Hydrogel adhesives show promise for gastric ulcer treatment, while facing challenges in endoscopic delivery, wet adhesion, and long-term gastric retention. Here, we engineered a sequential pH-responsive adhesive (PNMH) by polymerizing β-carboxylic-amide-functionalized N-acryloyl phenylalanine and hydroxyethyl acrylamide. Acid-induced protonation followed by hydrolysis of the β-carboxylic amide drives a pH-triggered quadruple evolution of intermolecular interactions from electrostatic repulsion to hydrophobicity-assisted hydrogen bonding, then to hydrophobicity-assisted electrostatic interaction, and finally to cation-π interaction. This unique mechanism enables facile endoscopic administration of PNMH and ultrafast gelation within ∼4 s upon exposure to gastric acid, forming a robust network and simultaneously displacing interfacial water to achieve immediate tissue adhesion (∼24.1 kPa). Furthermore, the interfacial adhesion strength with wet gastric tissue progressively intensifies to 34.3 kPa in the early stage of hydrolysis while maintaining long-term interfacial integration over 30 days under simulated gastric conditions. Moreover, PNMH exhibits a prolonged in vivo residence time of more than 4 days through in situ injection into the rat stomach. Rat and pig experiments demonstrate that PNMH, as a durable shield, protects ulcers from gastric acid/pepsin erosion and orchestrates healing through attenuating immune activation, suppressing matrix metalloproteinase-9 overexpression and promoting cytoskeleton-driven restoration of the mucosal barrier. Our work presents an advanced molecular design strategy for gastric-resistant polymer adhesives and provides a promising candidate for clinical gastric ulcer treatment.

Gastric perforation repair demands adhesive hydrogels that couple robust sealing with controlled drug release to overcome the challenges of continuous peristalsis and the oxidative wound microenvironment. Herein, we developed a reactive oxygen species (ROS)-responsive dynamic hydrogel formed by incorporating a ROS-cleavable tannic acid-2-formylphenylboronic acid (TA-FPBA) complex into an imine-crosslinked network made of 4-arm polyethylene glycol benzaldehyde (4-arm-PEG-CHO) and ε-poly-L-lysine (ε-PLL) through tandem dynamic iminoboronate and boronate ester bonds, denoted as PEG-PL-TA1 hydrogel. The hydrogel exhibited rapid in situ gelation (∼64 s), robust tissue adhesion (∼25.7 kilopascal), and sufficient burst pressure (∼128.8 millimeters of mercury) for effective gastric sealing. Upon exposure to elevated ROS levels at the wound site, boronate ester bonds were cleaved to trigger the on-demand release of TA. The released TA demonstrated potent antioxidant activity, protecting gastric epithelial cells from oxidative damage and preserving viability. In vivo outcomes of gastric perforation treatments in rats revealed that the PEG-PL-TA1 hydrogel synergistically sealed the defect while modulating the wound microenvironment by alleviating oxidative stress and shifting immune balance toward repair, ultimately accelerating perforation repair. Our work provides a promising design strategy for dynamic hydrogels for controlled drug release and offers a potential therapeutic strategy for clinical gastric perforation treatment.

BACKGROUND:Colorectal cancer (CRC) is a prevalent malignancy with significant mortality rates globally. Understanding the genetic and molecular mechanisms underlying CRC development is crucial for improving therapeutic strategies. METHOD:In this study, we utilized cis-eQTL summary data to identify genes potentially causally associated with CRC. The expression levels of candidate genes in tumor and normal tissues were compared using the GEPIA2 database. The correlations between FUT8 expression and cellular functions, tumor mutation burden, immune checkpoint genes, and immune infiltration were analyzed. Molecular docking was performed to identify potential drugs targeting FUT8, and the effects of the selected drug on cell proliferation were evaluated using the MTT assay. Additionally, the cellular thermal shift assay (CETSA) was employed to assess the interaction between the drug and the target protein. RESULTS:We identified 19 genes with eQTLs potentially associated with CRC, among which six eQTLs were associated with increased CRC risk, including FUT8. FUT8 was significantly overexpressed in CRC tumor tissues and correlated with various cellular functions such as stemness, invasion, EMT, and metastasis. Higher FUT8 expression was associated with higher tumor mutation burden and significant correlations with multiple immune checkpoint genes. Molecular docking identified VE-822 as a promising drug candidate targeting FUT8, which demonstrated inhibitory effects on CRC cell proliferation. The CETSA results indicated that VE ‒ 822 could bind to FUT8 and improve its thermal stability. CONCLUSION:FUT8 is a crucial gene that causes colon cancer and is linked to tumour immunity. VE-822 is a promising candidate for treating CRC by targeting FUT8.

BACKGROUND:Cellular senescence is associated with various hepatic diseases. Stimulator of interferon genes (STING) signaling has been identified as a significant driver of cellular senescence and hepatic stellate cells (HSCs) activation. The blockade of STING signaling serves as a potential strategy to halt senescence. However, little is known about the anti-aging natural compound inhibiting STING signaling to date. PURPOSE:To screen natural compound targeting STING signaling, and to unearth its pharmacological actions and molecular mechanisms. METHODS:Natural compound inhibiting STING signaling was identified using RT-PCR, and anti-aging effects were systematically evaluated in doxorubicin (Dox)-induced senescent cells and natural aging mice, respectively. Exact pharmacological effects and molecular mechanisms were thoroughly investigated using inhibitors and agonists of the STING signaling, STING dimerization assay, bioinformatic analysis, Western blotting, immunoprecipitation, immunofluorescence and cell thermal shift assay. RESULTS:Here, marketed drug berberine (BBR), a natural compound, was identified as an inhibitor of STING signaling and a potential candidate for attenuating hepatic senescence. Mechanistically, STING was indeed overexpressed and over-activated to induce the production of interferon-beta (IFN-β) and other senescence-associated secretory phenotypes (SASPs), thereby initiating senescence process and HSCs activation in response to cell stress. We unexpectedly found that BBR upregulated mannose 6-phosphate receptor (M6PR) in senescent cells rather than normal cells, which could bind to STING and sort it to and reside in endosomes for degradation, further suppressing the STING signaling and cellular senescent phenotypes. Importantly, unless M6PR was knocked down, anti-aging effects of BBR were difficult to reverse even after the reversal of STING expression, because M6PR made STING strong residence in endosomes. CONCLUSION:These results support BBR as a promising candidate for attenuating hepatic senescence and unveil the straight-forward yet vital role of M6PR in BBR-mediated anti-aging effects by sorting STING into and reside in endosomes for degradation.

Wound dressings with asymmetrical adhesion performances and biological activity are urgently needed for the treatment of tissue/organ injuries. Herein, an antioxidative and Janus hydrogel (Tempo-FPF) composed of 2,2,6,6-tetramethylpiperidine-1-oxyl functionalized poly(ethylene imine) (PEI-Tempo), 2-formylphenylboronic acid (2-FPBA) and poly(vinyl alcohol) (PVA) is developed based on tandem dynamic iminoboronate and boronate ester bonds. The addition of PEI and 2-FPBA onto the top of the precursor hydrogel formed by PEI-Tempo, 2-FPBA, and PVA can endow the Tempo-FPF hydrogel with asymmetric adhesion properties owing to the differences in crosslinking density and hydrophilicity between the two sides. Moreover, profiting from Tempo functionalization, the Tempo-FPF hydrogel exhibits outstanding free radical scavenging ability. In vivo outcomes of gastric perforation and liver incision treatments in rats reveal that the Tempo-FPF hydrogel can not only enable firm injury site sealing to inhibit gastric acid leakage and bleeding but also prevent the occurrence of tissue/organ adhesion. In vivo deep second-degree burn wound study demonstrates that the Tempo-FPF hydrogel can attenuate oxidative stress-induced inflammation response within the wound site to accelerate the reconstruction of skin tissues. This work provides a promising strategy for the design of potent antioxidative hydrogel dressings with on-demand adhesion behaviors for in vivo tissue/organ injury repair.

Basal cell carcinoma (BCC) is a common type of skin cancer that is increasing in prevalence worldwide. Previous genome-wide association studies (GWAS) have identified certain genetic loci associated with BCC. However, many potential disease-causing genes of BCC remain to be discovered. While the sonic hedgehog (SHH) signalling pathway and mutations in PTCH1/2 and SMO are well-established drivers of BCC pathogenesis, novel genetic factors may complement existing therapeutic targets such as vismodegib and sonidegib. The Mendelian Randomization (MR) study used multiple omics datasets including expression quantitative trait loci (eQTL), methylation quantitative trait loci (mQTL), and protein quantitative trait loci (pQTL) to identify genetic factors associated with an increased risk of developing BCC. Transcriptome analysis of the GEO database then verified the specific expression of key genes. In addition, in vitro experiments were used to silence the key gene to observe the effect of this gene on the proliferation ability of A431 cells. Combined with the multi-omics MR Analysis results, six CpG sites were identified with the RCC2 gene associated with BCC risk. Additionally, single-cell transcriptome analysis confirmed the specific expression of RCC2 in the BCC cohort. In the in vitro validation experiment, siRCC2-1/2 was transfected into the A431 cells, significantly decreasing the expression of RCC2 in the cells. Moreover, the proliferation of A431 cells was significantly inhibited after RCC2 was knocked down. We identified a risk gene RCC2 associated with BCC by MR-based bioinformatics analysis and demonstrated that inhibition of RCC2 inhibited the proliferation of A431 in vitro. These findings provide new strategies for targeted therapy of BCC.

The development of polymer materials for water decontamination makes a significant contribution to environmental protection and public health. Herein, we report the preparation of metallacage-crosslinked free-standing supramolecular networks by photo-induced copolymerization of acrylate metallacages and butyl methacrylate for water decontamination. The integration of metallacages into polymer networks endows the networks good capability for generating singlet oxygen via photosensitization, making them serve as a type of decontamination materials that can effectively eliminate diverse organic pollutants and bacterial contaminants. This study not only provides a mild and effective strategy for the preparation of metallacage-cored supramolecular networks via photo-induced copolymerization but also explores their applications for photocatalytic dye degradation and bacterial killing, which will promote the future development of metallacage-based supramolecular materials for photocatalytic applications.

Background Vorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30–35%) respond to SAHA and the response is not always sustainable. Thus, understanding the mechanisms underlying evasive resistance in this cancer is an unmet medical need to improve the efficacy of current therapies.Purpose This study aims to identify factors contributing to resistance against SAHA in CTCL and ways to mitigate it.Methods and results In this study, we demonstrated that attenuated reactive oxygen species (ROS) induces the expression of interleukin (IL)-2Rα, one of the IL-2 receptors, which drives resistance to SAHA in CTCL. We also determined that cantharidin could overcome SAHA resistance to CTCL by blocking IL-2Rα-related signaling via ROS-dependent manner. Mechanistically, accelerated translation of IL-2Rα contributes to excessive IL-2Rα protein formation as a result of reduced ROS levels in SAHA-resistant CTCL. At the same time, amplified IL-2R signals are evidenced by strengthened interaction of IL-2Rβ with IL-2Rγ and Janus kinase/signal transducer and activator of transcription molecules, and by increased expression of protein kinase B (AKT)/mTOR and mitogen-activated protein kinase signaling. Moreover, cantharidin, an active constituent of Mylabris used in traditional Chinese medicine, markedly increased ROS levels, and thereby restrained IL-2Rα translation, resulting in suppression of downstream pathways in SAHA-resistant cells. Cantharidin is also found to synergize with SAHA and triggers SAHA-resistant cell death via IL-2R signaling both in vitro and in vivo.Conclusion Our study uncovers a novel molecular mechanism of acquired SAHA resistance and also suggests that using cantharidin is a potential approach to overcome CTCL therapy resistance. Our findings underlie the therapeutic potential of cantharidin in treating CTCL.

A “gear-driven”-type chirality transfer mechanism has been proposed to illustrate the multiple-step chirality transfer of TPE-based supramolecular organic frameworks (SOFs) for peptides.

Purpose:We conducted a multicenter cross-sectional study in central and western China to explore the association between inflammatory diet and stomach cancer odds.Patients and Methods:Participants from five hospitals in the central and western regions were collected. All participants completed the questionnaire we provided before the gastroscopy examination, which includes inquiries about risk factors for stomach cancer and food frequency. All participants underwent gastroscopy, and a mucosal biopsy was confirmed pathologically. Pathological findings were classified as chronic gastritis group, precancerous lesions group and stomach cancer group. Dietary Inflammatory Index (DII) scores were calculated based on the frequency of food occurrences in the questionnaire, and finally SPSS was used to calculate the correlation between variables.Results:A total of 1162 patients were included in this study, including 668 cases of chronic gastritis, 411 cases of precancerous lesions, and 83 cases of cancer. A single factor analysis was conducted to examine the risk factors of stomach cancer, revealing a significant association between a pro-inflammatory diet and the stomach cancer odds (p value < 0.05). The results of binary classification analysis further confirmed that a pro-inflammatory diet is a risk factor for stomach cancer 【odds ratio (OR) =7.400)】. Moreover, correlation analysis demonstrated a positive correlation between the severity of gastric mucosal diseases and an inflammatory diet (including anti-inflammatory and pro-inflammatory diets) (rs=0.274, p-value < 0.001).Conclusion:Pro-Inflammatory diet is a risk factor for stomach cancer, and may accelerate the progression of stomach mucosal disease.

The Notch signaling is a key molecular pathway that regulates cell fate and development. Aberrant Notch signaling can lead to carcinogenesis and progression of malignant tumors. However, current therapies targeting Notch pathway lack specificity and induce high toxicity. In this report, a tumor microenvironment-responsive and injectable hydrogel is designed to load plasmid DNA complexes as a cascade gene delivery system to achieve precise Notch-targeted gene therapy of colorectal cancer (CRC). The hydrogels are prepared through cross-linking between phenylboric acid groups containing poly(oligo(ethylene glycol)methacrylate) (POEGMA) and epigallocatechin gallate (EGCG), used to load the complexes between plasmid DNA encoding short hairpin RNAs of Notch1 (shNotch1) and fluorinated polyamidoamine (PAMAM-F) (PAMAM-F/shNotch1). In response to low pH and H 2 O 2 in tumor microenvironment, the hydrogel can be dissociated and release the complexes for precise delivery of shNotch1 into tumor cells and inhibit Notch1 activity to suppress malignant biological behaviors of CRC. In the subcutaneous tumor model of CRC, PAMAM-F/shNotch1-loaded hydrogels can accurately attenuate Notch1 activity and significantly inhibit tumor growth without affecting Notch signal in adjacent normal tissues. Therefore, this therapeutic system can precisely inhibit Notch1 signal in CRC with high responsiveness and low toxicity, providing a promising Notch-targeted gene therapeutic for human malignancy.

Elevated temperatures can deactivate tissues in the burn wound area, allowing pathogenic bacteria to multiply on the wound surface, ultimately leading to local or systemic infection. An ideal burn dressing should provide antibacterial properties and facilitate painless dressing changes. Silk microfibers coated with poly (2, 3, 4-trihydroxybenzaldehyde) (referred to as mSF@PTHB) to in situ reduce AgNO3 to silver nanoparticles (AgNPs) in a hydrazide hyaluronic acid-based hydrogel are utilized. The findings indicate a more homogeneous distribution of the silver elements compared to directly doped AgNPs, which also conferred antioxidant and antibacterial properties to the hydrogel. Moreover, hydrogels containing pH-responsive dynamic acylhydrazone bonds can undergo a gel-sol transition in a weak acid environment, leading to the painless removal of adhesive hydrogel dressings. Notably, the on-demand replaceable self-healing antioxidant hydrogel dressing exhibits antibacterial effects and cytocompatibility in vitro, and the wound-healing performance of the hydrogel is validated by treating a burn mouse model with full-thickness skin defects. It is demonstrated that hydrogel dressings offer a viable therapeutic approach to prevent infection and facilitate the healing of burn wounds.

The development of supramolecular hosts which can efficiently encapsulate photosensitizers to improve the photodynamic efficacy holds great promise for cancer therapy. Here, we report two perylene diimide-based metallacages that can form stable host–guest complexes with planar conjugated molecules including polycyclic aromatic hydrocarbons and photosensitizers (hypocrellin A). Such host–guest complexation not only prevents the aggregation of photosensitizers in aqueous environments, but also offers fluorescence resonance energy transfer (FRET) from the metallacage to the photosensitizers to further improve the singlet oxygen generation (ΦΔ = 0.66). The complexes are further assembled with amphiphilic polymers, forming nanoparticles with improved stability for anticancer study. Both in vitro and in vivo studies indicate that the nanoparticles display excellent anticancer activities upon light irradiation, showing great potential for cancer photodynamic therapy. This study provides a straightforward and effective approach for enhancing the photosensitivity of conventional photosensitizers via host–guest complexation-based FRET, which will open a new avenue for host–guest chemistry-based supramolecular theranostics.

Development of bioadhesives that can be facilely delivered by endoscope and exhibit instant and robust adhesion with gastric tissues to promote gastric ulcer healing remains challenging. In this study, an advanced bioadhesive is prepared through free radical polymerization of ionized N-acryloyl phenylalanine (iAPA) and N-[tris (hydroxymethyl) methyl] acrylamide (THMA). The precursory polymer solution exhibits low viscosity with the capability for endoscope delivery, and the hydrophilic-hydrophobic transition of iAPA upon exposure to gastric acid can trigger gelation through phenyl groups assisted multiple hydrogen bonds formation and repel water molecules on tissue surface to establish favorable environment for interfacial interactions between THMA and functional groups on tissues. The in-situ formed hydrogel features excellent stability in acid environment (14 days) and exhibits firm wet adhesion to gastric tissue (33.4 kPa), which can efficiently protect the wound from the stimulation of gastric acid and pepsin. In vivo studies reveal that the bioadhesive can accelerate the healing of ulcers by inhibiting inflammation and promoting capillary formation in the acetic acid-induced gastric ulcer model in rats. Our work may provide an effective solution for the treatment of gastric ulcers clinically.

Skin is one of the most vulnerable tissues,but there is a lack of injectable bioactive hydrogel dressings,which possess high strength,antiswelling capacity,and wet tissue adhesiveness,but also a rapid gelling process to enable rapid hemostasis,sutureless wound closure,and scarless healing of infected skin wounds[1-5].A new injectable,antibacterial,and multifunctional hydrogel dressings based on poly(citric acid-co-polyethylene glycol)-g-dopamine(PCPD)and amino-terminated Pluronic F127(APF)mi-celles loaded with astragaloside IV(AS)was developed for this pur-pose,as shown in Fig.1A[6].

Owing to their appealing three-dimensional structures and tunable photophysical properties, emissive metallacages have been widely applied in recognition and sensing, adsorption and separation, catalysis, etc . Recently, the application of emissive metallacages in biomedical fields has emerged as a hot research topic, because multiple biological functionalities can be facilely integrated into metallacage-based platforms to deliver different functions. In this review, the applications of emissive metallacages in bio-imaging, delivery and cancer theranostics are systematically summarized. The dilemmas and challenges of metallacage-based biomedical materials are also raised at the end of this review. We hope this review would provide some guidance for the construction of novel emissive metallacages with biological functions, and further advance the development of emissive metallacages as biomedical materials.

Chirality transfer for natural chiral biomolecules can reveal the indispensable role of chiral structures in life and can be used to develop the chirality-sensing biomolecular recognition. Here, we report the synthesis and characterization of a series of achiral supramolecular organic frameworks (SOF-1, SOF-2, and SOF-3), constructed from cucurbit[8]uril (CB[8]) and tetraphenylethene (TPE) derivatives (1, 2, and 3), respectively, as chirality-sensing platforms to explore their chirality transfer mechanism for peptides in water. Given the right-handed (P) and left-handed (M) rotational conformation of TPE units and the selective binding of CB[8] to aromatic amino acids, these achiral SOFs can be selectively triggered in water by peptides containing N-terminal tryptophan (W) and phenylalanine (F) residues into their P- or M-rotational conformation, exhibiting significantly different circular dichroism (CD) spectra. Although various peptides have the same L-type chiral configuration, they can induce positive CD signals of SOF-1 and negative CD signals of SOF-2 and SOF-3, respectively. Based on the structural analysis of the linkage units between CB[8] and TPE units in these SOFs, a “gear-driven”-type chirality transfer mechanism has been proposed to visually illustrate the multiple-step chirality transfer process from the recognition site in the CB[8]’s cavity to TPE units. Furthermore, by utilizing the characteristic CD signals generated through the “gear-driven”-type chirality transfer, a series of SOFs can serve as chiroptical sensor arrays to effectively recognize and distinguish various peptides based on their distinctive CD spectra.