Calcium ions induced ι-carrageenan-based gel-coating deposited on zein nanoparticles for encapsulating the curcumin.

Zein, curcumin (Cur), and ι-carrageenan (ιCar) were used to prepare core-shell biopolymer nanoparticles (Zein-Cur-ιCar). These nanoparticles consisted of a nutraceutical-loaded protein core (curcumin-loaded zein nanoparticles) and a gelled polysaccharide shell (calcium cross-linked ι-carrageenan). The size, charge, morphology, and interactions of the nanoparticles were characterized by dynamic light scattering, zeta-potential analysis, scanning electron microscopy, and Fourier Transform infrared analysis. Ionic bridging, electrostatic attraction, hydrogen bonding, and hydrophobic attraction were involved in particle formation. The high encapsulation efficiency (93.2%) and loading capacity (6.2%) indicated that curcumin was well encapsulated within nanoparticles with optimized compositions (zein:ι-carrageenan 100:40). These particles had relatively small diameters (351.8 nm) and effectively delayed the light and thermal degradation of curcumin. Moreover, the curcumin within the nanoparticles was released in a sustained manner under simulated gastrointestinal conditions, which may improve its oral bioavailability. In summary, calcium carrageenan-coated zein nanoparticles have potential for the encapsulation, protection, and controlled release of hydrophobic nutrients.

Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning.

ABSTRACT: Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits. In brain physiology, highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli. Once the brain switches its functional states, microglia are recruited to specific sites to exert their immune functions, including the release of cytokines and phagocytosis of cellular debris. The crosstalk of microglia between neurons, neural stem cells, endothelial cells, oligodendrocytes, and astrocytes contributes to their functions in synapse pruning, neurogenesis, vascularization, myelination, and blood-brain barrier permeability. In this review, we highlight the neuron-derived "find-me," "eat-me," and "don't eat-me" molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development. This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease, thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.

In-situ construction of TiO2 polymorphic junction nanoarrays without cocatalyst for boosting photocatalytic hydrogen generation.

There are significant challenges in developing technologies for high-yield photocatalytic hydrogen production reactions. Current photocatalytic materials face three key problems: low utilization of light, rapid recombination of photogenerated electron-hole pairs, and a limited number of active sites during photocatalytic reactions. As a result, these materials only improve one or two of the three steps involved in photocatalytic hydrogen production reactions. Consequently, achieving simultaneous multifunctional synergy to enhance the efficiency of all three processes is difficult. Here, we report an in situ dissolution-recrystallisation approach to design and fabricate a three-dimensional TiO2 rutile/anatase (AE-TiO2) array photocatalytic material for photocatalytic hydrolysis applications. It is shown that the unique 3D nanoarray structure and in situ fabrication of the AE-TiO2 homojunction with synergistic effects among the components lead to an increase in light harvesting efficiency, charge transport separation efficiency and surface active sites, which remarkably improve the photocatalytic hydrolysis performance. The prepared AE-TiO2 homojunction materials realizes a maximal photoactivity of 4 µmol cm-2·h-1, which is 39 times larger than that of pure TiO2 rutile nanorods.

[Retracted] Downregulation of long non­coding RNA GACAT1 suppresses proliferation and induces apoptosis of NSCLC cells by sponging microRNA­422a.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the flow cytometric data shown in Fig. 2E on p. 662 were strikingly similar to data appearing in different form in a pair of other research articles written by different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been submitted for publication elsewhere prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 47: 659­667, 2021; DOI: 10.3892/ijmm.2020.4826].

Enhanced curcumin transportation across epithelial barrier by mucus-permeable soy protein nanoparticles-mediated dual transcytosis pathways.

Nanocarrier-delivered bioactive compounds are highly desirable for their improved stability and applicability, but their bioavailability is still limited due to the strong mucus and epithelial cell barriers. Herein, a series of self-assembled soy protein nanoparticles (SPNPs) with different mucus permeabilities were prepared and their delivery efficiency upon Curcumin (Cur) encapsulation was evaluated. Results demonstrated that the formed SPNPs-Cur exhibited high compatibility and cellular antioxidant accessibility. Besides, SPNPs enhanced the cellular uptake and transmembrane permeation of Cur, especially promoted the transportation of proto-Cur in addition to Cur metabolites. The SPNPs with the rapid mucus diffusion capacity presented more efficient transcytosis across the Caco-2 cell monolayer, which was mediated by a combination of paracellular and transcellular pathways. This work verified that mucus-permeable soy protein nanoparticles could be a promising delivery system for improving the bioavailability of bioactive compounds.

Biological activities and mass fragmentation pathways of meroterpenoid cochlioquinones from plant pathogenic fungus Bipolaris sorokiniana.

Cochlioquinones are a member of meroterpenoids that partially possessed phenolic hydroxyls with potential antioxidant activities. This study investigated the mass fragmentation pathways, antioxidant, cytotoxic, and phytotoxic activities of cochlioquinone analogs. The mass fragmentation pathways of cochlioquinones (1-7) were firstly analyzed using UPLC-Q-TOF-MS/MS, in which Retro Diels-Alder reaction, neutral loss, and McLafferty rearrangement were the main cleavage patterns. Compound 8 and 9 (a unique new analog) were then isolated in target. Cochlioquinones (4-6, 9) displayed strong antioxidant activities for DPPH radical scavenging assay as the first antioxidant effects report. In addition, 1-9 exhibited cytotoxic activities against B16 cells (IC50 from 1.91 to 12.33 µM) and Hep G2 cells (IC50 from 3.21 to 77.15 µM), and 5, 7, and 8 showed phytotoxic activities against foxtail leaves. These biological activities imply that cochlioquinones can be as antioxidant agents for food additives or bioactive molecules for cancer drugs and pesticides.

High titer (>100 g/L) ethanol production from pretreated corn stover hydrolysate by modified yeast strains.

Developing a reliable lignocellulose pretreatment method to extract mixed sugars and engineering efficient strains capable of utilizing xylose are crucial for advancing cellulosic ethanol production. In this study, chemical and characterization analyses revealed that alkali cooking can significantly remove lignin from lignocellulose crops. The highest amount of mixed sugar was obtained from corn stover hydrolysates with a 15 % solid loading. Our genetically engineered yeast strain ΔsnR4, derived from a well-staged WXY70, demonstrated excellent performance in low 10 % solids loading corn stover hydrolysate, producing a high ethanol yield of 0.485 g/g total sugars. When a combined NaOH-ball milling pretreatment strategy was applied at high solids loading, ΔsnR4 exhibited the maximum ethanol titer of 110.9 g/L within 36 h, achieving an ethanol yield of 92.9 % theoretical maximum. Therefore, ΔsnR4 is highly compatible with high solid loading NaOH-ball milling pretreatment, making it a potential candidate for industrial cellulosic ethanol.

An innovative processing driven efficient transformation of rare ginsenosides enhances anti-platelet aggregation potency of notoginseng by integrated analyses of processing-(chemical) profiling-pharmacodynamics.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burk.) F. H. Chen, a valuable Chinese herb medicine, shows a characteristic bi-directional regulation of hemostasis and activating blood circulation with ginsenosides as the predominant bioactive compounds and is a typical representative of "processing triggered heteropotency". AIM OF THE STUDY: Processing triggered heteropotency, one of the unique theories and practices in traditional Chinese medicine, refers to that the processing will lead to change in physical and chemical properties, and eventually disparate efficacy of the crude drugs, yet the optimum process and underlying mechanism remains unclear. In this study, using Panax notoginseng (PN) as a representative sample, a processing-(chemical) profiling-pharmacodynamics (3-P) relationship was proposed to investigate the processing mechanism of PN. MATERIALS AND METHODS: Firstly, a temperature programmed steaming process was designed to evaluate the steaming triggered chemical transformation of triterpene saponins and the corresponding enhancement in anti-platelet aggregation activity. The steaming process was programed from the conventional 100 °C-150 °C in a time course of 0-12 h, aiming to achieve the maximized conversion of rare ginsenosides (RGs), and dynamic profile of ginsenosides were constructed by a UPLC-Q-TOF-MS/MS analysis. Then, a processing-(chemical) profiling-pharmacodynamics (3-P) relationship was assessed by using the grey relational analysis (GRA) and orthogonal projections to latent structures (OPLS), and validated by bioactive fraction of 140 °C steamed PN. Subsequently, the P2Y12-ligand binding affinity of potential candidates was analyzed by molecular docking. Finally, the dynamic changes of ginsenosides during steaming of SPN were quantitatively detected by UPLC-QQQ-MS/MS. RESULTS: A total of 48 differential ginsenosides were characterized and monitored including the primary and secondarily transformed saponins. The higher temperature steaming especially at 140 °C induces not only the predominant production of the RGs, but also the stronger anti-platelet aggregation activity. The 3-P relationship showed the fraction (3) of 140 °C steamed PN rich in RGs exhibits the most predominant efficacy, in which, a series of RGs including ginsenosides Rg5, Rk1, 20(S/R)-Rg3 were proven to be potent components. Molecular docking analysis suggested that ginsenosides Rg5 and Rk1 showed more strong interaction with the platelet P2Y12 receptor. Quantitative analysis found 140 °C-2h PN possessed highest contents of Rk1 and Rg5 and total RGs. CONCLUSIONS: The integrated 3-P strategy uncovered the promising ginsenosides with anti-platelet effect, thereby revealing the material basis of PN steaming, which could provide a new enlightenment for the investigation of processing mechanism of traditional Chinese medicines.

TMT-based quantitative proteomics reveals the protective mechanism of tenuigenin after experimental intracerebral hemorrhage in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Tenuigenin (TNG) is an extract obtained from Polygalae Radix. It possesses anti-inflammatory, antioxidant, and neuroprotective properties. However, the potential mechanism of TNG in intracerebral hemorrhage (ICH) has not been well studied. AIM OF THE STUDY: In the present study, we aimed to identify the prospective mechanism of TNG in treating ICH. MATERIALS AND METHODS: A total of 120 mice were divided into five groups: Sham group, ICH + vehicle group, ICH + TNG(8 mg/kg), ICH + TNG(16 mg/kg), and ICH + TNG(32 mg/kg). The modified Garcia test and beam walking test were carried out at 24 h and 72 h after ICH. Brain water content, haematoma volume and hemoglobin content examinations were performed at 72 h after ICH. TMT-based quantitative proteomics combined with bioinformatics analysis methods was used to distinguish differentially expressed proteins (DEPs) to explore potential pharmacological mechanisms. Western blotting was performed to validate representative proteins. RESULTS: Our results showed that the optimal dose of TNG was 16 mg/kg, which could markedly improve neurological functions, and reduce cerebral oedema, haematoma volume and hemoglobin levels 72 h after ICH. A total of 404 DEPs (353 up-and 51 downregulated) were identified in the ICH + vehicle vs. sham group, while 342 DEPs (306 up-and 36 downregulated) and 76 DEPs (28 up-and 48 downregulated) were quantified in the TNG vs. sham group and TNG vs. ICH + vehicle group, respectively. In addition, a total of 26 DEPs were selected according to strict criteria. Complement and coagulation cascades were the most significantly enriched pathways, and two proteins (MBL-C and Car1) were further validated as hub molecules. CONCLUSIONS: Our results suggested that the therapeutic effects of TNG on ICH were closely associated with the complement system, and that MBL-C and Car1 might be potential targets of TNG for the treatment of ICH.

Integrative proteome and metabolome analyses reveal molecular basis underlying growth and nutrient composition in the Pacific oyster, Crassostrea gigas.

In order to comprehend the molecular basis of growth, nutrient composition, and color pigmentation in oysters, comparative proteome and metabolome analyses of two selectively bred oyster strains with contrasting growth rate and shell color were used in this study. A total of 289 proteins and 224 metabolites were identified differentially expressed between the two strains. We identified a series of specifically enriched functional clusters implicated in protein biosynthesis (RPL4, MRPS7, and CARS), fatty acid metabolism (ACSL5, PEX3, ACOXI, CPTIA, FABP6, and HSD17B12), energy metabolism (FH, PPP1R7, CLAM2, and RGN), cell proliferation (MYB, NFYC, DOHH, TOP2a, SMARCA5, and SMARCC2), material transport (ABCB1, ABCB8, VPS16, and VPS33a), and pigmentation (RDH7, RDH13, Retsat, COX15, and Cyp3a9). Integrated proteome and metabolome analyses indicate that fast-growing strain utilize energy-efficient mechanisms of ATP generation while promoting protein and polyunsaturated fatty acid synthesis, activating the cell cycle to increase cell proliferation and thus promoting their biomass increase. These results uncovered molecular mechanisms underlying growth regulation, nutrition quality, and pigmentation and provided candidate biomarkers for molecular breeding in oysters. SIGNIFICANCE: Rapid growth has always been the primary breeding objective to increase the production profits of Pacific oyster (Crassostrea gigas), while favorable nutritional quality and beautiful color add commercial value. In recent years, proteomic and metabolomic techniques have been widely used in marine organisms, although these techniques are seldom utilized to study oyster growth and development. In this study, two C. gigas strains with contrasted phenotypes in growth and shell color provided an ideal model for unraveling the molecular basis of growth and nutrient composition through a comparison of the proteome and metabolome. Since proteins and metabolites are the critical undertakers and the end products of cellular regulatory processes, identifying the differentially expressed proteins and metabolites would allow for discovering biomarkers and pathways that were implicated in cell growth, proliferation, and other critical functions. This work provides valuable resources in assistance with molecular breeding of oyster strains with superior production traits of fast-growth and high-quality nutrient value.

Soil conditioners promote the formation of Fe-bound organic carbon and its stability.

The close association of soil organic carbon (SOC) with Fe oxides is an important stabilization mechanism for soil organic matter (SOM) against biodegradation. Soil conditioners are of great importance in improving soil quality and soil health. Yet it remains unclear how different conditioners would affect the fractionation of SOC, particularly the Fe-bound organic carbon (Fe-OC). Field-based experiments were conducted in farmland to explore the fractionation of organic carbon (OC) and Fe oxides under the effects of three different soil conditioners (mineral, organic, and microbial conditioners). The results showed that all soil conditioners increased the total OC and Fe-OC contents, with the contribution of Fe-OC to total OC increasing from 1.57% to 2.99%. The low OC/Fe molar ratio indicated that surface adsorption played a crucial role in soil Fe-OC accumulation. Nuclear magnetic resonance (NMR) results suggested that soil conditioner altered the composition of SOM, accelerating O-alkyl C degradation and increasing recalcitrant alkyl C and aromatic C sequestration. Scanning electron microscopy with energy dispersive spectroscopy (SEM-EDS) analysis indicated that all conditioners promoted the association of OC and Fe oxides. Furthermore, comprehensive analysis of 13C isotope and synchrotron radiation-based Fourier transform infrared (SR-FTIR) spectroscopy showed that the mineral conditioner enhanced the association of microbial-derived OC and Fe oxides, whereas the organic conditioner increased the association of plant-derived OC with Fe oxides. These findings provide important insights into the potential mechanisms through which soil conditioners regulate the stability of OC and guide agricultural management.

Bioactive metabolites reveal the therapeutic consistency of epimedii folium from multi-plant sources for the treatment of kidney-yang deficiency.

ETHNOPHARMACOLOGICAL RELEVANCE: Epimedii Folium (Yin-yang-huo in Chinese), a traditional and commonly used herbal medicine (HM), is a representative of multi-plant sources. To date, little is known about the reasons for similar therapeutic effects of this HM from multi-plant sources. AIM OF THE STUDY: To investigate the underlying reasons for the similar pharmacological effects of Epimedii Folium from two botanical sources (Epimedium koreanum Nakai and Epimedium wushanense T. S. Ying). MATERIALS AND METHODS: Firstly, the phytochemicals of the extracts of E. koreanum and E. wushanense were systematically analyzed. Meanwhile, their pharmacological effects on kidney-yang deficiency (KYD) syndrome were evaluated in rats induced by hydrocortisone. Subsequently, we proposed a combined effect index (CEI) to assess the effects of two plants on the secretion of testosterone by combing the system exposure of twelve active components in vivo with their regulation activities of testosterone production in vitro. Moreover, the label-free proteomics and Western blot analysis were conducted to evaluate the possible mechanism of Epimedii Folium from two botanical sources. RESULTS: E. koreanum and E. wushanense exhibited similar pharmacological effects on KYD syndrome with promoting the mating behaviors and testosterone levels of rats, although there is a certain difference in the main components between two plants. The CEI analysis showed that there was no difference (P > 0.05) in the sum of CEIs of two Epimedium, indicating that their similar therapeutic effects are attributed to bioactive metabolites in vivo. Furthermore, Epimedii Folium can regulate testosterone production in rat Leydig cell via reversing expressions of key steroidogenic enzymes, such as steroidogenic acute regulatory protein (StAR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD). CONCLUSION: Our results supply critical evidence for the similar pharmacological effects of two Epimedium species, acting by consistent bioactive components directly exposing in vivo, not chemical compositions presenting in herbs. It provides a reasonable scientific basis for understanding of the HMs originated from multi-plant sources for the same clinical application.

Phase transformation of Cr(VI) host-mineral driven by citric acid-aided mechanochemical approach for advanced remediation of chromium ore processing residue-contaminated soil.

The slow release of Cr(VI) from chromium ore processing residue-contaminated soil (COPR-soil) poses a significant environmental and health risk, yet advanced remediation techniques are still insufficient. Here, the slow-release behavior of Cr(VI) in COPR-soil is observed and attributed to the embedded Cr(VI) in the lattice of vaterite due to the isomeric substitution of CrO42- for CO32-. A citric acid-aided mechanochemical approach with FeS2/ZVI as reductive material was developed and found to be highly effective in remediating COPR-soil. Almost all Cr(VI) in COPR-soil, including Cr(VI) embedded in the minerals, are reduced with a reduction efficiency of 99.94%. Cr(VI) reduction kinetics indicate that the Cr(VI) reduction rate constant in the presence of citric acid was 4.8 times higher compared to its absence. According to the Raman spectroscopy, X-ray diffraction (XRD), and Electron Probe X-ray Micro-Analyzer (EPMA) analysis, the reduction of Cr(VI) embedded in vaterite was mainly attributed to the citric acid-induced protonation effect. That is, under the protonation effect, the embedded Cr(VI) could be released from vaterite through its phase transformation to calcite, whose affinity to Cr(VI) is low. While the reduction of released Cr(VI) could be promoted due to the complexation of citric acid with disulfide groups on FeS2/ZVI. The results of long-term stability tests demonstrated that the remediated COPR-soil exhibited excellent long-term stability, which may also be associated with improved utilization of available carbon and electron donors by the Cr(VI) reducing bacteria (Proteobacteria)-dominated microbial community in the presence of citric acid, thereby promoting to establish a stable reducing microenvironment. Collectively, these findings will further our understanding of the reduction remediation of COPR-soil, especially in the case of Cr(VI) embedded in minerals.

CTSC promoted the migration and invasion of glioma cells via activation of STAT3/SERPINA3 axis.

Cathepsin C (CTSC) has been reported to be upregulated in several cancers, however, there are still many missing links about the role of CTSC in glioma. To address this knowledge gap, the present study employed bioinformatics analysis, Transwell assay, RT-qPCR and Western blot assays to investigate the expression level of CTSC in glioma tissues, its relationship with survival period, and its effect on the migration and invasion ability of glioma cells. The findings revealed that CTSC was upregulated in glioma and was associated with poor prognosis. Moreover, CTSC was found to promote cell migration and invasion abilities as well as epithelial-mesenchymal transition (EMT). A further study found that CTSC induced SERPINA3 and STAT3 expression in glioma cells. Additionally, we demonstrated that STAT3 signaling mediated upregulation of SERPINA3 expression by CTSC. In sum, our findings suggest that CTSC activates the STAT3/SERPINA3 axis to promote migration and invasion of glioma cells, which may lead to new potential therapeutic approaches for humans with cancer.

Structure, ligands, and roles of GPR126/ADGRG6 in the development and diseases.

Adhesion G protein-coupled receptors (aGPCRs) are the second largest diverse group within the GPCR superfamily, which play critical roles in many physiological and pathological processes through cell-cell and cell-extracellular matrix interactions. The adhesion GPCR Adgrg6, also known as GPR126, is one of the better-characterized aGPCRs. GPR126 was previously found to have critical developmental roles in Schwann cell maturation and its mediated myelination in the peripheral nervous system in both zebrafish and mammals. Current studies have extended our understanding of GPR126-mediated roles during development and in human diseases. In this review, we highlighted these recent advances in GPR126 in expression profile, molecular structure, ligand-receptor interactions, and associated physiological and pathological functions in development and diseases.

X-box binding protein 1 caused an imbalance in pyroptosis and mitophagy in immature rats with di-(2-ethylhexyl) phthalate-induced testis toxicity.

As a widely used plasticizer, di-(2-ethylhexyl) phthalate (DEHP) is known to induce significant testicular injury. However, the potential mechanism and effects of pubertal exposure to DEHP on testis development remain unclear. In vivo, postnatal day (PND) 21 male rats were gavaged with 0, 250, and 500 mg/kg DEHP for ten days. Damage to the seminiferous epithelium and disturbed spermatogenesis were observed after DEHP exposure. Meanwhile, oxidative stress-induced injury and pyroptosis were activated. Both endoplasmic reticulum (ER) stress and mitophagy were involved in this process. Monoethylhexyl phthalate (MEHP) was used as the biometabolite of DEHP in vitro. The GC-1 and GC-2 cell lines were exposed to 0, 100 µM, 200 µM, and 400 µM MEHP for 24 h. Reactive oxygen species (ROS) generation, oxidative stress damage, ER stress, mitophagy, and pyroptosis were significantly increased after MEHP exposure. The ultrastructure of the ER and mitochondria was destroyed. X-box binding protein 1 (XBP1) was observed to be activated and translocated into the nucleus. ROS generation was inhibited by acetylcysteine. The levels of antioxidative stress, ER stress, mitophagy, and pyroptosis were decreased as well. After the administration of the ER stress inhibitor 4-phenyl-butyric acid, both mitophagy and pyroptosis were inhibited. Toyocamycin-induced XBP1 down-regulation decreased the levels of mitophagy and pyroptosis. The equilibrium between pyroptosis and mitophagy was disturbed by XBP1 accumulation. In summary, our findings confirmed that DEHP induced a ROS-mediated imbalance in pyroptosis and mitophagy in immature rat testes via XBP1. Moreover, XBP1 might be the key target in DEHP-related testis dysfunction.

Dysfunction of visual novelty detection in physical but not social anhedonia in a non-clinical sample

Background/objective: Despite its obvious motivational impairment, anhedonia as a transdiagnostic psychopathological construct is accompanied by deficits in attention function. Previous studies have identified voluntary attention anomalies in anhedonia, but its involuntary attention has received less study. Method: Using a visual novelty oddball task, the current event-related potential study assessed electrophysical correlates underlying mismatch detection in anhedonia with a non-clinical sample. Well-matched healthy control (N = 28; CNT), social anhedonia (N = 27; SA), and physical anhedonia (N = 26; PA) groups were presented standard, target, and perceptually novel stimuli while their EEG was recording. Results: The PA group relative to the CNT group exhibited a reduced N2 to novel stimuli but not to target stimuli. In contrast, the SA group as compared to the other two groups showed comparable N2 responses to both target and novel stimuli. Control analyses indicated that these patterns were unaffected by depression symptoms. Conclusions: These findings suggest that anhedonia is a heterogenous construct associated with impairments in early detection of visual novelty in physical but not social anhedonia, highlighting that dysfunction in involuntary attention may play a mediating role in the development, maintenance, and consequences of anhedonia-related psychopathology. (AU)

Werner Salt as Nickel and Ammonia Source for Photochemical Synthesis of Primary Aryl Amines.

Cheap, stable and easy-to-handle Werner ammine salts have been known for more than a century; but they have been rarely used in organic synthesis. Herein, we report that the Werner hexammine complex [Ni(NH3)6]Cl2 can be used as both a nitrogen and a catalytic nickel source that allow for the efficient amination of aryl chlorides in the presence of a catalytic amount of  bipyridine ligand under the irradiation of 390-395 nm light without the need of any additional catalysts. More than 80 aryl chlorides, including more than 20 drug molecules, were aminated, demonstrating the practicality and generality of this method in synthetic chemistry. A slow NH3 release mechanism is in operation, obviating the problem of catalyst poisoning. Still interestingly, we show that the Werner salt can be easily recovered and reused, solving the problem of easy deactivation and difficult recovery of transition metal nickel catalysts. The protocol thus provides an efficient new strategy for the synthesis of primary aryl amines.

Triggering endogenous Z-RNA sensing for anti-tumor therapy through ZBP1-dependent necroptosis.

ZBP1 senses viral Z-RNAs to induce necroptotic cell death to restrain viral infection. ZBP1 is also thought to recognize host cell-derived Z-RNAs to regulate organ development and tissue inflammation in mice. However, it remains unknown how the host-derived Z-RNAs are formed and how these endogenous Z-RNAs are sensed by ZBP1. Here, we report that oxidative stress strongly induces host cell endogenous Z-RNAs, and the Z-RNAs then localize to stress granules for direct sensing by ZBP1 to trigger necroptosis. Oxidative stress triggers dramatically increase Z-RNA levels in tumor cells, and the Z-RNAs then directly trigger tumor cell necroptosis through ZBP1. Localization of the induced Z-RNAs to stress granules is essential for ZBP1 sensing. Oxidative stress-induced Z-RNAs significantly promote tumor chemotherapy via ZBP1-driven necroptosis. Thus, our study identifies oxidative stress as a critical trigger for Z-RNA formation and demonstrates how Z-RNAs are directly sensed by ZBP1 to trigger anti-tumor necroptotic cell death.

Mirabegron and antimuscarinics for treating ureteral stent-related symptoms: a systematic review and meta-analysis of RCTs.

Objective: We conducted a meta-analysis to assess the efficacy and safety of mirabegron (50 mg/day) and antimuscarinics in treating ureteral stent-related symptoms (SRSs). Methods: All randomized controlled trials (RCTs) were identified by searching PubMed, Embase, Web of Science, and Cochrane Library. The RevMan version 5.3.0 software was used for statistical analysis. Results: This meta-analysis included five RCTs involving 317 patients. A fixed effects model revealed that mirabegron was superior to antimuscarinics in treating urinary symptoms (MD -1.39, 95% CI -2.63 to -0.15, p = 0.03) and general health (MD -1.65, 95% CI -2.60 to -0.69, p = 0.0007) 1 week after treatment initiation. We observed no significant differences in body pain (MD 0.05, 95% CI -1.06 to 1.15, p = 0.94), work performance (MD -0.86, 95% CI -1.77 to 0.06, p = 0.07), and sexual matters (MD 0.03, 95% CI -0.77 to 0.83, p = 0.94). Two weeks after treatment initiation, the ureteral stent symptom questionnaire (USSQ) revealed no significant differences between the two groups. The mirabegron group demonstrated a significant improvement in the quality of life (QoL) (MD -0.18, 95% CI -0.34 to -0.01, p = 0.03), while the International Prostate Symptom Score did not reveal a significant difference between the two groups (MD -0.74, 95% CI -1.79 to 0.32, p = 0.17). Regarding safety, a pooled data analysis presented that the incidence of constipation was lower in the mirabegron group (OR 0.10, 95% CI 0.01 to 0.77, p = 0.03). The mirabegron and antimuscarinics groups did not differ significantly concerning the risk of dry mouth (OR 0.15, 95% CI 0.02 to 1.27, p = 0.08). Conclusion: Mirabegron is superior to antimuscarinics in alleviating ureteral SRSs and improving QoL. Additionally, mirabegron 50 mg/day presented safety with a lower incidence of constipation.