynucleotides (ODNs) on collagen-induced arthritis (CIA) in rats and explored the underlying mechanisms. DCs treated with BIIC and NF-κB decoy ODNs exhibited features of immature DCs with low levels of costimulatory molecule (CD80 and CD86) expression. The development of arthritis in rats with CIA injected with BIIC + NF-κB decoy ODN-propagated DCs (BIIC–decoy DCs) was significantly ameliorated compared to that in rats injected with BIIC-propagated DCs or ­phosphate-buffered saline. We also found that the BIIC–decoy DCs exerted antiarthritis effects by inhibiting self-lymphocyte proliferative response and suppressing IFN-γ and anti-BIIC antibody production and inducing IL-10 antibody production. Additionally, antihuman serum antibodies were successfully produced in the rats treated with BIIC–decoy DCs but not in those treated with NF-κB decoy ODN-propagated DCs; moreover, the BIIC–decoy DCs did not affect immune function in the normal rats. These findings suggested that NF-κB decoy ODN-modified DCs loaded with a specific antigen might offer a practical method for the treatment of human RA. Keywords: NF-κB decoy oligodeoxynucleotides, collagen-induced arthritis, dendritic cells, rheumatoid arthritis

Electromagnetic shielding fabric (ESF) is a novel electromagnetic shielding product with portability, flexibility, and good mechanical properties. However, the existing ESFs suffer from poor washing fastness of coating and poor comfort performance in terms of hand-feel characteristic. In this study, a core layer-coated yarn (CLCY) was successfully spun using a carboxylic acid-functionalized multi-walled carbon nanotube/polypyrrole/Fe3O4 composite suspension with polyvinyl butyral as an adhesive agent. To better explore the properties, the original fabric and treated fabrics, viz., core layer-coated fabric (CLCF) and surface layer-coated fabric (SLCF), were characterized by several methods. Scanning electron microscopic observations revealed that the coating was on the core layer in CLCF. In addition, the Fourier-transform infrared spectroscopy and X-ray diffraction spectroscopy results revealed that the composition of the coating corresponds with that in the multi-composite suspension. Moreover, the coating of CLCY formed a conductive path with good conductivity in the core layer, but the conductivity of the coating on the surface layer of SLCF deteriorated sharply after washing. Further, compared with the original fabric and SLCF, CLCF has highest breaking strength (after 10 washes), and keeps a relatively good hand-feel characteristic. Finally, the evaluated electromagnetic interference shielding characteristics reveal that the fastness of coating affects the electromagnetic shielding effectiveness, suggesting that the wrapped protection of outside staple fibers in CLCF reduce the loss of coating in the core layer during washing. However, the coating on the surface layer in SLCF could be washed away easily. [ABSTRACT FROM AUTHOR]

Background: The tongue squamous cell carcinoma (TSCC) is an oral malignant tumor arising from the squamous epithelium of the tongue mucosa, characterized by a high malignant degree, invasive growth, early lymph node metastasis, and poor prognosis. Paclitaxel, represented by docetaxel, is now the standard first-line treatment for head and neck squamous cell carcinoma. Docetaxel, which belongs to the class of drugs known as paclitaxel, is an antitumor drug that inhibits cell mitosis and proliferation. Its adverse effects include myelosuppression, hair loss, gastrointestinal reactions, fluid retention, and allergic reactions. However, hypokalemia is rare, most cases are mild or moderate, and severe hypokalemia is seldom reported., Case Summary: During chemotherapy with docetaxel and cisplatin, a patient with TSCC developed severe hypokalemia. His potassium level was found to have been reduced to 1.85 mmol/L at the most critical situation. The patient had grade 1 muscle strength in all four limbs and could not perform any action, which was considered to be a sign of severe hypokalemia. Measures taken included intravenous infusion via micro-pump, intravenous injection, and oral potassium supplement, which gradually improved muscle strength and serum potassium levels. The patient survived the critical period of severe hypokalemia after chemotherapy. He was generally in good condition following treatment and discharged in stable condition., Conclusion: Docetaxel may cause severe hypokalemia with hypomagnesemia and the mechanism for this is not yet known to researchers yet. This means that nurses specializing in chemotherapy must exercise a high degree of responsibility, closely observe the patient's reaction to the anticancer medication, notice any symptoms of adverse effects early. It is necessary to be considerate regarding individual differences between patients when selecting chemotherapy regimens and adhere to the principle of individualized treatment. Following multiple cycles of chemotherapy, patients should be aware of the accumulation of toxic side effects and receive blood tests reviewed within 24 hours of completion. It is essential to monitor electrolyte levels in patients suffering from severe gastrointestinal reactions to avoid complications that may result in death., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Cataracts are a common ophthalmic disease and postoperative vision recovery is crucial to patient quality of life. Rational and efficient care models play an important role in promoting vision recovery., Aim: To evaluate the clinical effectiveness of procedural nursing care combined with communication intervention in vision recovery after cataract ultrasound emulsification., Methods: A randomized controlled study was conducted on 100 patients with cataracts who underwent ultrasound emulsification surgery. They were randomly assigned to an experimental group or a control group. The experimental group received procedural nursing combined with Connect, Introduce, Communicate, Ask, Respond, Exit (CICARE) communication intervention, whereas the control group received conventional nursing. The effectiveness of the nursing model was assessed by comparing differences in vision recovery, pain scores, and mental health status between the two groups., Results: It was found that over time the visual acuity of patients in both groups gradually recovered and patients in the experimental group had lower pain scores and superior mental health status than the control group ( P < 0.05)., Conclusion: Procedural nursing combined with CICARE communication intervention has positive effects on vision recovery in patients after cataract ultrasound emulsification., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely unexplored. To identify the potential role of Zeb1 in remodeling the tumor immune microenvironment in breast cancer, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT; Zeb1 cKO (MMTV-Cre;PyMT; Zeb1 fl/fl ) mice. We found that the recruitment of M2-type tumor-associated macrophages (TAMs) was significantly reduced in tumors from PyMT; Zeb1 cKO mice, and their tumor suppressive effects were weakened. Mechanistically, Zeb1 played a crucial role in transcriptionally promoting the production of Cxcl1 in tumor cells. In turn, Cxcl1 activated the Cxcr2-Jak-Stat3 pathway to induce M2 polarization of TAMs in a paracrine manner, which eventually led to T-cell inactivation and impaired the antitumor immune response in breast cancer. Our results collectively revealed an important role of Zeb1 in remodeling the tumor microenvironment, suggesting a novel therapeutic intervention for the treatment of advanced breast cancer., Competing Interests: None., (AJCR Copyright © 2024.)

A photocatalytic method for the ring-closing 1,7-enyne metathesis using the α-amino radical as an alkene deconstruction auxiliary is present. Preliminary mechanistic studies suggest that intramolecular 1,5-hydrogen atom transfer is the key to the generation and β-scission of the α-amino radical, while the dearomatization of arenes and ring opening of cyclopropanes are the key to construct spirocyclic quinolin-2-ones. This approach highlights the potential of ring-closing 1,7-enyne metathesis, providing a green, efficient, and step-economical way for the synthesis of spirocyclic quinolin-2-ones.

Background: The global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH., Methods: We obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages., Results: We observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation., Conclusion: We identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K-AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH., (© 2024. The Author(s).)

Pathological pain, a multifaceted and debilitating ailment originating from injury or post-injury inflammation of the somatosensory system, poses a global health challenge. Despite its ubiquity, reliable therapeutic strategies remain elusive. To solve this problem, resveratrol, a naturally occurring nonflavonoid polyphenol, has emerged as a potential beacon of hope owing to its anti-inflammatory, antioxidant, and immunomodulatory capabilities. These properties potentially position resveratrol as an efficacious candidate for the management of pathological pain. This concise review summaries current experimental and clinical findings to underscore the therapeutic potential of resveratrol in pathological pain, casting light on the complex underlying pathophysiology. Our exploration suggests that resveratrol may exert its analgesic effect by the modulating pivotal signaling pathways, including PI3K/Akt/mTOR, TNFR1/NF-κB, MAPKs, and Nrf2. Moreover, resveratrol appears to attenuate spinal microglia activation, regulate primary receptors in dorsal root sensory neurons, inhibit pertinent voltage-gated ion channels, and curb the expression of inflammatory mediators and oxidative stress responses. The objective of this review is to encapsulate the pharmacological activity of resveratrol, including its probable signaling pathways, pharmacokinetics, and toxicology pertinent to the treatment of pathological pain. Hopefully, we aim to map out promising trajectories for the development of resveratrol as a potential analgesic., (© 2023 John Wiley & Sons Ltd.)

Acetylshikonin (AS) is an active component of Lithospermum erythrorhizon Sieb. et Zucc that exhibits activity against various cancers; however, the underlying mechanisms of AS against oesophageal squamous carcinoma (ESCC) need to be elusive. The research explores the anti-cancer role and potential mechanism of AS on ESCC in vitro and in vivo, providing evidences for AS treatment against ESCC. In this study, we firstly demonstrated that AS treatment effectively inhibits cell viability and proliferation of ESCC cells. In addition, AS significantly induces G1/S phage arrest and promotes apoptosis in ESCC cell lines. Further studies reveal that AS induces ER stress, as observed by dose- and time-dependently increased expression of BIP, PDI, PERK, phosphorylation of eIF 2α , CHOP and splicing of XBP1. CHOP knockdown or PERK inhibition markedly rescue cell apoptosis induced by AS. Moreover, AS treatment significantly inhibits ESCC xenograft growth in nude mice. Elevated expression of BIP and CHOP is also observed in xenograft tumours. Taken together, AS inhibits proliferation and induces apoptosis through ER stress-activated PERK/eIF 2α /CHOP pathway in ESCC, which indicates AS represents a promising candidate for ESCC treatment., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: The Forkhead box M1 factor (FOXM1) is a crucial activator for cancer cell proliferation. While FOXM1 has been shown to promote hepatocellular carcinoma (HCC) progression, its transcriptional mechanisms remain incompletely understood., Methods: We performed an in-house tissue microarray on 313 HCC and 37 non-HCC tissue samples, followed by immunohistochemical staining. Gene chips and high throughput sequencing data were used to assess FOXM1 expression and prognosis. To identify candidate targets of FOXM1, we comprehensively reanalyzed 41 chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets. We predicted FOXM1 transcriptional targets in HCC by intersecting candidate FOXM1 targets with HCC overexpressed genes and FOXM1 correlation genes. Enrichment analysis was employed to address the potential mechanisms of FOXM1 underlying HCC. Finally, single-cell RNA sequencing analysis was performed to confirm the transcriptional activity of FOXM1 on its predicted targets., Results: This study, based on 4235 HCC tissue samples and 3461 non-HCC tissue samples, confirmed the upregulation of FOXM1 in HCC at mRNA and protein levels (standardized mean difference = 1.70 [1.42, 1.98]), making it the largest multi-centered study to do so. Among HCC patients, FOXM1 was increased in Asian and advanced subgroups, and high expression of FOXM1 had a strong ability to differentiate HCC tissue from non-HCC tissue (area under the curve = 0.94, sensitivity = 88.72%, specificity = 87.24%). FOXM1 was also shown to be an independent exposure risk factor for HCC, with a pooled hazard ratio of 2.00 [1.77, 2.26]. The predicted transcriptional targets of FOXM1 in HCC were predominantly enriched in nuclear division, chromosomal region, and catalytic activity acting on DNA. A gene cluster encoding nine transcriptional factors was predicted to be positively regulated by FOXM1, promoting the cell cycle signaling pathway in HCC. Finally, the transcriptional activity of FOXM1 and its targets was supported by single-cell analysis of HCC cells., Conclusions: This study not only confirmed the upregulation of FOXM1 in HCC but also identified it as an independent risk factor. Moreover, our findings enriched our understanding of the complex transcriptional mechanisms underlying HCC pathogenesis, with FOXM1 potentially promoting HCC progression by activating other transcription factors within the cell cycle pathway., (© 2023. The Author(s).)

FAM64A is a mitogen-induced regulator of the metaphase and anaphase transition. Here, we found that FAM64A messenger RNA (mRNA) and protein expression levels were higher in gastric cancer tissue than in normal mucosa (p < .05). FAM64A methylation was negatively correlated with FAM64A mRNA expression (p < .05). The differentially expressed genes of FAM64A were mainly involved in digestion, potassium transporting or exchanging ATPase, contractile fibers, endopeptidase, and pancreatic secretion (p < .05). The FAM64A-related genes were principally categorized into ubiquitin-mediated proteolysis, cell cycle, chromosome segregation and mitosis, microtubule binding and organization, metabolism of amino acids, cytokine receptors, lipid droplet, central nervous system, and collagen trimer (p < .05). FAM64A protein expression was lower in normal gastric mucosa than intestinal metaplasia, adenoma, and primary cancer (p < .05), negatively correlated with older age, T stage, lymphatic and venous invasion, tumor, node, metastasis stage, and dedifferentiation (p < .05), and associated with a favorable overall survival of gastric cancer patients. FAM64A overexpression promoted proliferation, antiapoptosis, migration, invasion, and epithelial-mesenchymal transition via the EGFR/Akt/mTOR/NF-κB, while the opposite effect was observed for FAM64A knockdown. FAM64A also induced chemoresistance directly or indirectly through lipid droplet formation via ING5. These results suggested that upregulation of FAM64A expression might induce aggressive phenotypes, leading to gastric carcinogenesis and its subsequent progression. Thus, FAM64A could be regarded as a prognosis biomarker and a target for gene therapy., (© 2023 The Authors. Drug Development Research published by Wiley Periodicals LLC.)

The Escherichia coli-produced human papillomavirus (HPV) 16/18 bivalent vaccine (Cecolin) has received prequalification by the World Health Organization based on its high efficacy and good safety profile. We aimed to evaluate the immunogenicity and safety of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine (Cecolin 9) through the randomized, blinded phase 2 clinical trial. Eligible healthy women aged 18-45 years were randomly (1:1) allocated to receive three doses of 1.0 mL (270 µg) of Cecolin 9 or placebo with a 0-1-6-month schedule. The primary endpoint was the seroconversion rate and geometric mean titer of neutralizing antibodies (nAbs) one month after the full vaccination course (month 7). The secondary endpoint was the safety profile including solicited adverse reactions occurring within 7 d, adverse events (AEs) occurring within 30 d after each dose, and serious adverse events (SAEs) occurring during the 7-month follow-up period. In total, 627 volunteers were enrolled and randomly assigned to Cecolin 9 (n = 313) or placebo (n = 314) group in Jiangsu Province, China. Almost all participants in the per-protocol set for immunogenicity (PPS-I) seroconverted for nAbs against all the nine HPV types at month 7, while two failed to seroconvert for HPV 11 and one did not seroconvert for HPV 52. The incidence rates of total AEs in the Cecolin 9 and placebo groups were 80.8% and 72.9%, respectively, with the majority of them being mild and recovering shortly. None of the SAEs were considered related to vaccination. In conclusion, the E. coli-produced 9-valent HPV (9vHPV) vaccine candidate was well tolerated and immunogenic, which warrants further efficacy studies in larger populations., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Feng-Zhu Zheng and Qiu-Fen Zhang report being either current employees of Xiamen Innovax; Guang Sun report being current employees of and have stock options in Xiamen Innovax. All other authors declare that they have no conflict of interest., (Copyright © 2023 Science China Press. Published by Elsevier B.V. All rights reserved.)

An unprecedented three-component [2 + 2 + 1] annulation cascade of indoles with aryldiazonium salts and polyhalomethanes or acetone is presented by dual hydrogen atom transfer (HAT) and C-H functionalization. By employing readily accessible aryldiazonium salts as the radical initiators and electrophiles and polyhalomethanes and acetone as the C1 units, this method unprecedentedly constructs a pyrazole ring on an indole ring skeleton through the formation of two C-N bonds and a C-C bond in a single reaction.

Background: Patients with non-small cell lung cancer (NSCLC) who develop brain metastases (BM) have a poor prognosis. This study aimed to construct a clinical prediction model to determine the overall survival (OS) of NSCLC patients with BM., Methods: A total of 300 NSCLC patients with BM at the Yunnan Cancer Centre were retrospectively analysed. The prediction model was constructed using the least absolute shrinkage and selection operator-Cox regression. The bootstrap sampling method was employed for internal validation. The performance of our prediction model was compared using recursive partitioning analysis (RPA), graded prognostic assessment (GPA), the update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA), the basic score for BM (BSBM), and tumour-lymph node-metastasis (TNM) staging., Results: The prediction models comprising 15 predictors were constructed. The area under the curve (AUC) values for the 1-year, 3-year, and 5-year time-dependent receiver operating characteristic (curves) were 0.746 (0.678-0.814), 0.819 (0.761-0.877), and 0.865 (0.774-0.957), respectively. The bootstrap-corrected AUC values and Brier scores for the prediction model were 0.811 (0.638-0.950) and 0.123 (0.066-0.188), respectively. The time-dependent C-index indicated that our model exhibited significantly greater discrimination compared with RPA, GPA, Lung-molGPA, BSBM, and TNM staging. Similarly, the decision curve analysis demonstrated that our model displayed the widest range of thresholds and yielded the highest net benefit. Furthermore, the net reclassification improvement and integrated discrimination improvement analyses confirmed the enhanced predictive power of our prediction model. Finally, the risk subgroups identified by our prognostic model exhibited superior differentiation of patients' OS., Conclusion: The clinical prediction model constructed by us shows promise in predicting OS for NSCLC patients with BM. Its predictability is superior compared with RPA, GPA, Lung-molGPA, BSBM, and TNM staging., Competing Interests: The authors declare there are no competing interests., (©2023 Hou et al.)

Neuropeptides with the C-terminal Wamide (Trp-NH 2 ) 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 EC 50 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 EC 50 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 (EC 50 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.

Background: This study aimed to identify preoperative and postoperative risk factors of venous thromboembolism (VTE) after gastrectomy in gastric cancer (GC) patients., Methods: 757 GC patients underwent gastrectomy at our institution and 246 patients with elevated postoperative D-dimer levels who received Doppler ultrasonography of lower/upper extremity veins were enrolled. Clinicopathological factors data were collected, and the differences in clinicopathological factors between postoperative VTE (+) and VTE (-) groups were analyzed. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors of postgastrectomy VTE., Results: Of 246 patients with elevated postgastrectomy D-dimer concentrations, 74 patients showed thrombosis in lower/upper extremity veins. Among preoperative factors, age, WBC level, D-dimer concentration, and blood glucose level were significantly higher in the postoperative VTE (+) group. Among the postoperative factors, hemoglobin level was significantly lower in the postoperative VTE (+) group. Among the pathological factors, tumor stage, depth of invasion and TNM classification indicated higher malignancy in the postoperative VTE (+) group. Univariate logistic regression analysis indicated age, preoperative blood glucose level, postoperative hemoglobin level, tumor stage, depth of invasion, and TNM classification as the independent risk factors for postgastrectomy VTE, whereas multivariate logistic regression analysis revealed age and tumor stage as independent risk factors for postgastrectomy VTE., Conclusion: Our study revealed that age, preoperative blood glucose level, postoperative anemia, and tumor malignancy were independent risk factors for GC patients exhibiting postgastrectomy VTE. Therefore, the perioperative monitoring, assessment and management of risk factors are important in achieving better outcomes after gastrectomy., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

The restoration of mangrove in coastal wetlands of China has been started since the 1990s. However, various pollutants, especially for heavy metals (HMs), contained in wastewater might present a significant risk to mangrove forests during the restoration. In this study, sediments of five typical mangrove wetlands with varying restoration years and management measures in the Greater Bay Area were collected to evaluate the distribution fractions and potential ecological risk of HMs. Cd (0.2-1.6 mg/kg) was found in high concentrations in the exchangeable fraction (37.8-71.5%), whereas Cu (54.2-94.8 mg/kg), Zn (157.6-332.6 mg/kg), Cr (57.7-113.6 mg/kg), Pb (36.5-89.9 mg/kg), and Ni (29.7-69.5 mg/kg) primarily presented in residual fraction (30.8-91.9%). According to the geo-accumulation index (I geo ) analysis, sediment Cd presented a high level of pollution (3 ≤ I geo  ≤ 4), while Zn and Cu were associated with moderately pollution (1 ≤ I geo  ≤ 2). Besides, high ecological risk of Cd was found in sediments of five mangroves, with risk assessment code (RAC) ranging from 45.9 to 84.2. Redundancy analysis revealed that the content of NO 3 - -N concentration affected the distribution of HMs geochemical fractions. High concentration of HMs in QA and NS sampling sites was caused by the formerly pollutants discharge, resulting in these sediments still with a higher HM pollution level after the plant of mangrove for a long period. Fortunately, strict drainage standards for industrial activities in Shenzhen significantly availed for decreasing HMs contents in mangrove sediments. Therefore, future works on mangrove conversion and restoration should be linked to the water purification in the GBA.3 - -N concentration affected the distribution of HMs geochemical fractions. High concentration of HMs in QA and NS sampling sites was caused by the formerly pollutants discharge, resulting in these sediments still with a higher HM pollution level after the plant of mangrove for a long period. Fortunately, strict drainage standards for industrial activities in Shenzhen significantly availed for decreasing HMs contents in mangrove sediments. Therefore, future works on mangrove conversion and restoration should be linked to the water purification in the GBA., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with high mortality rates. Viral and bacterial coinfection is the primary cause of AECOPD. How coinfection with these microbes influences host inflammatory response and the gut microbiota composition is not entirely understood., Methods: We developed a mouse model of AECOPD by cigarette smoke exposure and sequential infection with influenza H1N1 virus and non-typeable Haemophilus influenzae (NTHi). Viral and bacterial titer was determined using MDCK cells and chocolate agar plates, respectively. The levels of cytokines, adhesion molecules, and inflammatory cells in the lungs were measured using Bio-Plex and flow cytometry assays. Gut microbiota was analyzed using 16S rRNA gene sequencing. Correlations between cytokines and gut microbiota were determined using Spearman's rank correlation coefficient test., Results: Coinfection with H1N1 and NTHi resulted in more severe lung injury, higher mortality, declined lung function in COPD mice. H1N1 enhanced NTHi growth in the lungs, but NTHi had no effect on H1N1. In addition, coinfection increased the levels of cytokines and adhesion molecules, as well as immune cells including total and M1 macrophages, neutrophils, monocytes, NK cells, and CD4 + T cells. In contrast, alveolar macrophages were depleted. Furthermore, coinfection caused a decline in the diversity of gut bacteria. Muribaculaceae , Lactobacillus , Akkermansia , Lachnospiraceae , and Rikenella were further found to be negatively correlated with cytokine levels, whereas Bacteroides was positively correlated., Conclusion: Coinfection with H1N1 and NTHi causes a deterioration in COPD mice due to increased lung inflammation, which is correlated with dysbiosis of the gut microbiota., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Li, Lin, Xiao, Liu, Mai, Zhou, Zeng, Cheng, Weng, Zhao, Chen, Jiang, Chen, Deng, Xie, Yang, Xia and Yang.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Ding, Guo, Wang, Liu, Jiang, Li, Fu, Chen, Mei, Zhang, Zhou and Jing.)

Background: A safe and highly efficacious Escherichia coli ( E. coli )-produced HPV 16/18 bivalent vaccine has been prequalified by the World Health Organization. Here, we conducted a single-center, open-label, dose-escalation phase 1 clinical trial to evaluate the safety and immunogenicity of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine., Method: Twenty-four eligible volunteers aged 18-45 years were enrolled in January 2019 in Dongtai, China and received 0.5 mL (135 μg) or 1.0 mL (270 μg) of the candidate vaccine with a 0/1/6-month dose-escalation schedule. Local and systemic adverse events (AEs) occurring within 30 days after each vaccination and serious adverse events (SAEs) occurring within 7 months were recorded. Blood samples from each participant were collected before and 2 days after the first and third vaccinations to determine changes in laboratory parameters. Serum IgG and neutralizing antibody (nAb) levels against each HPV type at month 7 were analyzed (ClinicalTrials.gov: NCT03813940)., Findings: The incidences of total AEs in the 135 μg and 270 μg groups were 66.7% and 83.3%, respectively. All AEs were mild or moderate, and no SAEs were reported. No clinically significant changes were found in paired blood indices before or after any of the vaccinations. All the participants in the per-protocol set except for two who failed to seroconvert for HPV 11 or 58 in the 135 μg group seroconverted at month 7 for both IgG and nAbs., Interpretation: The candidate E. coli -produced 9vHPV vaccine has been preliminarily proven to be well tolerated and immunogenic, which encourages further studies in large cohorts with a wider age range., Funding: This study was supported by the National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Fujian Province Health and Education Joint Research Program, Xiamen Science and Technology Plan Project, Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences of China, and Xiamen Innovax Biotechnology Co., Ltd., Competing Interests: F-Z Z (Feng-Zhu Zheng), and Q-FZ (Qiu-Fen Zhang) report being either current employees of Xiamen Innovax; G S (Guang-Sun) and H-R P (Hui-Rong Pan) report being current employees of and have stock options in Xiamen Innovax. No other potential conflicts of interest relevant to this article were reported., (© 2023 The Author(s).)

Oximes and hydroxylamines are a very important class of skeletons that not only widely exist in natural products and drug molecules, but also a class of synthon, which have been widely used in industrial production. Due to weak N-O σ bonds of oximes and hydroxylamines, they can be easily transformed into other functional groups by N-O bond cleavage. Therefore, the synthesis of N-heterocycle by using oximes and hydroxylamines as nitrogen sources has attracted wide attention. Recent advances for the synthesis of N-heterocycle through transition-metal-catalyzed and radical-mediated cyclization classified by the type of nitrogen sources and rings are summarized. In this paper, the recent advances in the N-O bond cleavage of oximes and hydroxylamines are reviewed. We hope that this review provides a new perspective on this field, and also provides a reference to develop environmentally friendly and sustainable methods.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women of reproductive age and features complex pathological symptoms and mechanisms. Existing medical treatments have, to some extent, alleviated the deterioration of PCOS. However, these strategies only temporarily control symptoms, with a few side effects and no preventive effect. Phytochemicals extracted from medicinal herbs and plants are vital for discovering novel drugs. In recent years, many kinds of research have proven that phytochemicals isolated from traditional Chinese medicine (TCM) and medicinal plants show significant potential in preventing, alleviating, and treating PCOS. Nevertheless, compared to the abundance of experimental literature and minimal specific-topic reviews related to PCOS, there is a lack of systematic reviews to summarize these advancements in this promising field. Under this background, we systematically document the progress of bioactive phytochemicals from TCM and medicinal plants in treating PCOS, including flavonoids, polyphenols, and alkaloids. According to the literature, these valuable phytochemicals demonstrated therapeutic effects on PCOS supported by in vivo and in vitro experiments, mainly depending on anti-inflammatory, antioxidation, improvement of hormone disorder and insulin resistance (IR), and alleviation of hyperinsulinemia. Based on the current progress, future research directions should emphasize 1) exploring bioactive phytochemicals that potentially mediate bone metabolism for the treatment of PCOS; 2) improving unsatisfactory bioavailability by using advanced drug delivery systems such as nanoparticles and antibody-conjugated drugs, as well as a chemical modification; 3) conducting in-depth research on the pathogenesis of PCOS to potentially impact the gut microbiota and its metabolites in the evolution of PCOS; 4) revealing the pharmacological effects of these bioactive phytochemicals on PCOS at the genetic level; and 5) exploring the hypothetical and unprecedented functions in regulating PCOS by serving as proteolysis-targeting chimeras and molecular glues compared with traditional small molecule drugs. In brief, this review aims to provide detailed mechanisms of these bioactive phytochemicals and hopefully practical and reliable insight into clinical applications concerning PCOS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Jiang, Chen, Wang, Tang, Guo, Diao, Cai, Yang, Bian and Xing.)

Type 2 diabetes mellitus (T2DM) is a metabolic disease with persistent hyperglycemia primarily caused by insulin resistance (IR). The number of diabetic patients globally has been rising over the past decades. Although significant progress has been made in treating diabetes mellitus (DM), existing clinical drugs for diabetes can no longer fully meet patients when they face complex and huge clinical treatment needs. As a traditional and effective medical system, traditional Chinese medicine (TCM) has a unique understanding of diabetes treatment and has developed many classic and practical prescriptions targeting DM. With modern medicine and pharmacy advancements, researchers have discovered that various bioactive metabolites isolated from TCM show therapeutic on DM. Compared with existing clinical drugs, these bioactive metabolites demonstrate promising prospects for treating DM due to their excellent biocompatibility and fewer adverse reactions. Accordingly, these valuable metabolites have attracted the interest of researchers worldwide. Despite the abundance of research works and specialized-topic reviews published over the past years, there is a lack of updated and systematic reviews concerning this fast-growing field. Therefore, in this review, we summarized the bioactive metabolites derived from TCM with the potential treatment of T2DM by searching several authoritative databases such as PubMed, Web of Science, Wiley Online Library, and Springer Link. For the convenience of readers, the content is divided into four parts according to the structural characteristics of these valuable compounds (flavonoids, terpenoids, alkaloids, and others). Meanwhile, the detailed mechanism and future directions of these promising compounds curing DM are also summarized in the related sections. We hope this review inspires increasingly valuable and significant research focusing on potential bioactive metabolites from TCM to treat DM in the future., Competing Interests: Z-JS is employed by the Sichuan Ant Recommendation Biotechnology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer XX declared a shared parent affiliation with the authors XL, JG, LQ, QH, HJ, XX to the handling editor at the time of review., (Copyright © 2022 Li, Geng-Ji, Quan, Qi, Sun, Huang, Jiang, Sun, Liu and Xie.)

As a Class II tumor suppressor, ING5 contains nuclear localization signal, plant homeodomain, novel conserved region, and leucine zipper-like domains. ING5 proteins form homodimer into a coil-coil structure, and heterodimers with ING4, histone H3K4me3, histone acetyltransferase (HAT) complex, Tip60, Cyclin A1/CDK2, INCA1 and EBNA3C for the transcription of target genes. The acetylated proteins up-regulated by ING5 are preferentially located in nucleus and act as transcription cofactors, chromatin and DNA binding functions, while those down-regulated by ING5 mostly in cytoplasm and contribute to metabolism. ING5 promotes the autoacetylation of HAT p300, p53, histone H3 and H4 for the transcription of downstream genes (Bax, GADD45, p21, p27 and so forth). Transcriptionally, YY1 and SRF up-regulate ING5 mRNA expression by the interaction of YY1-SRF-p53-ING5 complex with ING5 promoter. Translationally, ING5 is targeted by miR-196, miR-196a, miR-196b-5p, miR-193a-3p, miR-27-3p, miR-200b/200a/429, miR-1307, miR-193, miR-222, miR-331-3p, miR-181b, miR-543 and miR-196-b. ING5 suppresses proliferation, migration, invasion and tumor growth of various cancer cells via the suppression of EGFR/PI3K/Akt, IL-6/STAT3, Akt/NF-κB/NF-κB/MMP-9 or IL-6/CXCL12 pathway. ING5-mediated chemoresistance is closely linked to anti-apoptosis, overexpression of chemoresistant genes, the activation of PI3K/Akt/NF-κB and Wnt/β-catenin signal pathways. Histologically, ING5 abrogation in gastric stem-like and pdx1-positive cells causes gastric dysplasia and cancer, and conditional ING5 knockout in pdx1-positive and gastric chief cells increases MNU-induced gastric carcinogenesis. Intestinal ING5 deletion increases AOM/DSS- induced colorectal carcinogenesis and decreases high-fat-diet weight. The overexpression and nucleocytoplasmic translocation of ING5 are seen during carcinogenesis, and ING5 expression was inversely associated with aggressive behaviors and poor prognosis in a variety of cancers. These findings indicated that ING5 might be used for a molecular marker for carcinogenesis and following progression, and as a target for gene therapy if its chemoresistant function might be ameliorated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Xue and Jiang.)

The protostome leucokinin (LK) signaling system, including LK peptides and their G protein-coupled receptors, has been characterized in several species. Despite the progress, molecular mechanisms governing LK peptide-receptor interactions remain to be elucidated. Previously, we identified a precursor protein for Aplysia leucokinin-like peptides (ALKs) that contains the greatest number of amidated peptides among LK precursors in all species identified so far. Here, we identified the first ALK receptor from Aplysia, ALKR. We used cell-based IP1 activation assays to demonstrate that two ALK peptides with the most copies, ALK1 and ALK2, activated ALKR with high potencies. Other endogenous ALK-derived peptides bearing the FXXWX-amide motif also activated ALKR to various degrees. Our examination of cross-species activity of ALKs with the Anopheles LK receptor was consistent with a critical role for the FXXWX-amide motif in receptor activity. Furthermore, we showed, through alanine substitution of ALK1, the highly conserved phenylalanine (F), tryptophan (W), and C-terminal amidation were each essential for receptor activation. Finally, we used an artificial intelligence-based protein structure prediction server (Robetta) and Autodock Vina to predict the ligand-bound conformation of ALKR. Our model predicted several interactions (i.e., hydrophobic interactions, hydrogen bonds, and amide-pi stacking) between ALK peptides and ALKR, and several of our substitution and mutagenesis experiments were consistent with the predicted model. In conclusion, our results provide important information defining possible interactions between ALK peptides and their receptors. The workflow utilized here may be useful for studying other ligand-receptor interactions for a neuropeptide signaling system, particularly in protostomes., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

NiTi shape memory alloys (SMAs) are inevitably in contact with hydrogen in specific service environments, which can degrade their mechanical behaviors. In this work, the effect of hydrogen on the super-elasticity of NiTi SMA orthodontic wires is investigated experimentally and theoretically. Firstly, cathodic hydrogen charging was performed for the wires at a current density of 10A/m 2 with various charging times (2.5min, 5min, 7.5min and 10min) and charging lengths (20 mm, 40 mm, 60 mm and 80 mm) in 0.5 mol/L H2SO4+2 g/L CH4N2S electrolyte solution at room temperature. Then, ex-situ tension-unloading tests were carried out shortly after the hydrogen charging. The stress-strain responses showed a two-step martensite transformation (MT), i.e., the start stress of MT for the region with hydrogen charging is much larger than that without hydrogen charging. Based on the experimental observations, a diffusional-mechanically coupled constitutive model is constructed. Elastic strain, transformation strain, transformation-induced plasticity (TRIP) and hydrogen swelling deformation are considered. The effect of hydrogen on the thermo-mechanical behavior of NiTi SMA is taken into account by introducing the hydrogen concentration (HC)-dependent critical temperatures of MT and slip resistance of TRIP. The thermodynamic driving forces of MT and TRIP are derived from the constructed Helmholtz free energy and dissipation inequality. The balance equation of hydrogen diffusion is obtained by the chemical potential and Fick's diffusion law. To obtain the overall response of the wire with a heterogeneous HC field, a scale transition rule is proposed. The capability of the proposed model to describe the super-elasticity of NiTi SMA with various hydrogen charging times and charging lengths is validated by comparing the predicted results with the experimental ones., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The oxidation of hypophosphorous acid (H 3 PO 2 ) by a ruthenium(VI) nitrido complex, [(L)Ru VI (N)(OH 2 )] + ( Ru VI N ; L = N , N '-bis(salicylidene)- o -cyclohexyldiamine dianion), has been studied in aqueous acidic solutions at pH 0-2.50. The reaction has the following stoichiometry: 2[(L)Ru VI (N)(OH 2 )] + + 3H 3 PO 2 + H 2 O → 2[(L)Ru III (NH 2 P(OH) 2 )(OH 2 )] + + H 3 PO 3 . The pseudo-first-order rate constant, k obs , depends linearly on [H 3 PO 2 ], and the second-order rate constant k 2 depends on [H + ] according to the relationship k 2 = k [H + ]/([H + ] + K a ), where k is the rate constant for the oxidation of H 3 PO 2 molecule and K a is the dissociation constant of H 3 PO 2 . At 298.0 K and I = 1.0 M, k = (2.04 ± 0.19) × 10 -2 M -1 s -1 and K a = (6.38 ± 0.63) × 10 -2 M. A kinetic isotope effect (KIE) of 2.9 ± 0.1 was obtained when kinetic studies were carried out with D 3 PO 2 at pH 1.16, suggesting P-H bond cleavage in the rate-determining step. On the other hand, when the kinetics were determined in D 2 O, an inverse KIE of 0.21 ± 0.03 (H 3 PO 2 in H 2 O vs H 3 PO 2 in D 2 O) was found. On the basis of experimental results and DFT calculations, the proposed mechanism involves an acid-catalyzed tautomerization of H 2 P(O)(OH) to HP(OH) 2 ; the latter molecule is the reacting species which reacts with Ru VI N via a proton-coupled N-atom transfer pathway.

Licochalcone A (LA), a useful and valuable flavonoid, is isolated from Glycyrrhiza uralensis Fisch. ex DC. and widely used clinically in traditional Chinese medicine. We systematically updated the latest information on the pharmacology of LA over the past decade from several authoritative internet databases, including Web of Science, Elsevier, Europe PMC, Wiley Online Library, and PubMed. A combination of keywords containing "Licochalcone A," "Flavonoid," and "Pharmacological Therapy" was used to help ensure a comprehensive review. Collected information demonstrates a wide range of pharmacological properties for LA, including anticancer, anti-inflammatory, antioxidant, antibacterial, anti-parasitic, bone protection, blood glucose and lipid regulation, neuroprotection, and skin protection. LA activity is mediated through several signaling pathways, such as PI3K/Akt/mTOR, P53, NF-κB, and P38. Caspase-3 apoptosis, MAPK inflammatory, and Nrf2 oxidative stress signaling pathways are also involved with multiple therapeutic targets, such as TNF-α, VEGF, Fas, FasL, PI3K, AKT, and caspases. Recent studies mainly focus on the anticancer properties of LA, which suggests that the pharmacology of other aspects of LA will need additional study. At the end of this review, current challenges and future research directions on LA are discussed. This review is divided into three parts based on the pharmacological effects of LA for the convenience of readers. We anticipate that this review will inspire further research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Xie, Jiang, Huang, Tong, Li, Xie and Liu.)

Objective: Sepsis has a high morbidity and mortality and is prone to cause acute kidney injury (AKI). Here, we aimed to demonstrate the function and molecular mechanism of microRNA-543 (miR-543) in septic AKI., Materials and Methods: MiR-543 inhibitor or NC was transfected into LPS-treated HK-2 cells to observe lipopolysaccharide (LPS)-induced inflammation and apoptosis. The detection of inflammation and apoptosis of HK-2 cells relies on Western blot, quantitative Reverse-Transcription Polymerase Chain Reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining., Results: MiR-543 expression was increased in LPS-treated HK-2 cells. By transfecting miR-543 inhibitor into HK-2 cells, miR-543 expression was dramatically reduced. The downregulation of miR-543 remarkably inhibited the inflammation and apoptosis, which was manifested by the reduction of inflammatory cytokines (TNF-α, IL-6, IL-1β), the reversal of apoptosis-related proteins expression (Bcl-1, Bax), the increase of cell viability and the decrease of the proportion of apoptotic cells. The result of Luciferase activity assay demonstrated that miR-543 directly targets Bcl-2., Conclusions: MiR-543 expression was increased in LPS-treated HK-2 cells, and silencing miR-543 could inhibit LPS-induced inflammation and apoptosis in HK-2 cells via targeting Bcl-2.

JC polyoma virus (JCPyV) is a ubiquitous polyoma virus that infects the individual to cause progressive multifocal leukoencephalopathy and malignancies. Here, we found that T-antigen knockdown suppressed proliferation, glycolysis, mitochondrial respiration, migration, and invasion, and induced apoptosis and G 2 arrest. The reverse was true for T-antigen overexpression, with overexpression of Akt, survivin, retinoblastoma protein, β-catenin, β-transducin repeat-containing protein (TRCP), and inhibitor of growth (ING)1, and the underexpression of mammalian target of rapamycin (mTOR), phosphorylated (p)-mTOR, p-p38, Cyclin D1, p21, vascular endothelial growth factor (VEGF), ING2, and ING4 in hepatocellular and pancreatic cancer cells and tissues. In lens tumor cells, T antigen transcriptionally targeted viral carcinogenesis, microRNAs in cancer, focal adhesion, p53, VEGF, phosphoinositide 3 kinase-Akt, and Forkhead box O signaling pathways, fructose and mannose metabolism, ribosome biosynthesis, and choline and pyrimidine metabolism. At a metabolomics level, it targeted protein digestion and absorption, aminoacryl-tRNA biosynthesis, biosynthesis of amino acids, and the AMPK signal pathway. At a proteomic level, it targeted ribosome biogenesis in eukaryotes, citrate cycle, carbon metabolism, protein digestion and absorption, aminoacryl-tRNA biosynthesis, extracellular-matrix-receptor interaction, and biosynthesis of amino acids. In lens tumor cells, T antigen might interact with various keratins, ribosomal proteins, apolipoproteins, G proteins, ubiquitin-related proteins, RPL19, β-catenin, β-TRCP, p53, and CCAAT-enhancer-binding proteins in lens tumor cells. T antigen induced a more aggressive phenotype in mouse and human cancer cells due to oncogene activation, inactivation of tumor suppressors, and disruption of metabolism, cell adhesion, and long noncoding RNA-microRNA-target axes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Xue, Jin, Jiang and Cui.)

Background: The crotonylation of histones is discovered of late as one of the post-translational modifications (PTMs) that can regulate gene expression. However, the function of crotonylation on nonhistone proteins in vascular smooth muscle cells (VSMCs) is unclear. Here, we aim to find the cellular characteristics of crotonylated nonhistone proteins and the cross talk with ubiquitinated proteins in VSMC phenotypic remodeling using the modified omics and proteomic analysis., Methods: We performed the modified omics and proteomic analysis of VSMCs before and after the stimulation with platelet-derived growth factor-BB (PDGF-BB). The crotonylated and ubiquitinated pan-antibody was used to enrich proteins and then subjected to a high-throughput mass spectrometry analysis. The enrichment analysis was performed within differentially modified proteins in regard to GO terms, KEGG, and protein domains., Results: As a result, there were 2,138 crotonylation sites in 534 proteins and 1,359 ubiquitination sites corresponding to 657 proteins. These crotonylated proteins detected after PDGF-BB stimulation might be involved in various vital cellular pathways and carry out important functions in VSMCs. Some of them closely took part in significant physiological processes of VSMC phenotypic remodeling, including glycolysis/gluconeogenesis, vascular smooth muscle contraction, and the PI3K-Akt signaling pathway. Furthermore, the KEGG pathway enrichment analysis showed the involvement of ubiquitinated proteins in the physiological processes of VSMC phenotypic remodeling, including glycolysis/gluconeogenesis, vascular smooth muscle contraction, RAS signaling pathway, or the PI3K-Akt signaling pathway. A cross talk analysis showed that there were 199 sites within the 177 proteins modified by crotonylation and ubiquitination simultaneously. Protein-protein interaction (PPI) network analysis indicated that crotonylated and ubiquitinated proteins play an important role in cellular bioprocess commonly and possibly have a synergistic effect., Conclusion: In summary, our bioinformatics analysis shows that the crotonylation and ubiquitination of nonhistone proteins play an essential role in VSMC phenotypic transformation induced by PDGF-BB stimulation. The cross talk between crotonylation and ubiquitination in glycolysis is possibly a novel mechanism during VSMC phenotypic remodeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cao, Chen, Ma, Yue, Jiang and Dong.)

Acetylshikonin (ASK) is a natural naphthoquinone derivative of traditional Chinese medicine Lithospermum erythrorhyzon. It has been reported that ASK has bactericidal, anti-inflammatory and antitumour effects. However, whether ASK induces apoptosis and autophagy in acute myeloid leukaemia (AML) cells and the underlying mechanism are still unclear. Here, we explored the roles of apoptosis and autophagy in ASK-induced cell death and the potential molecular mechanisms in human AML HL-60 cells. The results demonstrated that ASK remarkably inhibited the cell proliferation, viability and induced apoptosis in HL-60 cells through the mitochondrial pathway, and ASK promoted cell cycle arrest in the S-phase. In addition, the increased formation of autophagosomes, the turnover from light chain 3B (LC3B) I to LC3B II and decrease of P62 suggested the induction of autophagy by ASK. Furthermore, ASK significantly decreased PI3K, phospho-Akt and p-p70S6K expression, while enhanced phospho-AMP-activated protein kinase (AMPK) and phospho-liver kinase B1(LKB1) expression. The suppression of ASK-induced the conversion from LC3B I to LC3B II caused by the application of inhibitors of AMPK (compound C) demonstrated that ASK-induced autophagy depends on the LKB1/AMPK pathway. These data suggested that the autophagy induced by ASK were dependent on the activation of LKB1/AMPK signalling and suppression of PI3K/Akt/mTOR pathways. The cleavage of the apoptosis-related markers caspase-3 and caspase-9 and the activity of caspase-3 induced by ASK were markedly reduced by inhibitor of AMPK (compound C), an autophagy inhibitor 3-methyladenine (3-MA) and another autophagy inhibitor chloroquine (CQ). Taken together, our data reveal that ASK-induced HL-60 cell apoptosis is dependent on the activation of autophagy via the LKB1/AMPK and PI3K/Akt-regulated mTOR signalling pathways., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The antagonistic effect of selenium (Se) against cadmium (Cd)-induced breast carcinogenesis was reported, but underlying mechanisms were unclear. The aim of this study was to identify the epigenetically regulated genes and biological pathways mediating the antagonistic effect. We exposed MCF-7 cells to Cd and Se alone or simultaneously. Cell proliferation was assessed by MTT assay, and differential epigenome (DNA methylation, microRNA, and long non-coding RNA) was obtained by microarrays. We cross-verified the epigenetic markers with differential transcriptome, and the ones modulated by Cd and Se in opposite directions were regarded to mediate the antagonistic effect. The epigenetically regulated genes were validated by using gene expression data in human breast tissues. We further assessed the biological functions of these validated genes. Our results showed that Se alleviated the proliferative effect of Cd on MCF-7 cell. A total of 10 epigenetically regulated genes were regarded to mediate the antagonistic effect, including APBA2, KIAA0895, DHX35, CPEB3, SVIL, MYLK, ZFYVE28, ABLIM2, GRB10, and PCDH9. Biological function analyses suggested that these epigenetically regulated genes were involved in multiple cancer-related pathways, such as focal adhesion and PI3K/Akt pathway. In conclusion, we provided evidence that Se antagonized the Cd-induced breast carcinogenesis via epigenetic modification and revealed the critical pathways., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Oxidative stress-related cartilage degeneration, synovitis, and joint pain play vital roles in the progress of osteoarthritis (OA). Anti-oxidative stress agents not only prevent structural damage progression but also relieve OA-related pain. In this study, we investigated the therapeutic effect of methylene blue (MB), a classical and important anti-oxidant with strong neural affinity. Experimental OA was established in rats by radial transection of medial collateral ligament and medial meniscus (MCLT + MMT) of the right knee joint. The OA rats received intra-articular injection of MB (1 mg/kg) every week starting one week after surgery. We showed that MB administration exerted significant cartilage protection, synovitis inhibition as well as pain relief in OA rats. In human chondrocytes and fibroblast-like synoviocytes, MB significantly attenuated tert-butyl hydroperoxide (TBHP)-induced inflammatory response and oxidative stress. We demonstrated that these effects of MB resulted from dual targets of important antioxidant enzymes, Nrf2 and PRDX1, which also mutually reinforcing and participated in an interaction. Furthermore, we found that calcitonin gene-related peptide (CGRP), a neural inflammatory mediator, was accumulated around the vessel in synovium and subchondral bone in OA rats and in TBHP-treated primary cortical neurons; MB administration significantly inhibited CGRP expression through upregulation of Nrf2 and PRDX1. Taken together, these results suggest that MB ameliorates oxidative stress via Nrf2/PRDX1 regulation to prevent progression and relieve pain of OA., (© 2021. The Author(s).)

Neuropeptides, as pervasive intercellular signaling molecules in the CNS, modulate a variety of behavioral systems in both protostomes and deuterostomes. Allatostatins are neuropeptides in arthropods that inhibit the biosynthesis of juvenile hormones. Based on amino acid sequences, they are divided into three different types in arthropods: allatostatin A, allatostatin B, allatostatin C. Allatostatin C (AstC) was first isolated from Manduca sexta, and it has an important conserved feature of a disulfide bridge formed by two cysteine residues. Moreover, AstC appears to be the ortholog of mammalian somatostatin, and it has functions in common with somatostatin, such as modulating feeding behaviors. The AstC signaling system has been widely studied in arthropods, but minimally studied in molluscs. In this study, we seek to identify the AstC signaling system in the marine mollusc Aplysia californica. We cloned the AstC precursor from the cDNA of Aplysia. We predicted a 15-amino acid peptide with a disulfide bridge, i.e., AstC, using NeuroPred. We then cloned two putative allatostatin C-like receptors and through NCBI Conserved Domain Search we found that they belonged to the G protein-coupled receptor (GPCR) family. In addition, using an inositol monophosphate 1 (IP1) accumulation assay, we showed that Aplysia AstC could activate one of the putative receptors, i.e., the AstC-R, at the lowest EC 50 , and AstC without the disulfide bridge (AstC') activated AstC-R with the highest EC 50 . Moreover, four molluscan AstCs with variations of sequences from Aplysia AstC but with the disulfide bridge activated AstC-R at intermediate EC 50 . In summary, our successful identification of the Aplysia AstC precursor and its receptor (AstC-R) represents the first example in molluscs, and provides an important basis for further studies of the AstC signaling system in Aplysia and other molluscs., (© 2022. The Author(s).)

Recently accumulated evidence has indicated that the nucleomembrane shuttling of cellular proteins is common, which provides new insight into the subcellular translocation and biological functions of proteins synthesized in the cytoplasm. The present study aimed to clarify the trafficking of proteins between the plasma membrane and nucleus. These proteins primarily consist of transmembrane receptors, membrane adaptor proteins, adhesive proteins, signal proteins and nuclear proteins, which contribute to proliferation, apoptosis, chemoresistance, adhesion, migration and gene expression. The proteins frequently undergo cross‑talk, such as the interaction of transmembrane proteins with signal proteins. The transmembrane proteins undergo endocytosis, infusion into organelles or proteolysis into soluble forms for import into the nucleus, while nuclear proteins interact with membrane proteins or act as receptors. The nucleocytosolic translocation involves export or import through nuclear membrane pores by importin or exportin. Nuclear proteins generally interact with other transcription factors, and then binding to the promoter for gene expression, while membrane proteins are responsible for signal initiation by binding to other membrane and/or adaptor proteins. Protein translocation occurs in a cell‑specific manner and is closely linked to cellular biological events. The present review aimed to improve understanding of cytosolic protein shuttling between the plasma membrane and nucleus and the associated signaling pathways.

Objective: To observe the genotypes and composition ratio of thalassemia in couples of reproductive age, and provide a reference for the prevention and control of thalassemia in Haikou., Methods: Gene diagnosis was performed in 2 494 subjects who were screened for thalassemia before marriage or prenatal by cross-breakpoint PCR, PCR-reverse dot hybridization, and PCR-electrophoresis., Results: A total of 1 037 thalassemia gene carriers were detected in 2 494 samples, with a detection rate of 41.57%, of which 75.02% was α-thalassemia, 18.61% was β-thalassemia, and 6.36% was α-β complex thalassemia. There were 778 cases of α-thalassemia, mainly of deletion type, accounting for 76.99% (599/778). Twenty genotypes were detected, the highest three was -- SEA /αα (33.42%, 260/778), -α 3.7 /αα(23.91%, 186/778), and -α 4.2 /αα(19.02%, 148/778), respectively. A rare HKαα/-α 3.7 was detected, who immigrated from other province. There were 193 cases of β-thalassemia, all of them were light (β 0 /β A or β + /β A ). Eight genotypes were detected, the highest two was 41-42M/N (74.61%, 144/193) and 654M/N (10.36%, 20/193), respectively. There were 66 cases of α-β compound type of thalassemia, 15 genotypes were detected, the highest three was αα WS /αα complex 41-42M/N (28.79%, 19/66), -α 3.7 /αα complex 41-42M/N, and -α 4.2 /αα complex 41-42M/N (16.67%, 11/66 for both)., Conclusion: In Haikou city, the gene carrying rate of thalassemia is very high, and the genotype distribution is different from other cities in Hainan Province, attention should be paid to the impact of population inflow on the frequency spectrum change of local thalassemia gene.

Objective: To analyze the DNA sequences and clinical phenotypes of four cases with rare thalassemia to improve its recognition and accurate diagnosis. Methods: The DNA sequence characteristics of four cases with rare thalassemia diagnosed from May 2014 to December 2019 were retrospectively analyzed, and related literature was reviewed. Results: The results of the routine gene test for thalassemia indicated that the common three type of deletion and three point mutations in hemoglobin alpha 1/2 (HBA1/A2) , and 16 point mutations in hemoglobin beta (HBB) gene were unable to be detected in cases 1-3, and case 4 was--SEA. However, the results of HBA1/A2 and HBB whole-genome sequencing revealed that the four cases had a point mutation of HBB:c.347C>A, HBB:c.1A>G, HBB:c.393T>G, and HBA2: c.301-1G>A (IVS II-142 G>A) , respectively. Meanwhile, the father, aunt, and grandfather of case 2 carried the HBB:c.1 A>G heterozygous point mutation. Conclusion: The novel mutations in HBB and HBA2 genes, resulting in a rare thalassemia, were revealed. Among them, the HBB:c.347C>A, HBB:c.1A>G, and HBA2:c.301-1G>A (IVS II-142 G>A) mutations were first reported in Chinese patients with thalassemia. Contrarily, HBB:c.393T>G mutation has not yet been recorded in the databases of human hemoglobin variants and thalassemia. The discovery of these novel nucleotide variants in this study would enrich the DNA mutation gene database of thalassemia.

Acute kidney injury (AKI) occurs in 30%-70% of critically ill patients. Multiple organ failure (MOF), which is most often secondary to hypotension and septicemia, is a global public health problem. The prognosis of patients is poor. Currently, there is no specific therapeutic method. Finding new therapeutic targets is significant to improve the prognosis of AKI patients. This study explores expressions and related mechanisms of miR-212 and Kruppel-like factor 4 (KLF4) in rats with AKI. Sixty Wistar rats were randomly divided into 6 groups: Control group, sham operation group, model group, miR-212-agomir group, miR-212-antagomir group, miR-212-agomir+APTO-253 (joint group), n = 10. The expressions of miR-212, KLF4, inflammatory factors [tumor necrosis factor α (TNF-α), interleukin 6 (IL-6)], oxidative stress factors [superoxide dismutase (SOD), malondialdehyde (MDA)], and apoptosis-related proteins (bax, bcl-2) in renal tissue of rats were detected, and the relationship between miR-212 and KLF4 and the severity of AKI in rats were analyzed. The expression level of miR-212 increased (P < 0.05) and the expression level of KLF4 decreased (P < 0.05) in renal tissue of rats with AKI. miR-212 was negatively correlated with KLF4 expression (P < 0.05). MiR-212 was positively correlated with expressions of TNF-α, IL-6, MDA, and bax (P < 0.05), negatively correlated with expressions of SOD and bcl-2 (P < 0.05), KLF4 was negatively correlated with expressions of TNF-α, IL-6, MDA and bax (P < 0.05), and positively correlated with expressions of SOD and bcl-2 (P < 0.05). MiR-212 mimics can inhibit the luciferase activity of Wt-KLF4 (P < 0.05), and miR-212 inhibitor can promote the luciferase activity of Wt-KLF4 (P < 0.05). Down-regulation of miR-212 plays a protective role by targeting up-regulation of KLF4 to inhibit renal tissue inflammation, oxidative stress, and apoptosis in rats with AKI, which may be a potential target for clinical treatment of AKI in the future.

A 60-year-old man was hospitalized because of numbness and weakness in the right upper limb. Magnetic resonance imaging revealed a large mass in the right upper lobe invading the right eighth cervical and first thoracic nerve root. Biopsy pathology confirmed primary lung adenocarcinoma with a clinical stage of cT4N0M0 IIIA, negative for anaplastic lymphoma kinase fusion gene and epidermal growth factor receptor mutations but positive for programmed death ligand 1 (3%). Neoadjuvant tislelizumab and chemotherapy were offered to this patient with Pancoast tumor, and tumor shrinkage of 71% was achieved. After the operation, surgical pathology indicated pathologic complete response (pCR). Circulating tumor cells testing was negative after the first adjuvant treatment. In this case, we provide real-world evidence of encouraging pCR with neoadjuvant tislelizumab and chemotherapy for a patient with Pancoast tumor., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Aim: To compare the rotational stability of Toric intraocular lens (IOLs) implantation combined with four-eyelet or two-eyelet capsular tension rings (CTRs) in eyes with high myopia and cataract., Methods: This prospective randomized controlled interventional study included 33 eyes which had preoperative corneal astigmatism ≥1.5 D and ocular axial length ≥25.5 mm. These eyes were randomly divided into two groups to undergo phacoemulsification and toric IOL implantation with either four-eyelet CTR implantation (group A, n =16) or two-eyelet CTR implantation (group B, n =17). Uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), phoropter examination results, and toric IOL rotation degrees were tested 6mo after the surgery., Results: In both groups, the toric IOL was in the capsular sac 6mo after surgery. The difference between the two groups in terms of visual outcome was not found to be statistically significant ( P >0.05) at a follow-up of 6mo. The mean residual astigmatism values were 0.56±0.22 D and 0.92±0.24 D in A and B groups, respectively ( P <0.001). The mean rotation degree of IOL was 1.00°±0.73° in group A and 3.53°±1.46° in group B ( P <0.001)., Conclusion: In cataract patients with high myopia and astigmatism, four-eyelet CTR can effectively increase the rotation stability of toric IOLs, achieving the desired goal of correcting corneal astigmatism., (International Journal of Ophthalmology Press.)

To investigate the molecular mechanisms underlying islet dysfunction and insulin resistance in diet-induced diabetes, we conducted temporal RNA sequencing of tissues responsible for insulin secretion (islets) and action (liver) every 4 weeks in mice on high-fat (HFD) or chow diet for 24 weeks, linking to longitudinal profile of metabolic characteristics. The diverse responses of α, β, and δ cells to glucose and palmitate indicated HFD-induced dynamic deterioration of islet function from dysregulation to failure. Insulin resistance developed with variable time course in different tissues. Weighted gene co-expression network analysis and Ingenuity Pathway Analysis implicated islets and liver jointly programmed β-cell compensatory adaption via cell proliferation at early phase and irreversible islet dysfunction by inappropriate immune response at later stage, and identified interconnected molecules including growth differentiation factor 15. Frequencies of T cell subpopulation showed an early decrement in Tregs followed by increases in Th1 and Th17 cells during progression to diabetes., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Objectives: Selenium (Se) was a potential anticancer micronutrient with proposed epigenetic effect. However, the Se-induced epigenome in breast cancer cells was yet to be studied., Methods: The profiles of DNA methylation, microRNA (miRNA), long non-coding RNA (lncRNA), and message RNA (mRNA) in breast cancer cells treated with sodium selenite were examined by microarrays. We verified the epigenetic modifications by integrating their predicted target genes and differentially expressed mRNAs. The epigenetically regulated genes were further validated in a breast cancer cohort by associating with tumor progression. We conducted a series of bioinformatics analyses to assess the biological function of these validated genes and identified the critical genes., Results: The Se-induced epigenome regulated the expression of 959 genes, and 349 of them were further validated in the breast cancer cohort. Biological function analyses suggested that these validated genes were enriched in several cancer-related pathways, such as PI3K/Akt and metabolic pathways. Based on the degrees of expression change, hazard ratio difference, and connectivity, NEDD4L and FMO5 were identified as the critical genes., Conclusions: These results confirmed the epigenetic effects of sodium selenite and revealed the epigenetic profiles in breast cancer cells, which would help understand the mechanisms of Se against breast cancer., (Copyright © 2020 Elsevier GmbH. All rights reserved.)