Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

The specialized sesquiterpenoids produced by the genus Elephantopus L.: Chemistry, biological activities and structure-activity relationship exploration.

The genus Elephantopus L. is a valuable resource rich in sesquiterpenoids with structural diversity and various bioactivities, showing great potential for applications in medicinal field and biological industry. Up to now, over 129 sesquiterpenoids have been isolated and identified from this plant genus, including 114 germacrane-type, 7 guaianolide-type, 5 eudesmane-type, 1 elemanolide-type, and 2 bis-sesquiterpenoids. These sesquiterpenoids were reported to show a diverse range of pharmacological properties, including cytotoxic, anti-tumor, anti-inflammatory, antimicrobial, and antiprotozoal. Consequently, some of them were identified as active scaffolds in the design and development of drugs. Considering that there is currently no overview available that covers the sesquiterpenoids and their biological activities in the Elephantopus genus, this article aims to comprehensively review the chemical structures, biosynthetic pathways, pharmacological properties, and structure-activity relationship of sesquiterpenoids found in the Elephantopus genus, which will establish a theoretical framework that can guide further research and exploration of sesquiterpenoids from Elephantopus plants as promising therapeutic agents.

Exploring the Immunomodulatory Properties of Red Onion (Allium cepa L.) Skin: Isolation, Structural Elucidation, and Bioactivity Study of Novel Onion Chalcones Targeting the A2A Adenosine Receptor.

Onions are versatile and nutritious food widely used in various cuisines around the world. In our ongoing pursuit of bioactive substances with health benefits from red onion (Allium cepa L.) skin, a comprehensive chemical investigation was undertaken. Consequently, a total of 44 compounds, including three previously unidentified chalcones (1-3) were extracted from red onion skin. Of these isolates, chalcones 1-4 showed high affinity to A2A adenosine receptor (A2AAR), and chalcone 2 displayed the best binding affinity to A2AAR, with the IC50 value of 33.5 nM, good A2AAR selectivity against A1AR, A2BAR, and A3AR, and high potency in the cAMP functional assay (IC50 of 913.9 nM). Importantly, the IL-2 bioassay and the cell-mediated cytotoxicity assay demonstrated that chalcone 2 could boost T-cell activation. Furthermore, the binding mechanism of chalcone 2 with hA2AAR was elucidated by molecular docking. This work highlighted that the active chalcones in red onion might have the potential to be developed as A2AAR antagonists used in cancer immunotherapy.

Azofuran activation for annulative rearrangement enabled by gold(I)/Brønsted acid relay catalysis.

A novel gold(I)/Brønsted acid relay catalysis enabling azofuran activation to induce annulative rearrangement from 3-yne-1,2-diols and aryldiazonium tetrafluoroborates is reported, producing a series of furan-2-yl-substituted pyrrol-2-ones bearing a quaternary carbon center with good yields. Exchanging aryldiazonium tetrafluoroborate for azofuran led to skeletally identical but substituent-diverse furan-2-yl-containing pyrrol-2-ones with good yields, supporting the key azofuran activation and annulative rearrangement by gold/Brønsted acid relay catalysis.

Chemical diversity and biological activities of specialized metabolites from the genus Chaetomium: 2013-2022.

Chaetomium (Chaetomiaceae), a large fungal genus consisting of at least 400 species, has been acknowledged as a promising resource for the exploration of novel compounds with potential bioactivities. Over the past decades, emerging chemical and biological investigations have suggested the structural diversity and extensive potent bioactivity of the specialized metabolites in the Chaetomium species. To date, over 500 compounds with diverse chemical types have been isolated and identified from this genus, including azaphilones, cytochalasans, pyrones, alkaloids, diketopiperazines, anthraquinones, polyketides, and steroids. Biological research has indicated that these compounds possess a broad range of bioactivities, including antitumor, anti-inflammatory, antimicrobial, antioxidant, enzyme inhibitory, phytotoxic, and plant growth inhibitory activities. This paper summarizes current knowledge referring to the chemical structure, biological activity, and pharmacologic potency of the specialized metabolites in the Chaetomium species from 2013 to 2022, which might provide insights for the exploration and utilization of bioactive compounds in this genus both in the scientific field and pharmaceutical industry.

Construction of a Model of Nurse Engagement in Long-Term Care Facilities: A Moderated-Mediation Model.

Aim: The aim of the study is to test a moderated mediation model that focuses on job resources mediating the relationship between organizational climate and nurse engagement in the long-term care facilities and emotional intelligence moderates this mediated relationship. Background: The shortage of nurses is a global problem, especially in the long-term care facilities. We integrated and extended past research exploring the influence of nurse engagement and constructed a model of nurse engagement in the long-term care facilities. Method: A cross-sectional survey was conducted on 494 nurses in long-term care facilities. Nurses were asked to complete a survey of nurse engagement, organizational climate, job resources, and emotional intelligence. Results: The consequence demonstrated that organizational climate increased nurse engagement directly and indirectly via job resources. In addition, emotional intelligence plays a moderation role between organizational climate and job resources. Conclusion: These phenomena revealed that a good organizational climate and job resources enable nurses to be more engaged in work. Nurse with high-emotional intelligence can take advantage of resources and improve their engagement.

Chronic Pain and Quality of Life in Maintenance Hemodialysis Patients in China: A Multicenter, Cross-Sectional Study.

PURPOSE: Patients undergoing maintenance hemodialysis (MHD) frequently experience chronic pain, which can severely affect their quality of life (QOL). The objective of this study was to evaluate the prevalence of chronic pain in MHD patients and examine the factors associated with QOL. PATIENTS AND METHODS: A cross-sectional questionnaire-based survey was conducted between October 2020 and April 2021, 1204 MHD patients from nine hemodialysis units were screened for chronic pain in Chengdu, China, and 296 MHD patients with chronic pain were enrolled in this study. We analyzed data on clinicodemographic characteristics, pain interference and severity (Brief Pain Inventory), QOL (Medical Outcomes Study 36-item Short Form Health Survey - mental component summary [MCS] and physical component summary [PCS]), pain self-efficacy (Pain Self-Efficacy Questionnaire), and social support (Social Support Rating Scale). RESULTS: The prevalence of chronic pain in MHD patients was 26.74% in this study. The most common areas of pain were lower back (63.5%), lower limbs (55.0%), and head (33.5%), 36.5% did not implement any measures to relieve it. Of the patients who did receive pain treatment or medication, 56.9% reported that the measures they took had less than half of the pain relief. MHD patients with chronic pain had poor QOL based on scores on the MCS (53 ± 16.76) and PCS (40.56 ± 13.81). Stepwise multiple regression identified age, financial strain, pain interference, social support, and pain self-efficacy as independent predictors of QOL. Pain self-efficacy was significantly associated with social support (r = 0.5, p < 0.01), MCS (r = 0.69, p < 0.01), and PCS (r = 0.8, p < 0.01). The mediating effects of pain self-efficacy were 70.31% on the relationship between social support and MCS, and 75.62% on the relationship between social support and PCS. CONCLUSION: Chronic pain is prevalent and undermanaged in Chinese MHD patients, resulting in worse QOL. Healthcare providers should focus on pain management and the impact of psychosocial factors on patient QOL. Further research should deepen our understanding of how pain self-efficacy mediates the relationship between social support and QOL.

Photocatalytic Biheterocyclization of 1,7-Diynes for Accessing Skeletally Diverse Tricyclic 2-Pyranones.

A new and green route to skeletally diverse oxo-heterocyclic architectures such as pyrano[3,4-c]chromen-2-ones and pyrano[3,4-c]quinolin-2-ones is reported via an unprecedented photocatalytic Kharasch-type cyclization/1,5-(SN″)-substitution/elimination/6π-electrocyclization/double nucleophilic substitution cascade starting from easily available heteroatom-linked 1,7-diynes and low-cost CBrCl3. During this reaction process, the full scission of carbon-halogen bonds of BrCCl3 was realized to directly build two new rings, including a lactone scaffold, using H2O as the oxygen source of the ester group.

Prediction of a Competing Endogenous RNA Co-expression Network by Comprehensive Methods in Systemic Sclerosis-Related Interstitial Lung Disease.

Systemic sclerosis (SSc) is an immune-mediated connective tissue disease characterized by fibrosis of multi-organs, and SSc-related interstitial lung disease (SSc-ILD) is a leading cause of morbidity and mortality. To explore molecular biological mechanisms of SSc-ILD, we constructed a competing endogenous RNA (ceRNA) network for prediction. Expression profiling data were obtained from the Gene Expression Omnibus (GEO) database, and differential expressed mRNAs and miRNAs analysis was further conducted between normal lung tissue and SSc lung tissue. Also, the interactions of miRNA-lncRNA, miRNA-mRNA, and lncRNA-mRNA were predicted by online databases including starBase, LncBase, miRTarBase, and LncACTdb. The ceRNA network containing 11 lncRNAs, 7 miRNAs, and 20 mRNAs were constructed. Based on hub genes and miRNAs identified by weighted correlation network analysis (WGCNA) method, three core sub-networks-SNHG16, LIN01128, RP11-834C11.4(LINC02381)/hsa-let-7f-5p/IL6, LINC01128/has-miR-21-5p/PTX3, and LINC00665/hsa-miR-155-5p/PLS1-were obtained. Combined with previous studies and enrichment analyses, the lncRNA-mediated network affected LPS-induced inflammatory and immune processes, fibrosis development, and tumor microenvironment variations. The ceRNA network, especially three core sub-networks, may be served as early biomarkers and potential targets for SSc, which also provides further insights into the occurrence, progression, and accurate treatment of SSc at the molecular level.

Engaging 1,7-diynes in a photocatalytic Kharasch-type addition/1,5-(SN'')-substitution cascade toward ß-gem-dihalovinyl carbonyls.

A new and general photocatalytic Kharasch-type addition/1,5-(SN'')-substitution cascade of 1,7-diynes with alkyl halides such as BrCCl3 and CBr4 was reported for the first time, and used to produce 65 hitherto unreported ß-gem-dihalovinyl ketones/aldehydes with moderate to excellent yields in a highly regioselective manner. This reaction tolerates a wide scope of substrates, which offers a green and efficient entry to fabricate synthetically important ß-gem-dihalovinyl carbonyl scaffolds. Notably, the late-stage application of these resulting ß-gem-dihalovinyl carbonyls shows high and unique reactivity profiles and demonstrates the versatility of their derivatization.

Sulfiredoxin-1 is a promising novel prognostic biomarker for hepatocellular carcinoma.

Identifying novel prognostic biomarkers for hepatocellular carcinoma (HCC) and then, develop an effective individualized treatment strategy remain extremely warranted. The prognostic role of sulfiredoxin-1(SRXN1), an antioxidant enzyme, remains unknown in HCC. This study aimed to explore the prognostic implications of SRXN1 in HCC patients after partial hepatectomy. The expression of SRXN1 in HCC and normal tissue were analyzed using the patients from the public databases and Zhongshan Hospital. The Cox regression, Kaplan-Meier survival analysis, and time-dependent receiver operating characteristic curves were performed to identify the predictive role of SRXN1 expression on HCC patients. A prognostic nomogram based on SRXN1 expression was constructed and validated to further confirm the predictive power of SRXN1 as a prognostic biomarker. Finally, functional enrichment analysis and protein-protein interaction network analysis of SRXN1 and its associated genes were conducted. The results showed that SRXN1 was upregulated in HCC samples compared with the normal liver tissues. Patients with SRXN1 upregulation had shorter survival time. SRXN1 overexpression was significantly correlated with advanced clinicopathological parameters. The prognostic nomogram based on SRXN1 expression was proved to be more accurate than routine staging systems for the prediction of overall survival. Protein-protein interaction network analysis demonstrated the first neighbor genes of SRXN1 mainly participated in response to oxidative stress. In brief, SRXN1 could be a prognostic biomarker for the management of HCC.

Incidence, Prognostic Factors and Survival Outcome in Patients With Primary Hepatic Lymphoma.

Aim: The objective of our study was to investigate the epidemiologic characteristics, prognostic factors and survival in patients with primary hepatic lymphoma (PHL). Methods: PHL patients diagnosed between 1983 and 2015 were identified from the SEER database. The temporal trend in PHL incidence was assessed using joinpoint regression software. Overall survival(OS) and disease-specific survival (DSS) was evaluated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analysis was performed to identify the independent prognostic factors for OS and DSS. Nomograms to predict survival possibilities were constructed based on the identified independent prognostic factors. Results: A total of 1,182 patients were identified with PHL. The mean age was 61.7 ± 17.1 years with a male to female of 1.6:1. Diffuse large B-cell lymphoma (59.8%) was the most common histological subtype. The incidence of PHL steadily increasing by an annual percentage change (APC) of 2.6% (95% CI 2.0-3.2, P < 0.05). The 1-, 5-, and 10-year OS rates were 50.85, 39.6, and 30.4%, respectively, and the corresponding DSS rates were 55.3, 47.9, and 43.3%, respectively. Multivariate Cox regression analysis revealed that age, sex, race, marital status, histological subtype, surgery, and chemotherapy were independent prognostic factors for survival. Nomograms specifically for DLBCL were constructed to predict 1-, 5-, and 10-year OS and DSS possibility, respectively. The concordance index (C-index) and calibration plots showed the established nomograms had robust and accurate performance. Conclusion: PHL were rare but the incidence has been steadily increasing over the past four decades. Survival has improved in recent years. Surgery or chemotherapy could provide better OS and DSS. The established nomograms specifically for DLBCL were robust and accurate in predicting 1-, 5-, and 10-year OS and DSS.

Comparison of iRoot BP Plus and Calcium Hydroxide as Pulpotomy Materials in Permanent Incisors with Complicated Crown Fractures: A Retrospective Study.

INTRODUCTION: Calcium hydroxide has been used as a traditional pulpotomy agent for a long time but has some disadvantages. iRoot BP Plus (Innovative Bioceramix Inc, Vancouver, Canada) is a newly developed, ready-to-use calcium silicate-based bioactive ceramic with excellent bioactivity and sealing ability. However, whether iRoot BP Plus shows superiority over calcium hydroxide as a pulpotomy material on permanent incisors with complicated crown fractures remains unknown. METHODS: This research included 205 permanent incisors with complicated crown fractures. These teeth were treated with pulpotomy and divided into 2 groups according to the pulpotomy material (105 treated with iRoot BP Plus and 100 with calcium hydroxide). Clinical and radiographic information was collected during the 12- to 24-month follow-up period. The formation of reparative dentin bridges and pulp canal obliteration were analyzed using radiographs in both groups. RESULTS: The success rates for recall in the average follow-up period of 17.5 ± 4.4 months (12-24 months) after pulpotomy treatment were significantly different between the 2 groups, with 99% for the iRoot BP Plus group and 93% for the calcium hydroxide group. Reparative dentin bridges were observed in 92.4% of the iRoot BP Plus group and 90% of the calcium hydroxide group, but the difference was not significant. Pulp canal obliteration was observed in 2 teeth (2%) in each group. CONCLUSIONS: The success rates obtained in our study indicate that iRoot BP Plus as a pulpotomy agent can be a suitable alternative to calcium hydroxide to manage complicated crown fractures.

MicroRNA­187 is an independent prognostic factor in lung cancer and promotes lung cancer cell invasion via targeting of PTRF.

MicroRNAs (miRNAs) are involved in the progression of different types of cancers giving new hope for cancer treatment. The role and regulatory mechanism of microRNA­187 (miR­187) are largely unknown. In the present study, 74 patients with non­small cell lung cancer (NSCLC) were selected. Tumor tissues and matched normal tissues were collected for determining the expression level of miR­187. Cell research was performed to detect the function of miR­187. The expression level was measured and miR­187 was found to be overexpressed in the NSCLC cell lines and tissues. Overexpression of miR­187 promoted cell proliferation in the A549 and H1650 cell lines. Moreover, overexpression of miR­187 also promoted cell migration and invasion. Polymerase I and transcript release factor (PTRF) was identified as a target of miR­187. Overexpression of miR­187 suppressed the expression of PTRF. Knockdown of PTRF promoted lung cancer cell invasion, and overexpression of PTRF had a negative effect on lung cancer cell invasion. The PTRF messenger RNA (mRNA) levels in cancer tissues were significantly lower than those in their adjacent normal lung tissues as determined by real­time PCR (RT­PCR). The expression of the PTRF protein was significantly weaker than that in the adjacent normal lung tissues using immunohistochemical staining. The findings revealed that miR­187 promotes cell growth and invasion by targeting PTRF and miR­187 may be a new prognostic factor for NSCLC.

Synchronous unilateral basal cell adenoma of the parotid gland: A case report.

The current study reports the case of a 68-year-old male who presented with a 4-month history of a painless slow-growing mass in the left parotid region. Magnetic resonance imaging revealed two independent, round lesions in the superficial and deep lobes of the parotid gland on the left side, respectively. A total parotidectomy was performed and basal cell adenomas (BCAs) were identified by histopathological examination. At the 6-month follow-up examination, no sign of recurrence was found. This study describes the clinical features of a rare case of synchronous unilateral BCA in the parotid gland and also provides a review of the literature.

[Studies on screening of matrix and permeation enhancer of sustained-release patches of duliang].

OBJECTIVE: To screen the matrix and permeation enhancer of Duliang Patches. METHODS: Based on L9 (3(4)) orthogonal experimental design, the content of imperatorin of the release rate and transdermal osmolality were regarded as evaluation indexes to optimize the matrix and permeation enhancer of patches suing of Drug dissolution tester and Franz diffusion cell. RESULTS: The best prescriplion of sustained-release patch of Duliang was: the quality percentage content of the starch, sodium carboxymethyl cellulose, glycerin, azone, propylene glycol and PEG400 was 6%, 2%, 30%, 1%, 15% and 2.5% respectively. The release behavior of sustained-release patches of Duliang tallied with Higuchi equation and the effect of sustained-release was apparent. CONCLUSION: The sustained-release patches of Duliang have good property of sustained-release and transdermal in vitro and the stability of patches is also sound while the release in vivo awaits further inspection.