Electrochemical Oxidative Difunctionalization of Diazo Compounds with Diselenides and Nucleophiles.

An electrochemical oxidative difunctionalization of diazo compounds with diselenides and nucleophiles has been developed. This innovative approach yields a diverse array of selenium-containing pyrazole esters and alkoxy esters, overcoming the limitations of traditional synthesis methods. Remarkably, various nucleophiles, including acids, alcohols, and pyrazoles, can be seamlessly incorporated. Notably, this protocol boasts high atom efficiency, excellent functional group tolerance, and good efficiency and operates under transition metal- and oxidant-free conditions, distinguishing it in the field.

Design, docking optimization, and evaluation of biotin-PEG4-1,8-naphthalimide as a potent and safe antitumor agent with dual targeting of ferroptosis and DNA.

A set of biotin-polyethylene glycol (PEG)-naphthalimide derivatives 4a-4h with dual targeting of ferroptosis and DNA were designed and optimized using docking simulation as antitumor agents. Docking simulation optimization results indicated that biotin-PEG4-piperazine-1,8-naphthalimide 4d should be the best candidate among these designed compounds 4a-4h, and therefore, we synthesized and evaluated it as a novel antitumor agent. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and MGC-803 and U251 xenograft models identified 4d as a good candidate antitumor agent with potent efficacy and safety profiles, compared with amonafide and temozolomide. The findings of the docking simulations, fluorescence intercalator displacement (FID), western blot, comet, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transmission electron microscopy, and BODIPY-581/591-C11, FerroOrange, and dihydroethidium (DHE) fluorescent probe assays revealed that 4d could induce DNA damage, affect DNA synthesis, and cause cell cycle arrest in the S phase in MGC-803 cells. Also, it could induce lipid peroxidation and thus lead to ferroptosis in MGC-803 cells, indicating that it mainly exerted antitumor effects through dual targeting of ferroptosis and DNA. These results suggested that it was feasible to design, optimize using docking simulation, and evaluate the potency and safety of biotin-PEG-1,8-naphthalimide as a antitumor agent with dual targeting of ferroptosis and DNA, based on a multi-target drug strategy.

Norditerpenoid alkaloids from Aconitum refractum var. circinatum as autophagy inducers.

A total of twenty-two diterpenoid alkaloids, including ten unprecedented ones, namely refractines C-L, were isolated from the roots of Aconitum refractum (Finet et Gagnep.) Hand.-Mazz. Refractine C was the first example of a natural diterpenoid alkaloid wherein C-19 is linked to N position by an oxaziridine ring. Refractine L was a rare glycosidic diterpenoid alkaloid with fructofuranoside. Most of the isolated compounds obtained from a previous study were screened for their anti-inflammatory and myocardial protective activities. The autophagy-inducing effects of some of these compounds on RAW 264.7 cells were evaluated by assessing the expression of microtubule-associated protein 1 light chain 3 (LC3-II/LC3-I). Results revealed that some compounds exerted varying levels of inhibitory effects on the proliferative activity of RAW 264.7 cells.

Antitumor effects of Cypaliuruside F from Cyclocarya paliurus on HepG2 cells.

An undescribed dammarane triterpenoid saponin Cypaliuruside F was isolated from the leaves of Cyclocarya paliurus in our preliminary study. The MTT assay, flow cytometry, cell scratch, and DAPI staining were used to detect the antitumor effects of Cypaliuruside F on HepG2 cells. Subsequently, network pharmacology and molecular docking analysis were used to analyse the key targets of Cypaliuruside F against HCC. In addition, a Western blot was performed to determine the effects of Cypaliuruside F on the expression of key proteins in HepG2 cells. The experimental results indicated that the damarane triterpenoid saponin Cypaliuruside F from Cyclocarya paliurus inhibits the proliferation of HepG2 cells by inducing apoptosis and cell cycle arrest. These changes may promote the apoptosis of HepG2 cells by inhibiting the expression of mTOR, STAT3, and Bcl-2 while activating Bax.

Real-world pharmacological treatment of pregnant patients with rheumatic diseases from China: a retrospective analysis from 2016 to 2021.

Introduction: We investigated trends in the use of therapeutic drugs for pregnant patients with rheumatic diseases in nine Chinese cities (Beijing, Chengdu, Guangzhou, Harbin, Hangzhou, Shanghai, Shenyang, Tianjin, and Zhengzhou) to provide a reference for drug use in clinic. Methods: Outpatient prescription data for pregnant patients diagnosed with rheumatic diseases in nine cities across China in 2016-2021 were extracted from the Hospital Prescription Cooperation Project of the Hospital Pharmacy Professional Committee of the Chinese Pharmaceutical Association. A retrospective analysis was then performed, incorporating data on patient age, defined daily doses (DDDs), defined daily cost (DDC), and other metrics. Results: In 2016-2020, more than 70% of the pregnant patients diagnosed with rheumatic diseases in these nine cities were 25 to < 35 years of age. The most common rheumatic diseases during pregnancy were antiphospholipid antibody syndrome (APS) and systemic lupus erythematosus (SLE). In terms of the routine use of daily therapeutic drugs, the DDDs of low molecular weight heparins (LMWHs), glucocorticoids, and immunosuppressive agents dominated the top three. Intravenous immunoglobulin (IVIG) and tumor necrosis factor inhibitors (TNFi) have been used since 2019 and had been in the forefront of the DDC. Conclusion: The number and total cost of prescriptions for therapeutic drugs of pregnancy complicated by rheumatic diseases, have increased significantly over the study interval. Conventional therapeutic drugs, especially glucocorticoids, LMWHs, and hydroxychloroquine were the most widely used drugs in pregnant patients with rheumatic diseases. However, IVIG and TNFi, relatively high cost, have shown gradual increases in clinical use since 2019.

HIF-1α and adaptor protein LIM and senescent cell antigen-like domains protein 1 axis promotes tubulointerstitial fibrosis by interacting with vimentin in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II. KEY RESULTS: Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin. CONCLUSION AND IMPLICATIONS: We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.

Evaluation of aconitine cardiotoxicity with a heart-on-a-particle prepared by a microfluidic device.

A heart-on-a-particle model based on multicompartmental microgel is proposed to simulate the heart microenvironment and study the cardiotoxicity of drugs. The relevant microgel was fabricated by a biocompatible microfluidic-based approach, where heart function-related HL-1 and HUVEC cells were arranged in separate compartments. Finally, the mechanism of aconitine-induced heart toxicity was elucidated using mass spectrometry and molecular biotechnology.

Synthesis and biological evaluation of lycoctonine derivatives with cardiotonic and calcium channels inhibitory activities.

In our previous study, a screening of a variety of lycotonine-type diterpenoid alkaloids were screened for cardiotonic activity revealed that lycoctonine had moderate cardiac effect. In this study, a series of structurally diverse of lycoctonine were synthesized by modifying on B-ring, D-ring, E-ring, F-ring, N-atom or salt formation on lycoctonine skeleton. We evaluated the cardiotonic activity of the derivatives by isolated frog heart, aiming to identify some compounds with significantly enhanced cardiac effects, among which compound 27 with a N-isobutyl group emerged as the most promising cardiotonic candidate. Furthermore, the cardiotonic mechanism of compound 27 was preliminarily investigated. The result suggested that the cardiotonic effect of compound 27 is related to calcium channels. Patch clamp technique confirmed that the compound 27 had inhibitory effects on CaV1.2 and CaV3.2, with inhibition rates of 78.52 % ± 2.26 % and 79.05 % ± 1.59 % at the concentration of 50 µM, respectively. Subsequently, the protective effect of 27 on H9c2 cells injury induced by cobalt chloride was tested. In addition, compound 27 can alleviate CoCl2-induced myocardial injury by alleviating calcium overload. These findings suggest that compound 27 was a new structural derived from lycoctonine, which may serve as a new lead compound for the treatment of heart failure.

Impacts of continuous quality improvement on wound pain in the puncture site of arteriovenous fistula in haemodialysis patient.

This study analyses the effects of a continuous quality improvement nursing model on wound pain at the arteriovenous fistula (AVF) puncture site in patients undergoing haemodialysis. Forty haemodialysis patients from the First Affiliated Hospital of Chongqing Medical University, from September 2020 to December 2022, were selected as study subjects. They were randomly divided into an observation group and a control group. The control group received conventional nursing care, while the observation group was treated with a continuous quality improvement nursing model. The study compared the impact of these nursing approaches on pain intensity post-AVF puncture, wound visual analogue scale scores, self-rating anxiety scale, self-rating depression scale, quality of life scores and patient satisfaction with nursing care. In the observation group, the proportion of patients experiencing moderate to severe pain during AVF puncture was lower than that in the control group, whereas the proportion of patients with no pain or mild pain was higher (P = 0.008). After nursing, the observation group exhibited significantly lower wound visual analogue scale scores, self-rating anxiety scale scores, and self-rating depression scale scores compared to the control group (P < 0.001), with a significantly higher quality of life score (P < 0.05). The nursing satisfaction rate was 95.00% in the observation group, significantly higher than the 65.00% in the control group (P = 0.018). The continuous quality improvement nursing model significantly reduces wound pain at the AVF puncture site in haemodialysis patients, alleviates negative emotions, enhances the quality of life, and achieves high patient satisfaction. It is thus a highly recommendable approach in nursing practice.

[Factors Influencing Willingness of Farmers to Pay for Agricultural Non-point Source Pollution Control Based on Distributed Cognitive Theory].

The analysis of the willingness of individual farmers to cover costs is an important basis for measuring the economic value of agricultural non-point pollution management， and determining the ecological and economic value of rural surface pollution control is a necessary measure to internalize the externalities of agricultural production. Based on the analysis of the hierarchy of factors influencing the cognition of farmers， this study constructed a theoretical framework based on distributed cognition theory to analyze their willingness to pay for agricultural non-point source pollution control from the perspective of individual farmers. On the basis of this framework， we used the Double-Hurdle model to empirically test the overall process of farmers'willingness to pay and their willingness to pay the amount for agricultural non-point source pollution control by combining 531 microscopic research datapoints in Guanzhong， Shaanxi Province. The results showed that： ① the number of farmers with willingness to pay for agricultural non-point source pollution control was 267， accounting for 50.30% of the total sample， and the average value of willingness to pay was 1 469.77 yuan·hm-2； the total economic value of agricultural non-point source pollution control in Shaanxi Province in 2020 was estimated to be 5.791 billion yuan based on the expected value of the willingness to pay level of the research sample. ② Farmers'willingness to pay for agricultural non-point source pollution control was influenced by the combined effects of personal， regional， and cultural forces， and the effects of each dimension were similar； farmers' willingness to pay for agricultural non-point source pollution control was mainly influenced by the cultural force factor， and the effects of personal and regional forces were very limited. ③ The results of the regressions by income level showed that personal and cultural strengths had a significant impact on the willingness to pay among the low-income group but did not contribute to the increase in the willingness to pay.

Diterpenoid Alkaloids from Delphinium liangshanense.

Two new C19-diterpenoid alkaloids of the lycoctonine-type (liangshanine A and liangshanine B) and nineteen known compounds (3-21) were isolated from the whole plant of Delphinium liangshanense W. T. Wang, and all the compounds were identified by different spectroscopic analyses, such as IR, HR-ESI-MS and NMR. All the compounds were isolated from this plant for the first time and tested for the anti-proliferation effects on MH7 A and SF9 cells to figure their anti-rheumatoid arthritis and anti-insect activity, but none of them showed remarkable activity.

Expert consensus on the diagnosis, treatment, and prevention of respiratory syncytial virus infections in children.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading global cause of respiratory infections and is responsible for about 3 million hospitalizations and more than 100,000 deaths annually in children younger than 5 years, representing a major global healthcare burden. There is a great unmet need for new agents and universal strategies to prevent RSV infections in early life. A multidisciplinary consensus development group comprising experts in epidemiology, infectious diseases, respiratory medicine, and methodology aims to develop the current consensus to address clinical issues of RSV infections in children. DATA SOURCES: The evidence searches and reviews were conducted using electronic databases, including PubMed, Embase, Web of Science, and the Cochrane Library, using variations in terms for "respiratory syncytial virus", "RSV", "lower respiratory tract infection", "bronchiolitis", "acute", "viral pneumonia", "neonatal", "infant" "children", and "pediatric". RESULTS: Evidence-based recommendations regarding diagnosis, treatment, and prevention were proposed with a high degree of consensus. Although supportive care remains the cornerstone for the management of RSV infections, new monoclonal antibodies, vaccines, drug therapies, and viral surveillance techniques are being rolled out. CONCLUSIONS: This consensus, based on international and national scientific evidence, reinforces the current recommendations and integrates the recent advances for optimal care and prevention of RSV infections. Further improvements in the management of RSV infections will require generating the highest quality of evidence through rigorously designed studies that possess little bias and sufficient capacity to identify clinically meaningful end points.

In vitro and in†vivo biological evaluation of Lappaconitine derivatives as potential anti-inflammatory agents.

Natural products and their derivatives are a precious treasure in the pursuit of potent anti-inflammatory drugs. In this work, we measured the toxicity of 78 LA derivatives at 20 µM using MTT, then we evaluated the NO release of compounds without obvious toxicity in LPS-induced RAW.264.7 by Griess reagent, we identified three compounds, namely compounds 6, 19, 70, which exhibited promising anti-inflammatory potential. These compounds exhibited IC50 values of 10.34±2.05 µM, 18.18±4.80 µM and 15.66±0.88 µM. In addition, through ELISA kits, compounds 6, 19, 70 significantly reduce the production of inflammatory factors (TNF-α, IL-6, IL-1ß). Real-time PCR and western blot analysis showed that compounds 6, 19, 70 inhibited the mRNA and protein expression of iNOS and COX-2. Notably, compound 6 exhibited the most potent inhibitory activity. In vitro, it inhibits LPS-induced phosphorylation of NF-κB p65, IκBα, ERK1/2, JNK, and p38 MAPKs in RAW264.7 cells. In vivo, compound 6 potently inhibits the secretion of inflammatory mediators and neutrophil activation in ALI mice. Our findings suggest that compound 6 may be a potential anti-inflammatory drug.

Value of Intrauterine Autologous Platelet-Rich Plasma Therapy on Endometrial Receptivity: A Literature Review.

Endometrial receptivity is an important factor that influences embryo implantation. Thus, it is important to identify an applicable approach to improve endometrial receptivity in women undergoing assisted reproductive technology. Recently, growing evidence has indicated that intrauterine platelet-rich plasma (PRP) infusion is an effective method to obtain a satisfactory reproductive outcome by increasing endometrial thickness and improving endometrial receptivity. Therefore, the present review aims to outline the possible mechanisms of PRP on endometrial receptivity and summarize the present literature on the effects of PRP therapy in improving endometrial receptivity.

Analysis of prognostic factors in patients with emergency sepsis.

BACKGROUND: Emergency sepsis is a common and serious infectious disease, and its prognosis is influenced by a number of factors. AIM: To analyse the factors influencing the prognosis of patients with emergency sepsis in order to provide a basis for individualised patient treatment and care. By retrospectively analysing the clinical data collected, we conducted a comprehensive analysis of factors such as age, gender, underlying disease, etiology and site of infection, inflammatory indicators, multi-organ failure, cardiovascular function, therapeutic measures, immune status and severity of infection. METHODS: Data collection: Clinical data were collected from patients diagnosed with acute sepsis, including basic information, laboratory findings, medical history and treatment options. Variable selection: Variables associated with prognosis were selected, including age, gender, underlying disease, etiology and site of infection, inflammatory indicators, multi-organ failure, cardiovascular function, treatment measures, immune status and severity of infection. Data analysis: The data collected are analysed using appropriate statistical methods such as multiple regression analysis and survival analysis. The impact of each factor on prognosis was assessed according to prognostic indicators, such as survival, length of stay and complication rates. RESULTS: Descriptive statistics: Descriptive statistics were performed on the data collected from the patients, including their basic characteristics and clinical presentation. CONCLUSION: Type 2 diabetes mellitus were independent factors affecting the prognosis of patients with sepsis.

Synthesis and Biological Evaluation of Novel 2-Amino-1,4-Naphthoquinone Amide-Oxime Derivatives as Potent IDO1/STAT3 Dual Inhibitors with Prospective Antitumor Effects.

Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound NK3 demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC50 = 0.06 µM), leading to its selection for further investigation. The direct interactions between compound NK3 and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound NK3 revealed key interactions between NK3 and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound NK3 displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound NK3 exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.

Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation.

(-)-Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9 ]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation, and subsequent merged MBH-Tsuji-Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)-euptox A (2) in 8 steps from commercially available monoterpene (-)-carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2 O2 -treated SH-SY5Y and PC12 cells.

C19-diterpenoid alkaloids from Aconitum refractum var. circinatum.

Two unprecedented aconitine-type C19-diterpenoid alkaloids, refractines A-B (1-2), along with 12 known compounds (3-14) were isolated from the roots of Aconitum refractum (Finet et Gagnep.) Hand. -Mazz. Their structures were elucidated based on extensive spectroscopic analyses, including 1D and 2D NMR, IR, and HR-ESI-MS data. All compounds were tested for inhibitory activities against NO production in LPS induced RAW 264.7 macrophages, compounds 10 and 14 had slight inhibited NO production with rate of 29.4% and 22.1% at the concentration of 30 µM, respectively.