Subscaling of a cytosolic RNA binding protein governs cell size homeostasis in the multiple fission alga Chlamydomonas.

Coordination of growth and division in eukaryotic cells is essential for populations of proliferating cells to maintain size homeostasis, but the underlying mechanisms that govern cell size have only been investigated in a few taxa. The green alga Chlamydomonas reinhardtii (Chlamydomonas) proliferates using a multiple fission cell cycle that involves a long G1 phase followed by a rapid series of successive S and M phases (S/M) that produces 2n daughter cells. Two control points show cell-size dependence: the Commitment control point in mid-G1 phase requires the attainment of a minimum size to enable at least one mitotic division during S/M, and the S/M control point where mother cell size governs cell division number (n), ensuring that daughter distributions are uniform. tny1 mutants pass Commitment at a smaller size than wild type and undergo extra divisions during S/M phase to produce small daughters, indicating that TNY1 functions to inhibit size-dependent cell cycle progression. TNY1 encodes a cytosolic hnRNP A-related RNA binding protein and is produced once per cell cycle during S/M phase where it is apportioned to daughter cells, and then remains at constant absolute abundance as cells grow, a property known as subscaling. Altering the dosage of TNY1 in heterozygous diploids or through mis-expression increased Commitment cell size and daughter cell size, indicating that TNY1 is a limiting factor for both size control points. Epistasis placed TNY1 function upstream of the retinoblastoma tumor suppressor complex (RBC) and one of its regulators, Cyclin-Dependent Kinase G1 (CDKG1). Moreover, CDKG1 protein and mRNA were found to over-accumulate in tny1 cells suggesting that CDKG1 may be a direct target of repression by TNY1. Our data expand the potential roles of subscaling proteins outside the nucleus and imply a control mechanism that ties TNY1 accumulation to pre-division mother cell size.

New targets and designed inhibitors of ASAP Arf-GAPs derived from structural characterization of the ASAP1/440-kD ankyrin-B interaction.

ASAP1 and its paralog ASAP2 belong to a PI4,5P2-dependent Arf GTPase-activating protein (Arf-GAP) family capable of modulating membrane and cytoskeletal dynamics. ASAPs regulate cell adhesive structures such as invadosomes and focal adhesions during cell attachment and migration. Malfunctioning of ASAP1 has been implicated in the malignant phenotypes of various cancers. Here, we discovered that the SH3 domain of ASAP1 or ASAP2 specifically binds to a 12-residue, positively charged peptide fragment from the 440 kDa giant ankyrin-B, a neuronal axon specific scaffold protein. The high-resolution structure of the ASAP1-SH3 domain in complex with the gAnkB peptide revealed a non-canonical SH3-ligand binding mode with high affinity and specificity. Structural analysis of the complex readily uncovered a consensus ASAP1-SH3 binding motif, which allowed the discovery of a number of previously unknown binding partners of ASAP1-SH3 including Clasp1/Clasp2, ALS2, ß-Pix, DAPK3, PHIP, and Limk1. Fittingly, these newly identified ASAP1 binding partners are primarily key modulators of the cytoskeletons. Finally, we designed a cell-penetrating, highly potent ASAP1 SH3 domain binding peptide with a Kd ∼7 nM as a tool for studying the roles of ASAPs in different cellular processes.

Selectivity Control by Relay Catalysis in CO and CO2 Hydrogenation to Multicarbon Compounds.

ConspectusThe hydrogenative conversion of both CO and CO2 into high-value multicarbon (C2+) compounds, such as olefins, aromatic hydrocarbons, ethanol, and liquid fuels, has attracted much recent attention. The hydrogenation of CO is related to the chemical utilization of various carbon resources including shale gas, biomass, coal, and carbon-containing wastes via syngas (a mixture of H2 and CO), while the hydrogenation of CO2 by green H2 to chemicals and liquid fuels would contribute to recycling CO2 for carbon neutrality. The state-of-the-art technologies for the hydrogenation of CO/CO2 to C2+ compounds primarily rely on a direct route via Fischer-Tropsch (FT) synthesis and an indirect route via two methanol-mediated processes, i.e., methanol synthesis from CO/CO2 and methanol to C2+ compounds. The direct route would be more energy- and cost-efficient owing to the reduced operation units, but the product selectivity of the direct route via FT synthesis is limited by the Anderson-Schulz-Flory (ASF) distribution. Selectivity control for the direct hydrogenation of CO/CO2 to a high-value C2+ compound is one of the most challenging goals in the field of C1 chemistry, i.e., chemistry for the transformation of one-carbon (C1) molecules.We have developed a relay-catalysis strategy to solve the selectivity challenge arising from the complicated reaction network in the hydrogenation of CO/CO2 to C2+ compounds involving multiple intermediates and reaction channels, which inevitably lead to side reactions and byproducts over a conventional heterogeneous catalyst. The core of relay catalysis is to design a single tandem-reaction channel, which can direct the reaction to the target product controllably, by choosing appropriate intermediates (or intermediate products) and reaction steps connecting these intermediates, and arranging optimized yet matched catalysts to implement these steps like a relay. This Account showcases representative relay-catalysis systems developed by our group in the past decade for the synthesis of liquid fuels, lower (C2-C4) olefins, aromatics, and C2+ oxygenates from CO/CO2 with selectivity breaking the limitation of conventional catalysts. These relay systems are typically composed of a metal or metal oxide for CO/CO2/H2 activation and a zeolite for C-C coupling or reconstruction, as well as a third or even a fourth catalyst component with other functions if necessary. The mechanisms for the activation of H2 and CO/CO2 on metal oxides, which are distinct from that on the conventional transition or noble metal surfaces, are discussed with emphasis on the role of oxygen vacancies. Zeolites catalyze the conversion of intermediates (including hydrocracking/isomerization of heavier hydrocarbons, methanol-to-hydrocarbon reactions, and carbonylation of methanol/dimethyl ether) in the relay system, and the selectivity is mainly controlled by the Brønsted acidity and the shape-selectivity or the confinement effect of zeolites. We demonstrate that the thermodynamic/kinetic matching of the relay steps, the proximity and spatial arrangement of the catalyst components, and the transportation of intermediates/products in sequence are the key issues guiding the selection of each catalyst component and the construction of an efficient relay-catalysis system. Our methodology would also be useful for the transformation of other C1 molecules via controlled C-C coupling, inspiring more efforts toward precision catalysis.

Recent Advances of Benzodithiophene-Based Donor Materials for Organic Solar Cells.

Recently, the power conversion efficiency (PCE) of organic solar cells (OSCs) has increased dramatically, making a big step toward the industrial application of OSCs. Among numerous OSCs, benzodithiophene (BDT)-based OSCs stand out in achieving efficient PCE. Notably, single-junction OSCs using BDT-based polymers as donor materials have completed a PCE of over 19%, indicating a dramatic potential for preparing high-performance large-scale OSCs. This paper reviews the recent progress of OSCs based on BDT polymer donor materials (PDMs). The development of BDT-based OSCs is concisely summarized. Meanwhile, the relationship between the structure of PDMs and the performance of OSCs is further described in this review. Besides, the development and prospect of single junction OSCs are also discussed.

Paeoniflorin protects hepatocytes from APAP-induced damage through launching autophagy via the MAPK/mTOR signaling pathway.

BACKGROUND: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies. PURPOSE: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms. METHODS: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques. RESULTS: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury. CONCLUSIONS: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.

Natural products targeting macroautophagy signaling in hepatocellular carcinoma therapy: Recent evidence and perspectives.

Hepatocellular carcinoma (HCC), presently the second leading cause of global cancer-related mortality, continues to pose significant challenges in the realm of medical oncology, impacting both clinical drug selection and mechanistic research. Recent investigations have unveiled autophagy-related signaling as a promising avenue for HCC treatment. A growing body of research has highlighted the pivotal role of autophagy-modulating natural products in inhibiting HCC progression. In this context, we provide a concise overview of the fundamental autophagy mechanism and delineate the involvement of autophagic signaling pathways in HCC development. Additionally, we review pertinent studies demonstrating how natural products regulate autophagy to mitigate HCC. Our findings indicate that natural products exhibit cytotoxic effects through the induction of excessive autophagy, simultaneously impeding HCC cell proliferation by autophagy inhibition, thereby depriving HCC cells of essential energy. These effects have been associated with various signaling pathways, including PI3K/AKT, MAPK, AMPK, Wnt/ß-catenin, Beclin-1, and ferroautophagy. These results underscore the considerable therapeutic potential of natural products in HCC treatment. However, it is important to note that the present study did not establish definitive thresholds for autophagy induction or inhibition by natural products. Further research in this domain is imperative to gain comprehensive insights into the dual role of autophagy, equipping us with a better understanding of this double-edged sword in HCC management.

Peptide vaccine from cancer-testis antigen ODF2 can potentiate the cytotoxic T lymphocyte infiltration through IL-15 in non-MSI-H colorectal cancer.

About 85% of patients with colorectal cancer (CRC) have the non-microsatellite instability-high (non-MSI-H) subtype, and many cannot benefit from immune checkpoint blockade. A potential reason for this is that most non-MSI-H colorectal cancers are immunologically "cold" due to poor CD8+ T cell infiltration. In the present study, we screened for potential cancer-testis antigens (CTAs) by comparing the bioinformatics of CD8+ T effector memory (Tem) cell infiltration between MSI-H and non-MSI-H CRC. Two ODF2-derived epitope peptides, P433 and P609, displayed immunogenicity and increased the proportion of CD8+ T effector memory (Tem) cells in vitro and in vivo. The adoptive transfer of peptide pool-induced CTLs inhibited tumor growth and enhanced CD8+ T cell infiltration in tumor-bearing NOD/SCID mice. The mechanistic study showed that knockdown of ODF2 in CRC cells promoted interleukin-15 expression, which facilitated CD8+ T cell proliferation. In conclusion, ODF2, a CTA, was negatively correlated with CD8+ T cell infiltration in "cold" non-MSI-H CRC and was selected based on the results of bioinformatics analyses. The corresponding HLA-A2 restricted epitope peptide induced antigen-specific CTLs. Immunotherapy targeting ODF2 could improve CTA infiltration via upregulating IL-15 in non-MSI-H CRC. This tumor antigen screening strategy could be exploited to develop therapeutic vaccines targeting non-MSI-H CRC.

N-Type Small Molecule Electron Transport Layers with Excellent Surface Energy and Moisture Resistance Siloxane for Non-Fullerene Organic Solar Cells.

Electron transport layers (ETLs) generally contain polar groups for enhancing performance and reducing the work function. Nevertheless, the polar group with high surface energy may cause inferior interfacial compatibility, which challenges the ETLs to balance stability and performance. Here, two conjugated small molecules of ETLs with low surface energy siloxane, namely PDI-Si and PDIN-Si, are synthesized. The siloxane with low surface energy not only enhances the interfacial compatibility between ETLs and active layers but also improves the moisture-proof stability of the device. Impressively, the amine-functionalized PDIN-Si can simultaneously exhibit conspicuous n-type self-doping properties and outstanding moisture-proof stability. The optimization of interfacial contact and morphology enables the PM6:Y6-based OSC with PDIN-Si to achieve a power conversion efficiency (PCE) of 15.87%, which is slightly superior to that of classical ETL PDINO devices (15.27%), and when the PDIN-Si film thickness reaches 28 nm, the PCE remains at 13.19% (≈83%), which indicates that PDIN-Si has satisfactory thickness insensitivity to facilitate roll-to-roll processing. Excitingly, after 120 h of storage in an environment with humidity above 45%, the unencapsulated device with PDIN-Si as ETL remains at 75% of the initial PCE value, while the device with PDINO as ETL is only 50%.

Natural products targeting signaling pathways associated with regulated cell death in gastric cancer: Recent advances and perspectives.

Gastric cancer (GC) is one of the most serious gastrointestinal malignancies with high morbidity and mortality. The complexity of GC process lies in the multi-phenotypic linkage regulation, in which regulatory cell death (RCD) is the core link, which largely dominates the fate of GC cells and becomes a key determinant of GC development and prognosis. In recent years, increasing evidence has been reported that natural products can prevent and inhibit the development of GC by regulating RCDs, showing great therapeutic potential. In order to further clarify its key regulatory characteristics, this review focused on specific expressions of RCDs, combined with a variety of signaling pathways and their crosstalk characteristics, sorted out the key targets and action rules of natural products targeting RCD. It is highlighted that a variety of core biological pathways and core targets are involved in the decision of GC cell fate, including the PI3K/Akt signaling pathway, MAPK-related signaling pathways, p53 signaling pathway, ER stress, Caspase-8, gasdermin D (GSDMD), and so on. Moreover, natural products target the crosstalk of different RCDs by modulating above signaling pathways. Taken together, these findings suggest that targeting various RCDs in GC with natural products is a promising strategy, providing a reference for further clarifying the molecular mechanism of natural products treating GC, which warrants further investigations in this area.

Paeoniflorin Protects against Acetaminophen-Induced Liver Injury in Mice via JNK Signaling Pathway.

BACKGROUND: Drug-induced liver injury (DILI), represented by acetaminophen (APAP), is a common cause of acute liver failure in clinics. Paeoniflorin (PF) has been proven to demonstrate a significant hepatoprotective effect. However, it is still unclear whether it can be a potential agent against hepatotoxicity induced by APAP. This study aimed to explore the preventive and therapeutic effects and mechanisms of PF on APAP-induced liver injury. METHODS: Different doses of PF (50, 100, and 200 mg/kg) were given to C57BL/6 male mice for five consecutive days. After 12 h of APAP (250 mg/kg i.p.) treatment, blood and liver tissues were collected and isolated for detection. RESULTS: The results showed that the therapeutic effects of PF on APAP mice were presented in the downregulation of the content of serum indices and significantly improved hepatic tissue edema and inflammatory infiltration. Meanwhile, PF reduces the level of the mitochondrial metabolic enzyme. Ulteriorly, it was found that PF has a downregulating effect on the apoptotic reaction and could inhibit the protein expression of CYP2E1/JNK signaling, which in turn reduces the damage of APAP. CONCLUSION: Our findings showed that PF acted as a protective agent against APAP-induced hepatotoxicity by inhibiting JNK-related signals, suggesting a novel insight into treating APAP-induced liver injury.

Functionalized Carbon Materials in Syngas Conversion.

Functionalized carbon materials are widely used in heterogeneous catalysis due to their unique properties such as adjustable surface properties, excellent thermal conductivity, high surface areas, tunable porosity, and moderate interactions with guest metals. The transformation of syngas into hydrocarbons (known as the Fischer-Tropsch synthesis) or oxygenates is an exothermic reaction and is typically catalyzed by transition metals dispersed on functionalized supports. Various carbon materials have been employed in syngas conversions not only for improving the performance or decreasing the dosage of expensive active metals but also for building model catalysts for fundamental research. This article provides a critical review on recent advances in the utilization of carbon materials, in particular the recently developed functionalized nanocarbon materials, for syngas conversions to either hydrocarbons or oxygenates. The unique features of carbon materials in dispersing metal nanoparticles, heteroatom doping, surface modification, and building special nanoarchitectures are highlighted. The key factors that control the reaction course and the reaction mechanism are discussed to gain insights for the rational design of efficient carbon-supported catalysts for syngas conversions. The challenges and future opportunities in developing functionalized carbon materials for syngas conversions are briefly analyzed.

Inhibition of PIM1 attenuates the stem cell-like traits of breast cancer cells by promoting RUNX3 nuclear retention.

Finding out the driver gene critical for the maintenance of breast cancer stem cells (BrCSCs) is important for designing a new strategy to eradicate these cells to improve patient's prognosis. Here, in our study, we revealed that PIM1, an oncogenic serine-threonine kinase and a well-proven contributor to the tumorigenesis of breast cancer, was involved in BrCSCs regulation and promised to be a new target for eradicating BrCSCs. In brief, PIM1 could enhance the stem cell-like traits of breast cancer cells by promoting the phosphorylation and cytoplasmic localization of RUNX3. The nuclear dislocation of RUNX3 disabled this tumour suppressor and led to breast cancer cells gaining stem cell-like traits. Inhibition of PIM1 significantly induced the nuclear retention of RUNX3, recovered its transcriptional function and attenuated the stem cell-like properties of breast cancer cells. Those findings deepened our understanding of PIM1's oncogenic effect, underlining the significance of PIM1 in designing a new strategy aimed at BrCSCs.

Confinement of Quantum Dots in between Monolayered Graphene Nanosheets for Arousing Boosted Multifarious Photoredox Selective Organic Transformation.

Transition metal chalcogenide quantum dots (TMC QDs) represent promising light-harvesting antennas because of their fascinating physicochemical properties including quantum confinement effect and suitable energy band structures. However, TMC QDs generally suffer from poor photoactivities and photostability due to deficiency of active sites and ultrafast recombination rate of photoinduced charge carriers. Here, we demonstrate how to rationally arouse the charge transfer kinetic of TMC QDs by close monolayered graphene (GR) encapsulation via a ligand-dominated layer-by-layer (LbL) assembly utilizing oppositely charged TMC QDs and GR nanosheets as the building blocks. The assembly units were spontaneously and intimately integrated in an alternate integration mode, thereby resulting in the multilayered three-dimensional (3D) TMC QDs/GR ensembles. It was unveiled that multifarious photoactivities of TMC QDs/GR nanocomposites toward versatile photoredox organic catalysis including photocatalytic aromatic alcohols oxidation to aldehydes and nitroaromatics reduction to amino derivatives under visible light irradiation are conspicuously boosted because of spatially multilayered monolayered GR encapsulation which are superior to those of TMC QDs counterparts. The substantially enhanced photoactivities of TMC QDs/GR nanocomposites arise from reasons including improved light absorption and enhanced charge separation efficacy because of GR encapsulation together with unique stacking mode between TMC QDs and GR endowed by LbL assembly. Our work would provide a promising and efficacious route to smartly accelerate the charge transfer kinetic of TMC QDs for solar energy conversion.

Partially Self-Transformed Transition-Metal Chalcogenide Interim Layer: Motivating Charge Transport Cascade for Solar Hydrogen Evolution.

Directional and high-efficiency charge transport to the target active sites of photocatalyst is central to boost the solar energy conversion but is retarded by the sluggish charge transfer kinetics and deficiency of active sites. Here, we report the elaborate design of cascade unidirectional charge transfer channel over spatially multilayered CdS@CdTe@MoS2 dual core-shell ternary heterostructures by partial transformation of CdS to CdTe interim layer followed by seamless encapsulation with an ultrathin MoS2 layer. The suitable energy-level alignment and unique coaxial multilayered assembly mode among the building blocks accelerate the interfacial charge separation and transport, endowing the CdS@CdTe@MoS2 heterostructures with conspicuously enhanced visible-light-driven photocatalytic hydrogen generation performances along with good photostability. The integrated roles of ultrathin CdTe intermediate layer in passivating the defect sites of CdS NWs framework, mediating the unidirectional charge transfer cascade and prolonging the charge lifetime, were ascertained. Besides, the crucial role of the outermost MoS2 layer as the metal-free cocatalyst in enriching the surface active sites for hydrogen evolution was also determined. Our work would provide new alternatives for finely tuning the charge flow toward promising solar-to-hydrogen conversion efficiency.

Metabolic reconstructions identify plant 3-methylglutaconyl-CoA hydratase that is crucial for branched-chain amino acid catabolism in mitochondria.

The proteinogenic branched-chain amino acids (BCAAs) leucine, isoleucine and valine are essential nutrients for mammals. In plants, BCAAs double as alternative energy sources when carbohydrates become limiting, the catabolism of BCAAs providing electrons to the respiratory chain and intermediates to the tricarboxylic acid cycle. Yet, the actual architecture of the degradation pathways of BCAAs is not well understood. In this study, gene network modeling in Arabidopsis and rice, and plant-prokaryote comparative genomics detected candidates for 3-methylglutaconyl-CoA hydratase (4.2.1.18), one of the missing plant enzymes of leucine catabolism. Alignments of these protein candidates sampled from various spermatophytes revealed non-homologous N-terminal extensions that are lacking in their bacterial counterparts, and green fluorescent protein-fusion experiments demonstrated that the Arabidopsis protein, product of gene At4g16800, is targeted to mitochondria. Recombinant At4g16800 catalyzed the dehydration of 3-hydroxymethylglutaryl-CoA into 3-methylglutaconyl-CoA, and displayed kinetic features similar to those of its prokaryotic homolog. When at4g16800 knockout plants were subjected to dark-induced carbon starvation, their rosette leaves displayed accelerated senescence as compared with control plants, and this phenotype was paralleled by a marked increase in the accumulation of free and total leucine, isoleucine and valine. The seeds of the at4g16800 mutant showed a similar accumulation of free BCAAs. These data suggest that 3-methylglutaconyl-CoA hydratase is not solely involved in the degradation of leucine, but is also a significant contributor to that of isoleucine and valine. Furthermore, evidence is shown that unlike the situation observed in Trypanosomatidae, leucine catabolism does not contribute to the formation of the terpenoid precursor mevalonate.

Identification of Putative Substrates of SEC2, a Chloroplast Inner Envelope Translocase.

Most chloroplast proteins are synthesized in the cytosol and imported into chloroplasts. Many imported proteins are further targeted to the thylakoid membrane and lumen by the SEC1, TAT, or SRP/ALB3 translocases. Others are targeted to the inner chloroplast envelope membrane by undescribed translocases. Recently, a second SEC system (SEC2) consisting of SCY2, SECE2, and SECA2 was found in the chloroplast envelope. Null mutants of SCY2 in Arabidopsis (Arabidopsis thaliana) exhibit a severe embryo-lethal phenotype. To investigate the function of the SEC2 system in plants, we used inducible RNA interference to knock down SCY2 in Arabidopsis. Seedlings cultured with inducer were chlorotic with aberrant chloroplasts and undeveloped thylakoids, indicating an essential role for SCY2 in chloroplast biogenesis beyond embryo development. In SCY2 down-regulated seedlings, several thylakoid membrane proteins, including SCY1, ALB3, and TATC, and inner envelope membrane proteins, including TIC40, TIC110, and FTSH12, were reduced substantially, suggesting that they may be SEC2 substrates. Additional insight was achieved by the in vitro reconstitution of protein integration into chloroplast membranes. The results show that SCY1 and ALB3 target directly to the thylakoid membrane and are likely independent of SEC2. FTSH12 was integrated into the envelope membrane in a coupled import-integration reaction that was impaired by the SECA inhibitor sodium azide. The stromal intermediate of TIC40 integrated into the envelope in a reaction that was largely inhibited when antibodies against epitope-tagged SCY2 or SECE2 were applied. These data demonstrate that the SEC2 translocase likely integrates a subset of inner envelope membrane proteins, such as FTSH12 and TIC40.

The Sec2 translocase of the chloroplast inner envelope contains a unique and dedicated SECE2 component.

Biogenesis of chloroplasts involves a series of protein trafficking events. Nuclear-encoded proteins are imported into the organelle, and then trafficked to various chloroplast locations by systems that are directly homologous to bacterial systems. Although the thylakoid-based systems have been studied extensively, much less is known about the systems that reside and function in the inner envelope membrane. One such system, the Sec2 system, is homologous to both the thylakoid-based Sec1 system and bacterial Sec systems, and may mediate both integration and translocation across the inner envelope. At a minimum, this system is expected to include three components, but only two, SCY2 and SECA2, have been identified in Arabidopsis. Bioinformatics and protein modeling were used to identify the protein encoded by At4g38490 as a candidate for the missing component (SECE2). Cellular localization, biochemistry, protein interaction assays in yeast, and co-immunoprecipitation experiments were used to establish that this protein is an integral membrane protein of the inner envelope, and specifically interacts with the SCY2 component in vivo. Sequence analyses indicated that SECE2 proteins are found in a variety of plants, and differ from the thylakoid SECE1 proteins in a stroma-exposed helical domain, which may contribute to their specificity. Finally, a genetic analysis indicated that SECE2 plays an essential role in plant growth and development.

The cardioprotective effect of dihydromyricetin prevents ischemia-reperfusion-induced apoptosis in vivo and in vitro via the PI3K/Akt and HIF-1α signaling pathways.

Reperfusion therapy is widely used to treat acute myocardial infarction (AMI). However, further injury to the heart induced by rapidly initiating reperfusion is often encountered in clinical practice. A lack of pharmacological strategies in clinics limits the prognosis of patients with myocardial ischemia-reperfusion injury (MIRI). Dihydromyricetin (DMY) is one of the most abundant components in vine tea, commonly known as the tender stems and leaves of Ampelopsis grossedentata. The aim of this study was to evaluate the cardioprotection of DMY against myocardial ischemia-reperfusion (I/R) injury and to further investigate the underlying mechanism. An I/R injury was induced by left anterior descending coronary artery occlusion in adult male rats in vivo and a hypoxia-reoxygenation (H/R) injury in H9c2 cardiomyocytes in vitro. We found that DMY pretreatment provided significant protection against I/R-induced injury, including enhanced antioxidant capacity and inhibited apoptosis in vivo and in vitro. This effect correlated with the activation of the PI3K/Akt and HIF-1α signaling pathways. Conversely, blocking Akt activation with the PI3K inhibitor LY294002 effectively suppressed the protective effects of DMY against I/R-induced injury. In addition, the PI3K inhibitor partially blocked the effects of DMY on the upregulation of Bcl-2, Bcl-xl, procaspase-3, -8, and -9 protein expression and the downregulation of HIF-1α, Bnip3, Bax, Cyt-c, cleaved caspase-3, -8, and -9 protein expression. Collectively, these results showed that DMY decreased the apoptosis and necrosis by I/R treatment, and PI3K/Akt and HIF-1α plays a crucial role in protection during this process. These observations indicate that DMY has the potential to exert cardioprotective effects against I/R injury and the results might be important for the clinical efficacy of AMI treatment.

[Bushen Huoxue Fang promotes the apoptosis of epithelial cells in the prostatic ductal system of rats with benign prostatic hyperplasia].

OBJECTIVE: To investigate the effects of Bushen Huoxue Fang (BSHX) on the apoptosis of epithelial cells in the prostatic ductal system of rats with benign prostatic hyperplasia (BPH) and its possible action mechanism. METHODS: One hundred 3- month-old male Wistar rats were randomly divided into four groups of equal number (control, castrated, BPH model, and BSHX). BPH models were made by subcutaneous injection of testosterone following castration; the rats in the BSHX group were treated intragastrically with BSHX at 2.34 g/ml after modeling, while those in the other two groups with equal volume of saline, all for 37 days. On the 38th day, all the rats were sacrificed and their prostates harvested for detection of the distribution of TGF-beta1 and alpha-actin and the count of positive cells in the prostatic ductal system by immunohistochemical staining. The apoptosis rate of epithelial cells in the prostatic ductal system was determined by TUNEL assay. RESULTS: The expression of TGF-beta1 was significantly increased in the rats of the BSHX group as compared with the BPH models in both the proximal prostatic duct ([15.28 +/- 4.30]% vs [36.42 +/- 8.10]%, P < 0.01) and the distal prostatic duct ([4.42 +/- 2.07]% vs [8.71 +/- 2.28 ]%, P < 0.05), while the expression of alpha-actin in the proximal duct was remarkably higher in the BSHX-treated rats than in the models ([28.14 +/- 7.43]% vs [18.28 +/- 4.07]%, P < 0.01), but lower than in the control animals ([33.57 +/- 6.85]%, P < 0.05). Compared with the control group, the BPH models and BSHX-treated rats both exhibited markedly decreased apoptosis of epithelial cells in the proximal prostatic duct ([39.42 +/- 9.20]% vs [3.86 +/- 1.34]%, P < 0.01, and [31.14 +/- 5.64]%, P < 0.01) and distal prostatic duct ([17.60 +/- 4.86]% vs [3.07 +/- 1.14]%, P < 0.01, and [12.37 +/- 2.25]%, P < 0.05). The apoptosis rate of epithelial cells in the prostatic ductal system was significantly higher in the BSHX-treated rats than in the BPH models (P < 0.01). CONCLUSION: By upregulating the expression of TGF-beta, BSHX can suppress the reduction of smooth muscle cells in the proximal prostatic duct, promote the apoptosis of prostatic epithelial cells, and thus effectively inhibit benign prostatic hyperplasia.

Immunotherapy revolutionizing brain metastatic cancer treatment: personalized strategies for transformative outcomes.

Brain metastatic cancer poses a significant clinical challenge, with limited treatment options and poor prognosis for patients. In recent years, immunotherapy has emerged as a promising strategy for addressing brain metastases, offering distinct advantages over conventional treatments. This review explores the evolving landscape of tumor immunotherapy in the context of brain metastatic cancer, focusing on the intricate interplay between the tumor microenvironment (TME) and immunotherapeutic approaches. By elucidating the complex interactions within the TME, including the role of immune cells, cytokines, and extracellular matrix components, this review highlights the potential of immunotherapy to reshape the treatment paradigm for brain metastases. Leveraging immune checkpoint inhibitors, cellular immunotherapies, and personalized treatment strategies, immunotherapy holds promise in overcoming the challenges posed by the blood-brain barrier and immunosuppressive microenvironment of brain metastases. Through a comprehensive analysis of current research findings and future directions, this review underscores the transformative impact of immunotherapy on the management of brain metastatic cancer, offering new insights and opportunities for personalized and precise therapeutic interventions.