Organoid modeling meets cancers of female reproductive tract.

Diseases of the female reproductive system, especially malignant tumors, pose a serious threat to women's health worldwide. One of the key factors limiting research progress in this area is the lack of representative models. Organoid technology, especially tumor organoids, has been increasingly applied in the study of female reproductive system tumors due to their high heterogeneity, close resemblance to the physiological state, easy acquisition and cultivation advantages. They play a significant role in understanding the origin and causes of tumors, drug screening, and personalized treatment and more. This article reviews the organoid models for the female reproductive system, focusing on the cancer research advancements. It discusses the methods for constructing tumor organoids of the female reproductive tract and summarizes the limitations of current research. The aim is to offer a reference for future development and application of these organoid models, contributing to the advancement of anti-tumor drugs and treatment strategies for female reproductive tract cancer patients.

Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates.

The current selection of ligands for both proteins of interest (POI) and E3 ubiquitin ligase significantly restricts the scope of targeted protein degradation (TPD) technologies. This study introduces cell-penetrating peptide-induced chimera conjugates (cp-PCCs) targeting the DHHC3 enzyme involved in PD-L1 palmitoylation. This approach disrupts PD-L1's immunosuppressive function, enhancing anti-tumor immunity. We developed cp-PCCs to degrade DHHC3, directly linking DHHC3-mediated PD-L1 palmitoylation to PD-L1 stability on tumor cells. Our research utilized both in vitro assays and in vivo experiments in immune checkpoint blockade-resistant mouse models. We focused on a CRBN-based cp-PCC named PCC16, which demonstrated a DC50 of 102 nmol for DHHC3 degradation and significantly reduced PD-L1 levels. In resistant models, PCC16 not only robustly downregulated PD-L1 but also exhibited substantial anti-tumor activity in vivo without significant toxicity. This outperformed traditional inhibitors, showcasing the potential of cp-PCC technology to bypass current PROTAC limitations. Our findings suggest that cp-PCCs offer a promising method for targeting PD-L1 through DHHC3 inhibition and support their continued exploration as a versatile tool in cancer immunotherapy, especially for tumors resistant to standard treatments.

The atypical Dof transcriptional factor OsDes1 contributes to stay-green, grain yield, and disease resistance in rice.

The regulation of leaf senescence and disease resistance plays a crucial role in determining rice grain yield and quality, which are important to meet the ever-increasing food demands of the world. Here, we identified an atypical Dof transcriptional factor OsDes1 that contributes to the stay-green phenotype, grain yield, and disease resistance in rice. The expression level of OsDes1 is positively associated with stay-green in natural variations of japonica rice, suggesting that OsDes1 would be alternatively used in breeding programs. Mechanistically, OsDes1 targets the promoter of the Rieske FeS protein gene OsPetC to activate its expression and interacts with OsPetC to protect against its degradation, thus promoting stay-green and ultimately improving the grain yield. OsDes1 also binds to the promoter region of defense-related genes, such as OsPR1b, and activates their expression, leading to enhanced disease resistance. These findings offer a potential strategy for breeding rice to enhance grain yield and disease resistance.

The role of tetrahydrocurcumin in disease prevention and treatment.

In recent decades, natural compounds derived from herbal medicine or dietary sources have played important roles in prevention and treatment of various diseases and have attracted more and more attention. Curcumin, extracted from the Curcumae Longae Rhizoma and widely used as food spice and coloring agent, has been proven to possess high pharmacological value. However, the pharmacological application of curcumin is limited due to its poor systemic bioavailability. As a major active metabolite of curcumin, tetrahydrocurcumin (THC) has higher bioavailability and stability than curcumin. Increasing evidence confirmed that THC had a wide range of biological activities and significant treatment effects on diseases. In this paper, we reviewed the research progress on the biological activities and therapeutic potential of THC on different diseases such as neurological disorders, metabolic syndromes, cancers, and inflammatory diseases. The extensive pharmacological effects of THC involve the modulation of various signaling transduction pathways including MAPK, JAK/STAT, NF-κB, Nrf2, PI3K/Akt/mTOR, AMPK, Wnt/ß-catenin. In addition, the pharmacokinetics, drug combination and toxicology of THC were discussed, thus providing scientific basis for the safe application of THC and the development of its dietary supplements and drugs.

A biocompatible pea protein isolate-derived bioink for 3D bioprinting and tissue engineering.

Three-dimensional bioprinting is a potent biofabrication technique in tissue engineering but is limited by inadequate bioink availability. Plant-derived proteins are increasingly recognized as highly promising yet underutilized materials for biomedical product development and hold potential for use in bioink formulations. Herein, we report the development of a biocompatible plant protein bioink from pea protein isolate. Through pH shifting, ethanol precipitation, and lyophilization, the pea protein isolate (PPI) transformed from an insoluble to a soluble form. Next, it was modified with glycidyl methacrylate to obtain methacrylate-modified PPI (PPIGMA), which is photocurable and was used as the precursor of bioink. The mechanical and microstructural studies of the hydrogel containing 16% PPIGMA revealed a suitable compress modulus and a porous network with a pore size over 100 µm, which can facilitate nutrient and waste transportation. The PPIGMA bioink exhibited good 3D bioprinting performance in creating complex patterns and good biocompatibility as plenty of viable cells were observed in the printed samples after 3 days of incubation in the cell culture medium. No immunogenicity of the PPIGMA bioink was identified as no inflammation was observed for 4 weeks after implantation in Sprague Dawley rats. Compared with methacrylate-modified gelatin, the PPIGMA bioink significantly enhanced cartilage regeneration in vitro and in vivo, suggesting that it can be used in tissue engineering applications. In summary, the PPIGMA bioink can be potentially used for tissue engineering applications.

Injectable Nanocomposite Immune Hydrogel Dressings: Prevention of Tumor Recurrence and Anti-Infection after Melanoma Resection.

Complex wound repair due to tumor recurrence and infection following tumor resection presents significant clinical challenges. In this study, a bifunctional nanocomposite immune hydrogel dressing, SerMA-LJC, is developed to address the issues associated with repairing infected damaged tissues and preventing tumor recurrence. Specifically, the immune dressing is composed of methacrylic anhydride-modified sericin (SerMA) and self-assembled nanoparticles (LJC) containing lonidamine (Lon), JQ1, and chlorine e6 (Ce6). In vitro and in vivo experiments demonstrate that the nanocomposite hydrogel dressing can trigger immunogenic cell death (ICD) and has a potent anti-tumor effect. Moreover, this dressing can mitigate the acidic microenvironment of tumor cells and suppress the overexpression of PD-L1 on the tumor cell surface, thereby altering the immunosuppressive tumor microenvironment and augmenting the anti-tumor immune response. Further, the RNA sequencing analysis revealed that the hydrogel dressing significantly impacts pathways associated with positive regulation of immune response, apoptotic process, and other relevant pathways, thus triggering a potent anti-tumor immune response. More importantly, the dressing generates a substantial amount of reactive oxygen species (ROS), which can effectively kill Staphylococcus aureus and promote infectious wound healing. In conclusion, this dual-function nanocomposite immune hydrogel dressing exhibits promise in preventing tumor recurrence and promoting infectious wound healing.

An Anti-Oxidative Bioink for Cartilage Tissue Engineering Applications.

Since chondrocytes are highly vulnerable to oxidative stress, an anti-oxidative bioink combined with 3D bioprinting may facilitate its applications in cartilage tissue engineering. We developed an anti-oxidative bioink with methacrylate-modified rutin (RTMA) as an additional bioactive component and glycidyl methacrylate silk fibroin as a biomaterial component. Bioink containing 0% RTMA was used as the control sample. Compared with hydrogel samples produced with the control bioink, solidified anti-oxidative bioinks displayed a similar porous microstructure, which is suitable for cell adhesion and migration, and the transportation of nutrients and wastes. Among photo-cured samples prepared with anti-oxidative bioinks and the control bioink, the sample containing 1 mg/mL of RTMA (RTMA-1) showed good degradation, promising mechanical properties, and the best cytocompatibility, and it was selected for further investigation. Based on the results of 3D bioprinting tests, the RTMA-1 bioink exhibited good printability and high shape fidelity. The results demonstrated that RTMA-1 reduced intracellular oxidative stress in encapsulated chondrocytes under H2O2 stimulation, which results from upregulation of COLII and AGG and downregulation of MMP13 and MMP1. By using in vitro and in vivo tests, our data suggest that the RTMA-1 bioink significantly enhanced the regeneration and maturation of cartilage tissue compared to the control bioink, indicating that this anti-oxidative bioink can be used for 3D bioprinting and cartilage tissue engineering applications in the future.

Natural self-healing injectable hydrogels loaded with exosomes and berberine for infected wound healing.

Complete and rapid healing of infected skin wounds remains a challenge in current clinical treatment. In this study, we prepared a self-healing injectable CK hydrogel by crosslinking two natural polysaccharides, carboxymethyl chitosan and oxidized konjac glucomannan, based on the Schiff base bond. To enhance the biological function of the hydrogel, we multi-functionalized hydrogen by loading it with berberine (BBR) and stem cell-derived exosomes (Exo), forming a composite hydrogel, CK@BBR&Exo, which could be injected directly into the wound through a needle and adhered to the wound. Furthermore, the self-healing properties of CK@BBR&Exo increased its usefulness and service life. Additionally, the drug-loaded CK@BBR&Exo hydrogel was versatile, inhibiting bacterial growth, regulating the inflammatory response, and promoting neovascularization in infected skin wounds, thus achieving the rapid healing of infected skin wounds. These results suggest that the CK@BBR&Exo-injectable self-healing hydrogel is an ideal dressing for treating infected skin wounds.