Interactome Analysis of ClpX Reveals Its Regulatory Role in Metabolism and Photosynthesis in Cyanobacteria.

Protein homeostasis is essential for cyanobacteria to maintain proper cellular function under adverse and fluctuating conditions. The AAA+ superfamily of proteolytic complexes in cyanobacteria plays a critical role in this process, including ClpXP, which comprises a hexameric ATPase ClpX and a tetradecameric peptidase ClpP. Despite the physiological effects of ClpX on growth and photosynthesis, its potential substrates and underlying mechanisms in cyanobacteria remain unknown. In this study, we employed a streptavidin-biotin affinity pull-down assay coupled with label-free proteome quantitation to analyze the interactome of ClpX in the model cyanobacterium Synechocystis sp. PCC 6803 (hereafter Synechocystis). We identified 503 proteins as potential ClpX-binding targets, many of which had novel interactions. These ClpX-binding targets were found to be involved in various biological processes, with particular enrichment in metabolic processes and photosynthesis. Using protein-protein docking, GST pull-down, and biolayer interferometry assays, we confirmed the direct association of ClpX with the photosynthetic proteins, ferredoxin-NADP+ oxidoreductase (FNR) and phycocyanin subunit (CpcA). Subsequent functional investigations revealed that ClpX participates in the maintenance of FNR homeostasis and functionality in Synechocystis grown under different light conditions. Overall, our study provides a comprehensive understanding of the extensive functions regulated by ClpX in cyanobacteria to maintain protein homeostasis and adapt to environmental challenges.

Gansulinema gen. nov. and Komarkovaeasiopsis gen. nov.: Novel Oculatellacean genera (Cyanobacteria) isolated from desert soils and hot spring.

To increase the understanding of simple thin filamentous cyanobacteria in harsh environmental areas, we previously isolated and identified four strains (XN101, XN102, GS121, NX122) from desert soils and hot spring in China. As a result, two new Oculatellacean genera of these four strains, Gansulinema gen. nov. and Komarkovaeasiopsis gen. nov., are described based on a polyphasic approach. The ultrastructure of these strains showed a similar arrangement of peripheral thylakoids with three to four parallel layers, indicating that they belonged to the orders Nodosilineales, Oculatellales, or Leptolyngbyales. In the 16S rRNA gene phylogeny, two sequences of the Gansulinema strains and the two sequences of the Komarkovaeasiopsis strains formed two independent and robust clusters, within the order Oculatellales. The 16S rRNA gene sequences of strains of Komarkovaeasiopsis and Gansulinema showed low identity to each other (≤93.2%) and to other sequences of the Oculatellacean genera (≤94.5% and ≤93.3%, respectively). Furthermore, the 16S-23S internal transcribed spacer rRNA region secondary structures of strains of Komarkovaeasiopsis and Gansulinema were not consistent with all existing descriptions of Oculatellacean taxa. These data suggest that cyanobacterial communities are rich sources of new taxa in under-exploited areas, such as desert soils and hot spring in China.

Vitexin attenuates chronic kidney disease by inhibiting renal tubular epithelial cell ferroptosis via NRF2 activation.

BACKGROUND: Chronic kidney disease (CKD) involves a variety of pathological processes, and ferroptosis plays a vital role in CKD progression. Targeting ferroptosis is a promising strategy for the treatment of CKD. However, inhibitors of ferroptosis have not been used in the clinical treatment of CKD. Vitexin is a natural flavonoid with many biological activities and protective effects against various diseases. However, whether vitexin can prevent the progression of CKD is not known. METHODS: In vivo, the effect of vitexin on CKD was evaluated by using mouse models of unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion (UIR). Western blotting, Sirius red staining and transmission electron microscopy were used to analyze renal tubular injury, interstitial fibrosis, and inflammation in the kidneys of UUO and UIR mice. In vitro, CCK8 assays and lipid peroxidation assays were performed to analyze cell viability and lipid peroxidation in human renal tubular epithelial cells (HK2 cells) induced by erastin. The activation of renal fibroblasts (NRK-49 F cells) was also analyzed. Additionally, an in-silico protein-drug docking model and coimmunoprecipitation were performed to determine the direct substrate of vitexin. RESULTS: In vivo, vitexin treatment significantly ameliorated renal tubular injury, interstitial fibrosis, and inflammation in the kidneys of UUO and UIR mice. Additionally, our results showed that vitexin significantly attenuated UUO- and UIR-induced ferroptosis in renal tubular epithelial cells by upregulating glutathione peroxidase 4 (GPX4) protein levels and inhibiting lipid peroxidation in mouse kidneys. In vitro, treatment with vitexin inhibited erastin-induced ferroptosis in HK2 cells. Moreover, vitexin inhibited the expression of collagen I and α-SMA (alpha-smooth muscle actin) in NRK-49 F cells induced by the supernatant of erastin-treated HK2 cells. Mechanistically, our results suggested that vitexin could activate the NRF2/heme oxygenase-1 (HO-1) pathway by inhibiting the KEAP1- and ubiquitination-mediated degradation of NRF2, thereby increasing the expression of GPX4, and further inhibiting lipid peroxidation and ferroptosis. Additionally, knockout of NRF2 greatly inhibited the antiferroptotic effects of vitexin. CONCLUSIONS: Taken together, our results indicate that vitexin can protect against renal tubular epithelial cell ferroptosis in CKD by activating the KEAP1/NRF2/HO-1 pathway and is a promising drug to treat CKD.

Sef1, rapid-cycling Brassica napus for large-scale functional genome research in a controlled environment.

KEY MESSAGE: We demonstrated a short-cycle B. napus line, Sef1, with a highly efficient and fast transformation system, which has great potential in large-scale functional gene analysis in a controlled environment. Rapeseed (Brassica napus L.) is an essential oil crop that accounts for a considerable share of global vegetable oil production. Nonetheless, studies on functional genes of B. napus are lagging behind due to the complicated genome and long growth cycle, this is largely due to the limited availability of gene analysis and modern genome editing-based molecular breeding. In this study, we demonstrated a short-cycle semi-winter-type Brassica napus 'Sef1' with very early-flowering and dwarf phenotype, which has great potential in large-scale indoor planting. Through the construction of an F2 population of Sef1 and Zhongshuang11, bulked segregant analysis (BSA) combined with the rape Bnapus50K SNP chip assay method was used to identify the early-flowering genes in Sef1, and a mutation in BnaFT.A02 was identified as a major locus significantly affecting the flowering time in Sef1. To further investigate the mechanism of early flowering in Sef1 and discover its potential in gene function analysis, an efficient Agrobacterium-mediated transformation system was established. The average transformation efficiency with explants of hypocotyls and cotyledons was 20.37% and 12.8%, respectively, and the entire transformation process took approximately 3 months from explant preparation to seed harvest of transformed plants. This study demonstrates the great potential of Sef1 for large-scale functional gene analysis.

Myricetin is effective and selective in inhibiting imatinib-resistant chronic myeloid leukemia stem and differentiated cells through targeting eIF4E.

Although imatinib has revolutionized the treatment of chronic myeloid leukemia (CML), s develop resistance to imatinib when progress to blast phase and relapse. Myricetin, a flavonoid compound found in natural plants, has multiple biological functions. In this study, we show that myricetin demonstrated potent efficacy in imatinib-resistant CML CD34 + stem/progenitor cells with less toxicity in normal bone marrow. Myricetin is also active against imatinib-resistant CML bulk cells. The in vitro observations on the therapeutic effects of myricetin were translatable to in vivo imatinib-resistant CML xenograft mouse models. Mechanism studies showed that myricetin decreased the phosphorylation of eIF4E and Ak strain transforming, and the protein level of c-Myc and Cyclin D1. Rescue studies using eIF4E (S209D) and (S209A) confirmed that eIF4E phosphorylation inhibition was the mechanism of myricetin's action in CML. Our results suggest that myricetin may be a potential lead for drug development to overcome imatinib resistance in CML.

Genome-Wide Analysis of the BBX Genes in Platanus × acerifolia and Their Relationship with Flowering and/or Dormancy.

The B-BOX (BBX) gene family is widely distributed in animals and plants and is involved in the regulation of their growth and development. In plants, BBX genes play important roles in hormone signaling, biotic and abiotic stress, light-regulated photomorphogenesis, flowering, shade response, and pigment accumulation. However, there has been no systematic analysis of the BBX family in Platanus × acerifolia. In this study, we identified 39 BBX genes from the P. × acerifolia genome, and used TBtools, MEGA, MEME, NCBI CCD, PLANTCARE and other tools for gene collinearity analysis, phylogenetic analysis, gene structure, conserved domain analysis, and promoter cis-element analysis, and used the qRT-PCR and transcriptome data for analyzing expression pattern of the PaBBX genes. Collinearity analysis indicated segmental duplication was the main driver of the BBX family in P. × acerifolia, and phylogenetic analysis showed that the PaBBX family was divided into five subfamilies: I, II, III, IV and V. Gene structure analysis showed that some PaBBX genes contained super-long introns that may regulate their own expression. Moreover, the promoter of PaBBX genes contained a significant number of cis-acting elements that are associated with plant growth and development, as well as hormone and stress responses. The qRT-PCR results and transcriptome data indicated that certain PaBBX genes exhibited tissue-specific and stage-specific expression patterns, suggesting that these genes may have distinct regulatory roles in P. × acerifolia growth and development. In addition, some PaBBX genes were regularly expressed during the annual growth of P. × acerifolia, corresponding to different stages of flower transition, dormancy, and bud break, indicating that these genes may be involved in the regulation of flowering and/or dormancy of P. × acerifolia. This article provided new ideas for the study of dormancy regulation and annual growth patterns in perennial deciduous plants.

Function deficiency of GhOMT1 causes anthocyanidins over-accumulation and diversifies fibre colours in cotton (Gossypium hirsutum).

Naturally coloured cotton (NCC) fibres need little or no dyeing process in textile industry to low-carbon emission and are environment-friendly. Proanthocyanidins (PAs) and their derivatives were considered as the main components causing fibre coloration and made NCCs very popular and healthy, but the monotonous fibre colours greatly limit the wide application of NCCs. Here a G. hirsutum empurpled mutant (HS2) caused by T-DNA insertion is found to enhance the anthocyanidins biosynthesis and accumulate anthocyanidins in the whole plant. HPLC and LC/MS-ESI analysis confirmed the anthocyanidins methylation and peonidin, petunidin and malvidin formation are blocked. The deficiency of GhOMT1 in HS2 was associated with the activation of the anthocyanidin biosynthesis and the altered components of anthocyanidins. The transcripts of key genes in anthocyanidin biosynthesis pathway are significantly up-regulated in HS2, while transcripts of the genes for transport and decoration were at similar levels as in WT. To investigate the potential mechanism of GhOMT1 deficiency in cotton fibre coloration, HS2 mutant was crossed with NCCs. Surprisingly, offsprings of HS2 and NCCs enhanced PAs biosynthesis and increased PAs levels in their fibres from the accumulated anthocyanidins through up-regulated GhANR and GhLAR. As expected, multiple novel lines with improved fibre colours including orange red and navy blue were produced in their generations. Based on this work, a new strategy for breeding diversified NCCs was brought out by promoting PA biosynthesis. This work will help shed light on mechanisms of PA biosynthesis and bring out potential molecular breeding strategy to increase PA levels in NCCs.

Regulatory roles of three miRNAs on allergen mRNA expression in Tyrophagus putrescentiae.

BACKGROUND: Tyrophagus putresecentiae is an important mite species in rural and urban environments, causing sensitization and allergic disease. While evidence suggests that microRNAs (miRNAs) may regulate the expression of allergen-encoding genes, no study has directly investigated this possibility. Here, this gap was addressed by profiling miRNAs and elucidating their target allergen messenger RNAs (mRNAs) in this mite species. METHODS: Small RNA and transcriptome libraries were constructed for eggs, larvae, nymphs, and adults. After deep miRNA and whole-transcriptome sequencing were performed, the miRNA and allergen-encoding mRNA regulatory networks were explored. RESULTS: A total of 540 miRNAs were identified, including 155 with expression levels differing significantly across the four mite developmental stages (p < .01), 59 of which were novel. The mRNA expression for allergens was higher for Tyr p 1 in adults than in other developmental stages; Tyr p 2-5, 7, 10, 13, 33, and 34 in immature stages; and Tyr p 28, 35, and 36 in eggs and adults. A combined miRNA and transcriptome bioinformatics analysis showed that allergen Tyr p 3 was regulated by miRNA PC-5p-5698441_1, Tyr p 4 was regulated by PC-5p-7050653_1, and Tyr p 34 was regulated by PC-5p-5534223_1 and PC-5p-5698441_1. These three allergen mRNA and three miRNAs were identified using qRT-PCR, and their regulatory roles were confirmed by double-fluorescent reporter gene system and site-directed mutagenesis technology. CONCLUSIONS: For the first time, allergen mRNA expression and miRNAs were profiled throughout the life cycle for an allergen-producing mite, and the results showed that miRNAs bind to target allergen mRNAs to regulate their expression.

Dermatophagoides pteronyssinus allergen Der p 22: Cloning, expression, IgE-binding in asthmatic children, and immunogenicity.

BACKGROUND: Dust mite extract contains multiple components that, while useful in clinical allergy diagnosis and treatment, can cause serious side effects. Defining components of dust mite extract is important their contributions to allergic disease. This study aimed to characterize a novel dust mite allergen, Der p 22. METHODS: We amplified the cDNA encoding Der p 22 from total RNA of the mite Dermatophagoides pteronyssinus, and inserted it into an expression construct for transformation to competent cells. Purified recombinant (r) Der p 22 was tested for IgE-binding reactivity in sera obtained from children with allergic asthma by the Affiliated Wuxi Children's Hospital of Nanjing Medical University (Jiangsu, China). rDer p 22 also was used to challenge BALB/c mice to assess effects on T helper cells and cytokine levels and applied to cultured lung epithelial cells to evaluate apoptosis and cytokine secretion. RESULTS: rDer p 22 bound to IgE in 93.75% of sera from pediatric allergic asthma patients. Mice challenged with rDer p 22 had altered Th1/Th2 ratios in spleen and lymph, and lower levels of cytokines IFN-γ but higher levels of IL-4 and IL-10 in alveolar lavage fluid compared with controls (p < .05). Cultured lung epithelial cells had greater apoptosis rates and exhibited higher levels of IL-6, IL-8, and GM-CSF when treated with rDer p 22 compared with control treatment (p < .05). CONCLUSIONS: Recombinant Der p 22 exhibited high IgE-binding rates in allergic children, indicating the activity of the recombinant protein and suggesting this novel allergen may be appropriate for inclusion in an allergy diagnostic workup. This finding is supported by in vitro and mouse in vivo studies showing rDer p 22 induced strong allergenic reactivity and apoptosis.

ADT-OH inhibits malignant melanoma metastasis in mice via suppressing CSE/CBS and FAK/Paxillin signaling pathway.

Hydrogen sulfide (H2S) is widely recognized as the third endogenous gas signaling molecule and may play a key role in cancer biological processes. ADT-OH (5-(4-hydroxyphenyl)-3H-1,2-dithiocyclopentene-3-thione) is one of the most widely used organic donors for the slow release of H2S and considered to be a potential anticancer compound. In this study, we investigated the antimetastatic effects of ADT-OH in highly metastatic melanoma cells. A tail-vein-metastasis model was established by injecting B16F10 and A375 cells into the tail veins of mice, whereas a mouse footpad-injection model was established by injecting B16F10 cells into mouse footpads. We showed that administration of ADT-OH significantly inhibited the migration and invasion of melanoma cells in the three different animal models. We further showed that ADT-OH dose-dependently inhibited the migration and invasion of B16F10, B16F1 and A375 melanoma cells as evaluated by wound healing and Transwell assays in vitro. LC-MS/MS and bioinformatics analyses revealed that ADT-OH treatment inhibited the EMT process in B16F10 and A375 cells by reducing the expression of FAK and the downstream response protein Paxillin. Overexpression of FAK reversed the inhibitory effects of ADT-OH on melanoma cell migration. Moreover, after ADT-OH treatment, melanoma cells showed abnormal expression of the H2S-producing enzymes CSE/CBS and the AKT signaling pathways. In addition, ADT-OH significantly suppressed the proliferation of melanoma cells. Collectively, these results demonstrate that ADT-OH inhibits the EMT process in melanoma cells by suppressing the CSE/CBS and FAK signaling pathways, thereby exerting its antimetastatic activity. ADT-OH may be used as an antimetastatic agent in the future.

Effects of resilience on impulsivity, cognition and depression during protracted withdrawal among Chinese male methamphetamine users.

BACKGROUND: Methamphetamine (METH) dependence is a complex and dynamic public health problem. Long-term abuse of METH can increase numerous risks of mental and physical problems. Currently, the methods to reduce METH dependence and improve the withdrawal symptoms are limited and ineffective. Resilience is seen as a multidimensional and dynamic capability to recover or bounce back from stressful events and is also generally considered as a protective factor against mental dysfunction. METHODS: One hundred thirty-four males with METH dependence were consecutively recruited from Huanglong Compulsory Isolated Detoxification Center between 2019 and 2021, of whom 112 were into the group. The Connor-Davidson Resilience Scale (CD-RISC), Self-rating depression scale (SDS), Self-rating anxiety scale (SAS), Barratt Impulsiveness Scale-11(BIS-11), and the Repeatable Battery for the Assessment of Neuropsychological Status (Rbans) were used to evaluate resilience, depression, anxiety, impulsivity, and cognition respectively. RESULTS: The results mainly indicated that high resilience group showed lower SDS, SAS and BIS-11 scores than low resilience group (all p < 0.05). Besides, the total scores of Rbans were higher in high resilience groups than low resilience group (both p < 0.05). Moreover, linear regression results showed that resilience may be influenced by the scores of SDS and SAS. CONCLUSIONS: Resilience is negatively correlated with impulsivity and depression. Besides, it is also positively associated with cognitive function. Drug users with higher resilience may have a strong ability to mobilize psychological resources to create a good psychological environment, which may have a positive effect on the relief or improvement of symptoms.

Integrative Analysis of Expression Profiles of mRNA and MicroRNA Provides Insights of Cotton Response to Verticillium dahliae.

Cotton Verticillium wilt, caused by the notorious fungal phytopathogen Verticillium dahliae (V. dahliae), is a destructive soil-borne vascular disease and severely decreases cotton yield and quality worldwide. Transcriptional and post-transcriptional regulation of genes responsive to V. dahliae are crucial for V. dahliae tolerance in plants. However, the specific microRNAs (miRNAs) and the miRNA/target gene crosstalk involved in cotton resistance to Verticillium wilt remain largely limited. To investigate the roles of regulatory RNAs under V. dahliae induction in upland cotton, mRNA and small RNA libraries were constructed from mocked and infected roots of two upland cotton cultivars with the V. dahliae-sensitive cultivar Jimian 11 (J11) and the V. dahliae-tolerant cultivar Zhongzhimian 2 (Z2). A comparative transcriptome analysis revealed 8330 transcripts were differentially expressed under V. dahliae stress and associated with several specific biological processes. Moreover, small RNA sequencing identified a total of 383 miRNAs, including 330 unique conserved miRNAs and 53 novel miRNAs. Analysis of the regulatory network involved in the response to V. dahliae stress revealed 31 differentially expressed miRNA−mRNA pairs, and the up-regulation of GhmiR395 and down-regulation of GhmiR165 were possibly involved in the response to V. dahliae by regulating sulfur assimilation through the GhmiR395-APS1/3 module and the establishment of the vascular pattern and secondary cell wall formation through GhmiR165-REV module, respectively. The integrative analysis of mRNA and miRNA expression profiles from upland cotton lays the foundation for further investigation of regulatory mechanisms of resistance to Verticillium wilt in cotton and other crops.

Identification and functional analysis of a pollen fertility-associated gene GhGLP4 of Gossypium hirsutum L.

KEY MESSAGE: Cotton male fertility-associated gene GhGLP4, encoding a germin-like protein, is essential for anthers development by keeping ROS homeostasis through reducing H2O2 level. Utilization of heterosis is an important way to increase cotton yield and improve fiber quality in hybrid cotton development programs. Male sterility is used in the development of cotton hybrids to reduce the cost of hybrid seed production by eliminating the process of emasculation. From the transcriptome analysis of genic male sterile mutant (ms1) and its background C312 of G. hirsutum, a gene encoding germin-like protein (GhGLP4) was found significantly down-regulated in different developmental stages of ms1 anthers. To explore the gene function in cotton fertility, GhGLP4 was further studied and interfered by virus-induced gene silencing. In the GhGLP4 interfered cotton lines, the expression level of GhGLP4 was significantly decreased in the stamens, and the down-regulation of GhGLP4 resulted in pollen sac closure, stigma exertion, filament shortening, decrease in the number of anthers and complete male sterility. The expression levels of respiratory burst oxidase homologs (Rboh, NADPH oxidase) were significantly altered. Further investigation showed that the SOD activity decreased while the H2O2 content increased in the atypical stamens. These results indicated that GhGLP4 gene affected the cotton anther development through maintenance of ROS homeostasis by H2O2 reduction.

Identification and characterization of PaGL1-like genes from Platanus acerifolia related to the regulation of trichomes.

KEY MESSAGE: Two PaGL1-like genes were identified in London plane and functional in Arabidopsis, moreover, may play an important role in the regulation of trichome development in London plane. Trichome development is governed by a complex regulatory network. In Arabidopsis, subgroup 15 of the R2R3 MYB transcription factor family, which includes GLABRA1 (GL1), is involved in trichome development. In this study, we isolated and characterized two PaGL1-like genes from London plane (Platanus acerifolia). Sequence alignment and phylogenetic analysis indicated that these PaGL1-like genes are homologous to AtGL1. Quantitative real-time PCR (qRT-PCR) analysis showed that PaGL1-like1 was expressed in all of the tested organs taken from adult London plane trees, including trichomes, petioles after trichome removal, stems after trichome removal, and leaves after trichome removal, and also in the roots, cotyledons, hypocotyls and true leaves of seedlings. By contrast, the PaGL1-like2 was expressed only in the trichomes and leaves after trichome removal from adult trees, and in the cotyledons and true leaves of seedlings. Overexpression of PaGL1-like genes caused trichome abortion when transferred into wild type Arabidopsis and promoted trichome formation in the gl1 mutant. The expression profiles of some trichome-related genes were changed in transgenic Arabidopsis lines, and yeast two-hybrid analysis indicated that PaGL1-like proteins can directly interact with trichome-related bHLH proteins from both P. acerifolia and Arabidopsis. These results suggest that PaGL1-like genes are functional in Arabidopsis and may play an important role in the regulation of trichome development in London plane.

Correction: A new non-fullerene acceptor based on the combination of a heptacyclic benzothiadiazole unit and a thiophene-fused end group achieving over 13% efficiency.

Correction for 'A new non-fullerene acceptor based on the combination of a heptacyclic benzothiadiazole unit and a thiophene-fused end group achieving over 13% efficiency' by Yunqiang Zhang et al., Phys. Chem. Chem. Phys., 2019, DOI: .

CSCD: a database for cancer-specific circular RNAs.

Circular RNA (circRNA) is a large group of RNA family extensively existed in cells and tissues. High-throughput sequencing provides a way to view circRNAs across different samples, especially in various diseases. However, there is still no comprehensive database for exploring the cancer-specific circRNAs. We collected 228 total RNA or polyA(-) RNA-seq samples from both cancer and normal cell lines, and identified 272 152 cancer-specific circRNAs. A total of 950 962 circRNAs were identified in normal samples only, and 170 909 circRNAs were identified in both tumor and normal samples, which could be further used as non-tumor background. We constructed a cancer-specific circRNA database (CSCD, http://gb.whu.edu.cn/CSCD). To understand the functional effects of circRNAs, we predicted the microRNA response element sites and RNA binding protein sites for each circRNA. We further predicted potential open reading frames to highlight translatable circRNAs. To understand the association between the linear splicing and the back-splicing, we also predicted the splicing events in linear transcripts of each circRNA. As the first comprehensive cancer-specific circRNA database, we believe CSCD could significantly contribute to the research for the function and regulation of cancer-associated circRNAs.

A new non-fullerene acceptor based on the combination of a heptacyclic benzothiadiazole unit and a thiophene-fused end group achieving over 13% efficiency.

A new non-fullerene acceptor, namely Y10, based on dithienothiophen[3,2-b]-pyrrolobenzothiadiazole (TPBT) as the central core and 2-(6-oxo-5,6-dihydro-4H-cyclopenta[c]thiophen-4-ylidene)malononitrile (TC) as the electron-deficient end group, has been designed and synthesized. Y10 reveals a narrow optical energy gap (Eoptg) of 1.35 eV with a broad absorption band from 600 to 900 nm. A wide bandgap polymer, J11, as the donor material (Eoptg = 1.96 eV) is used to blend with Y10 for the construction of organic solar cell devices, which achieve an impressive power conversion efficiency (PCE) of 13.46% with an open circuit voltage (Voc) of 0.89 V, a short circuit current (Jsc) of 21.21 mA cm-2, and a fill factor (FF) of 71.55%, with thermal annealing treatment at 100 °C for 5 min and 0.8 wt% 1-chloronaphthalene (CN) as an additive. These results indicate that the incorporation of the TPBT unit as the central core and the TC unit as the electron-deficient end group provides an efficient strategy for the construction of high performance solar cells.

Tiliroside attenuates acute kidney injury by inhibiting ferroptosis through the disruption of NRF2-KEAP1 interaction.

BACKGROUND: Ferroptosis, an iron-dependent process that regulates cell death. Emerging evidences suggest that ferroptosis induces acute kidney injury (AKI) progression, and inhibiting ferroptosis provides an effect strategy for AKI treatment. The disruption of the NRF2-KEAP1 protein to protein interaction (PPI) induces NRF2 activation, which provides a promising strategy that can identify new ferroptosis inhibitors. A previous study revealed that tiliroside, a glycosidic flavonoid extracted from Edgeworthia chrysantha Lindl (buds), has anti-neuroinflammatory and neuroprotective effects via NRF2 activation. However, the mechanism through which tiliroside activates NRF2 is unknown, and it remains unclear whether it has protective effects against AKI. PURPOSE: To investigate whether tiliroside has protective effects against AKI in mice and the associated mechanisms. METHODS: Possible tiliroside substrates were analyzed using molecular docking. Cisplatin- and ischemia-reperfusion injury (IRI)-induced AKI mouse models and HK2 cells model were constructed to evaluate the protective effects of tiliroside. CRISPR/Cas9 mediated NRF2 knockout HK2 cells were used to verify whether NRF2 mediates tiliroside protective effects. RESULTS: In vivo, our results showed that tiliroside treatment preserved kidney functions in AKI mice models, as showed by lower levels of serum creatinine (SCr), blood urea nitrogen (BUN), and renal injury markers, including neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1), compared with the mice in control groups. In vitro, tiliroside treatment greatly ameliorated cisplatin-induced ferroptosis through NRF2 activation in cultured HK2 cells, as evidenced by the protective effects of tiliroside being greatly blunted after the knockout of NRF2 in HK2 cells. Mechanistic studies indicated that tiliroside promoted NRF2/GPX4 pathway activation and ferroptosis inhibition, perhaps via the disruption of the NRF2-KEAP1 PPI. CONCLUSION: Together, our results demonstrate that tiliroside may serve as a NRF2-KEAP1 PPI inhibitor and prevents ferroptosis-induced AKI, indicating its potential for clinical AKI treatment.

ADT-OH exhibits anti-metastatic activity on triple-negative breast cancer by combinatorial targeting of autophagy and mitochondrial fission.

High basal autophagy and enhanced mitochondrial fission in triple-negative breast cancer (TNBC) cells support cell migration and promote plasticity of cancer cell metabolism. Here, we suggest a novel combination therapy approach for the treatment of TNBC that targets Drp1-mediated mitochondrial fission and autophagy pathways. Hydrogen sulfide (H2S) mediates a myriad of biological processes, including autophagy and mitochondrial function. In this study, we demonstrated that 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), one of the most widely utilized sustained-release H2S donors, effectively suppresses metastasis of TNBC cells in the absence of proliferation inhibition in vitro and in vivo. ADT-OH treatment ameliorated autophagy flux by suppressing autophagosome formation and induced mitochondrial elongation through decreasing expression of dynamin-related protein 1 (Drp1) and increasing expression of mitochondrial fusion protein (Mfn2). At the same time, ADT-OH downregulated mitophagy flux and inhibited mitochondrial function, eventually leading to the inhibition of migration and invasion in TNBC cells. In vivo, intraperitoneal administration of ADT-OH revealed a potent anti-metastatic activity in three different animal models, the MDA-MB-231 orthotopic xenograft model, the 4T1-Luci orthotopic model and the 4T1-Luci tail vein metastasis model. However, ADT-OH has an extremely low water solubility, which is a significant barrier to its effectiveness. Thus, we demonstrated that the solubility of ADT-OH in water can be improved significantly by absorption with hydroxypropyl-ß-cyclodextrin (CD). Remarkably, the obtained CD-ADT-OH demonstrated superior anti-cancer effect to ADT-OH in vivo. Altogether, this study describes a novel regulator of mammalian mitochondrial fission and autophagy, with potential utility as an experimental therapeutic agent for metastatic TNBC.