Targeting ferroptosis in gastric cancer: Strategies and opportunities.

Ferroptosis is a novel form of programmed cell death morphologically, genetically, and biochemically distinct from other cell death pathways and characterized by the accumulation of iron-dependent lipid peroxides and oxidative damage. It is now understood that ferroptosis plays an essential role in various biological processes, especially in the metabolism of iron, lipids, and amino acids. Gastric cancer (GC) is a prevalent malignant tumor worldwide with low early diagnosis rates and high metastasis rates, accounting for its relatively poor prognosis. Although chemotherapy is commonly used to treat GC, drug resistance often leads to poor therapeutic outcomes. In the last several years, extensive research on ferroptosis has highlighted its significant potential in GC therapy, providing a promising strategy to address drug resistance associated with standard cancer therapies. In this review, we offer an extensive summary of the key regulatory factors related to the mechanisms underlying ferroptosis. Various inducers and inhibitors specifically targeting ferroptosis are uncovered. Additionally, we explore the prospective applications and outcomes of these agents in the field of GC therapy, emphasizing their capacity to improve the outcomes of this patient population.

Application of biomimetic nanovaccines in cancer immunotherapy: A useful strategy to help combat immunotherapy resistance.

Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.

Radioiodine-refractory differentiated thyroid cancer: Molecular mechanisms and therapeutic strategies for radioiodine resistance.

Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is difficult to treat with radioactive iodine because of the absence of the sodium iodide transporter in the basement membrane of thyroid follicular cells for iodine uptake. This is usually due to the mutation or rearrangement of genes and the aberrant activation of signal pathways, which result in abnormal expression of thyroid-specific genes, leading to resistance of differentiated thyroid cancer cells to radioiodine therapy. Therefore, inhibiting the proliferation and growth of RAIR-DTC with multikinase inhibitors and other drugs or restoring its differentiation and then carrying out radioiodine therapy have become the first-line treatment strategies and main research directions. The drugs that regulate these kinases or signaling pathways have been studied in clinical and preclinical settings. In this review, we summarized the major gene mutations, gene rearrangements and abnormal activation of signaling pathways that led to radioiodine resistance of RAIR-DTC, as well as the medicine that have been tested in clinical and preclinical trials.

Inubritantrimers A-D: Trimerized Sesquiterpenoid [4 + 2] Adducts Featuring a Distinctive Spiro-Polycyclic Scaffold from Inula britannica.

Inubritantrimer A (1), a trace trimerized sesquiterpenoid [4 + 2] adduct featuring an unusual exo-exo type spiro-polycyclic scaffold, together with three new endo-exo [4 + 2] adducts, inubritantrimers B-D (2-4), were discovered from the flowers of Inula britannica. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, and ECD approaches. 1 is characterized as a novel exo-exo trimer, synthesized biogenetically from three sesquiterpenoid monomers, featuring a unique linkage of C-11/C-1', C-13/C-3' and C-13'/C-3″, C-11'/C-1″ through a two-step exo [4 + 2] cycloaddition process. Compounds 1-4 exhibited modest cytotoxicity against breast cancer cells with IC50 values in the range of 5.84-12.01 µM.

High-Performance Piezoelectric Nanogenerator of BTO-PVDF Nanofibers for Wearable Sensing.

Piezoelectric nanogenerator (PENG) produces stable electrical signals in response to external mechanical stimuli and holds promise in the fields of flexible sensors and smart wearable devices. In practice, a high-performance PENG with a straightforward structure and exceptional reliability is deeply desired. This study optimally synthesizes piezoelectric composites comprising polyvinylidene fluoride (PVDF) incorporated with barium titanate (BTO) nanoparticles (NPs) and fabricated a PENG with heightened sensitivity by using the electrospinning technique. The polar ß-phase content of the dual-optimized BTO-PVDF (barium titanate and polyvinylidene fluoride) electrospun fiber reaches up to 82.39%. In the bending mode, it achieves a remarkable maximum open-circuit voltage of 19.152 V, a transferred charge of 8.058 nC, and an output voltage per unit area of 2.128 V cm- 2. Under vertical pressure conditions, the BP-PENG exhibits an impressive voltage of 12.361 V while the force is 2.156 N, demonstrating a notable pressure sensing sensitivity of 5.159 V kPa-1, with an excellent linear relationship. Furthermore, the BP-PENG displays sensitive sensing features in monitoring hand movements. The sensitive response and high performance make it promising for applications in human motion monitoring and smart wearable devices.

Cysteine-induced growth of jagged gold bipyramids from penta-twinned nanorod seeds.

The understanding on the growth mechanism of complex gold nanostructures both experimentally and theoretically can guide their design and fabrication toward various applications. In this work, we report a cysteine-directed overgrowth of penta-twinned nanorod seeds into jagged gold bipyramids with discontinuous stepped {hhk} facets. By monitoring the growth process, we find that {hhk} facets with large k/h values (∼7) are formed first at two ends of the nanorods, followed by the protrusion of the middle section exposing {hhk} facets with smaller indices (k/h ∼ 2-3). Molecular dynamics simulations indicate that the strong adsorption of cysteine molecules on {110} facets is likely responsible for the formation of stepped {hhk} facets, and the stronger adsorption of cysteine molecules on {hhk} facets with smaller k/h compared to that on {hhk} facets with larger k/h is a possible cause of the discontinuity of {hhk} facets at the middle of gold bipyramids. The obtained jagged gold bipyramids display large field enhancement under illumination due to their sharp nanostructures, demonstrating their application potentials in surface-enhanced spectroscopy and catalysis.

VGLL4 promotes vascular endothelium specification via TEAD1 in the vascular organoids and human pluripotent stem cells-derived endothelium model.

BACKGROUND: We have shown that Hippo-YAP signaling pathway plays an important role in endothelial cell differentiation. Vestigial-like family member 4 (VGLL4) has been identified as a YAP inhibitor. However, the exact function of VGLL4 in vascular endothelial cell development remains unclear. In this study, we investigated the role of VGLL4, in human endothelial lineage specification both in 3D vascular organoid and 2D endothelial cell differentiation. METHODS AND RESULTS: In this study, we found that VGLL4 was increased during 3D vascular organoids generation and directed differentiation of human embryonic stem cells H1 towards the endothelial lineage. Using inducible ectopic expression of VGLL4 based on the piggyBac system, we proved that overexpression of VGLL4 in H1 promoted vascular organoids generation and endothelial cells differentiation. In contrast, VGLL4 knockdown (heterozygous knockout) of H1 exhibited inhibitory effects. Using bioinformatics analysis and protein immunoprecipitation, we further found that VGLL4 binds to TEAD1 and facilitates the expression of endothelial master transcription factors, including FLI1, to promote endothelial lineage specification. Moreover, TEAD1 overexpression rescued VGLL4 knockdown-mediated negative effects. CONCLUSIONS: In summary, VGLL4 promotes EC lineage specification both in 3D vascular organoid and 2D EC differentiation from pluripotent stem cell, VGLL4 interacts with TEAD1 and facilitates EC key transcription factor, including FLI1, to enhance EC lineage specification.

Telecoupling between urban expansion and forest ecosystem service loss through cultivated land displacement: A case study of Zhejiang Province, China.

Urbanization can either directly occupy forests or indirectly lead to forest loss elsewhere through cultivated land displacement, resulting in further forest fragmentation and ecosystem service (ES) loss. However, the effects of urban expansion on forest area and ESs are unknown, and this is especially true for indirect effects. Taking Zhejiang Province, China, a typical deforested province, as an example, this study quantified the direct and indirect effects of urban expansion on forest area and five ESs (timber yield, water yield, carbon sequestration, soil conservation, and biodiversity) from 2000 to 2020, explored the relationship between forest structure (forest proportion, mean patch area, edge density, and mean euclidean nearest neighbor distance) change and ESs, and revealed the telecoupling of urban expansion and forest loss and cascade effects among urbanization, deforestation, forest structure, and ESs. The results indicated that the indirect forest loss (4.30%-6.15%) caused by cultivated land displacement due to urban expansion was larger than the direct forest loss (2.42%). Urban expansion has a greater negative impact on carbon sequestration (6.40%-8.20%), water yield (6.08%-7.78%), and biodiversity (5.79%-7.44%) than on timber yield (4.77%-6.17%) and soil conservation (4.43%-5.77%). The indirect forest ES loss was approximately 2.83-4.34 times greater than the direct forest ES loss. Most forest ESs showed a nonlinear significant positive correlation with changes in forest proportion and mean patch area and a significant nonlinear negative correlation with changes in edge density and mean Euclidean nearest neighbor distance (p < 0.05). There is telecoupling between urban expansion in one region and forest ES loss in other distant regions. This study contributes to guiding sustainable forest conservation and management globally.

Global potential distribution of mangroves: Taking into account salt marsh interactions along latitudinal gradients.

Mangrove is one of the most productive and sensitive ecosystems in the world. Due to the complexity and specificity of mangrove habitat, the development of mangrove is regulated by several factors. Species distribution models (SDMs) are effective tools to identify the potential habitats for establishing and regenerating the ecosystem. Such models usually include exclusively environmental factors. Nevertheless, recent studies have challenged this notion and highlight the importance of including biotic interactions. Both factors are necessary for a mechanistic understanding of the mangrove distribution in order to promote the protection and restoration of mangroves. Thus, we present a novel approach of combining environmental factors and interactions with salt marsh for projecting mangrove distributions at the global level and within latitudinal zones. To test the salt marsh interaction, we fit the MaxEnt model with two predicting sets: (1) environments only and (2) environments + salt marsh interaction index (SII). We found that both sets of models had good predictive ability, although the SII improved model performance slightly. Potential distribution areas of mangrove decrease with latitudes, and are controlled by biotic and abiotic factors. Temperature, precipitation and wind speed are generally critical at both global scale and ecotones along latitudes. SII is important on global scale, with a contribution of 5.9%, ranking 6th, and is particularly critical in the 10-30°S and 20-30°N zone. Interactions with salt marsh, including facilitation and competition, are shown to affect the distribution of mangroves at the zone of coastal ecotone, especially in the latitudinal range from 10° - 30°. The contribution of SII to mangrove distribution increases with latitudes due to the difference in the adaptive capacity of salt marsh plants and mangroves to environments. Totally, this study identified and quantified the effects of salt marsh on mangrove distribution by establishing the SII. The results not only facilitate to establish a more accurate mangrove distribution map, but also improve the efficiency of mangrove restoration by considering the salt marsh interaction in the mangrove management projects. In addition, the method of incorporating biotic interaction into SDMs through establish the biotic interaction index has contributed to the development of SDMs.

S-Nitrosylated CuS Hybrid Hydrogel Patches with Robust Antibacterial and Repair-Promoting Activity for Infected Wound Healing.

Development of wound dressing with robust antibacterial and repair-promoting activity has always been an urgent biomedical task during the past years. The therapeutic effect of current hydrogel dressings containing single bioactive agent like nanoparticle or gas is still unsatisfactory for the treatment of infected wound. Herein, a CuS/NO co-loaded hydrogel (CuS/NO Gel) is proposed, which is constructed by sequential polymerization, reduction, and S-nitrosylation of CuS hybrid hydrogel with disulfide bonds. These CuS/NO Gel patches show good mechanical stability, high photothermal activity and excellent biocompatibility. When being applied to treat infected wound, CuS/NO Gel can not only eliminate infection effectively by the synergistic effect of mild photothermal heating and boosted NO release in infection phase, but also promote vascularization and collagen deposition due to the synchronous supply of Cu ion nutrients and low concentration NO signaling molecules in wound repair phase. Compared to hydrogel dressings with individual active agent (CuS Gel or NO Gel), CuS/NO Gel exhibits better antibacterial and repair-promoting activity both in vitro and in vivo. Therefore, this CuS/NO Gel holds great promise in the future clinical treatment against infected wound.

Increased uptake of deep soil water promotes drought resistance in mixed forests.

The intensity and frequency of droughts are projected to rise in recent years and adversely affect forests. Thus, information on plant water use and acclimation during and after droughts is crucial. This study used the stable isotope and thermal dissipation probes to detect the water-use adaptation of mixed forests to drought using a precipitation gradient control experiment in the field. The results showed that Platycladus orientalis and Quercus variabilis mainly absorbed stable water from deep soil layers during the drought (32.05% and 28.2%, respectively). The synergetic nocturnal sap flow in both species replenished the water loss, but P. orientalis experienced a greater decline in transpiration acclimation to drought. The transpiration of Q. variabilis remained high since it was mainly induced by radiation. After short-term exposure to drought, P. orientalis majorly obtained shallow soil water, confirming its sensitivity to shallow water. Contrarily, Q. variabilis mainly absorbed stable water from deep soil layers regardless of the soil water content. Therefore, these findings suggest that Q. variabilis cannot physiologically adjust to extreme drought events, possibly limiting their future distributions and altering the composition of boreal forests.

Dual inhibition of MYC and SLC39A10 by a novel natural product STAT3 inhibitor derived from Chaetomium globosum suppresses tumor growth and metastasis in gastric cancer.

Gastric cancer remains one of the most common deadly diseases and lacks effective targeted therapies. In the present study, we confirmed that the signal transducer and activator of transcription 3 (STAT3) is highly expressed and associated with a poor prognosis in gastric cancer. We further identified a novel natural product inhibitor of STAT3, termed XYA-2, which interacts specifically with the SH2 domain of STAT3 (Kd= 3.29 µM) and inhibits IL-6-induced STAT3 phosphorylation at Tyr705 and nuclear translocation. XYA-2 inhibited the viability of seven human gastric cancer cell lines with 72-h IC50 values ranging from 0.5 to 0.7 µΜ. XYA-2 at 1 µΜ inhibited the colony formation and migration ability of MGC803 (72.6% and 67.6%, respectively) and MKN28 (78.5% and 96.6%, respectively) cells. In the in vivo studies, intraperitoneal administration of XYA-2 (10 mg/kg/day, 7 days/week) significantly suppressed 59.8% and 88.8% tumor growth in the MKN28-derived xenograft mouse model and MGC803-derived orthotopic mouse model, respectively. Similar results were obtained in a patient-derived xenograft (PDX) mouse model. Moreover, XYA-2 treatment extended the survival of mice bearing PDX tumors. The molecular mechanism studies based on transcriptomics and proteomics analyses indicated that XYA-2 might exert its anticancer activity by synergistically inhibiting the expression of MYC and SLC39A10, two downstream genes of STAT3 in vitro and in vivo. Together, these findings suggested that XYA-2 may be a potent STAT3 inhibitor for treating gastric cancer, and dual inhibition of MYC and SLC39A10 may be an effective therapeutic strategy for STAT3-activated cancer.

Trienomycin A-simplified analogs: Synthesis and anti-neuroinflammatory activity.

A series of novel trienomycin A (TA)-mimetic compounds (5a-p) have been designed, synthesized, and evaluated for their in vitro anti-neuroinflammatory and neuroprotective activities. Among them, compounds 5h, 5n, and 5o exhibits relatively strong NO inhibitory activity in LPS-activated BV-2 cells with the EC50 values of 12.4, 17.3, and 8.9 µM, respectively. Moreover, 5h showed evidently neuroprotective effect against H2O2-induced PC-12 cells without cytotoxicity at 20 µM. Overall, these compounds can provide a better understanding of the structure-activity relationship of TA and furnish research ideas for anti-neuroinflammatory and neuroprotective agents.

Design and synthesis of proteolysis-targeting chimeras (PROTACs) as degraders of glutathione peroxidase 4.

Ferroptosis is a new type of regulated, non-apoptotic cell death driven by iron-dependent phospholipid peroxidation. Inducing cell ferroptosis by inactivating glutathione peroxidase 4 (GPX4) has been considered as an effective cancer treatment strategy, but only few GPX4 inhibitors have been reported to date. Targeted protein degradation is receiving increasing attention in the discovery and development of therapeutic modality, particularly proteolysis targeting chimeras (PROTACs). Herein, we reported the design, synthesis, and evaluation of different types of GPX4-targeting PROTACs using ML162 derivatives and ligands for CRBN/VHL E3 ligases. Among them, CRBN-based PROTAC GDC-11 showed a relatively balanced biological profile in GPX4 degradation (degradation rate of 33% at 10 µM), cytotoxicity (IC50 = 11.69 µM), and lipid peroxides accumulation (2-foldincreaserelatedtoDMSO), suggesting a typical characteristic of ferroptosis. In silico docking and quantum chemistry theoretical calculations provided a plausible explanation for the moderate degrading effect of these synthesized PROTACs. Overall, this work lays the foundation for subsequent studies of GPX4-targeting PROTACs, and further design and synthesis of GPX4-targeting degrader are currently in progress in our group, which will be reported in due course.

A Soluble Porous Coordination Polymer for Fluorescence Sensing of Explosives and Toxic Anions under Homogeneous Environment.

In the past decades, porous coordination polymers (PCPs) based fluorescent (FL) sensors have received intense attention due to their promising applications. In this work, a soluble Zn-PCP is presented as a sensitive probe towards explosive molecules, chromate, and dichromate ions. In former reports, PCP sensors were usually ground into fine powders and then dispersed in solvents to form FL emulsion for sensing applications. However, their insoluble characters would cause the sensing accuracy which is prone to interference from environmental effects. While in this work, the as-made PCP could be directly soluble in organic solvents to form a clear solution with bright blue emission, representing the first soluble PCP based fluorescence sensor to probe explosive molecules under a homogeneous environment. Moreover, the FL PCP solution also shows sensitive detection behaviors towards the toxic anions of CrO42- and Cr2O72-, which exhibit a good linear relationship between the fluorescence intensity of Zn-PCP and the concentrations of both analytes. This work provides a reference for designing task-specific PCP sensors utilized under a homogeneous environment.

Soil calcium prompts organic carbon accumulation after decadal saline-water irrigation in the Taklamakan desert.

Soil organic carbon (SOC), as a crucial measure of soil quality, is typically low in arid regions due to salinization, which is a global issue. How soil organic carbon changes with salinization is not a simple concept, as high salinity simultaneously affects plant inputs and microbial decomposition, which exert opposite effects on SOC accumulation. Meanwhile, salinization could affect SOC by altering soil Ca2+ (a salt component), which stabilizes organic matter via cation bridging, but this process is often overlooked. Here, we aimed to explore i) how soil organic carbon changes with salinization induced by saline-water irrigation and ii) which process drives soil organic carbon content with salinization, plant inputs, microbial decomposition, or soil Ca2+ level. To this end, we assessed SOC content, plant inputs represented by aboveground biomass, microbial decomposition revealed by extracellular enzyme activity, and soil Ca2+ along a salinity gradient (0.60-31.09 g kg-1) in the Taklamakan Desert. We found that, in contrast to our prediction, SOC in the topsoil (0-20 cm) increased with soil salinity, but it did not change with the aboveground biomass of the dominant species (Haloxylon ammodendron) or the activity of three carbon-cycling relevant enzymes (ß-glucosidase, cellulosidase, and N-acetyl-beta-glucosaminidase) along the salinity gradient. Instead, SOC changed positively with soil exchangeable Ca2+, which increased linearly with salinity. These results suggest that soil organic carbon accumulation could be driven by increases in soil exchangeable Ca2+ under salinization in salt-adapted ecosystems. Our study provides empirical evidence for the beneficial impact of soil Ca2+ on organic carbon accumulation in the field under salinization, which is apparent and should not be disregarded. In addition, the management of soil carbon sequestration in salt-affected areas should be taken into account by adjusting the soil exchangeable Ca2+ level.

Impacts of land use/land cover and soil property changes on soil erosion in the black soil region, China.

Soil erosion (SE) is seriously threatening grain production and the ecological environment in the black soil region. Understanding the impact of changes in land use/land cover (LULC) and soil properties on SE is critical for agricultural sustainability and soil management. However, the contribution of soil property changes to SE is often ignored in existing studies. This study analyzed changes in LULC and soil properties from 1980 to 2020 in the black soil region, China. Then, the revised universal soil loss equation was used to explore the spatiotemporal changes of SE from 1980 to 2020. Finally, the contribution of LULC change and soil property change to SE was separated by scenario comparison. The results showed that cropland increased (by 24,157 km2) at the expense of grassland and forest from 1980 to 2020. Sand in cropland decreased by 21.95%, while the silt, clay, and SOC increased by 21.37%, 1.43%, and 15.38%, respectively. Soil erodibility in cropland increased greatly (+9.85%), while in forest and grassland decreased (-6.05% and -4.72%). LULC change and soil properties change together aggravated SE in the black soil region. LULC change and soil property change resulted in a 22% increase in SE, of which LULC change resulted in a 14% increase, and soil property change resulted in an 8% increase. Agricultural development policy was the main reason driving LULC change. The combination of LULC change, climatic factors, and long-term tillage resulted in changes in soil properties. Ecosystem management and policy can reduce SE through vegetation restoration and soil improvement. This study can provide important references for soil conservation and agricultural development in the black soil region.

Vegetation restoration thresholds under different vegetation types and altitude gradients in the Sichuan-Yunnan ecological shelter, China.

Determining the threshold for the response of ecosystem services (ESs) to vegetation change is critical for ecological restoration, and once the threshold is exceeded, ESs may be inhibited. Vegetation type and altitude are important factors affecting ESs. However, the nonlinear effects of vegetation change on ESs and their threshold under different vegetation types and altitude gradients are not clear. This study selected the Sichuan-Yunnan ecological shelter as the study area. Four ESs (water yield (WY), carbon storage (CS), soil conservation (SC), and water purification (WP)) were quantified by using the Integrated Valuation of Ecosystem Services and Trade-offs model. The differences in ESs among different vegetation types were identified. Variance analysis was used to explore the spatial differences in ESs under different altitude gradients. The inflection point of the promoting effect of vegetation cover on ESs was taken as the threshold, and elastic analysis was used to determine the impact threshold of fractional vegetation cover (FVC) on ESs. The threshold represents the inflection point at which vegetation cover promotes ESs. The results showed that the CS, SC, and WP of the natural forest were higher than those of the plantation, while the WY was lower than that of the plantation. WY, CS, and SC remained higher in the high-altitude regions, while nitrogen export was higher in the low-altitude regions. FVC was positively correlated with nitrogen export in the low-altitude regions and negatively correlated with WY in the high-altitude regions. FVC had a promoting effect on ESs, and the promoting effect was weakened beyond the threshold. The thresholds of FVC promoting ESs were 0.86, 0.79, 0.85, and 0.83 in natural forest, shrub, plantation, and grassland, respectively. The threshold of FVC promoting ESs in low-altitude regions was larger than that in high-altitude regions. This study can provide a theoretical basis for large-scale ecological management and moderate restoration.

A comprehensive review of protein-based carriers with simple structures for the co-encapsulation of bioactive agents.

The rational design and fabrication of edible codelivery carriers are important to develop functional foods fortified with a plurality of bioactive agents, which may produce synergistic effects in increasing bioactivity and functionality to target specific health benefits. Food proteins possess considerable functional attributes that make them suitable for the delivery of a single bioactive agent in a wide range of platforms. Among the different types of protein-based carriers, protein-ligand nanocomplexes, micro/nanoparticles, and oil-in-water (O/W) emulsions have increasingly attracted attention in the codelivery of multiple bioactive agents, due to the simple and convenient preparation procedure, high stability, matrix compatibility, and dosage flexibility. However, the successful codelivery of bioactive agents with diverse physicochemical properties by using these simple-structure carriers is a daunting task. In this review, some effective strategies such as combined functional properties of proteins, self-assembly, composite, layer-by-layer, and interfacial engineering are introduced to redesign the carrier structure and explore the encapsulation of multiple bioactive agents. It then highlights success stories and challenges in the co-encapsulation of multiple bioactive agents within protein-based carriers with a simple structure. The partition, protection, and release of bioactive agents in these protein-based codelivery carriers are considered and discussed. Finally, safety and application as well as challenges of co-encapsulated bioactive agents in the food industry are also discussed. This work provides a state-of-the-art overview of protein-based particles and O/W emulsions in co-encapsulating bioactive agents, which is essential for the design and development of novel functional foods containing multiple bioactive agents.

Targeting KRAS mutant cancers: from druggable therapy to drug resistance.

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.