Immunogenic cell death-based cancer vaccines: promising prospect in cancer therapy.

Tumor immunotherapy is a promising approach for addressing the limitations of conventional tumor treatments, such as chemotherapy and radiotherapy, which often have side effects and fail to prevent recurrence and metastasis. However, the effectiveness and sustainability of immune activation in tumor immunotherapy remain challenging. Tumor immunogenic cell death, characterized by the release of immunogenic substances, damage associated molecular patterns (DAMPs), and tumor associated antigens, from dying tumor cells (DTCs), offers a potential solution. By enhancing the immunogenicity of DTCs through the inclusion of more immunogenic antigens and stimulating factors, immunogenic cell death (ICD) based cancer vaccines can be developed as a powerful tool for immunotherapy. Integrating ICD nanoinducers into conventional treatments like chemotherapy, photodynamic therapy, photothermal therapy, sonodynamic therapy, and radiotherapy presents a novel strategy to enhance treatment efficacy and potentially improve patient outcomes. Preclinical research has identified numerous potential ICD inducers. However, effectively translating these findings into clinically relevant applications remains a critical challenge. This review aims to contribute to this endeavor by providing valuable insights into the in vitro preparation of ICD-based cancer vaccines. We explored established tools for ICD induction, followed by an exploration of personalized ICD induction strategies and vaccine designs. By sharing this knowledge, we hope to stimulate further development and advancement in the field of ICD-based cancer vaccines.

Exosome-mimetic vesicles derived from fibroblasts carrying matrine for wound healing.

Background: Chronic skin wounds are a leading cause of hospital admissions and reduced life expectancy among older people and individuals with diabetes. Delayed wound healing is often attributed to a series of cellular abnormalities. Matrine, a well-studied component found in Sophora flavescens, is recognized for its anti-inflammatory effects. However, its impact on wound healing still remains uncertain. This study aims to explore the potential of matrine in promoting wound healing. Methods: In this study, we utilized gradient extrusion to produce fibroblast-derived exosome-mimetic vesicles as carriers for matrine (MHEM). MHEM were characterized using transmission electron microscopy and dynamic light scattering analysis. The therapeutic effect of MHEM in wound healing was explored in vitro and in vivo. Results: Both matrine and MHEM enhanced the cellular activity as well as the migration of fibroblasts and keratinocytes. The potent anti-inflammatory effect of matrine diluted the inflammatory response in the vicinity of wounds. Furthermore, MHEM worked together to promote angiogenesis and the expression of transforming growth factor ß and collagen I. MHEM contained growth factors of fibroblasts that regulated the functions of fibroblasts, keratinocytes and monocytes, which synergistically promoted wound healing with the anti-inflammatory effect of matrine. Conclusions: MHEM showed enhanced therapeutic efficacy in the inflammatory microenvironment, for new tissue formation and angiogenesis of wound healing.

Adoptive cell therapy for solid tumors beyond CAR-T: Current challenges and emerging therapeutic advances.

Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) is a highly specific anti-tumor immunotherapy that has shown promise in the treatment of hematological malignancies. However, there has been a slow progress toward the treatment of solid tumors owing to the complex tumor microenvironment that affects the localization and killing ability of the CAR cells. Solid tumors with a strong immunosuppressive microenvironment and complex vascular system are unaffected by CAR cell infiltration and attack. To improve their efficacy toward solid tumors, CAR cells have been modified and upgraded by "decorating" and "pruning". This review focuses on the structure and function of CARs, the immune cells that can be engineered by CARs and the transformation strategies to overcome solid tumors, with a view to broadening ideas for the better application of CAR cell therapy for the treatment of solid tumors.

JAK1/JAK2 degraders based on PROTAC for topical treatment of atopic dermatitis.

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease. The Janus kinase (JAK) has been identified as a target in AD, as it regulates specific inflammatory genes and adaptive immune responses. However, the efficacy of topically applied JAK inhibitors in AD is limited due to the unique structure of skin. We synthesized JAK1/JAK2 degraders (JAPT) based on protein degradation targeting chimeras (PROTACs) and prepared them into topical preparations. JAPT exploited the E3 ligase to mediate ubiquitination and degradation of JAK1/JAK2, offering a promising AD therapeutic approach with low frequency and dosage. In vitro investigations demonstrated that JAPT effectively inhibited the release of pro-inflammatory cytokines and reduced inflammation by promoting the degradation of JAK. In vivo studies further confirmed the efficacy of JAPT in degrading JAK1/JAK2, leading to a significant suppression of type I, II, and III adaptive immunity. Additionally, JAPT demonstrated a remarkable reduction in AD severity, as evidenced by improved skin lesion clearance and AD severity scores (SCORAD). Our study revealed the therapeutic potential of JAPT, surpassing conventional JAK inhibitors in the treatment of AD, which suggested that JAPT could be a promising topically applied anti-AD drug targeting the JAK-STAT signaling pathway.

Transdermal delivery of Fn14 siRNA using a novel composite ionic liquid for treatment of psoriasis-like skin lesions.

Psoriasis is a chronic inflammatory skin disease characterised by the abnormal proliferation of keratinocytes and dysregulation of immune cells. The upregulation of fibroblast growth factor-inducible molecule 14 (Fn14) in psoriatic lesions has been linked to the development of psoriasis. Transdermal delivery of siRNAs for Fn14 inhibition is challenging. In this study, we developed a composite ionic liquid (CIL) for the transdermal delivery of Fn14 siRNA (siFn14) into keratinocytes, with the aim of modulating the inflammatory response associated with psoriasis. The results showed that CIL-siFn14 effectively suppressed Fn14 expression, resulting in a reduction in both the Psoriasis Area and Severity Index (PASI) score and skin thickness. Furthermore, CIL-siFn14 effectively inhibited the abnormal proliferation of keratinocytes, decreased the production of inflammatory factors associated with psoriasis, prevented the over-activation of CD4+ and CD8+ T cells, and restored the balance of Type 1 T helper (Th1), Th2, Th17 and Treg cells. In conclusion, our findings unveiled the critical role of Fn14 in the pathogenesis of psoriasis and demonstrated the potential of CIL-siFn14 as a novel and effective topical treatment for its management.

Codelivery of ERCC2 small interfering RNA and cisplatin with macrophage-derived mimetic nanovesicles for enhanced bladder cancer treatment.

Cisplatin-based chemotherapy plays a vital role in the management of muscle-invasive bladder cancer (MIBC); however, off-tumor toxicity and resistance often lead to cancer recurrence and eventual treatment failure. The loss of function of the nucleotide excision repair gene excision repair cross-complementing rodent repair deficiency gene 2 ( ERCC2 ) in cancer cells correlates with sensitivity to cisplatin, while its overexpression causes cisplatin resistance. Small interfering RNA (siRNA) knockdown of ERCC2 combined with cisplatin treatment may improve therapeutic outcomes in patients with bladder cancer. Here, we aimed to develop macrophage-derived mimetic nanovesicles (MNVs) as a nanoplatform for the simultaneous delivery of cisplatin and ERCC2 siRNA for enhancing the efficacy of bladder cancer chemotherapy. The cellular uptake, gene down-regulation, tumor inhibition effects, and biosafety of the synthesized nanodrugs (MNV-Co) as a synergistic therapeutic strategy for MIBC were evaluated in vitro and in vivo . The results indicated high efficacy of MNV-Co against MIBC and low off-tumor toxicity. Furthermore, by down-regulating ERCC2 mRNA and protein levels, MNV-Co improved chemosensitivity, promoted cancer cell apoptosis, and effectively suppressed tumor growth. This study presents a potential approach for delivering cisplatin and ERCC2 siRNA concurrently to treat bladder cancer using a biomimetic nanosystem.

Combining network pharmacology, molecular docking, molecular dynamics simulation, and experimental verification to examine the efficacy and immunoregulation mechanism of FHB granules on vitiligo.

Background: Fufang Honghua Buji (FHB) granules, have proven efficacy against vitiligo in long-term clinical practice. However, its major active chemical components and molecular mechanisms of action remain unknown. The purpose of this study was to confirm the molecular mechanism of FHB's therapeutic effect on vitiligo utilizing network pharmacology, molecular docking, and molecular dynamics simulation prediction, as well as experimental verification. Methods: Traditional Chinese Medicine Systems Pharmacology (TCMSP) and HERB databases were used to obtain the chemical composition and action targets of FHB. Online Mendelian Inheritance in Man (OMIM), DrugBank, DisGeNET, GeneCards, and Therapeutic Target Database (TTD) databases were applied to screen for vitiligo-related targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed through the Matascape database. Molecular docking and dynamics simulation methods were for the analysis of the binding sites and binding energies between the FHB's active components and the targets. Finally, a vitiligo mouse model was created, and the therapeutic effect and molecular mechanism of action of FHB were validated using enzyme linked immunosorbent assay (ELISA), western blot (WB), and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Additionally, hematoxylin-eosin staining (HE) and blood biochemical assays were conducted to assess the biosafety of FHB. Result: The screening of chemical composition and targets suggested that 94 genetic targets of FHB were associated with vitiligo. The bioinformatics analysis suggested that luteolin, quercetin, and wogonin may be major active components, and nuclear factor-kappa B p65 subunit (RELA), signal transducer, and activator of transcription (STAT) 3 and RAC-alpha serine/threonine-protein kinase (AKT) 1 may be potential targets of FHB-vitiligo therapy. Molecular docking and dynamics simulation further demonstrated that luteolin, quercetin, and wogonin all bound best to STAT3. Through experimental verification, FHB has been demonstrated to alleviate the pathogenic characteristics of vitiligo mice, suppress the JAK-STAT signaling pathway, reduce inflammation, and increase melanogenesis. The in vivo safety evaluation experiments also demonstrated the non-toxicity of FHB. Conclusions: FHB exerts anti-inflammatory and melanogenesis-promoting effects via the effect of multi-component on multi-target, among which the JAK-STAT pathway is a validated FHB-vitiligo target, providing new ideas and clues for the development of vitiligo therapy.

Lycorine transfersomes modified with cell-penetrating peptides for topical treatment of cutaneous squamous cell carcinoma.

BACKGROUND: Topical anticancer drugs offer a potential therapeutic modality with high compliance for treating cutaneous squamous cell carcinoma (cSCC). However, the existing topical treatments for cSCC are associated with limited penetrating ability to achieve the desired outcome. Therefore, there remains an urgent requirement to develop drugs with efficient anticancer activity suitable for treating cSCC and to overcome the skin physiological barrier to improve the efficiency of drug delivery to the tumor. RESULTS: We introduced lycorine (LR) into the topical treatment for cSCC and developed a cell-penetrating peptide (CPP)-modified cationic transfersome gel loaded with lycorine-oleic acid ionic complex (LR-OA) (LR@DTFs-CPP Gel) and investigated its topical therapeutic effects on cSCC. The anti-cSCC effects of LR and skin penetration of LR-OA transfersomes were confirmed. Simultaneously, cationic lipids and modification of R5H3 peptide of the transfersomes further enhanced the permeability of the skin and tumor as well as the effective delivery of LR to tumor cells. CONCLUSIONS: Topical treatment of cSCC-xenografted nude mice with LR@DTFs-CPP Gel showed effective anticancer properties with high safety. This novel formulation provides novel insights into the treatment and pathogenesis of cSCC.

Predator Presence Alters Intestinal Microbiota in Mussel.

Intestinal microbes are essential participants in host vital activities. The composition of the microbiota is closely related to the environmental factors. Predator presence may impact on intestinal microbiota of prey. In the present study, stone crab Charybdis japonica was used as potential predator, an external stress on mussel Mytilus coruscus, to investigate the intestinal microbiota alteration in M. coruscus. We set up two forms of predator presence including free crab and trapped crab, with a blank treatment without crab. The composition of intestinal microbiota in mussels among different treatments showed significant differences by 16S rRNA techniques. The biodiversity increased with trapped crab presence, but decreased with free crab presence. Neisseria, the most abundant genus, fell with the presence of crabs. Besides, the Arcobacter, a kind of pathogenic bacteria, increased with free crab presence. Regarding PICRUTs analysis, Environmental Information Processing, Genetic Information Processing and Metabolism showed differences in crab presence treatments compared with the blank, with a bit higher in the presence of free crab than trapped crab. In conclusion, trapped crab effects activated the metabolism and immunity of the intestinal flora, but free crabs made mussels more susceptible to disease and mortality, corresponding to the decreased biodiversity and the increased Arcobacter in their intestine.

Noval advance of histone modification in inflammatory skin diseases and related treatment methods.

Inflammatory skin diseases are a group of diseases caused by the disruption of skin tissue due to immune system disorders. Histone modification plays a pivotal role in the pathogenesis and treatment of chronic inflammatory skin diseases, encompassing a wide range of conditions, including psoriasis, atopic dermatitis, lupus, systemic sclerosis, contact dermatitis, lichen planus, and alopecia areata. Analyzing histone modification as a significant epigenetic regulatory approach holds great promise for advancing our understanding and managing these complex disorders. Additionally, therapeutic interventions targeting histone modifications have emerged as promising strategies for effectively managing inflammatory skin disorders. This comprehensive review provides an overview of the diverse types of histone modification. We discuss the intricate association between histone modification and prevalent chronic inflammatory skin diseases. We also review current and potential therapeutic approaches that revolve around modulating histone modifications. Finally, we investigated the prospects of research on histone modifications in the context of chronic inflammatory skin diseases, paving the way for innovative therapeutic interventions and improved patient outcomes.

Tachyplesin I Analogue Peptide as an Effective Antimicrobial Agent against Candida albicans-Staphylococcus aureus Poly-Biofilm Formation and Mixed Infection.

Microbial biofilms are difficult to tackle in many infectious diseases. Candida albicans and Staphylococcus aureus are prevalent symbiotic strains in polymicrobial biofilms, which showed enhanced antimicrobial resistance and made identifying effective treatment techniques more difficult. The antibiofilm abilities of tachplesin I analogue peptide (TP11A) and tachplesin I were investigated quantitatively in this study. Both inhibited C. albicans monomicrobial, S. aureus monomicrobial, and C. albicans-S. aureus polymicrobial biofilms quite well. TP11A suppressed the biofilm- and virulence-related genes of C. albicans (hwp 1) and S. aureus (ica A, fnb B, agr A, hla, nor A, and sig B) in the mixed biofilm, according to quantitative reverse transcription polymerase chain reaction analysis. We created an injectable thermosensitive in situ PLEL@TP11A gel system by simply adding TP11A into poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PLEL). Using C. albicans-S. aureus mixed infected wound models of mice, the in vivo therapeutic effect of TP11A and PLEL@TP11A in polymicrobial infections was investigated. The findings revealed that TP11A and PLEL@TP11A could efficiently reduce bacterial and fungal burden in wound infections, as well as accelerated wound healing. Based on above findings, TP11A might be an effective antimicrobial against C. albicans-S. aureus poly-biofilm formation and mixed infection.

Metabolism heterogeneity in melanoma fuels deactivation of immunotherapy: Predict before protect.

Malignant melanoma is widely acknowledged as the most lethal skin malignancy. The metabolic reprogramming in melanoma leads to alterations in glycolysis and oxidative phosphorylation (OXPHOS), forming a hypoxic, glucose-deficient and acidic tumor microenvironment which inhibits the function of immune cells, resulting in a low response rate to immunotherapy. Therefore, improving the tumor microenvironment by regulating the metabolism can be used to improve the efficacy of immunotherapy. However, the tumor microenvironment (TME) and the metabolism of malignant melanoma are highly heterogeneous. Therefore, understanding and predicting how melanoma regulates metabolism is important to improve the local immune microenvironment of the tumor, and metabolism regulators are expected to increase treatment efficacy in combination with immunotherapy. This article reviews the energy metabolism in melanoma and its regulation and prediction, the integration of immunotherapy and metabolism regulators, and provides a comprehensive overview of future research focal points in this field and their potential application in clinical treatment.

Antimicrobial Peptides: The Promising Therapeutics for Cutaneous Wound Healing.

Chronic wound infections have caused an increasing number of deaths and economic burden, which necessitates wound treatment options. Hitherto, the development of functional wound dressings has achieved reasonable progress. Antibacterial agents, growth factors, and miRNAs are incorporated in different wound dressings to treat various types of wounds. As an effective antimicrobial agent and emerging wound healing therapeutic, antimicrobial peptides (AMPs) have attracted significant attention. The present study focuses on the application of AMPs in wound healing and discusses the types, properties and formulation strategies of AMPs used for wound healing. In addition, the clinical trial and the current status of studies on "antimicrobial peptides and wound healing" are elaborated through bibliometrics. Also, the challenges and opportunities for further development and utilization of AMP formulations in wound healing are discussed.

Impact of Initial Feeding and Molting on Tachypleus tridentatus Gut Microbiota.

Tri-spine horseshoe crabs (HSCs) Tachypleus tridentatus have been facing the threat of population depletion for decades, and the physiology and microbiology of their early life stages are lacking. To explore what directs the change of juvenile T. tridentatus gut microbiota and how gut microbiota change, by using 16S rRNA sequencing of gut samples we detected the intestinal microbiome of juvenile HSCs and compared the impact of initial molting and initial feeding, as well as the effect of environment. Results showed that the predominant phyla in the gut microbial community of juvenile HSCs are Proteobacteria and Bacteroidetes. The richness and diversity of intestinal microbes greatly decreased after initial molting. Microbial-mediated functions predicted by PICRUSt showed that "Signal Transduction", "Cellular Processes and Signaling", "Infective Diseases" and "Digestive System" pathways significantly increased in 2nd instars. As for the effect of environment, the connection between living environment and the intestinal microbiome started to manifest after initial molting. Unexpectedly, initial feeding treatment slightly affected the intestinal microbiome of T. tridentatus in the early life stage, whereas the effect of initial molting was significant. The present study provided the first insight into the gut microbiota of T. tridentatus, and the findings led a new sight to explain what guide the change of gut microbiota.