Electrochemical response mechanism of DNA damaged cells: DNA damage repair and purine metabolism activation.

In modern society, due to the sharp increase in pollutants that cause DNA damage, there is a growing demand for innovative detection techniques and biomarkers. In this paper, the electrochemical behavior of HepG2 cells exposed to CdCl2 was investigated, and the electrochemical response mechanism of DNA damage was identified by exploring the correlation between the DNA damage response and purine metabolism. Western blot analysis revealed that the expression levels of ATM and Ku70 increased at 0.3 µM CdCl2, indicating a DNA damage response and activation of DNA repair processes. Simultaneously, elevated expression levels of PRPP aminotransferase, HPRT, and XOD were observed, leading to an increase in intracellular purine levels and electrochemical signals. The expression of Ku70 peaked at 0.5 µM CdCl2, indicating the highest DNA repair activity. The expression profiles of these purine metabolism proteins mirrored those of Ku70, suggesting a strong correlation between the activation of purine metabolism and DNA damage repair. Consistently, intracellular purine levels exhibited a similar trend, leading to corresponding changes in electrochemical signals. In summary, electrochemical using intracellular purines as biomarkers has the potential to emerge as a novel method for detecting early DNA damage.

Preliminary survey of three mosquito-borne viruses using a self-established multiplex RT-qPCR assay in Chinese blood donors.

BACKGROUND: Mosquito-borne pathogens pose a significant threat to both human health and blood safety. The primary mosquito-borne viruses that present this threat are Zika virus, Chikungunya virus, and Dengue virus. At present, there are limited efficacious vaccines or therapeutic drugs for the prevention and treatment of these viral infections. Blood donors can remain asymptomatically infected and unfortunately, screening for these three viruses in Chinese blood donors are not mandatory, leaving the residual risk to transfusion recipients uncertain. OBJECTIVE: To address this, we developed a single-tube multiplex RT-qPCR assay for ZCD detection and was preliminarily employed to screen a total of 10,566 blood donations in Nanning Blood Center in order to assess the prevalence risk of these pathogens in blood donors. RESULTS: None of the blood samples was reactive for ZCD by nucleic acid test (NAT). One out of 173 donations (1/173, 0.58 %) was IgG positive for ZIKV and 14 (14/173, 8.4 %) were IgG positive for DENV. None of these 173 donations was IgG positive for Chikungunya virus. These findings suggest that the prevalence of ZCD infection in blood donors in Nanning is very low although past DENV infection (IgG positive) was relatively common. CONCLUSION: A single-tube multiplex RT-qPCR assay for simultaneous detection of ZCD viruses was successfully established and applied for screening in blood donors. The residual risk of ZCD infection through transfusion is currently low in Nanning, China. The NAT assay for ZCD will serve as a technical reserve in response to future epidemic or pandemic of mosquito-borne pathogens.

Melatonin Induces Analgesic Effects through MT2 Receptor-Mediated Neuroimmune Modulation in the Mice Anterior Cingulate Cortex.

Neuropathic pain (NP) represents a considerable clinical challenge, profoundly impacting patients' quality of life. Presently, pharmacotherapy serves as a primary approach for NP alleviation, yet its efficacy often remains suboptimal. Melatonin (MLT), a biologically active compound secreted by the pineal gland, has long been associated with promoting and maintaining sleep. Although recent studies suggest analgesic effects of MLT, the underlying mechanism remains largely unknown, particularly its impact on the cortex. In this study, we induced an NP model in mice through spared nerve injury (SNI) and observed a considerable, dose-dependent alleviation in NP symptoms following intraperitoneal or anterior cingulate cortex (ACC) administration of MLT. Our findings further indicated that the NP management of MLT is selectively mediated by MLT-related receptor 2 (MT2R), rather than MT1R, on neurons and microglia within the ACC. Transcriptome sequencing, complemented by bioinformatics analysis, implicated MLT in the modulation of Gα(i) and immune-inflammatory signals. Specifically, MLT inhibited the excitability level of pyramidal cells in the ACC by activating the Gα(i) signaling pathway. Simultaneously, MLT attenuated M1 polarization and promoted M2 polarization of microglia, thereby mitigating the inflammatory response and type II interferon response within the ACC. These findings unveil a hitherto unrecognized molecular mechanism: an MLT-mediated neuroimmune modulation pathway in the ACC mediated by MT2R. This elucidation sheds light on the regulatory character of MLT in chronic nociceptive pain conditions, offering a prospective therapeutic strategy for NP management.

Toxicological mechanism of cannabidiol (CBD) exposure on zebrafish embryonic development.

Cannabidiol (CBD) is the main component of plant Cannabis (Cannabis sativa), which exhibits strong antioxidant and anti-inflammatory activities. With the legalization of CBD in the United States, it is an inevitable tendency for its global legalization in the future. Therefore, it has become an urgent task to conduct the toxicological evaluation of CBD before clinical application. In this study, the developmental toxicities of CBD on zebrafish embryos were systematically evaluated, and the mechanisms were revealed. The results showed that the phenotype of liver degeneration was observed in 96 hpf zebrafish embryos after 0.1-5 µmol/L CBD exposure, further RT-qPCR experiments indicated that the above result may attributed by the alterations of FABP10A, GCLC, and GSR. Besides, 1 and 5 µmol/L CBD contributed to the developmental toxicities of heart and eye in zebrafish embryos, characterizing by the decrease in heart rate, the phenotype of pericardial edema, and the reduce of eye area. Compared to other organs, the liver of zebrafish displayed the most sensitive characteristic to CBD exposure, as 0.1 µmol/L CBD already led to the phenotype of liver degeneration. In summary, this paper provided theoretical supports for CBD toxicology research, and laid the foundation for its future clinical application.

The roles of lipids and inflammation in the association between the triglyceride-glucose index and arterial stiffness: evidence from two large population-based surveys.

BACKGROUND: The triglyceride-glucose (TyG) index is a risk marker for arterial stiffness; however, the extent to which the TyG index is associated with arterial stiffness via lipids and inflammation remains unknown. The first aim was to probe the relationship between the TyG index and arterial stiffness in two surveys. The second aim was to clarify whether lipids and inflammation mediate this relationship. METHODS: The sample size of 13,726 U.S. individuals from the National Examination Survey (NHANES) and 3,964 Chinese individuals from the China Health and Retirement Longitudinal Study (CHARLS 2015) were enrolled. Weighted multivariate logistic and linear regression models, as well as restricted cubic spline (RCS) and mediation analyses, were utilized to estimate complex relationships between the TyG index, arterial stiffness, lipids (non-high-density lipoprotein cholesterol [non-HDL-C]) and inflammation (C-reactive protein [CRP]) biomarkers. RESULTS: A total of 3,420 U.S. patients and 992 Chinese patients were diagnosed with increased arterial stiffness. Regression analyses demonstrated that higher quartiles of the TyG index were associated with a greater incidence of increased arterial stiffness (NHANES: OR = 2.610, 95% CI = 2.043-3.334, P < 0.001; CHARLS: OR = 1.579, 95% CI = 1.057-2.360, P < 0.001). Participants with a higher TyG index/higher CRP level or with a higher TyG index/higher non-HDL-C level had the highest incidence of increased arterial stiffness in the two surveys. The results were still consistent when the sensitivity analysis was implemented with stricter clinical cut-off values of non-HDL-C. Mediation analysis verified that lipids (mediated effect: ß = 0.012, P < 0.001 in NHANES; ß = 0.020, P < 0.001 in CHARLS) and inflammation (mediated effect: ß = 0.003, P < 0.001 in NHANES; ß = 0.006, P < 0.001 in CHARLS) partially mediated this relationship. CONCLUSIONS: These results indicated a positive linear correlation between the TyG index, non-HDL-C level, CRP level and increased arterial stiffness in two surveys. Furthermore, lipids and inflammation could partly mediate the correlation of the TyG index with arterial stiffness in both surveys.

[The Reduction of CD4+ T Lymphocytes after the Treatment of Follicular Lymphoma with the Bendamustine Containing Regimen May Predict the Occurrence of Infection and Efficacy].

OBJECTIVE: To investigate the effectiveness, safety, and related prognostic factors of the treatment of follicular lymphoma (FL) with a regimen containing Bendamustine. METHODS: The clinical data of 129 FL patients who were treated with Bendamustine containing regimen were collected from January 1,2020 to October 30,2022 in the Hematology Department of Lianyungang Second People's Hospital and Jiangsu Provincial People's Hospital. The patients were divided into three groups: Bendamustine plus Rituximab (BR), Bendamustine plus Obinutuzumab (GB), Rituximab + Cyclophosphamide + Epirubicin / Doxorubicin + Vindesine + Prednisone (R-CHOP). The efficacy, safety and related prognostic factors of the treatment of FL with a regimen based on Bendamustine were retrospectively analyzed. RESULTS: The ORR was 98% for the BR group, 94% for the GB group, and 72.3% for the R-CHOP group, while the CR rate was 61.2%,70% and 40.4%, respectively. The ORR and CR rates of the R-CHOP group were statistically different from those of the BR group and GB group (P < 0.05). The 3-year PFS rate of the BR group, GB group, and R-CHOP group was 89.6%, 90.9%, 48.9%, respectively. There was a statistically significant difference in 3-year PFS between the R-CHOP group, BR group, and GB group (P < 0.05), while there was no statistically significant difference in 3-year OS（P ＞0.05）. Hematological adverse reactions were mainly bone marrow suppression. Lymphocytes and CD4+T lymphocytes decreased to the lowest level about 6 months after treatment, and the incidence of lymphopenia in BR group and GB group was higher than that in R-CHOP group, with a statistical difference (P < 0.05). The higher incidence of non-Hematological adverse reactions were pulmonary infection, EB virus infection, hepatitis B virus reactivation, and gastrointestinal reactions without statistical difference in 3 groups (P >0.05), and were all controllable. The Receiver operating characteristic of CD4+T lymphocyte count showed that AUC of BR group was 0.802, and the critical value was 258/uL; AUC of GB group was 0.754 with a critical value of 322/uL. CONCLUSION: The treatment of FL with the Bendamustine containing regimen has good efficacy and controllable adverse reactions, but lymphocytopenia was significant after treatment, and the curative efficacy in combination with various CD20 monoclonal antibodies was different. The lowest CD4+T lymphocyte count can be used as a predictive factor for the occurrence of infection and efficacy of the Bendamustine containing regimen for FL.

CACIMAR: cross-species analysis of cell identities, markers, regulations, and interactions using single-cell RNA sequencing data.

Transcriptomic analysis across species is increasingly used to reveal conserved gene regulations which implicate crucial regulators. Cross-species analysis of single-cell RNA sequencing (scRNA-seq) data provides new opportunities to identify the cellular and molecular conservations, especially for cell types and cell type-specific gene regulations. However, few methods have been developed to analyze cross-species scRNA-seq data to uncover both molecular and cellular conservations. Here, we built a tool called CACIMAR, which can perform cross-species analysis of cell identities, markers, regulations, and interactions using scRNA-seq profiles. Based on the weighted sum models of the conserved features, we developed different conservation scores to measure the conservation of cell types, regulatory networks, and intercellular interactions. Using publicly available scRNA-seq data on retinal regeneration in mice, zebrafish, and chick, we demonstrated four main functions of CACIMAR. First, CACIMAR allows to identify conserved cell types even in evolutionarily distant species. Second, the tool facilitates the identification of evolutionarily conserved or species-specific marker genes. Third, CACIMAR enables the identification of conserved intracellular regulations, including cell type-specific regulatory subnetworks and regulators. Lastly, CACIMAR provides a unique feature for identifying conserved intercellular interactions. Overall, CACIMAR facilitates the identification of evolutionarily conserved cell types, marker genes, intracellular regulations, and intercellular interactions, providing insights into the cellular and molecular mechanisms of species evolution.

Chinese characters carry special anatomical connotations.

In the domain of anatomy, some Chinese characters in anatomical terms possess distinctive morphological significance. Chinese characters evolved from pictographic characters, with some of these pictographs being created by ancient people based on their own body structure. This implies that the comprehension and depiction of the human body structure have been integral since the inception of Chinese characters, and this knowledge has been passed down and developed through the continued inheritance of Chinese characters. Even today, certain characters retain the appearance to reflect the shape of the human body structure. By examining the characters related to vertebrae, cranial fontanel and heart, we can find the unique and enduring link between Chinese characters and the fields of anatomy as well as Chinese traditional medicine.

Photoredox/Bismuth Relay Catalysis Enabling Reductive Alkylation of Nitroarenes with Aldehydes.

The effective transition metal-free photoredox/bismuth dual catalytic reductive dialkylation of nitroarenes with benzaldehydes has been reported. The nitroarene reduction through visible light-driven photoredox catalysis was integrated with subsequent reductive dialkylation of anilines under bismuth catalysis to enable the cascade reductive alkylation of nitroarenes with carbonyls. Salient features of this relay catalysis system include mild reaction conditions, no requirement for transition metal catalysts, easy handling, step-economy, and high selectivity.

The Impact of Regulatory Reforms in China on Drug Lag: The Role of Clinical Development Strategies.

In recent years, there has been significant focus on China's new drug lag, but relevant research is limited. This study explores the reasons for drug lag by assessing the impact of reforms in China's drug review system, particularly focusing on the influence of clinical development strategies. This study selected drugs first launched in the United States between 2017 and 2022, examining absolute and relative lag between China and the first-launch country (including submission and review lag). These delays with drugs approved in the European Union and Japan during the same period were compared with uncover the roots of delays in China, further identifying potential factors that could reduce these delays. The results indicate that the National Medical Products Administration (NMPA) has a longer relative lag compared with the European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA). The submission lag time of the NMPA significantly surpasses that of the EMA and PMDA, whereas the review lag time of the NMPA exceeds that of the PMDA but falls short of the EMA. Focusing on clinical trial strategies, bridging trials and multiregional clinical trials (MRCTs) are typically required by the NMPA in East Asia, resulting in longer clinical delay time. Whereas the EMA and PMDA primarily require international MRCTs in Europe and America, with a clinical delay of < 5 months. It is evident that there is a significant gap in clinical trial durations between China and other countries. Further optimization of clinical trial management is necessary to address the lag for new drugs in China.

Evaluation on purine metabolism in human skin fibroblast cells exposed to oxygenated polycyclic aromatic hydrocarbons.

A rapid and sensitive assessment of the toxicity of oxygenated polycyclic aromatic hydrocarbons (OPAHs), widely distributed persistent organic pollutants in the environment, is crucial for human health. In this study, using high-performance liquid chromatography, the separation and detection of four purines, xanthine (X), guanine (G), adenine (A), and hypoxanthine (HX) in cells were performed. The aim was to evaluate the cytotoxicity of three OPAHs, namely 1,4-benzoquinone (1,4-BQ), 1,2-naphthoquinone (1,2-NQ) and 9,10-phenanthrenequinone (9,10-PQ), with higher environmental concentrations, from the perspective of purine nucleotide metabolism in human skin fibroblast cells (HFF-1). The results revealed that the levels of G and A were low in HFF-1 cells, while the levels of HX and X showed a dose-response relationship with persistent organic pollutants concentration. With increased concentration of the three persistent organic pollutants, the purine metabolism in HFF-1 cells weakened, and the impact of the three persistent organic pollutants on purine metabolism in cells was in the order of 9,10-PQ > 1,4-BQ > 1,2-NQ. This study provided valuable insights into the toxic mechanisms of 1,4-BQ, 1,2-NQ and 9,10-PQ, contributing to the formulation of relevant protective measures and the safeguarding of human health.

The toxicity response of the electrochemical signal of the cell to the drug metabolized by the S9 system.

The electrochemical detection method of cytotoxicity using intracellular purines as biomarkers has shown great potential for in vitro drug toxicity evaluation. However, no electrochemical detection system based on an in vitro drug metabolism mechanism has been devised. In this paper, electrochemical voltammetry was used to investigate the effect of the S9 system on the electrochemical behavior of HepG2 cells, and benzo[a]pyrene, fluoranthene, and pyrene were employed to investigate the sensitivity of electrochemical signals of cells to the cytotoxicity of drugs metabolized by the S9 system. The results showed that, within 8 h of exposure to the S9 system, the electrochemical signal of HepG2 cells at 0.7 V did not alter noticeably. The levels of xanthine, guanine, hypoxanthine, and adenine in the cells were not significantly altered. Compared with the absence of S9 system metabolism, benzo[a]pyrene and fluoranthene processed by the S9 system decreased the electrochemical signal of the cells in a dose-dependent manner, while pyrene did not change it appreciably. HPLC also revealed that benzo[a]pyrene and fluoranthene metabolized by the S9 system decreased the intracellular purine levels, whereas pyrene had no effect on them before and after S9 system metabolism. The cytotoxicity results of the three drugs examined by electrochemical voltammetry and MTT assay showed a strong correlation and good agreement. The S9 system had no effect on the intracellular purine levels or the electrochemical signal of cells. When the drug was metabolized by the S9 system, variations in cytotoxicity could be precisely detected by electrochemical voltammetry.

Design of gum Arabic/gelatin composite microcapsules and their cosmetic applications in encapsulating tea tree essential oil.

Microencapsulation has been widely used to protect essential oils, facilitating their application in cosmetics. In this study, gelatin, gum arabic and n-butyl cyanoacrylate were used as wall materials, and composite microcapsules of tea tree essential oil (TTO) were prepared using a combination of composite coagulation and in situ polymerization methods. When the ratio of gelatin to gum arabic is 1 : 1, the ratio of TTO to n-butyl cyanoacrylate is 4 : 1, the curing time is 10 h, and the encapsulation efficiency (EE) under these conditions is 73.61%. Morphological observation showed that the composite capsule was a micron-sized spherical particle with an average particle size of 10.51 µm, and Fourier transform infrared spectroscopy (FT-IR) confirmed a complex coagulation reaction between gelatin and gum arabic, and the disappearance of the n-butyl cyanoacrylate peak indicated that the film was formed in a condensation layer. The thermogravimetric analysis (TGA) results showed that the composite capsule greatly improved the thermal stability of TTO. Rheological testing showed that the viscosity and viscoelasticity of the surface composite capsules have been improved. In addition, the composite capsule showed good stability in the osmotic environment and has good sustained-release performance and antioxidant capacity in the average human skin environment.

Bioaugmented ensiling of sweet sorghum with Pichia anomala and cellulase and improved enzymatic hydrolysis of silage via ball milling.

Sweet sorghum, as a seasonal energy crop, is rich in cellulose and hemicellulose that can be converted into biofuels. This work aims at investigating the effects of synergistic regulation of Pichia anomala and cellulase on ensiling quality and microbial community of sweet sorghum silages as a storage and pretreatment method. Furthermore, the combined pretreatment effects of ensiling and ball milling on sweet sorghum were evaluated by microstructure change and enzymatic hydrolysis. Based on membership function analysis, the combination of P. anomala and cellulase (PA + CE) significantly improved the silage quality by preserving organic components and promoting fermentation characteristics. The bioaugmented ensiling with PA + CE restructured the bacterial community by facilitating Lactobacillus and inhibiting undesired microorganisms by killer activity of P. anomala. The combined bioaugmented ensiling pretreatment with ball milling significantly increased the enzymatic hydrolysis efficiency (EHE) to 71%, accompanied by the increased specific surface area and decreased pore size/crystallinity of sweet sorghum. Moreover, the EHE after combined pretreatment was increased by 1.37 times compared with raw material. Hence, the combined pretreatment was demonstrated as a novel strategy to effectively enhance enzymatic hydrolysis of sweet sorghum.

Design of oleic acid/alkyl glycoside composite vesicles as cosmetics carrier: stability, skin permeability and antioxidant activity.

Biocompatible fatty acids are natural biological materials which exhibit widespread biomedical applications. Nevertheless, their application in vesicle forms is hampered by strong pH sensitivity and poor stability to changes in ionic strength, temperature, and storage. In the investigation, the incorporation of alkyl glycoside (APG), a surfactant with non-ionic properties, into the oleic acid (OA) vesicles was undertaken as a means to address this issue. The newly formed OA/APG composite vesicles form in a pH range of between 5.4 and 7.4, which is close to the pH range of the physiological environment. The stability studies results showed that the OA/APG composite vesicles have excellent stability in terms of ionic strengths, temperature and storage. The formation of NAR-loaded OA/APG composite vesicles was demonstrated through FT-IR, DSC and XRD. In vitro topical delivery and skin retention studies confirmed that the composite vesicles improve skin permeation rate and have better skin permeation behavior. Antioxidant activity experiments confirmed that the antioxidant effect composite vesicles were significantly increased as compared to the naringenin (NAR). This finding has theoretical implications for the use of drug-loaded fatty acid vesicles in cosmetics industries and topical delivery systems.

K2Cr2O7-induced DNA damage in HT1080 cells: Electrochemical signal response mechanism.

The existing DNA damage detection technology cannot meet the current detection requirements. It is critical to build new methods and discover novel biomarkers. In this study, alkaline comet and 8-OHDG ELISA assays were used to identify DNA damage in HT-1080 cells exposed to K2Cr2O7, and electrochemical behaviors of HT-1080 cells with DNA damage was studied. With an increase in K2Cr2O7 exposure time, two electrochemical signals from HT-1080 cells at 0.69 and 1.01 V steadily grew before decreasing after reaching their highest values. The electrochemical signal's initial response time and peak time decreased as the concentration of K2Cr2O7 increased. The duration of the high dose group was 0.5 and 1 h, while the low dose group was 1.5 and 6 h. Western blotting analysis revealed that DNA damage increased the expression of proteins involved in catabolism and de novo purine synthesis, particularly de novo purine synthesis. Expressions of PRPP amidotransferase, IMPDH, and ADA were all higher than those of ADSS, XOD, and GDA, which resulted in larger concentrations of hypoxanthine, guanine, and xanthine, and in turn improved electrochemical signaling. These findings suggest that intracellular purine identified by linear scan voltammetry is predicted to evolve as a marker of early DNA damage.

Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain.

Chronic pain often develops severe mood changes such as depression. However, how chronic pain leads to depression remains elusive and the mechanisms determining individuals' responses to depression are largely unexplored. Here we found that depression-like behaviors could only be observed in 67.9% of mice with chronic neuropathic pain, leaving 32.1% of mice with depression resilience. We determined that the spike discharges of the ventral tegmental area (VTA)-projecting lateral habenula (LHb) glutamatergic (Glu) neurons were sequentially increased in sham, resilient and susceptible mice, which consequently inhibited VTA dopaminergic (DA) neurons through a LHbGlu-VTAGABA-VTADA circuit. Furthermore, the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner. Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain. Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

Chelation-Assisted Iron-Catalyzed C-H Activations: Scope and Mechanism.

ConspectusTo improve the resource economy of molecular syntheses, researchers have developed strategies to directly activate otherwise inert C-H bonds, thus avoiding cumbersome and costly substrate prefunctionalizations. During the past two decades, remarkable progress in coordination chemistry has set the stage for developing increasingly viable metal catalysts for C-H activations. Despite remarkable advances, C-H activations are largely dominated by precious 4d and 5d transition metal catalysts based primarily on palladium, ruthenium, iridium, and rhodium, thus decreasing the inherent sustainable nature of the C-H activation approach. Therefore, advancing catalytic reactions based on Earth-abundant and less toxic 3d transition metals, especially nontoxic and inexpensive iron, represents a desirable and attractive alternative. While research had previously focused on 8-aminoquinoline directing groups in C-H activations, we have devised easily accessible, tunable, and clickable triazoles, which feature widespread applications in bioactive compounds and drugs, among others, as peptide isosteres. Thus, in contrast to other directing groups, the triazole group is a highly desirable structural motif and functions as a bioisostere in medicine and biology, where it is exploited to mimic amide bonds.This Account summarizes the evolution of chelation-assisted iron-catalyzed C-H activations via C-H, C-H/N-H, and C-H/N-H/C-C bond cleavages, with a topical focus on the most recent contributions of our team. Thus, the triazole-enabled iron catalysis has surfaced as a transformative platform for a large variety of C-H transformations, including arylations, alkylations, alkenylations, allylations, annulations, and alkynylations, achieved through C-H activations with organometallic reagents, organohalides, alkynes, alkenes, allenes, and bicyclopropylidenes among others. Consequently, we developed widely applicable methods for the versatile preparation of decorated arenes and heteroarenes, providing access to benzamides, isoquinolones, pyrrolones, pyridones, phenones, indoles, and isoindolinones, among others. Most of these reactions employed 1,2-dichloroisobutane (DCIB) as an oxidant. Notably, chemical-oxidant-free strategies were also developed, with the major breakthroughs being the use of internal oxidants in oxidative annulations, the use of resource-economic electrocatalysis, and the development of well-defined iron(0)-mediated catalysis. In addition, a highly enantioselective inner-sphere C-H alkylation of (aza)indoles was developed by designing novel remotely decorated N-heterocyclic carbene ligands with dispersion energy donors. In addition, detailed mechanistic experiments including kinetic analyses, intermediate isolation, Mößbauer spectroscopy, and computation provided strong support for the mode of catalysis operation, enabling unprecedented C-H activations. Thereby, low-valent iron catalysts paved the way toward weakly coordinating ketones and enantioselective iron-catalyzed C-H activations through organometallic intermediates.

Electrochemistry detection of estrogenic effect: Regulation of de novo purine synthesis and catabolism by gibberellin and fulvestrant.

The estrogenic effect of plant growth regulators has been received little attention, which leads to the lack of relevant toxicity data. In this study, the estrogenic effect induced by gibberellin with ERα-dependent manner was found by E-screen and western blot methods, and the electrochemical signals of MCF-7 cells regulated by gibberellin and fulvestrant were investigated. The results showed that the electrochemical signals of MCF-7 cells were increased by gibberellin, while reduced by fulvestrant significantly, and displayed an extremely sensitive response to the effects of estrogenic effect induced by ERα agonist and antagonist. Western blot results showed that the expressions of phosphoribosyl pyrophosphate amidotransferase and hypoxanthine nucleotide dehydrogenase in de novo purine synthesis and adenine deaminase in catabolism were more effective regulated by gibberellin and fulvestrant, resulting in significant changes of the levels of guanine, hypoxanthine and xanthine in cells, and then electrochemical signals. The results provide a theoretical basis for the establishment of new electrochemical detection method of the estrogenic effect of plant regulators.

Progress and Challenges of the New Conditional Approval Process in China: A Pooled Analysis From 2018 to 2021.

PURPOSE: To speed the review and approval of drugs and address pressing medical needs, China began to advocate for the implementation of the conditional approval process in 2017. We aimed to assess the implementation of the conditional approval process in China and further analyze its potential problems and future challenges. METHODS: This study examined the new drug approval with conditions in China between 2018 and 2021, based on an analysis of drug technical review documents from the Center for Drug Evaluation (CDE). Using publicly available information, we further analyzed the characteristics and results of pivotal clinical trials of conditionally approved drugs, postmarketing study requirements and progress. FINDINGS: Between 2018 and 2021, China conditionally approved 50 drugs, with 80% (40/50) being antineoplastic agents. Premarketing pivotal trials predominantly used single-arm clinical trials (83.7%, 41/49), while postmarketing trials mainly employed randomized controlled clinical trials (81.0%, 34/42). In oncology drugs, conditionally approved drugs with progression-free survival (PFS) and overall survival (OS) as primary endpoints achieved significant clinical value in terms of efficacy. However, there were also pivotal clinical trials with response rate (RR) as the primary endpoint that demonstrated lower clinical benefits (8.9% of drugs with RR below 20%). Safety analysis revealed substantial variations in the proportions of grade ≥3 adverse events (AEs) and serious adverse events (SAEs) across pivotal trials (Grade ≥ 3 AEs: 9.0%-99.0%; SAEs: 8.0%-83.0%). For nononcology drugs, pivotal trials also demonstrated an acceptable risk-benefit ratio but exhibited methodological issues. Meanwhile, Most postmarketing studies lacked completion date restrictions (43.2%, 17/47), and no requirements were specified for the transition to full approval. Furthermore, surrogate endpoints were primarily utilized both pre- and postmarketing, but the rational selection of surrogate endpoints remains to be investigated. IMPLICATIONS: The conditional approval process expedites patient access to drugs for serious diseases. However, challenges pertaining to evidence assessment during approval and design flaws in postmarketing studies exist in China's conditional approval system, necessitating future improvements.