A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.

ESCRTing Necroptosis.

Necroptosis is a highly inflammatory form of programmed cell death that results from MLKL-mediated disruption of the cell membrane. In this issue of Cell, Gong et al. challenge the notion that MLKL activation is a point of no return by identifying mechanisms to counterbalance necroptosis, sustain plasma membrane integrity, and prolong cell viability.

Transcriptional regulation of strigolactone signalling in Arabidopsis.

Plant hormones known as strigolactones control plant development and interactions between host plants and symbiotic fungi or parasitic weeds1-4. In Arabidopsis thaliana and rice, the proteins DWARF14 (D14), MORE AXILLARY GROWTH 2 (MAX2), SUPPRESSOR OF MAX2-LIKE 6, 7 and 8 (SMXL6, SMXL7 and SMXL8) and their orthologues form a complex upon strigolactone perception and play a central part in strigolactone signalling5-10. However, whether and how strigolactones activate downstream transcription remains largely unknown. Here we use a synthetic strigolactone to identify 401 strigolactone-responsive genes in Arabidopsis, and show that these plant hormones regulate shoot branching, leaf shape and anthocyanin accumulation mainly through transcriptional activation of the BRANCHED 1, TCP DOMAIN PROTEIN 1 and PRODUCTION OF ANTHOCYANIN PIGMENT 1 genes. We find that SMXL6 targets 729 genes in the Arabidopsis genome and represses the transcription of SMXL6, SMXL7 and SMXL8 by binding directly to their promoters, showing that SMXL6 serves as an autoregulated transcription factor to maintain the homeostasis of strigolactone signalling. These findings reveal an unanticipated mechanism through which a transcriptional repressor of hormone signalling can directly recognize DNA and regulate transcription in higher plants.

MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.

Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death.

Transcriptome Landscape of Human Folliculogenesis Reveals Oocyte and Granulosa Cell Interactions.

The dynamic transcriptional regulation and interactions of human germlines and surrounding somatic cells during folliculogenesis remain unknown. Using RNA sequencing (RNA-seq) analysis of human oocytes and corresponding granulosa cells (GCs) spanning five follicular stages, we revealed unique features in transcriptional machinery, transcription factor networks, and reciprocal interactions in human oocytes and GCs that displayed developmental-stage-specific expression patterns. Notably, we identified specific gene signatures of two cell types in particular developmental stage that may reflect developmental competency and ovarian reserve. Additionally, we uncovered key pathways that may concert germline-somatic interactions and drive the transition of primordial-to-primary follicle, which represents follicle activation. Thus, our work provides key insights into the crucial features of the transcriptional regulation in the stepwise folliculogenesis and offers important clues for improving follicle recruitment in vivo and restoring fully competent oocytes in vitro.

Ultrahigh Potassium Storage Capacity of Ca2Si Monolayer with Orderly Multilayered Growth Mechanism.

As the rising renewable energy demands and lithium scarcity, developing high-capacity anode materials to improve the energy density of potassium-based batteries (PBBs) is increasingly crucial. In this work, a unique orderly multilayered growth (OMLG) mechanism on a 2D-Ca2Si monolayer is theoretically demonstrated for potassium storage by first-principles calculations. The global-energy-minimum Ca2Si monolayer is a semiconductor with isotropic mechanical properties and remarkable electrochemical properties, such as a low potassium ion migration energy barrier of 0.07 eV and a low open circuit voltage ranging from 0.224 to 0.003 V. Most notably, 2D-Ca2Si demonstrates an ultrahigh theoretical specific capacity of 5459 mAh g-1 and a total specific capacity of 610 mAh g-1, reaching up to 89% of the capacity of a potassium metal anode. Remarkably, the OMLG mechanism facilitates stable, dendrite-free deposition of hcp-K metal layers on the 2D-Ca2Si surface, where the ultrahigh and gradually converging lattice match as the layers increase is the key to achieving theoretically near-infinite growth. The study theoretically demonstrates the Ca2Si monolayer a highly promising anode material, and offers a novel potassium storage strategy for designing 2D anode materials with high specific capacity, rapid potassium-ion migration, and good safety.

RIPK3 and caspase 8 collaborate to limit herpes simplex encephalitis.

Invasion of the brain by herpes simplex virus 1 (HSV1) can lead to the development of herpes simplex encephalitis (HSE) that is often associated with significant morbidity and mortality regardless of therapeutic intervention. Both virus and host immune factors dictate HSE onset and progression. Because programmed cell death pathways including necroptosis are important antiviral defense mechanisms in HSV1-associated peripheral diseases, they might also play critical roles in HSV1 neuropathogenesis. HSV1-encoded ICP6 prevents receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis during infection of human cells, but it also acts as a species-dependent inducer of necroptosis in murine cells and thereby restricts virus replication. We therefore used an established mouse model of HSE to investigate RIPK3-mediated necroptosis impact on HSV1 neuropathogenesis. Following corneal HSV1 inoculation, RIPK3 knockout mice showed increased susceptibility to HSE when compared with wildtype mice indicating RIPK3 helps to limit HSE progression. RIPK3-mediated defense against HSE was found to be independent of the kinase domain necessary to drive necroptosis implicating that a death independent function of RIPK3 protects against HSE. Conversely the pro-necroptotic kinase function RIPK3 served to limit viral replication in corneal tissue implicating a tissue-specific RIPK3 function in limiting HSV1. Further evaluation of the kinase-independent mechanism to restrict HSE revealed that the RIPK3 signaling partner, caspase 8, contributes to limiting HSE neuropathogenesis. Increased HSE susceptibility from loss of caspase 8 and RIPK3 correlated with decreased levels of chemokines, cytokines, and antiviral lymphocytes recruitment to the brain. We conclude that RIPK3 contributes toward host control of HSV1 replication in a tissue-specific fashion. Whereas RIPK3-mediated necroptosis restricts virus replication within the cornea, kinase-independent induction of inflammation by RIPK3 in collaboration with caspase 8 restricts virus replication within the brain during HSE neuropathogenesis.

Panaxadiol carbamate derivatives: Synthesis and biological evaluation as potential multifunctional anti-Alzheimer agents.

It is reported that panaxadiol has neuroprotective effects. Previous studies have found that compound with carbamate structure introduced at the 3-OH position of 20 (R) -panaxadiol showed the most effective neuroprotective activity with an EC50 of 13.17 µM. Therefore, we designed and synthesized a series of ginseng diol carbamate derivatives with ginseng diol as the lead compound, and tested their anti-AD activity. It was found that the protective effect of compound Q4 on adrenal pheochromocytoma was 80.6 ±â€¯10.85 % (15 µM), and the EC50 was 4.32 µM. According to the ELISA results, Q4 reduced the expression of Aß25-35 by decreasing ß-secretase production. Molecular docking studies revealed that the binding affinity of Q4 to ß-secretase was -49.67 kcal/mol, indicating a strong binding affinity of Q4 to ß-secretase. Western blotting showed that compound Q4 decreased IL-1ß levels, which may contribute to its anti-inflammatory effect. Furthermore, compound Q4 exhibits anti-AD activities by reducing abnormal phosphorylation of tau protein and activation of the mitogen activated protein kinase pathway. The learning and memory deficits in mice treated with Q4in vivo were significantly alleviated. Therefore, Q4 may be a promising multifunctional drug for the treatment of AD, providing a new way for anti-AD drugs.

Design, synthesis, and in vivo and in vitro biological screening of pseudolaric acid B derivatives as potential anti-tumor agents.

Pseudolaric Acid B (PAB), a natural product with remarkable anti-tumor activity, is a starting point for new anticancer therapeutics. We designed and synthesized 27 PAB derivatives and evaluated their anti-proliferative activities against four cancer cell lines: MCF-7, HCT-116, HepG2, and A549. Compared with unmodified PAB, the PAB derivatives showed stronger anti-proliferative activity. The ability of compound D3 (IC50 = 0.21 µM) to inhibit HCT-116 cells was approximately 5.3 times that of PAB (IC50 = 1.11 µM) and the antiproliferative action was unrelated to cytotoxicity (SI=20.38), indicating its superior safety profile (PAB; SI=0.95). Compound D3 effectively suppressed the EdU-positive rate and reduced colony formation, arrested HCT-116 cells in the S and G2/M phases and induced apoptosis. In vivo experiments further demonstrated low toxicity of compound D3 while suppressing tumor growth in mice. In summary, given its strong anti-proliferative effect and relative safety, further development of compound D3 is warranted.

Construction and validation of a prognostic model for overall survival time of patients with ovarian cancer by metabolism-related genes.

BACKGROUND: Ovarian cancer is a female-specific malignancy with high morbidity and mortality. The metabolic reprogramming of tumor cells is closely related to the biological behavior of tumors. METHODS: The prognostic signature of the metabolism-related gene (MRGs) was established by LASSO-Cox regression analysis. The prognostic signature of MRGs was also prognosticated in each clinical subgroup. These genes were subjected to functional enrichment analysis and tissue expression exploration. Analysis of the MRG prognostic signature in terms of immune cell infiltration and antitumor drug susceptibility was also performed. RESULTS: A MRG prognostic signature including 21 genes was established and validated. Most of the 21 MRGs were expressed at different levels in ovarian cancer than in normal ovarian tissue. The enrichment analysis suggested that MRGs were involved in lipid metabolism, membrane organization, and molecular binding. The MRG prognostic signature demonstrated the predictive value of overall survival time in various clinical subgroups. The monocyte, NKT, Tgd and Tex cell scores showed differences between the groups with high- and low-risk score. The antineoplastic drug analysis we performed provided information on ovarian cancer drug therapy and drug resistance. In vitro experiments verified that PLCH1 in 21 MRGs can regulate the apoptosis and proliferation of ovarian cancer cells. CONCLUSION: This metabolism-related prognostic signature was a potential prognostic factor in patients with ovarian cancer, demonstrating high stability and accuracy.

Bioactivities and Structure-Activity Relationships of Maslinic Acid Derivatives: A Review.

Maslinic acid has a variety of biological activities, such as anti-tumor, hypoglycemic, anti-inflammatory, and anti-parasitic. In order to enhance the biological activity of maslinic acid, scholars have carried out a lot of structural modifications, and found some more valuable maslinic acid derivatives. In this paper, the structural modification, biological activity, and structure-activity relationship of maslinic acid were reviewed, providing references for the development of maslinic acid.

Multiscale spatiotemporal characteristics and influencing factors of ecosystem service value of groundwater in China.

Ecosystem services are fundamental to human survival on Earth, but studies on ecosystem service value of groundwater (ESV-G) are rare. The multiscale characteristics and influencing factors of ESV-G in China from 2000 to 2020 were analyzed in this study. The results showed that ESV-G decreased first and then increased, the average ESV-G was 130.30 thousand yuan/km2, and ESV-G tended to shift towards middle level (second to fourth class). The Hu Line was the dividing line between the first class (more than half area) and the others. The AI and FRAC values indicated that the patches of ESV-G were more concentrated, with simpler shapes that were more amenable to governance at the province scale. Hot spots and cold spots were mainly located in the eastern and western parts of Hu Line, respectively. The ESV-G of the cold spots per unit area at the province scale was higher than that at the city scale, which indicated that the province scale had the potential for higher ESV-G per unit area and cost advantage. Precipitation and temperature were the main factors affecting ESV-G; the influence of human activities on ESV-G increased on a larger scale as time went by. Combination of precipitation and Digital Elevation Model (DEM) had the greatest influence on ESV-G among the combinational influencing factors. The province scale was the optimal scale to manage ESV-G. Climate change had led to the expansion of hot and cold spots of ESV-G, northern and southern areas should combine existing policies to carry out differentiated governance. This study extended the scope of ecosystem service value studies from land surface to underground, providing a scientific basis for the management of groundwater ecosystem.

Sialylated IgG in epithelial cancers inhibits antitumor function of T cells via Siglec-7.

Although effective, immune checkpoint blockade induces response in only a subset of cancer patients. There is an urgent need to discover new immune checkpoint targets. Recently, it was found that a class of sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed on the surface of T cells in cancer patients inhibit T cell activation through their intracellular immunosuppressive motifs by recognizing sialic acid-carrying glycans, sialoglycans. However, ligands of Siglecs remain elusive. Here, we report sialylated IgG (SIA-IgG), a ligand to Siglec-7, that is highly expressed in epithelial cancer cells. SIA-IgG binds Siglec-7 directly and inhibits TCR signals. Blocking of either SIA-IgG or Siglec-7 elicited potent antitumor immunity in T cells. Our study suggests that blocking of Siglec-7/SIA-IgG offers an opportunity to enhance immune function while simultaneously sensitizing cancer cells to immune attack.

Integration and interplay of machine learning and bioinformatics approach to identify genetic interaction related to ovarian cancer chemoresistance.

Although chemotherapy is the first-line treatment for ovarian cancer (OCa) patients, chemoresistance (CR) decreases their progression-free survival. This paper investigates the genetic interaction (GI) related to OCa-CR. To decrease the complexity of establishing gene networks, individual signature genes related to OCa-CR are identified using a gradient boosting decision tree algorithm. Additionally, the genetic interaction coefficient (GIC) is proposed to measure the correlation of two signature genes quantitatively and explain their joint influence on OCa-CR. Gene pair that possesses high GIC is identified as signature pair. A total of 24 signature gene pairs are selected that include 10 individual signature genes and the influence of signature gene pairs on OCa-CR is explored. Finally, a signature gene pair-based prediction of OCa-CR is identified. The area under curve (AUC) is a widely used performance measure for machine learning prediction. The AUC of signature gene pair reaches 0.9658, whereas the AUC of individual signature gene-based prediction is 0.6823 only. The identified signature gene pairs not only build an efficient GI network of OCa-CR but also provide an interesting way for OCa-CR prediction. This improvement shows that our proposed method is a useful tool to investigate GI related to OCa-CR.

Prognostic significance of positive peritoneal cytology in endometrial carcinoma based on ESGO/ESTRO/ESP risk classification: A multicenter retrospective study.

OBJECTIVE: This study aimed to determine the prognostic significance of positive peritoneal cytology (PC) on endometrial carcinoma (EC) patients under the ESGO/ESTRO/ESP risk classification. METHODS: This study retrospectively analyzed EC patients from 27 medical centers in China from 2000 to 2019. Patients were divided into three ESGO risk groups: low-risk, intermediate-risk and high-intermediate risk, and high-risk groups. The covariates were balanced by using the propensity score-based inverse probability of treatment weighting (PS-IPTW). The prognostic significance of PC was assessed by Kaplan-Meier curves and multivariate Cox regression analysis. RESULTS: A total of 6313 EC patients with PC results were included and positive PC was reported in 384 women (6.1%). The multivariate Cox analysis in all patients showed the positive PC was significantly associated with decreased PFS (hazard ratio [HR] 2.20, 95% confidence interval [CI] 1.55-3.13, P < 0.001) and OS (HR 2.25, 95% CI 1.49-3.40, P < 0.001),and the Kaplan-Meier curves also showed a poor survival in the intermediate and high-intermediate risk group (5-year PFS: 75.5% vs. 93.0%, P < 0.001; 5-year OS: 78.3% vs. 96.4%, P < 0.001); While in the low-risk group, there were no significant differences in PFS and OS between different PC status (5-year PFS: 93.1% vs. 97.3%, P = 0.124; 5-year OS: 98.6% vs. 98.2%, P = 0.823); in the high-risk group, significant difference was only found in PFS (5-year PFS: 62.5% vs. 77.9%, P = 0.033). CONCLUSION: Positive PC was an adverse prognostic factor for EC, especially in the intermediate and high-intermediate risk patients. Gynecologic oncologists should reconsider the effect of positive PC on different ESGO risk groups.

Intrinsic properties and extrinsic factors of food matrix system affecting the effectiveness of essential oils in foods: a comprehensive review.

Essential oils (EOs) have been proved as natural food preservatives because of their effective and wide-spectrum antimicrobial activity. They have been extensively explored for potential applications in food industry, and substantial progresses have been achieved. However well EOs perform in antibacterial tests in vitro, it has generally been found that a higher level of EOs is needed to achieve the same effect in foods. Nevertheless, this unsimilar effect has not been clearly quantified and elaborated, as well as the underlying mechanisms. This review highlights the influence of intrinsic properties (e.g., oils and fats, carbohydrates, proteins, pH, physical structure, water, and salt) and extrinsic factors (e.g., temperature, bacteria characteristics, and packaging in vacuum/gas/air) of food matrix systems on EOs action. Controversy findings and possible mechanism hypotheses are also systematically discussed. Furthermore, the organoleptic aspects of EOs in foods and promising strategies to address this hurdle are reviewed. Finally, some considerations about the EOs safety are presented, as well as the future trends and research prospects of EOs applications in foods. The present review aims to fill the evidenced gap, providing a comprehensive overview about the influence of the intrinsic and extrinsic factors of food matrix systems to efficiently orientate EOs applications.

Both intrinsic properties and extrinsic factors of food matrix affect the EOs action.EOs influence on the food organoleptic aspects were reviewed.Promising strategies for overcoming the organoleptic aspects of EOs were listed.Future research prospects are outlined to accelerate EOs application in foods.

Synthesis and structure-activity relationship studies of fusidic acid derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury (ALI) are severe forms of diffuse lung disease that impose a substantial health burden all over the world. In the United States, approximately 190,000 cases per year of ALI each year, with an associated 74,500 deaths per year. Anti-inflammatory therapy has become a reasonable approach for the treatment of patients with ALI. In this study, fusidic acid derivatives were used to design new anti-inflammatory compounds with high pharmacological activity and low toxicity. A total of 30 new fusidic acid derivatives were discovered, synthesized, and screened for their anti-inflammatory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells. Of them, b2 was found to be the most active, with a higher efficiency compared with fusidic acid and celecoxib in 10 µM. In vitro, we further measured b2 inhibited inflammatory factor NO (IC50 = 5.382 ± 0.655 µM), IL-6 (IC50 = 7.767 ± 0.871 µM), and TNF-α (IC50 = 7.089 ± 0.775 µM) and b2 inhibited inflammatory cytokines COX-2 and iNOS, ROS production, NF-κB/MAPK and Bax/Bcl-2 signaling pathway pathway. In vivo,b2 attenuated ALI pathological changes and inhibited inflammatory cytokines COX-2 and iNOS in lung tissue and NF-κB/MAPK and Bax/Bcl-2 signaling pathway. In conclusion, b2 may be a promising anti-inflammatory lead compound.

Cysteine protease cathepsin B mediates radiation-induced bystander effects.

The radiation-induced bystander effect (RIBE) refers to a unique process in which factors released by irradiated cells or tissues exert effects on other parts of the animal not exposed to radiation, causing genomic instability, stress responses and altered apoptosis or cell proliferation. Although RIBEs have important implications for radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain poorly understood. Here we use Caenorhabditis elegans as a model in which to study RIBEs, and identify the cysteine protease CPR-4, a homologue of human cathepsin B, as the first RIBE factor in nematodes, to our knowledge. CPR-4 is secreted from animals irradiated with ultraviolet or ionizing gamma rays, and is the major factor in the conditioned medium that leads to the inhibition of cell death and increased embryonic lethality in unirradiated animals. Moreover, CPR-4 causes these effects and stress responses at unexposed sites distal to the irradiated tissue. The activity of CPR-4 is regulated by the p53 homologue CEP-1 in response to radiation, and CPR-4 seems to exert RIBEs by acting through the insulin-like growth factor receptor DAF-2. Our study provides crucial insights into RIBEs, and will facilitate the identification of additional RIBE factors and their mechanisms of action.

Application of the Mannich reaction in the structural modification of natural products.

The Mannich reaction is commonly used to introduce N atoms into compound molecules and is thus widely applied in drug synthesis. The Mannich reaction accounts for a certain proportion of structural modifications of natural products. The introduction of Mannich bases can significantly improve the activity, hydrophilicity, and medicinal properties of compounds; therefore, the Mannich reaction is widely used for the structural modification of natural products. In this paper, the application of the Mannich reaction to the structural modification of natural products is reviewed, providing a method for the structural modification of natural products.

Research progress of natural products and their derivatives against Alzheimer's disease.

Alzheimer's disease (AD), a persistent neurological dysfunction, has an increasing prevalence with the aging of the world and seriously threatens the health of the elderly. Although there is currently no effective treatment for AD, researchers have not given up, and are committed to exploring the pathogenesis of AD and possible therapeutic drugs. Natural products have attracted considerable attention owing to their unique advantages. One molecule can interact with multiple AD-related targets, thus having the potential to be developed in a multi-target drug. In addition, they are amenable to structural modifications to increase interaction and decrease toxicity. Therefore, natural products and their derivatives that ameliorate pathological changes in AD should be intensively and extensively studied. This review mainly presents research on natural products and their derivatives for the treatment of AD.