Melatonin alleviates endoplasmic reticulum stress and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens.

Follicular atresia in chickens reduces the number of follicles that can further develop, leading to decrease egg laying. Endoplasmic reticulum stress (ERS) can initiate a unique pathway inducing the apoptosis of follicular granulosa cells, thus reducing egg laying. Melatonin (MEL) is involved in the regulation of follicle development, ovulation, and oocyte maturation, and is closely related to follicle fate. Mammalian target of Rapamycin (mTOR) signaling pathway plays an important role in cell growth regulation, and that there is a possible crosstalk between melatonin and mTOR activity in granular cells maturation and ovulation. This study aimed to investigate whether MEL inhibits ERS and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens. Frist, we established an in vitro ERS cell model using tunicamycin (TM). The results showed that different concentrations of TM exhibited dose-dependent inhibition of cell activity and induction of granulosa cells (P<0.01). Therefore, we chose 5 µg/mL of TM and a treatment time for 6 h as the optimal concentration for the following experiments. Then we investigate whether melatonin can inhibit ERS. TM treatment decreased the cell viability and Bcl-2 expression, increasing ROS levels and the mRNA expression of Grp78, ATF4, CHOP, PERK, eIF-2α, and BAX (P<0.01), whereas TM+MEL treatment significantly inhibited these changes (P<0.01). Then we explored whether melatonin protects follicular granulosa cells from ERS-induced apoptosis through the mammalian target of rapamycin (mTOR) signaling pathway by regulating ATF4, we found that ATF4 knockdown inhibited ERS by decreasing the expression of ERS-related genes and proteins and activating mTOR signaling pathway by increasing the protein expression of p4E-BP1 and pT389-S6K (P<0.001), while these changes were promoted by TM+si-ATF4+MEL treatment (P<0.01). These results indicate that MEL could alleviate TM-induced ERS by regulating ATF4 to activate mTOR signaling pathway in follicular granulosa cells, thus providing a new perspective for prolonging the laying cycle in chickens.

Achieving Nickel-Catalyzed Reductive C(sp2)-B Coupling of Bromoboranes via Reversing the Activation Sequence.

Transition metal-catalyzed reductive cross-couplings to build C-C/Si bonds have been developed, but the reductive cross-coupling to create the C(sp2)-B bond has not been explored. Herein, we describe a nickel-catalyzed reductive cross-coupling between aryl halides and bromoboranes to construct a C(sp2)-B bond. This protocol offers a convenient approach for the synthesis of a wide range of aryl boronate esters, using readily available starting materials. Mechanistic studies indicate that the key to the success of the reaction is the activation of the B-Br bond of bromoboranes with a Lewis base such as 2-MeO-py. The activation ensures that bromoboranes will react with the active nickel(I) catalyst prior to aryl halides, which is different from the sequence of the general nickel-catalyzed reductive C(sp2)-C/Si cross-coupling, where the oxidative addition of an aryl halide proceeds first. Notably, this approach minimizes the production of undesired homocoupling byproduct without the requirement of excessive quantities of either substrate.

The Interplay between Mitochondrial Dysfunction and Ferroptosis during Ischemia-Associated Central Nervous System Diseases.

Cerebral ischemia, a leading cause of disability and mortality worldwide, triggers a cascade of molecular and cellular pathologies linked to several central nervous system (CNS) disorders. These disorders primarily encompass ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and other CNS conditions. Despite substantial progress in understanding and treating the underlying pathological processes in various neurological diseases, there is still a notable absence of effective therapeutic approaches aimed specifically at mitigating the damage caused by these illnesses. Remarkably, ischemia causes severe damage to cells in ischemia-associated CNS diseases. Cerebral ischemia initiates oxygen and glucose deprivation, which subsequently promotes mitochondrial dysfunction, including mitochondrial permeability transition pore (MPTP) opening, mitophagy dysfunction, and excessive mitochondrial fission, triggering various forms of cell death such as autophagy, apoptosis, as well as ferroptosis. Ferroptosis, a novel type of regulated cell death (RCD), is characterized by iron-dependent accumulation of lethal reactive oxygen species (ROS) and lipid peroxidation. Mitochondrial dysfunction and ferroptosis both play critical roles in the pathogenic progression of ischemia-associated CNS diseases. In recent years, growing evidence has indicated that mitochondrial dysfunction interplays with ferroptosis to aggravate cerebral ischemia injury. However, the potential connections between mitochondrial dysfunction and ferroptosis in cerebral ischemia have not yet been clarified. Thus, we analyzed the underlying mechanism between mitochondrial dysfunction and ferroptosis in ischemia-associated CNS diseases. We also discovered that GSH depletion and GPX4 inactivation cause lipoxygenase activation and calcium influx following cerebral ischemia injury, resulting in MPTP opening and mitochondrial dysfunction. Additionally, dysfunction in mitochondrial electron transport and an imbalanced fusion-to-fission ratio can lead to the accumulation of ROS and iron overload, which further contribute to the occurrence of ferroptosis. This creates a vicious cycle that continuously worsens cerebral ischemia injury. In this study, our focus is on exploring the interplay between mitochondrial dysfunction and ferroptosis, which may offer new insights into potential therapeutic approaches for the treatment of ischemia-associated CNS diseases.

DDB2 and MDM2 genes are promising markers for radiation diagnosis and estimation of radiation dose independent of trauma and burns.

In the field of biodosimetry, the current accepted method for evaluating radiation dose fails to meet the need of rapid, large-scale screening, and most RNA marker-related studies of biodosimetry are concentrating on a single type of ray, while some other potential factors, such as trauma and burns, have not been covered. Microarray datasets that contain the data of human peripheral blood samples exposed to X-ray, neutron, and γ-ray radiation were obtained from the GEO database. Totally, 33 multi-type ray co-induced genes were obtained at first from the differentially expressed genes (DEGs) and key genes identified by weighted gene co-expression network analysis (WGCNA), and these genes were mainly enriched in DNA damage, cellular apoptosis, and p53 signaling pathway. Following transcriptome sequencing of blood samples from 11 healthy volunteers, 13 patients with severe burns, and 37 patients with severe trauma, 6635 trauma-related DEGs and 7703 burn-related DEGs were obtained. Through the exclusion method, a total of 12 radiation-specific genes independent of trauma and burns were identified. ROC curve analysis revealed that the DDB2 gene performed the best in diagnosis of all three types of ray radiation, while correlation analysis showed that the MDM2 gene was the best in assessment of radiation dose. The results of multiple-linear regression analysis indicated that such analysis could improve the accuracy in assessment of radiation dose. Moreover, the DDB2 and MDM2 genes remained effective in radiation diagnosis and assessment of radiation dose in an external dataset. In general, the study brings new insights into radiation biodosimetry.

Cross-Electrophile C-PIII Coupling of Chlorophosphines with Organic Halides: Photoinduced PIII and Aminoalkyl Radical Generation Enabled by Pnictogen Bonding.

Pnictogen bonding (PnB) has gained recognition as an appealing strategy for constructing novel architectures and unlocking new properties. Within the synthetic community, the development of a straightforward and much simpler protocol for cross-electrophile C-PIII coupling remains an ongoing challenge with organic halides. In this study, we present a simple strategy for photoinduced PnB-enabled cross-electrophile C-PIII couplings using readily available chlorophosphines and organic halides via merging single electron transfer (SET) and halogen atom transfer (XAT) processes. In this photomediated transformation, the PnB formed between chlorophosphines and alkyl amines facilitates the photogeneration of PIII radicals and α-aminoalkyl radicals through SET. Subsequently, the resulting α-aminoalkyl radicals activate C-X bonds via XAT, leading to the formation of carbon radicals. This methodology offers operational simplicity and compatibility with both aliphatic and aromatic chlorophosphines and organic halides.

Charge Transfer Complex-Enabled Synthesis of (Hetero)arylated m-Carboranes from m-Carborane Phosphonium Salts.

A photoinduced charge transfer complex (CTC)-enabled photoreduction of carborane phosphonium salts for the cage carbon (hetero)arylation of carboranes was developed. It offers a convenient approach for introducing a wide range of aryl and heteroaryl groups, such as pyrroles, thiophenes, indoles, thianaphthenes, benzofurans, pyridines, and benzenes, into carboranes. This strategy offers operational simplicity, mild reaction conditions, and a broad substrate scope, making it highly advantageous.

N-Heterocyclic Nitrenium-Catalyzed Photohomolysis of CF3SO2Cl for Alkene Trifluoromethylation.

N-Heterocyclic nitreniums (NHNs) have been utilized as Lewis acid catalysts to activate substrates with lone pairs. Alternative to their conventional applications, we have discovered that NHNs can also serve as charge transfer complex catalysts. Herein, we present another potential of NHNs by utilizing a weak interaction between NHNs and CF3SO2Cl. The method promotes CF3SO2Cl to undergo photohomolysis, resulting in the CF3 radical. Mechanistic studies suggested that the weak interaction could be due to the π-hole effect of NHNs.

Photocatalytic Charge-Transfer Complex Enables Hydroarylation of Alkenes for Heterocycle Synthesis.

Here, we report a photocatalytic charge-transfer complex (CTC) strategy for one electron reduction of alkenes using thiolate as a catalytic electron donor. This catalytic CTC system could engage hydroarylation of both activated and unactivated alkenes for the synthesis of various heterocycles. The reactions do not require any photocatalysts or acids and are easy to perform. Mechanistic studies revealed the formation of a CTC between catalytic thiolate and alkene.

The association of body mass index and its interaction with family history of dyslipidemia towards dyslipidemia in patients with type 2 diabetes: a cross-sectional study in Zhejiang Province, China.

Objectives: This study aimed to investigate the association between body mass index (BMI) and dyslipidemia and to explore the interaction between BMI and family history of dyslipidemia towards dyslipidemia in patients with type 2 diabetes. Methods: This cross-sectional study was conducted between March and November 2018 in Zhejiang Province, China. A total of 1,756 patients with type 2 diabetes were included, physical examination data, fasting blood samples and face-to-face questionnaire survey data were collected. Restricted cubic spline analysis was used to evaluate the association between BMI and the risk of dyslipidemia. Unconditional multivariable logistic regression was used to estimate the interaction between BMI and family history of dyslipidemia towards dyslipidemia. Results: The prevalence of dyslipidemia was 53.7% in the study population. The risk of dyslipidemia elevated with increased BMI value (p for non-linearity <0.05). After adjusting for covariates, individuals with high BMI (≥24 kg/m2) and a family history of dyslipidemia had a 4.50-fold (95% CI: 2.99-6.78) increased risk of dyslipidemia compared to the normal reference group, which was higher than the risk associated with high BMI alone (OR = 1.83, 95% CI: 1.47-2.28) or family history of dyslipidemia alone (OR = 1.79 95% CI: 1.14-2.83). Significant additive interaction between high BMI and a family history of dyslipidemia was detected, with RERI, AP, and SI values of 1.88 (95% CI: 0.17-4.10), 0.42 (95% CI: 0.02-0.62), and 2.16 (95% CI: 1.07-4.37), respectively. However, stratified by status of diabetes control, this additive interaction was only find significant among patients with controlled diabetes. Conclusion: Both high BMI and a family history of dyslipidemia were related with high risk of dyslipidemia. Moreover, there were synergistic interaction between these two factors. Patients with type 2 diabetes who had a family history of dyslipidemia were more susceptible to the negative impact of being overweight or obesity on dyslipidemia.

Evaluation of DDA Library-Free Strategies for Phosphoproteomics and Ubiquitinomics Data-Independent Acquisition Data.

Phosphoproteomics and ubiquitinomics data-independent acquisition (DIA) mass spectrometry (MS) data is typically analyzed by using a data-dependent acquisition (DDA) spectral library. The performance of various library-free strategies for analyzing phosphoproteomics and ubiquitinomics DIA MS data has not been evaluated. In this study, we systematically compare four commonly used DDA library-free approaches including Spectronaut's directDIA, DIA-Umpire, DIA-MSFragger, and in silico-predicted library for analysis of phosphoproteomics SWATH, DIA, and diaPASEF data as well as ubiquitinomics diaPASEF data. Spectronaut's directDIA shows the highest sensitivity for phosphopeptide detection not only in synthetic phosphopeptide samples but also in phosphoproteomics SWATH-MS and DIA data from real biological samples, when compared to the other three library-free strategies. For phosphoproteomics diaPASEF data, Spectronaut's directDIA and the in silico-predicted library based on DIA-NN identify almost the same number of phosphopeptides as a project-specific DDA spectral library. However, only about 30% of the total phosphopeptides are commonly identified, suggesting that the library-free strategies for phospho-diaPASEF data need further improvement in terms of sensitivity. For ubiquitinomics diaPASEF data, the in silico-predicted library performs the best among the four workflows and detects ∼50% more K-GG peptides than a project-specific DDA spectral library. Our results demonstrate that Spectronaut's directDIA is suitable for the analysis of phosphoproteomics SWATH-MS and DIA MS data, while the in silico-predicted library based on DIA-NN shows substantial advantages for ubiquitinomics diaPASEF MS data.

Visible-Light-Induced Photoreduction of Carborane Phosphonium Salts: Efficient Synthesis of Carborane-Oxindole-Pharmaceutical Hybrids.

Visible-light-induced photoreaction of carboranes is an effective approach to prepare carborane-containing compounds. While several methods involving boron-centered carboranyl radicals have been established, those for carbon-centered carboranyl radicals are underdeveloped, except for the UV-light-promoted photohomolysis. Herein, we describe a simple but effective approach to access carbon-centered carboranyl radicals by photoreduction of carborane phosphonium salts under blue light irradiation without using transition metals and photocatalysts. The utility of the method was demonstrated by successfully preparing a range of carborane-oxindole-pharmaceutical hybrids by radical cascade reactions. Computational and experimental studies suggest that the carbon-centered carboranyl radicals are generated by single-electron transfer of the photoactive charge-transfer complexes between the salts and the additive potassium acetate.

Visible-Light-Induced N-Heterocyclic Carbene-Catalyzed Single Electron Reduction of Mono-Fluoroarenes.

Fluoroarenes are abundant and readily available feedstocks. However, due to the high reduction potentials of mono-fluoroarenes, their photoreduction remains a continuing challenge, motivating the development of efficient activation modes to address this issue. This report presents the blue light-induced N-heterocyclic carbene (NHC)-catalyzed single electron reduction of mono-fluoroarenes for biaryl cross-couplings. We discovered that under blue light irradiation, NHC/tBuOK combination could construct powerful photoactive architectures to promote single electron transfer for Caryl -F bond reduction via forming highly reducing NHC radical anion. Notably, the strategy was also successful to reduce Caryl -O, Caryl -N, and Caryl -S bonds for biaryl cross-couplings.

Photoinduced N-Heterocyclic Nitrenium-Catalyzed Single Electron Reduction of Acyl Fluorides for Phenanthridine Synthesis.

Acyl fluorides are versatile reagents in organic synthesis. However, there is no precedent to employ acyl fluorides as acyl radical precursors. We herein report an N-heterocyclic nitrenium iodide salt-catalyzed photoreduction of acyl fluorides to produce acyl radicals, which could react with 2-isocyanobiaryls to afford various carbonyl phenanthridines.

Photoinduced halogen-bonding enabled synthesis of oxindoles and isoindolinones from aryl iodides.

We report the use of halogen bonding (XB) for the generation of aryl radicals from aryl halides under blue light irradiation and applied it in radical generation/1,5-hydrogen-atom transfer/radical cyclization cascade reactions for the synthesis of oxindoles and isoindolinones. On the basis of experimental studies, we propose that DBU can serve as a suitable XB acceptor with aryl halides for the formation of a photoactive electron donor and acceptor complex.

Metal-Free Generation of Acyl Radical via Photoinduced Single-Electron Transfer from Lewis Base to Acyl Chloride.

We herein describe a simple approach for generating acyl radical from acyl chloride via photoinduced single-electron transfer. It has been demonstrated that the generated acyl radicals could react with various substrates, including isocyanides, methacrylamides, alkenes, alkynes, and enynes, to afford diverse heterocycles (>10 classes). Mechanistic analyses show that a photoactive charge transfer complex between acyl chloride and a Lewis base additive is involved in enabling the photogeneration of the acyl radical. The study exemplifies a new and simple method of photoactivation of carbonyl compounds.

Catalytic charge transfer complex enabled difluoromethylation of enamides with difluoromethyltriphenylphosphonium bromide.

A catalytic charge transfer complex strategy that enabled difluoromethylation and ethoxycarbonylmonofluoromethylation of enamides with phosphonium bromine salts has been reported. This strategy also provides a convenient approach for the synthesis of functionalized oxindoles and 1,1-diphenylethylenes with easily available phosphonium bromine salts and a catalytic amount of iodine anion.

Sesquiterpene lactones from Artemisia vulgaris L. as potential NO inhibitors in LPS-induced RAW264.7 macrophage cells.

Twelve new guaianolide sesquiterpene lactones (1-12), along with ten known analogs (13-22) were isolated from an EtOH extract of the dried aerial parts of Artemisia vulgaris L. The new structures were elucidated via abundant spectroscopic data analyses (HRESIMS, IR, 1D, and 2D NMR), and the absolute configurations of these compounds were determined by X-ray crystallography and ECD calculations. The compounds (1-22) were identified as guaiane-type sesquiterpenes with characteristic α-methylene-γ-lactone and α,ß-unsaturated carbonyl moieties. All compounds were tested for their inhibitory activity against NO production in lipopolysaccharide-stimulated RAW264.7 macrophages. The isolated sesquiterpenoids dose-dependently exhibited an NO production inhibitory activity by inhibiting the expression of inducible NO oxidase (iNOS) and cyclooxygenase-2 (COX-2) with IC50 values ranging from 1.0 to 3.6 µM. The inhibitory effect on the NO production of the compounds (1-4 and 6-22) is better than that of the positive control (dexamethasone). The different substitutions of compounds on C-8 influence anti-inflammatory effects, as evidenced by the in silico analysis of related binding interactions of new compounds (1-12) with iNOS.

[Visual analysis on regulation of necroptosis with Chinese medicine based on VOSviewer and CiteSpace knowledge graphs].

The study was conducted by searching the literature related to the regulation of necroptosis with Chinese medicine from January 1, 2005 to December 31, 2021 in CNKI, VIP, Wanfang, Web of Science(WoS), and PubMed. The obtained literature were imported into NoteExpress for eliminating duplicates and screening, and the final included articles were imported into Excel to plot the publication trend. The core authors were identified according to Price's law, and VOSviewer 1.6.17 was used to draw a collaborative view of the core authors and sort the high-frequency keywords. Then CiteSpace 5.8.R3 was employed to analyze keywords clustering, burst, and timeline view. Finally, 98 Chinese articles and 72 English articles were included in the study. The number of publications on the regulation of necroptosis with Chinese medicine has been increasing year by year. China ranked among the top in the world in terms of the number of publications, and Chinese authors played a central role in this field. Specifically, LIU Hua published the most Chinese literature while CHEN X P had the most English publications. The collaborative view of the core authors showed more intra-team cooperation and less inter-team cooperation. The Chinese and English keywords formed ten clusters separately, indicating that the research hotspots of regulation of necroptosis with Chinese medicine mainly focused on disease, prescription, related factors, and mecha-nism. Further, the analysis of Chinese and English keywords revealed that regarding disease treatment, tumor, ischemia-reperfusion injury, neurodegenerative diseases, and inflammatory diseases were studied most. The Chinese medicines that received much attention in this field were curcumin, shikonin and tanshinone. The main protein factors involved were Ripk1, Ripk3, Mlkl, and TNF-α, and Ripk1/Ripk3/Mlkl and p53 signaling pathways were predominant. Moreover, single herbs and herbal monomers were the hotspots of the included articles. In the future, scholars need to expand the study of classical Chinese herbal compounds and explore their mechanism of action in the occurrence and development of various diseases, to provide new ideas and experimental basis for the treatment of clinical diseases with Chinese medicine.

N-Heterocyclic Nitreniums Can Be Employed as Photoredox Catalysts for the Single-Electron Reduction of Aryl Halides.

N-Heterocyclic nitrenium (NHN) salts, the analogues of N-heterocyclic carbenes, have attracted considerable interest. However, relatively little is known about their catalytic ability beyond their Lewis acid catalysis. Herein, we describe that NHNs can serve as catalytic electron acceptors for charge transfer complex photoactivations. We showcase that, under blue light irradiation, the NHN salts could catalyze the generation of aryl radicals from aryl halides.

DFT insight into asymmetric alkyl-alkyl bond formation via nickel-catalysed enantioconvergent reductive coupling of racemic electrophiles with olefins.

A DFT study has been conducted to understand the asymmetric alkyl-alkyl bond formation through nickel-catalysed reductive coupling of racemic alkyl bromide with olefin in the presence of hydrosilane and K3PO4. The key findings of the study include: (i) under the reductive experimental conditions, the Ni(ii) precursor is easily activated/reduced to Ni(0) species which can serve as an active species to start a Ni(0)/Ni(ii) catalytic cycle. (ii) Alternatively, the reaction may proceed via a Ni(i)/Ni(ii)/Ni(iii) catalytic cycle starting with a Ni(i) species such as Ni(i)-Br. The generation of a Ni(i) active species via comproportionation of Ni(ii) and Ni(0) species is highly unlikely, because the necessary Ni(0) species is strongly stabilized by olefin. Alternatively, a cage effect enabled generation of a Ni(i) active catalyst from the Ni(ii) species involved in the Ni(0)/Ni(ii) cycle was proposed to be a viable mechanism. (iii) In both catalytic cycles, K3PO4 greatly facilitates the hydrosilane hydride transfer for reducing olefin to an alkyl coupling partner. The reduction proceeds by converting a Ni-Br bond to a Ni-H bond via hydrosilane hydride transfer to a Ni-alkyl bond via olefin insertion. On the basis of two catalytic cycles, the origins for enantioconvergence and enantioselectivity control were discussed.