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Background: Self-emulsifying drug delivery system (SEDDS) is widely used to improve the oral bioavailability of hydrophobic drugs. Emulsion droplet size was revealed to be a critical parameter that influences the thermodynamic stability, drug solubility, and drug absorption of the SEDDS. A high proportion of surfactant and/or co-surfactant was usually employed to reduce the particle size, which may lead the low drug loading and undesirable gastrointestinal toxicity. Methods: This manuscript proposed a novel strategy to reduce the particle size of emulsions using the hybrid of medium and long-chain triglyceride (MCT and LCT) SEDDS without promoting the concentration of surfactants and co-surfactants. The composition of SEDDS was selected based on the drug solubility. Particle size distribution and zeta potential of emulsion particles were determined using the dynamic light scattering technique. The bioavailability of formulations was evaluated in a mouse model. Results: The particle size of the emulsion was reduced from 113.50 ± 0.34 nm (MCT SEDDS) and 371.60 ± 6.90 nm (LCT SEDDS) to 21.23 ± 0.30 nm (MCT&LCT SEDDS). Progesterone, a poorly water-soluble drug, was selected as the model drug in the investigation of SEDDS. The hybrid of MCT&LCT progesterone SEDDS exhibited reduced particle size, enlarged self-emulsifying ranges, and increased drug content in the aqueous phase after lipolysis compared with the conventional mono-MCT or LCT SEDDS. In addition, the bioavailability of progesterone in the MCT&LCT SEDDS formulation was 3.82-fold higher than that of Utrogestan® (a clinical oral administrated product) in a mouse model.

Background Wheat yield potential is intrinsically linked to the efficiency of photosynthetic carbon fixation and subsequent allocation to developing grains. While leaves are recognized as the dominant source of photosynthate, the molecular drivers governing temporal shifts in source tissue function during grain filling remain unresolved, leaving a critical gap in knowledge about the proteomic reprogramming underlying natural developmental transitions. Addressing this gap could reveal novel targets for enhancing carbohydrate partitioning efficiency and improving agronomic yield in wheat. Results This study presents a comprehensive temporal proteomic analysis of wheat source tissues (the flag leaf and -2nd leaf), from the initiation of the grain filling stage to the termination of source-to-sink transport (10–40 days after anthesis, DAA), using a data-independent acquisition (DIA)-based proteomics approach. Weighted gene co-expression network analysis (WGCNA) identified significant enrichment of photosynthesis-related proteins, carbohydrate metabolic enzymes, and cytokinin metabolic enzymes during the early grain filling stage (10–15 DAA). Integrated co-expression clustering and multiple expectation maximizations for motif elicitation (MEME) analysis revealed strong enrichment of Dof (DNA binding with one finger) transcription factor binding cis-elements in the promoters of carbohydrate synthesis-related genes. Additionally, through haplotype-phenotype association studies, we identified favorable Dof family haplotypes that were significantly associated with increased thousand-grain weight (TGW) and enhanced leaf chlorophyll content. Conclusions Our findings not only provided a systematic characterization of proteome dynamics in wheat source tissues during the grain filling stage, but also revealed several key regulatory proteins that may control carbohydrate accumulation in source tissues, offering potential new targets for breeding strategies aimed at improving wheat yield.

In this study, we developed novel porous starch (PS)/Lactobacillus (LS) microcapsules via in situ cross-linking with sodium trimetaphosphate (STMP), using Lactobacillus johnsonii (LJ), Lactobacillus acidophilus (LA), and Lactobacillus rhamnosus GG (LGG) as representative strains. Scanning electron microscopy (SEM) revealed that the cross-linked microcapsules (designated as PS/LS-CL: PS/LJ-CL, PS/LA-CL, PS/LGG-CL) formed aggregated structures with denser microarchitecture compared to uncross-linked porous starch/Lactobacillus microcapsules (designated as PS/LS: PS/LJ, PS/LA, PS/LGG). The encapsulation efficiencies of PS/LJ-CL, PS/LA-CL, and PS/LGG-CL (79.56%, 78.49%, and 55.96%, respectively) significantly surpassed those of their uncross-linked counterparts (67.92%, 58.68%, and 47.71%, p < 0.05). In addition, the cross-linked porous starch microcapsules improved the survival rate of Lactobacillus during simulated gastrointestinal digestion and long-time storage. Importantly, the oral gavage of PS/LS-CL, PS/LA-CL, and PS/LGG-CL significantly increased the amount of Lactobacillus. The colonization efficiency of all the tested Lactobacillus in mice was detected by both gradient dilution plate counting and quantitative real-time PCR (qRT-PCR). These findings indicate the potential function of the in situ cross-linked porous starch microcapsules as a robust delivery system to enhance the colonization of probiotics in vivo.

Statement of Problem: The high recurrence rate of denture stomatitis may be related to the strong resistance of fungi. Therefore, the method of providing biomaterials with antifungal properties is an attractive solution for improving microbial control.Purpose: Against the drug resistance of Candida albicans, this study aim to elucidate the photocatalytic antibacterial effect of TiO2-HAP nanocomposite-modified PMMA on Candida albicans through in vitro experiments, and to evaluate the potential impact of the mechanical properties, optical properties, cytotoxicity and contact angle of the modified PMMA, to provide a scientific basis for the development of denture base resins with minimum percentage of photocatalytic additives.Methods: In this study, TiO2-HAP nanoparticles were mixed with self-polymerized PMMA in different mass ratios, 0%wt was the control group. Various methods were used to characterize TiO2-HAP. Subsequently, the changes in mechanical and optical properties of the samples were measured, and Cell Counting Kit-8 (CCK-8) and cell live-death staining were used to detect the cytotoxicity of the samples to human gingival fibroblasts (HGFs) in vitro. The contact angle of the specimens was evaluated. The photocatalytic antibacterial activity of modified PMMA against Candida albicans was studied using a biofilm accumulation test and scanning electron microscopy.Results: TiO2-HAP nanocomposites have an acceptable structure. When the addition amount of TiO2-HAP is 1.0%wt, the PMMA material showed peak mechanical properties. When the additional amount is less than 1%wt, The patient is still aesthetically acceptable PMMA showed no significant cytotoxicity at doses below 2%wt. While TiO2-HAP modified PMMA containing only 1%wt showed up to 94% antibacterial efficiency against Candida albicans under visible light.Conclusion: Therefore, it is inferred that the optimal photocatalytic antimicrobial and mechanical properties of PMMA materials are achieved by adding 1%wt TiO2-HAP without causing significant changes in cytotoxicity and optical properties.

Colon-targeted oral drug delivery systems (CDDSs) are desirable for the treatment of ulcerative colitis (UC), which is a disease with high relapse and remission rates associated with immune system inflammation and dysregulation localized within the lining of the large bowel. However, the success of current available approaches used for colon-targeted therapy is limited. Budesonide (BUD) is a corticosteroid drug, and its rectal and oral formulations are used to treat UC, but the inconvenience of rectal administration and the systemic toxicity of oral administration restrict its long-term use. In this study, we designed and prepared colon-targeted solid lipid nanoparticles (SLNs) encapsulating BUD to treat UC by oral administration. A negatively charged surfactant (NaCS-C12) was synthesized to anchor cellulase-responsive layers consisting of polyelectrolyte complexes (PECs) formed by negatively charged NaCS and cationic chitosan onto the SLNs. The release rate and colon-specific release behavior of BUD could be easily modified by regulating the number of coated layers. We found that the two-layer BUD-loaded SLNs (SLN-BUD-2L) with a nanoscale particle size and negative zeta potential showed the designed colon-specific drug release profile in response to localized high cellulase activity. In addition, SLN-BUD-2L exhibited excellent anti-inflammatory activity in a dextran sulfate sodium (DSS)-induced colitis mouse model, suggesting its potential anti-UC applications.

As the second largest power source in the world, hydropower plays a crucial role in the operation of power systems. This paper focuses on the key issues of regulating hydropower stations participating in the spot market. It aims at the core challenges, such as the conflict of cascade hydro plants’ joint clearing, the lack of adaptability for different types of power supply bidding on the same platform, and the contradiction between long-term operation and the spot market. Through the construction of a water spillage management strategy and settlement compensation mechanism, the competitive abandoned water problem caused by mismatched quotations of cascade hydro plants can be solved. In order to achieve reasonable recovery of the power cost, a separate bidding mechanism and capacity cost recovery model are designed. Subsequently, the sufficient electricity supply constraint of the remaining period is integrated into the spot-clearing model, which can coordinate short-term hydropower dispatch with long-term energy storage demand. The operation of the Yunnan electricity spot market is being simulated to verify the effectiveness of the proposed method.

Background The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. Methods Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo . Results Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. Conclusion TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC. Graphical Abstract

The structural perfection and multivalency of dendrimers have made them useful for biodelivery and bioactivity via peripheral functionalization and the modulation of core-forming structures and dendrimer generations. Yet only few dendrimers have shown inherent therapeutic activity arising from their inner repeating units. Here, we report the synthesis and characterization of a polyacylthiourea dendrimer with inherent potent anticancer activity and the absence of cytotoxicity in mice. The poly(ethylene glycol)-functionalized fourth generation of the dendrimer, which can be efficiently synthesized from sequential click reactions of orthogonal monomers, displays low in vivo acute and subacute toxicities yet potently inhibits tumour growth and metastasis. The dendrimer’s in vivo anticancer activity arises from the depletion of bioavailable copper and the subsequent inhibition of angiogenesis and cellular proliferation. When compared with some clinically used cytotoxin drugs, the dendrimer exerts inherent anticancer activity via non-cytotoxic pathways and leads to higher therapeutic efficacy, yet without cytotoxin-induced side effects. A dendrimer that depletes bioavailable copper and leads to the suppression of tumour angiogenesis acts as a potent and non-cytotoxic anticancer therapeutic.

Chemotherapy treatments for cancer are always accompanied by a low concentration of drug delivered in the tumor area and severe side effects including systemic toxicity. Improving the concentration, biocompatibility, and biodegradability of regional chemotherapy drugs is a pressing challenge in the field of materials.PurposeChemotherapy treatments for cancer are always accompanied by a low concentration of drug delivered in the tumor area and severe side effects including systemic toxicity. Improving the concentration, biocompatibility, and biodegradability of regional chemotherapy drugs is a pressing challenge in the field of materials.N-Phenyloxycarbonyl-amino acids (NPCs) which exhibit significant tolerance to nucleophiles, such as water and hydroxyl-containing compounds, are promising monomers for the synthesis of polypeptides and polypeptoids. Cell line and mouse models were used to comprehensively explore how to enhance the tumor MRI signal and evaluate the therapeutic effect of Fe@POS-DOX nanoparticles.MethodsN-Phenyloxycarbonyl-amino acids (NPCs) which exhibit significant tolerance to nucleophiles, such as water and hydroxyl-containing compounds, are promising monomers for the synthesis of polypeptides and polypeptoids. Cell line and mouse models were used to comprehensively explore how to enhance the tumor MRI signal and evaluate the therapeutic effect of Fe@POS-DOX nanoparticles.In this study, poly(3,4-dihydroxy-L-phenylalanine)-b-polysarcosine (PDOPA-b-PSar, simplified as POS) was synthesized by the block copolymerization of DOPA-NPC with Sar-NPC. Fe@POS-DOX nanoparticles were prepared in order to utilize the strong chelation of catechol ligands to iron (III) cations and the hydrophobic interaction between DOX and DOPA block to deliver chemotherapeutics to tumor tissue. The Fe@POS-DOX nanoparticles exhibit high longitudinal relaxivity (r 1 = 7.06 mM-1·s-1) and act as T 1-weighted magnetic resonance (MR) imaging contrast agents. Further, the main focus was improving tumor site-specific bioavailability and achieving therapeutic effects through the biocompatibility and biodegradability of Fe@POS-DOX NPs. The Fe@POS-DOX treatment exhibited excellent antitumor effects.ResultsIn this study, poly(3,4-dihydroxy-L-phenylalanine)-b-polysarcosine (PDOPA-b-PSar, simplified as POS) was synthesized by the block copolymerization of DOPA-NPC with Sar-NPC. Fe@POS-DOX nanoparticles were prepared in order to utilize the strong chelation of catechol ligands to iron (III) cations and the hydrophobic interaction between DOX and DOPA block to deliver chemotherapeutics to tumor tissue. The Fe@POS-DOX nanoparticles exhibit high longitudinal relaxivity (r 1 = 7.06 mM-1·s-1) and act as T 1-weighted magnetic resonance (MR) imaging contrast agents. Further, the main focus was improving tumor site-specific bioavailability and achieving therapeutic effects through the biocompatibility and biodegradability of Fe@POS-DOX NPs. The Fe@POS-DOX treatment exhibited excellent antitumor effects.Upon intravenous injection, Fe@POS-DOX delivers DOX specifically to the tumor tissues, as revealed by MR, and leads to the inhibition of tumor growth without overt toxicity to normal tissues, thus displaying considerable potential for use in clinical applications.ConclusionUpon intravenous injection, Fe@POS-DOX delivers DOX specifically to the tumor tissues, as revealed by MR, and leads to the inhibition of tumor growth without overt toxicity to normal tissues, thus displaying considerable potential for use in clinical applications.

Background Tumor-associated macrophages (TAMs) contribute significantly to immunosuppression in colorectal cancer liver metastasis (CRLM), leading to high aggressiveness and poor prognosis. However, the key molecules involved in shaping TAMs toward the pro-tumoral phenotype in CRLM remain unclear, limiting the development of macrophage-mediated immunotherapies for CRLM. Results In this study, we showed that DICER1 was highly expressed in TAMs and closely associated with M2 polarization in CRLM. Knockdown of Dicer, encoded by DICER1 in humans (or Dicer1 in mice), skewed macrophages toward an anti-tumoral M1 phenotype, with increased expression of pro-inflammatory cytokines and tumor cell phagocytosis, thereby suppressing tumor growth in mice. An M2 macrophage-targeting nanosystem was developed to deliver Dicer1 siRNA for selectively downregulating Dicer expression in M2 macrophages. In situ manipulation of TAMs with the nanoparticle exerted a significant anti-tumor effect with an improved immune microenvironment in a CRLM mouse model. Macrophage depletion experiments further suggested that this effect was largely dependent on the presence of TAMs. Mechanistically, Dicer inhibition reprogrammed M2-like macrophages through downregulation of miR-148a-3p and miR-1981-5p. Conclusion Our study uncovered the central role of Dicer in the M2 polarization of TAMs, in turn suggesting a promising therapeutic strategy for CRLM. Graphical abstract