Impact of Different π-Bridges on the Photovoltaic Performance of A-D-D'-D-A Small Molecule-Based Donors.

Three small donor molecule materials (S1, S2, S3) based on dithiophene [2,3-d:2',3'-d']dithiophene [1,2-b:4,5-b']dithiophene (DTBDT) utilized in this study were synthesized using the Vilsmeier-Haack reaction, traditional Stille coupling, and Knoevenagel condensation. Then, a variety of characterization methods were applied to study the differences in optical properties and photovoltaic devices among the three. By synthesizing S2 using a thiophene π-bridge based on S1, the blue shift in ultraviolet absorption can be enhanced, the band gap and energy level can be reduced, the open circuit voltage (VOC) can be increased to 0.75 V using the S2:Y6 device, and a power conversion efficiency (PCE) of 3% can be achieved. Also, after developing the device using Y6, S3 introduced the alkyl chain of thiophene π-bridge to S2, which improved the solubility of tiny donor molecules, achieved the maximum short-circuit current (JSC = 10.59 mA/cm2), filling factor (FF = 49.72%), and PCE (4.25%). Thus, a viable option for future design and synthesis of small donor molecule materials is to incorporate thiophene π-bridges into these materials, along with alkyl chains, in order to enhance the device's morphology and charge transfer behavior.

The microglial P2Y6 receptor as a therapeutic target for neurodegenerative diseases.

Neurodegenerative diseases are associated with chronic neuroinflammation in the brain, which can result in microglial phagocytosis of live synapses and neurons that may contribute to cognitive deficits and neuronal loss. The microglial P2Y6 receptor (P2Y6R) is a G-protein coupled receptor, which stimulates microglial phagocytosis when activated by extracellular uridine diphosphate, released by stressed neurons. Knockout or inhibition of P2Y6R can prevent neuronal loss in mouse models of Alzheimer's disease (AD), Parkinson's disease, epilepsy, neuroinflammation and aging, and prevent cognitive deficits in models of AD, epilepsy and aging. This review summarises the known roles of P2Y6R in the physiology and pathology of the brain, and its potential as a therapeutic target to prevent neurodegeneration and other brain pathologies.

Discovery of a potent, Highly selective, and In vivo anti-inflammatory Efficacious, P2Y6R antagonist with a novel quinoline-pyrazole scaffold.

The P2Y6 receptor (P2Y6R), as a crucial member of the purine family, is a potential therapeutic target for the treatment of intestinal inflammation, tracheal inflammation and diabetes. We first discovered the hit compound (5a, IC50 = 168.5 nM against P2Y6R) through our in-house library screening. Then, further medicinal chemistry efforts were made to optimize compound 5a, and a potent P2Y6R antagonist (5 ab) with better antagonistic activity (IC50 = 19.6 nM) was obtained. The molecular docking, CETSA, SPR and pull-down results indicated that compound 5 ab displayed strong binding to P2Y6R. Also, compound 5 ab possessed high selectivity and satisfying oral bioactivity and pharmacokinetic profiles. In experiments with LPS-induced acute lung injury in mice, after treatment with compound 5 ab, the level of inflammatory factors IL-6, TNF-α and IL-ß were considerably decreased, the infiltration of immune cells was decreased. Further exploration revealed that 5 ab inhibited the expression and release of chemokines in lung tissue, suppressing the activation of the NLRP3 inflammasome. Compound 5 ab had certain anti-inflammatory abilities in vivo and in vitro. These results demonstrate that compound 5 ab is a potential P2Y6R antagonist and is worthy of further study.

Inner/Outer Side Chain Engineering of Non-Fullerene Acceptors for Efficient Large-Area Organic Solar Modules Based on Non-Halogenated Solution Processing in Air.

Achieving efficient and large-area organic solar modules via non-halogenated solution processing is vital for the commercialization yet challenging. The primary hurdle is the conservation of the ideal film-formation kinetics and bulk-heterojunction (BHJ) morphology of large-area organic solar cells (OSCs). A cutting-edge non-fullerene acceptor (NFA), Y6, shows efficient power conversion efficiencies (PCEs) when processed with toxic halogenated solvents, but exhibits poor solubility in non-halogenated solvents, resulting in suboptimal morphology. Therefore, in this study, the impact of modifying the inner and outer side-chains of Y6 on OSC performance is investigated. The study reveals that blending a polymer donor, PM6, with one of the modified NFAs, namely N-HD, achieved an impressive PCE of 18.3% on a small-area OSC. This modified NFA displays improved solubility in o-xylene at room temperature, which facilitated the formation of a favorable BHJ morphology. A large-area (55 cm2) sub-module delivered an impressive PCE of 12.2% based on N-HD using o-xylene under ambient conditions. These findings underscore the significant impact of the modified Y6 derivatives on structural arrangements and film processing over a large-area module at room temperature. Consequently, these results are poised to deepen the comprehension of the scaling challenges encountered in OSCs and may contribute to their commercialization.

Epigallocatechin Gallate Derivative Y6 Reverses Oxaliplatin Resistance in Hepatocellular Carcinoma via Targeting the MiR-338-3p/HIF-1α/TWIST Axis to Inhibit EMT.

BACKGROUND: The emergence of drug resistance to oxaliplatin (OXA) is one of the critical obstacles in the therapy of advanced Hepatocellular Carcinoma (HCC). As an ethyl derivative of the natural compound epigallocatechin gallate (epigallocatechin-3-gallate, EGCG), Y6 was found to be able to enhance the sensitivity of HCC cells to doxorubicin. This study aimed to investigate the effect of Y6 on oxaliplatin resistance in HCC. METHODS: MTT was used to determine the reversal effect of Y6 on OXA resistance. To further explore the reversal mechanism, we treated OXA alone or in combination with Y6 or EGCG in drugresistant cells and observed the morphological changes of the cells. At the same time, transwell assay was used to detect the invasion and migration ability of cells. Moreover, Real-time PCR and Western blot analysis were performed to determine the expression levels of the miR-338-3p gene, HIF-1α/Twist proteins, and EMT-related proteins. RESULTS: We found that Y6 could inhibit the proliferation of HCC cells and effectively reverse the drug resistance of oxaliplatin-resistant human liver cancer cells (SMMC-7721/OXA) to OXA, and the reversal effect was more significant than that of its lead drug EGCG. Most of the cells in the control group and OXA group showed typical mesenchymal-like cell morphology, while most of the cells in co-administration groups showed typical epithelioid cell morphology, and the ability of the cells to invade and migrate decreased dramatically, particularly in Y6 plus OXA group. At the same time, Y6 could up-regulate the EMT epithelial marker protein E-cadherin and down-regulate the interstitial marker protein Vimentin. In addition, in co-administration groups, the expression of miR-338-3p was up-regulated, while the expression of HIF-1α and Twist was down-regulated. CONCLUSION: Y6 significantly enhanced the susceptibility of drug-resistant cells to OXA, and the process may be related to the regulation of miR-338-3p/HIF-1α / TWIST pathway to inhibit EMT. Therefore, Y6 could be considered an effective medication resistance reversal agent, which could improve the therapeutic effect for hepatocellular cancer patients.

Mechanical stimulation-induced purinome priming fosters osteogenic differentiation and osteointegration of mesenchymal stem cells from the bone marrow of post-menopausal women.

BACKGROUND: Mechanical stimulation (MS) significantly increases the release of adenine and uracil nucleotides from bone marrow-derived mesenchymal stem cells (BM-MSCs) undergoing osteogenic differentiation. Released nucleotides acting via ionotropic P2X7 and metabotropic P2Y6 purinoceptors sensitive to ATP and UDP, respectively, control the osteogenic commitment of BM-MSCs and, thus, bone growth and remodelling. Yet, this mechanism is impaired in post-menopausal (Pm)-derived BM-MSCs, mostly because NTPDase3 overexpression decreases the extracellular accumulation of nucleotides below the levels required to activate plasma membrane-bound P2 purinoceptors. This prompted us to investigate whether in vitro MS of BM-MSCs from Pm women could rehabilitate their osteogenic commitment and whether xenotransplantation of MS purinome-primed Pm cells promote repair of critical bone defects in an in vivo animal model. METHODS: BM-MSCs were harvested from the neck of femora of Pm women (70 ± 3 years old) undergoing total hip replacement. The cells grew, for 35 days, in an osteogenic-inducing medium either submitted (SS) or not (CTR) to MS (90 r.p.m. for 30 min) twice a week. Increases in alkaline phosphatase activity and in the amount of osteogenic transcription factors, osterix and osteopontin, denoted osteogenic cells differentiation, while bone nodules formation was ascertain by the alizarin red-staining assay. The luciferin-luciferase bioluminescence assay was used to quantify extracellular ATP. The kinetics of the extracellular ATP (100 µM) and UDP (100 µM) catabolism was assessed by HPLC. The density of P2Y6 and P2X7 purinoceptors in the cells was assessed by immunofluorescence confocal microscopy. MS-stimulated BM-MSCs from Pm women were xenotransplanted into critical bone defects drilled in the great trochanter of femora of one-year female Wistar rats; bone repair was assessed by histological analysis 10 days after xenotransplantation. RESULTS: MS-stimulated Pm BM-MSCs in culture (i) release 1.6-fold higher ATP amounts, (ii) overexpress P2X7 and P2Y6 purinoceptors, (iii) exhibit higher alkaline phosphatase activity and overexpress the osteogenic transcription factors, osterix and osteopontin, and (iv) form larger bone nodules, than CTR cells. Selective blockage of P2X7 and P2Y6 purinoceptors with A438079 (3 µM) and MRS 2578 (0.1 µM), respectively, prevented the osteogenic commitment of cultured Pm BM-MSCs. Xenotransplanted MS purinome-primed Pm BM-MSCs accelerated the repair of critical bone defects in the in vivo rat model. CONCLUSIONS: Data suggest that in vitro MS restores the purinergic cell-to-cell communication fostering the osteogenic differentiation and osteointegration of BM-MSCs from Pm women, a strategy that may be used in bone regeneration and repair tactics.

Lipo/TK-CDN/TPP/Y6 nanoparticles inhibit cutaneous melanoma formation.

Stimulation of the innate immune stimulator of interferon genes (STING) pathway has been shown to boost anti-tumour immunity. Nevertheless, the systemic delivery of STING agonists to the tumour presents challenges. Therefore, we designed a cyclic dinucleotide (CDN)-based drug delivery system (DDS) combined photothermal therapy (PTT)/photodynamic therapy (PDT)/immunotherapy for cutaneous melanoma. We coencapsulated a reactive oxygen species (ROS)-responsive prodrug thioketone-linked CDN (TK-CDN), and photoresponsive agents chlorin E6 (Y6) within mitochondria-targeting reagent triphenylphosphonium (TPP)-modified liposomes (Lipo/TK-CDN/TPP/Y6). Lipo/TK-CDN/TPP/Y6 exhibited a photothermal effect similar to Y6, along with a superior cellular uptake rate. Upon endocytosis by B16F10 cells, Lipo/TK-CDN/TPP/Y6 generated large amounts of ROS under laser irradiation for PDT. Mice bearing B16F10 tumours were intravenously injected with Lipo/TK-CDN/TPP/Y6 and exposed to irradiation, resulting in a substantial inhibition of tumour growth. Exploration of the mechanism of anti-tumour action showed that Lipo/TK-CDN/TPP/Y6 had a stronger stimulation of STING activation and anti-tumour immune cell infiltration compared to other groups. Hence, the Lipo/TK-CDN/TPP/Y6 nanoparticles offer great potential as a DDS for targeted and on-demand drug release at tumour sites. These nanoparticles exhibit promise as a candidate for precise and controllable combination therapy in the treatment of tumours.

Broadband PM6Y6 coreshell hybrid composites for photocurrent improvement and light trapping.

Our research focuses on enhancing the broadband absorption capability of organic solar cells (OSCs) by integrating plasmonic nanostructures made of Titanium nitride (TiN). Traditional OSCs face limitations in absorption efficiency due to their thickness, but incorporating plasmonic nanostructures can extend the path length of light within the active material, thereby improving optical efficiency. In our study, we explore the use of refractory plasmonics, a novel type of nanostructure, with TiN as an example of a refractory metal. TiN offers high-quality localized surface plasmon resonance in the visible spectrum and is cost-effective, readily available, and compatible with CMOS technology. We conducted detailed numerical simulations to optimize the design of nanostructured OSCs, considering various shapes and sizes of nanoparticles within the active layer (PM6Y6). Our investigation focused on different TiN plasmonic nanostructures such as nanospheres, nanocubes, and nanocylinders, analyzing their absorption spectra in a polymer environment. We assessed the impact of their incorporation on the absorbed power and short-circuit current (Jsc) of the organic solar cell.

Detecting Visible to Near-Infrared II Light via CsPbBr3 Nanocrystals/Y6 Heterojunctions.

In the endeavor to develop advanced photodetectors (PDs) with superior performance, all-inorganic perovskites, recognized for their outstanding photoelectric properties, have emerged as highly promising materials. Due to their unique electronic structure and band characteristics, the majority of all-inorganic perovskite materials are not sensitive to near-infrared (NIR) light. Here, we demonstrate the fabrication of a high-performance broadband PD comprising CsPbBr3 perovskite NCs/Y6 planar heterojunctions. The incorporation of Y6 not only facilitates charge transfer from CsPbBr3 NCs to Y6 for enhancing photodetection performance under visible illumination but also broadens the absorption spectrum range of the whole device toward the NIR regime. As a result, the heterojunction PD exhibits a photo-to-dark-current ratio above 105, a dynamic range of 149.5 dB, and an impressive lowest detection limit of incident power density of 1.6 nW/cm2 under 505 nm illumination. In the NIR regime, where photon energy is below the bandgap of CsPbBr3, electron-hole pairs can still be produced in the Y6 layer even when illuminated at 1120 nm. Consequently, photodetection is uniquely possible in PDs that incorporate heterojunctions when the illumination wavelength is longer than 565 nm. At 850 nm, the heterojunction device is capable of detecting light with power densities as low as 1.3 µW/cm2 corresponding to a LDR of 99.8 dB. The exceptional performance is attributed to the creation of a heterojunction between CsPbBr3 NCs and Y6. These findings propose a novel approach for developing broadband PDs based on perovskite NC materials.

Advancing Integration of Direct C-H Arylation-Derived Star-Shaped Oligomers as Second Acceptors for Ternary Organic Solar Cells.

Organic solar cells (OSCs) could benefit from the ternary bulk heterojunction (BHJ), a method that allows for fine-tuning of light capture, cascade energy levels, and film shape, in order to increase their power conversion efficiency (PCE). In this work, the third components of PM6:Y6 and PM6:BTP-eC9 BHJs are a set of four star-shaped unfused ring electron acceptors (SSUFREAs), i.e., BD-IC, BFD-IC, BD-2FIC, and BFD-2FIC, that are facilely synthesized by direct C-H arylation. The four SSUFREAs all show complete complementary absorption with PM6, Y6, and BTP-eC9, which facilitates light harvesting and exciton collection. When BFD-2FIC is added as a third component, the PCEs of PM6:Y6 and PM6:BTP-eC9 binary BHJs are able to be improved from 15.31% to 16.85%, and from 16.23% to 17.23%, respectively, showing that BFD-2FIC is useful for most effective ternary OSCs in general, and increasing short circuit current (JSC) and better film morphology are two additional benefits. The ternary PM6:Y6:BFD-2FIC exhibits a 9.7% percentage of increase in PCE compared to the PM6:Y6 binary BHJ, which is one of the highest percentage increases among the reported ternary BHJs, showing the huge potential of BFD-2FIC for ternary BHJ OSCs.

Uracil as a biomarker for spatial pyrimidine metabolism in the development of gingivobuccal oral squamous cell carcinoma.

No biomarker has yet been identified that allows accurate diagnosis and prognosis of oral cancers. In this study, we investigated the presence of key metabolites in oral cancer using proton nuclear magnetic resonance (NMR) spectroscopy to identify metabolic biomarkers of gingivobuccal oral squamous cell carcinoma (GB-OSCC). NMR spectroscopy revealed that uracil was expressed in 83.09% of tumor tissues and pyrimidine metabolism was active in GB-OSCC; these results correlated well with immunohistochemistry (IHC) and RNA sequencing data. Based on further gene and protein analyses, we proposed a pathway for the production of uracil in GB-OSCC tissues. Uridinetriphosphate (UTP) is hydrolyzed to uridine diphosphate (UDP) by CD39 in the tumor microenvironment (TME). We hypothesized that UDP enters the cell with the help of the UDP-specific P2Y6 receptor for further processing by ENTPD4/5 to produce uracil. As the ATP reserves diminish, the weakened immune cells in the TME utilize pyrimidine metabolism as fuel for antitumor activity, and the same mechanism is hijacked by the tumor cells to promote their survival. Correspondingly, the differential expression of ENTPD4 and ENTPD5 in immune and tumor cells, respectively, indicatedtheir involvement in disease progression. Furthermore, higher uracil levels were detected in patients with lymph node metastasis, indicating that metastatic potential is increased in the presence of uracil. The presence of uracil and/or expression patterns of intermediate molecules in purine and pyrimidine pathways, such asCD39, CD73, and P2Y6 receptors together with ENTPD4 and ENTPD5, hold promise as biomarker(s) for oral cancer diagnosis and prognosis.

Astilbin inhibited neutrophil extracellular traps in gouty arthritis through suppression of purinergic P2Y6 receptor.

BACKGROUND: Gouty arthritis (GA), a common inflammatory condition triggered by monosodium urate crystal accumulation, often necessitates safer treatment alternatives due to the limitations of current therapies. Astilbin, a flavonoid from Smilax glabra Roxb, has demonstrated potential in traditional Chinese medicine for its anti-inflammatory properties. However, the anti-GA effect and its underlying mechanism have not been fully elucidated. PURPOSE: This study aimed to investigate the therapeutic potential of astilbin in GA, focusing on its effects on neutrophil extracellular traps (NETs), as well as the potential molecular target of GA both in vitro and in vivo. STUDY DESIGN: Firstly, astilbin inhibited the citrullinated histone H3 (Cit h3) protein levels and reduced the NETs formation in neutrophils stimulated by monosodium urate (MSU). Secondly, we wondered the effect of astilbin on migration of neutrophils and dimethyl-sulfoxide (DMSO)-differentiated HL-60 (dHL-60) cells under the stimulation of MSU. Then, the effect of astilbin on suppressing NETs through purinergic P2Y6 receptor (P2Y6R) and Interlukin-8 (IL-8)/ CXC chemokine receptor 2 (CXCR2) pathway was investigated. Also, the relationship between P2Y6R and IL-8/CXCR2 was explored in dHL-60 cells under stimulation of MSU. Finally, we testified the effect of astilbin on reducing NETs in GA through suppressing P2Y6R and then down-regulating IL-8/CXCR2 pathway. METHODS: MSU was used to induce NETs in neutrophils and dHL-60 cells. Real-time formation of NETs and migration of neutrophils were monitored by cell living imaging with or without MSU. Then, the effect of astilbin on NETs formation, P2Y6R and IL-8/CXCR2 pathway were detected by immunofluorescence (IF) and western blotting. P2Y6R knockdown dHL-60 cells were established by small interfering RNA to investigate the association between P2Y6R and IL-8/CXCR2 pathway. Also, plasmid of P2Y6R was used to overexpress P2Y6R in dHL-60 cells, which was employed to explore the role of P2Y6R in astilbin inhibiting NETs. Within the conditions of knockdown and overexpression of P2Y6R, migration and NETs formation were assessed by transmigration assay and IF staining, respectively. In vivo, MSU-induced GA mice model was established to assess the effect of astilbin on inflammation by haematoxylin-eosin and ELISA. Additionally, the effects of astilbin on neutrophils infiltration, NETs, P2Y6R and IL-8/CXCR2 pathway were analyzed by IF, ELISA, immunohistochemistry (IHC) and western blotting. RESULTS: Under MSU stimulation, astilbin significantly suppressed the level of Cit h3 and NETs formation including the fluorescent expressions of Cit h3, neutrophils elastase, myeloperoxidase, and intra/extracellular DNA. Also, results showed that MSU caused NETs release in neutrophils as well as a trend towards recruitment of dHL-60 cells to MSU. Astilbin could markedly decrease expressions of P2Y6R and IL-8/CXCR2 pathway which were upregulated by MSU. By silencing P2Y6R, the expression of IL-8/CXCR2 pathway and migration of dHL-60 cells were inhibited, leading to the suppression of NETs. These findings indicated the upstream role of P2Y6R in the IL-8/CXCR2 pathway. Moreover, overexpression of P2Y6R was evidently inhibited by astilbin, causing a downregulation in IL-8/CXCR2 pathway, migration of dHL-60 cells and NETs formation. These results emphasized that astilbin inhibited the IL-8/CXCR2 pathway primarily through P2Y6R. In vivo, astilbin administration led to marked reductions in ankle swelling, inflammatory infiltration as well as neutrophils infiltration. Expressions of P2Y6R and IL-8/CXCR2 pathway were evidently decreased by astilbin and P2Y6R inhibitor MRS2578 either alone or in combination. Also, astilbin and MRS2578 showed notable effect on reducing MSU-induced NETs formation and IL-8/CXCR2 pathway whether used alone or in combination, parallelly demonstrating that astilbin decreased NETs formation mainly through P2Y6R. CONCLUSION: This study revealed that astilbin suppressed NETs formation via downregulating P2Y6R and subsequently the IL-8/CXCR2 pathway, which evidently mitigated GA induced by MSU. It also highlighted the potential of astilbin as a promising natural therapeutic for GA.

Microglial P2Y6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis.

Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-κB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium extruder ("CalEx") expression recapitulates multiple features of P2Y6 knockout, including reduced lysosome biogenesis and phagocytic interactions. Ultimately, P2Y6 knockout mice retain more CA3 neurons and better cognitive task performance during epileptogenesis. Our results demonstrate that P2Y6 signaling impacts multiple aspects of myeloid cell immune function during epileptogenesis.

Baicalin inhibited PANX-1/P2Y6 signaling pathway activation in porcine aortic vascular endothelial cells infected by Glaesserella parasuis.

Glaesserella parasuis can induce endothelial barrier damage in piglets, although the mechanism by which this pathogen triggers inflammatory damage remains unclear. Baicalin possesses anti-inflammatory and anti-oxidant activities. However, whether baicalin can relieve endothelial barrier damage caused by Glaesserella parasuis infection has not yet been studied. Hence, we evaluated the ability of baicalin to counteract the changes induced by Glaesserella parasuis in porcine aortic vascular endothelial cells. The results showed that Glaesserella parasuis could upregulate the expression of pannexin 1 channel protein and promote the release of adenosine triphosphate, adenosine diphosphate, adenosine 3'-monophosphate, uridine triphosphate, uridine diphosphate, and uridine monophosphate in porcine aortic vascular endothelial cells. The expression level of purinergic receptor P2Y6 was upregulated in porcine aortic vascular endothelial cells triggered by Glaesserella parasuis. In addition, Glaesserella parasuis could activate phospholipase C-protein kinase C and myosin light chain kinase-myosin light chain signaling pathways in porcine aortic vascular endothelial cells. Baicalin could inhibit pannexin 1 channel protein expression, reduce adenosine triphosphate, adenosine diphosphate, adenosine 3'-monophosphate, uridine triphosphate, uridine diphosphate, and uridine monophosphate release, and attenuate the expression level of P2Y6 in porcine aortic vascular endothelial cells induced by Glaesserella parasuis. Baicalin could also reduce the activation of phospholipase C-protein kinase C and myosin light chain kinase-myosin light chain signaling pathways in porcine aortic vascular endothelial cells triggered by Glaesserella parasuis. Our study report that Glaesserella parasuis could promote pannexin 1 channel protein expression, induce nucleosides substance release, and P2Y6 expression in porcine aortic vascular endothelial cells and baicalin could inhibit the expression levels of pannexin 1, nucleosides substance, and P2Y6 in the porcine aortic vascular endothelial cells induced by Glaesserella parasuis, which might be served as some targets for treatment of inflammation disease caused by Glaesserella parasuis.

Molecular-Level Insight into Impact of Additives on Film Formation and Molecular Packing in Y6-based Organic Solar Cells.

Additive engineering is widely utilized to optimize film morphology in active layers of organic solar cells (OSCs). However, the role of additive in film formation and adjustment of film morphology remains unclear at the molecular level. Here, taking high-efficiency Y6-based OSC films as an example, this work thus employs all-atom molecular-dynamics simulations to investigate how introduction of additives with different π-conjugation degree thermodynamically and dynamically impacts nanoscale molecular packings. These results demonstrate that the van der Waals (vdW) interactions of the Y6 end groups with the studied additives are strongest. The larger the π-conjugation degree of the additive molecules, the stronger the vdW interactions between additive and Y6 molecules. Due to such vdW interactions, the π-conjugated additive molecules insert into the neighboring Y6 molecules, thus opening more space for relaxation of Y6 molecules to trigger more ordered packing. Increasing the interactions between the Y6 end groups and the additive molecules not only accelerates formation of the Y6 ordered packing, but also induces shorter Y6-intermolecular distances. This work reveals the fundamental molecular-level mechanism behind film formation and adjustment of film morphology via additive engineering, providing an insight into molecular design of additives toward optimizing morphologies of organic semiconductor films.

Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cß/store-operated calcium entry/calreticulin/scavenger receptor A pathways.

BACKGROUND AND AIMS: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. METHODS: The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. RESULTS: The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cß/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. CONCLUSIONS: Macrophage P2Y6R regulates phospholipase Cß/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.

19.32% Efficiency Polymer Solar Cells Enabled by Fine-Tuning Stacking Modes of Y-Type Molecule Acceptors: Synergistic Bromine and Fluorine Substitution of the End Groups.

The success of Y6-type nonfullerene small molecule acceptors (NF-SMAs) in polymer solar cells (PSCs) can be attributed to their unique honeycomb stacking style, which leads to favorable thin-film morphologies. The intermolecular interactions related to the crystallization tendency of these NF-SMAs is closely governed by their electron accepting end groups. For example, the high performance Y6 derivative L8-BO (BTP-4F) presents three types of stacking modes in contrast to two stacking modes of Y6. Hence, it is ultimately interesting to obtain more insight on the packing properties and the preferences influenced by chemical modifications such as end group engineering. This work designs and synthesizes asymmetric and symmetric L8-BO derivatives with brominated end groups and explores the stacking preferences in various modes. The asymmetric BTP-3FBr displays an optimized crystallization tendency and thin film morphology, leading to a decent power conversion efficiency (PCE) of 18.34% in binary devices and a top PCE of 19.32% in ternary devices containing 15 wt% IDIC as the second acceptor.

Fluorinated curcumin derivative (Shiga-Y6) modulates the level of thioredoxin-interacting protein (TXNIP) in a mouse model of diabetes.

Thioredoxin interacting protein (TXNIP) has emerged as a significant regulator of ß-cell mass and loss, rendering it an attractive target for treating diabetes. We previously showed that Shiga-Y6, a fluorinated curcumin derivative, inhibited TXNIP mRNA and protein expression in vitro, raising the question of whether the same effect could be translated in vivo. Herein, we examined the effect of Shiga-Y6 on TNXIP levels and explored its therapeutic potential in a mouse model of diabetes, Akita mice. We intraperitoneally injected Shiga-Y6 (SY6; 30 mg/kg of body weight) or vehicle into 8-week-old Akita mice for 28 consecutive days. On day 29, the mice were euthanized, following which the serum levels of glucose, insulin, and glucagon were measured using ELISA, the expression of TXNIP in pancreatic tissue lysates was determined using western blotting, and the level of ß-cell apoptosis was assessed using the TUNEL assay. TXNIP levels in the pancreatic tissue of Akita mice were significantly elevated compared with wild-type (WT) mice. Shiga-Y6 administration for 28 days significantly lowered those levels compared with Akita mice that received vehicle to a level comparable to WT mice. In immunohistochemical analysis, both α- to ß-cell ratio and the number of apoptotic ß-cells were significantly reduced in SY6-treated Akita mice, compared with vehicle-treated Akita mice. Findings from the present study suggest a potential of Shiga-Y6 as an antidiabetic agent through lowering TXNIP protein levels and ameliorating pancreatic ß-cells apoptosis.

P2Y6 Receptor Activation Aggravates NLRP3-dependent Microglial Pyroptosis via Downregulation of the PI3K/AKT Pathway in a Mouse Model of Intracerebral Hemorrhage.

Pro-inflammatory signals generated after intracerebral hemorrhage (ICH) trigger a form of regulated cell death known as pyroptosis in microglia. White matter injury (WMI) refers to the condition where the white matter area of the brain suffers from mechanical, ischemic, metabolic, or inflammatory damage. Although the p2Y purinoceptor 6 (P2Y6R) plays a significant role in the control of inflammatory reactions in central nervous system diseases, its roles in the development of microglial pyroptosis and WMI following ICH remain unclear. In this study, we sought to clarify the role of P2Y6R in microglial pyroptosis and WMI by using an experimental mouse model of ICH. Type IV collagenase was injected into male C57BL/6 mice to induce ICH. Mice were then treated with MRS2578 and LY294002 to inhibit P2Y6R and phosphatidylinositol 3-kinase (PI3K), respectively. Bio-conductivity analysis was performed to examine PI3K/AKT pathway involvement in microglial pyroptosis. Quantitative Real-Time PCR, immunofluorescence staining, and western blot were conducted to examine microglial pyroptosis and WMI following ICH. A modified Garcia test, corner turning test, and forelimb placement test were used to assess neurobehavior. Hematoxylin-eosin staining (HE) was performed to detect cells damage around hematoma. Increases in the expression of P2Y6R, NLRP3, ASC, Caspase-1, and GSDMD were observed after ICH. P2Y6R was only expressed on microglia. MRS2578, a specific inhibitor of P2Y6R, attenuated short-term neurobehavioral deficits, brain edema and hematoma volume while improving both microglial pyroptosis and WMI. These changes were accompanied by decreases in pyroptosis-related proteins and pro-inflammatory cytokines both in vivo and vitro. Bioinformatic analysis revealed an association between the PI3K/AKT pathway and P2Y6R-mediated microglial pyroptosis. The effects of MRS2578 were partially reversed by treatment with LY294002, a specific PI3K inhibitor. P2Y6R inhibition alleviates microglial pyroptosis and WMI and ameliorates neurological deficits through the PI3K/AKT pathway after ICH. Consequently, targeting P2Y6R might be a promising approach for ICH treatment.

Enhanced Photovoltaic Properties of Y6 Derivatives with Asymmetric Terminal Groups: A Theoretical Insight.

Y6 derivatives with asymmetric terminal groups have attracted considerable attention in recent years. However, the effects of the asymmetric modification of terminal groups on the photovoltaic performance of Y6 derivatives are not well understood yet. Therefore, we designed a series of Y6-based acceptors with asymmetric terminal groups by endowing them with various electron-withdrawing abilities and different conjugated rings to conduct systematic research. The electron-withdrawing ability of the Y6-D1 terminal group (substituted by IC-2F and IC-2NO2 terminals) is strongest, followed by Y6 (substituted by two same IC-2F terminals), Y6-D2 (substituted by IC-2F and 2-(4-oxo-4,5-dihydro-6H-cyclopenta[b]thiophen-6-ylidene)malononitrile terminals), Y6-D4 (substituted by IC-2F and indene ring), and Y6-D3 (substituted by IC-2F and thiazole ring). Computed results show that A-A stacking is the main molecular packing mode of Y6 and four other asymmetric Y6 derivatives. The ratios of A-A stacking face-on configuration of Y6-D1, Y6-D2, Y6-D3, Y6-D4, and Y6 are 51.6%, 55.0%, 43.5%, 59.3%, and 62.4%, respectively. Except for Y6-D1 substituted by the IC-2F and IC-2NO2 (the strongest electron-withdrawing capacity) terminal groups, the other three asymmetric molecules are mainly electron-transporting and can therefore act as acceptors. The open-circuit voltages of organic solar cells (OSCs) based on Y6-D2, Y6-D3, and Y6-D4, except for Y6-D1, may be higher than those of OSCs based on the Y6 acceptor because of their higher energy levels of lowest unoccupied molecular orbital (LUMO). PM6/Y6-D3 and PM6/Y6-D4 have better light absorption properties than PM6/Y6 due to their higher total oscillator strength. These results indicate that Y6-D3 and Y6-D4 can be employed as good acceptors.