Formononetin attenuates psoriasiform inflammation by regulating interferon signaling pathway.

BACKGROUND: Psoriasis is a long-lasting, inflammatory, continuous illness caused through T cells and characterized mainly by abnormal growth and division of keratinocytes. Currently, corticosteroids are the preferred option. However, prolonged use of traditional topical medication can lead to adverse reactions and relapse, presenting a significant therapeutic obstacle. Improved alternative treatment options are urgently required. Formononetin (FMN) is a representative component of isoflavones in Huangqi (HQ) [Astragalus membranaceus (Fisch.) Bge.]. It possesses properties that reduce inflammation, combat oxidation, inhibit tumor growth, and mimic estrogen. Although FMN has been shown to ameliorate skin barrier devastation via regulating keratinocyte apoptosis and proliferation, there are no reports of its effectiveness in treating psoriasis. OBJECTIVE: Through transcriptomics clues and experimental investigation, we aimed to elucidate the fundamental mechanisms underlying FMN's action on psoriasis. MATERIALS AND METHODS: Cell viability was examined using CCK8 assay in this study. The results of analysis of differentially expressed genes (DEGs) between FMN-treated HaCaT cells and normal HaCaT cells using RNA-sequencing (RNA-seq) were presented on volcano plots and heatmap. Enrichment analysis was conducted on DEGs using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), and results were validated through RT-qPCR verification. After 12 days of FMN treatment in psoriasis mouse model, we gauged the PASI score and epidermis thickness. A variety of techniques were used to assess FMN's effectiveness on inhibiting inflammation and proliferation related to psoriasis, including RT-qPCR, HE staining, western blot, and immunohistochemistry (IHC). RESULTS: The findings indicated that FMN could suppress the growth of HaCaT cells using CCK8 assay (with IC50 = 40.64 uM) and 20 uM FMN could reduce the level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to the greatest extent. FMN-treated HaCaT cells exhibited 985 up-regulated and 855 down-regulated DEGs compared to normal HaCaT cells. GO analysis revealed that DEGs were linked to interferon (IFN) signaling pathway. Furthermore, FMN improved pathological features, which encompassed decreased erythema, scale, and thickness scores of skin lesions in psoriasis mouse model. In vivo experiments confirmed that FMN down-regulated expression of IFN-α, IFN-ß, IFN-γ, decreased secretion of TNF-α and IL-17 inflammatory factors, inhibited expression of IFN-related chemokines included Cxcl9, Cxcl10, Cxcl11 and Cxcr3 and reduced expression of transcription factors p-STAT1, p-STAT3 and IFN regulatory factor 1 (IRF1) in the imiquimod (IMQ) group. CONCLUSIONS: In summary, these results suggested that FMN played an anti-inflammatory and anti-proliferative role in alleviating psoriasis by inhibiting IFN signaling pathway, and FMN could be used as a potential therapeutic agent.

Dissolving Microneedle-Based Cascade-Activation Nanoplatform for Enhanced Photodynamic Therapy of Skin Cancer.

Purpose: Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O2 consumption during PDT would diminish its therapeutic effect. Herein, we developed a strategy using the combination of PDT and hypoxia-activated bioreductive drug tirapazamine (TPZ). Methods: TPZ was linked to DSPE-PEG-NHS forming DSPE-PEG-TPZ to solve leakage of water-soluble TPZ and serve as an antitumor agent and monomer molecule further forming the micellar. Chlorin e6 (Ce6) was loaded in DSPE-PEG-TPZ forming DSPE-PEG-TPZ@Ce6 (DPTC). To further improve tumor infiltration and accumulation, hyaluronic acid was adopted to make DPTC-containing microneedles (DPTC-MNs). Results: Both in vitro and in vivo studies consistently demonstrated the synergistic antitumor effect of photodynamic therapy and TPZ achieved by DPTC-MNs. With laser irradiation, overexpressions of PDT tolerance factors NQO1 and HIF-1α were inhibited by this PDT process. Conclusion: The synergistic effect of PDT and TPZ significantly improved the performance of DPTC-MNs in the treatment of melanoma and cutaneous squamous cell carcinoma and has good biocompatibility.

The epidermal lipid-microbiome loop and immunity: Important players in atopic dermatitis.

BACKGROUND: The promotion of epidermal barrier dysfunction is attributed to abnormalities in the lipid-microbiome positive feedback loop which significantly influences the imbalance of the epithelial immune microenvironment (EIME) in atopic dermatitis (AD). This imbalance encompasses impaired lamellar membrane integrity, heightened exposure to epidermal pathogens, and the regulation of innate and adaptive immunity. The lipid-microbiome loop is substantially influenced by intense adaptive immunity which is triggered by abnormal loop activity and affects the loop's integrity through the induction of atypical lipid composition and responses to dysregulated epidermal microbes. Immune responses participate in lipid abnormalities within the EIME by downregulating barrier gene expression and are further cascade-amplified by microbial dysregulation which is instigated by barrier impairment. AIM OF REVIEW: This review examines the relationship between abnormal lipid composition, microbiome disturbances, and immune responses in AD while progressively substantiating the crosstalk mechanism among these factors. Based on this analysis, the "lipid-microbiome" positive feedback loop, regulated by immune responses, is proposed. KEY SCIENTIFIC CONCEPTS OF REVIEW: The review delves into the impact of adaptive immune responses that regulate the EIME, driving AD, and investigates potential mechanisms by which lipid supplementation and probiotics may alleviate AD through the up-regulation of the epidermal barrier and modulation of immune signaling. This exploration offers support for targeting the EIME to attenuate AD.

Costunolide mitigates inflammation and promotes extracellualr matrix integrity of thoracic aortic dissection by inhibiting NF-κB signaling.

BACKGROUND: Thoracic aortic dissection (TAD) is one of the most fatal cardiovascular diseases. One of its important pathological characteristics is the local inflammatory response. Many studies have found that Macrophage polarization plays an extremely critical role in the inflammatory progression and tissue remodeling of TAD. Costunolide (CTD) has an improving effect on oxidative stress and inflammation in the body. However, whether it can promote the integrity of extracellular matrix in Aortic dissection and its mechanism are still unclear. METHODS: The male C57BL/6J mice were used to construct an animal model of TAD with ß-aminopropionitrile (BAPN) (100 mg/kg/day, lasting for 28 days), and then CTD (10 mg/kg or 100 mg/kg) was injected intraperitoneally for 28 days to check the survival rate, TAD incidence, aortic morphology and other indicators of the mice. Using hematoxylin-eosin (HE), Masson, Elastin van Gieson (EVG) staining, immunofluorescence (IF), and immunohistochemical staining, the study aimed to determine the therapeutic effects of CTD on an animal model with BAPN-induced TAD. To enhance the examination of the regulatory mechanism of CTD, we conducted transcriptome sequencing on arterial tissues of mice in both the BAPN group and the BAPN + CTD100 group. Next, ANG II were used to construct TAD model in vascular smooth muscle cells (VMSCs). The effects of CTD on the proliferation, migration, invasion, and apoptosis of ANG II-induced cells are to be detected. The expression of MMP2, MMP9, P65, and p-P65 in each group will be examined using Western blot. Finally, the overexpression of IκB kinaseß (IKKß) will be established in VMSCs cells to further explore the protective function of CTD. RESULTS: The result showed that CTD significantly inhibited BAPN induced mortality and TAD incidence in the animal model, improved aortic vascular morphology, promoted the integrity of extracellular matrix in TAD, reduced tissue inflammation, reduced the accumulation of M1 macrophage, promoted M2 macrophage polarization, and reduced the expression of NF-κB pathway related proteins. Mechanistically, CTD significantly weakened the proliferation, migration, invasion, and apoptosis. p-P65 protein expression of TAD cells were induced by ANG II and IKK-ß. CONCLUSION: CTD has the potential to alleviate inflammation, VSMC apoptosis, MMP2/9 levels, and enhance extracellular matrix integrity in TAD by inhibiting the NF-κB signaling pathway.

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.

Targeting tumor-associated macrophages: Novel insights into immunotherapy of skin cancer.

BACKGROUND: The incidence of skin cancer is currently increasing, and conventional treatment options inadequately address the demands of disease management. Fortunately, the recent rapid advancement of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has ushered in a new era for numerous cancer patients. However, the efficacy of immunotherapy remains suboptimal due to the impact of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), a major component of the TME, play crucial roles in tumor invasion, metastasis, angiogenesis, and immune evasion, significantly impacting tumor development. Consequently, TAMs have gained considerable attention in recent years, and their roles have been extensively studied in various tumors. However, the specific roles of TAMs and their regulatory mechanisms in skin cancer remain unclear. AIM OF REVIEW: This paper aims to elucidate the origin and classification of TAMs, investigate the interactions between TAMs and various immune cells, comprehensively understand the precise mechanisms by which TAMs contribute to the pathogenesis of different types of skin cancer, and finally discuss current strategies for targeting TAMs in the treatment of skin cancer. KEY SCIENTIFIC CONCEPTS OF OVERVIEW: With a specific emphasis on the interrelationship between TAMs and skin cancer, this paper posits that therapeutic modalities centered on TAMs hold promise in augmenting and harmonizing with prevailing clinical interventions for skin cancer, thereby charting a novel trajectory for advancing the landscape of immunotherapeutic approaches for skin cancer.

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.

Nanocarrier-Mediated Immunogenic Cell Death for Melanoma Treatment.

Melanoma, a highly aggressive skin tumor, exhibits notable features including heterogeneity, a high mutational load, and innate immune escape. Despite advancements in melanoma treatment, current immunotherapies fail to fully exploit the immune system's maximum potential. Activating immunogenic cell death (ICD) holds promise in enhancing tumor cell immunogenicity, stimulating immune amplification response, improving drug sensitivity, and eliminating tumors. Nanotechnology-enabled ICD has emerged as a compelling therapeutic strategy for augmenting cancer immunotherapy. Nanoparticles possess versatile attributes, such as prolonged blood circulation, stability, and tumor-targeting capabilities, rendering them ideal for drug delivery. In this review, we elucidate the mechanisms underlying ICD induction and associated therapeutic strategies. Additionally, we provide a concise overview of the immune stress response associated with ICD and explore the potential synergistic benefits of combining ICD induction methods with the utilization of nanocarriers.

Synergism and attenuation of triptolide through prodrug engineering combined with liposomal scaffold strategy to enhance inhibition in pancreatic cancer.

The prognosis of pancreatic cancer (PCa) is extremely poor because of its resistance to conventional therapies. Many previous studies have demonstrated that triptolide (TPL) has a potent tumoricidal activity on PCa. However, the clinical application of TPL in tumor therapy has been greatly limited by its poor aqueous solubility, short half-time, high toxicity and inefficient delivery. Here, through the engineering of prodrug technology combined with the nanodrug-delivery system (NDDS) strategy, we modified the main active site of TPL C14-OH by esterification reaction to obtain a highly lipophilic prodrug, and then encapsulated the drug in a phospholipid bilayer in liposomal vehicles through the thin-film hydration method for efficient delivery. A delivery system based on TPL lignocerate liposomes (TPL-LA-lip) for drug loading for targeted therapy against PCa was established. Our results showed that TPL-LA demonstrates exceptional compatibility with the phospholipid layer of liposomes, thereby enhancing drug retention in liposomal vehicle and improving tumor targeting and cellular uptake. Moreover, The system of TPL-LA-lip exhibited a sustained drug release profile in vitro, and intravenous administration significantly impedes tumor progression while reducing the toxicity of TPL in the PCa mouse model. These results demonstrated that the prodrug-loaded liposomes could significantly reduce the toxicity of TPL and enhance the biosafety. Overall, this prodrug approach is a simple and effective method to transform the highly toxic TPL into a safe and efficacious nanomedicine with excellent in vivo tolerability for PCa treatment.

Nanomedicine-induced programmed cell death enhances tumor immunotherapy.

BACKGROUND: There has been widespread concern about the high cancer mortality rate and the shortcomings of conventional cancer treatments. Immunotherapy is a novel oncology therapy with high efficiency and low side effects, which is a revolutionary direction for clinical oncology treatment. However, its clinical effectiveness is uneven. Based on the redefinition and reclassification of programmed cell death (PCD) (divided into necroptosis, ferroptosis, pyroptosis, and autophagy), the role of nanomedicine-induced PCD in cancer therapy has also received significant attention. Clinical and preclinical studies have begun to combine PCD with immunotherapy. AIM OF REVIEW: In this article, we present recent research in tumor immunotherapy, provide an overview of how nanomedicine-induced PCD is involved in tumor therapy, and review how nanomedicine-induced PCD can improve the limitations of immunotherapy to enhance tumor immunotherapy. The future development of nanomedicine-mediated PCD tumor therapy and tumor immunotherapy is also proposed Key scientific concepts of overview Nanomedicine-induced PCD is a prospective method of tumor immunotherapy. Nanomedicines increase tumor site penetration and targeting ability, and nanomedicine-mediated PCD activation can stimulate powerful anti-tumor immune effects, which has a good contribution to immunotherapy of tumors.

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.

Advance and Challenges in the Treatment of Skin Diseases with the Transdermal Drug Delivery System.

Skin diseases are among the most prevalent non-fatal conditions worldwide. The transdermal drug delivery system (TDDS) has emerged as a promising approach for treating skin diseases, owing to its numerous advantages such as high bioavailability, low systemic toxicity, and improved patient compliance. However, the effectiveness of the TDDS is hindered by several factors, including the barrier properties of the stratum corneum, the nature of the drug and carrier, and delivery conditions. In this paper, we provide an overview of the development of the TDDS from first-generation to fourth-generation systems, highlighting the characteristics of each carrier in terms of mechanism composition, penetration method, mechanism of action, and recent preclinical studies. We further investigated the significant challenges encountered in the development of the TDDS and the crucial significance of clinical trials.

Biomimetic liposomal nanozymes improve breast cancer chemotherapy with enhanced penetration and alleviated hypoxia.

BACKGROUND: Doxorubicin (Dox) has been recommended in clinical guidelines for the standard-of-care treatment of breast cancer. However, Dox therapy faces challenges such as hypoxia, acidosis, H2O2-rich conditions and condensed extracellular matrix in TME as well as low targeted ability. METHODS: We developed a nanosystem H-MnO2-Dox-Col NPs based on mesoporous manganese dioxide (H-MnO2) in which Dox was loaded in the core and collagenase (Col) was wrapped in the surface. Further the H-MnO2-Dox-Col NPs were covered by a fusion membrane (MP) of inflammation-targeted RAW264.7 cell membrane and pH-sensitive liposomes to form biomimetic MP@H-MnO2-Dox-Col for in vitro and in vivo study. RESULTS: Our results shows that MP@H-MnO2-Dox-Col can increase the Dox effect with low cardiotoxicity based on multi-functions of effective penetration in tumor tissue, alleviating hypoxia in TME, pH sensitive drug release as well as targeted delivery of Dox. CONCLUSIONS: This multifunctional biomimetic nanodelivery system exhibited antitumor efficacy in vivo and in vitro, thus having potential for the treatment of breast cancer.

Physical therapy in diabetic foot ulcer: Research progress and clinical application.

Diabetes foot ulcer (DFU) is one of the most intractable complications of diabetes and is related to a number of risk factors. DFU therapy is difficult and involves long-term interdisciplinary collaboration, causing patients physical and emotional pain and increasing medical costs. With a rising number of diabetes patients, it is vital to figure out the causes and treatment techniques of DFU in a precise and complete manner, which will assist alleviate patients' suffering and decrease excessive medical expenditure. Here, we summarised the characteristics and progress of the physical therapy methods for the DFU, emphasised the important role of appropriate exercise and nutritional supplementation in the treatment of DFU, and discussed the application prospects of non-traditional physical therapy such as electrical stimulation (ES), and photobiomodulation therapy (PBMT) in the treatment of DFU based on clinical experimental records in ClinicalTrials.gov.

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.

Effect and mechanism of longkui yinxiao soup in treating psoriasis in mice.

Objective: Longkui Yinxiao Soup is a traditional Chinese medicine formula used to treat psoriasis for decades. Although Longkui Yinxiao Soup showed promising efficacy in clinical practice, the regulatory mechanisms of Longkui Yinxiao Soup remain elusive. This study aimed to explore the underlying mechanisms of Longkui Yinxiao Soup in a psoriasis-like mouse model. Methods: Longkui Yinxiao Soup was quality controlled by determining the contents of imperatorin and rhoifolin using high-performance liquid chromatography. The imiquimod-induced psoriasis-like mouse model was used to study the therapeutic effect and mechanism of Longkui Yinxiao Soup. The histopathological skin changes were observed by hematoxylin and eosin staining; the infiltration of proliferating proteins, proliferating cell nuclear antigen and Ki67, in skin tissues were observed by immunohistochemical analysis; and the inflammatory factors such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-23, and IL-17 in serum were detected using enzyme-linked immunosorbent assay. RNA sequencing and bioinformatic analysis were used to predict the mechanism of LYS against psoriasis. mRNA expressions of p38, extracellular regulated protein kinases (ERK), mitogen-activated protein kinase 3 (MEK3), mitogen-activated protein kinase 6 (MEK6), RAP1 GTPase activating protein (Rap1gap), and Rap1 were determined using real-time quantitative polymerase chain reaction. The expression levels of proteins related to Rap1-mitogen-activated protein kinase signaling pathways were measured by Western blotting. Results: A quality-control method for Longkui Yinxiao Soup was successfully established using imperatorin and rhoifolin as content determination indexes. Longkui Yinxiao Soup significantly ameliorated the psoriatic symptoms in mice. The serum levels of inflammatory cytokines such as IL-6, TNF-α, IL-23, and IL-17 were decreased, and the expression levels of antigen identified by monoclonal antibody Ki67 (Ki67) and PCNA in skin tissues were downregulated. Moreover, the inhibition of Rap1-MAPK signaling pathways by Longkui Yinxiao Soup was detected. Conclusion: This study confirmed the antipsoriatic activity of Longkui Yinxiao Soup in psoriasis-like mice. This might be due to the inhibition of inflammatory factor secretion, keratinocyte proliferation, and the Rap1-MAPK signal pathway.

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy.

Hematotoxicity is the most common long-term adverse event (AE) after chimeric antigen receptor T-cell (CAR T) therapy. However, patients who receive CAR T therapy in pivotal clinical trials are subjected to restrictive selection criteria, and this means that rare but fatal toxicities are underestimated. Here, we systematically analyzed CAR T-associated hematologic AE using the US Food and Drug Administration Adverse Event Reporting System (FAERS) between January 2017 and December 2021. Disproportionality analyses were performed using reporting odds ratios (ROR) and information component (IC); the lower limit of the ROR and IC 95% confidence interval (CI) (ROR025 and IC025) exceeding one and zero was considered significant, respectively. Among the 105,087,611 reports in FAERS, 5,112 CAR T-related hematotoxicity reports were identified. We found 23 significant over-reporting hematologic AE (ROR025 >1) compared to the full database, of which hemophagocytic lymphohistiocytosis (HLH; n=136 [2.7%], ROR025 = 21.06), coagulopathy (n=128 [2.5%], ROR025 = 10.43), bone marrow failure (n=112 [2.2%], ROR025 = 4.88), disseminated intravascular coagulation (DIC; n=99 [1.9%], ROR025 = 9.64), and B-cell aplasia (n=98 [1.9%], ROR025 = 118.16, all IC025 > 0) were highly under-reported AE in clinical trials. Importantly, HLH and DIC led to mortality rates of 69.9% and 59.6%, respectively. Lastly, hematotoxicity-related mortality was 41.43%, and 22 death-related hematologic AE were identified using LASSO regression analysis. These findings could help clinicians in the early detection of those rarely reported but lethal hematologic AE, thus reducing the risk of severe toxicities for CAR T recipients.

Research and Application of Kupffer Cell Thresholds for BSA Nanoparticles.

Over the past decade, the dose of nanoparticles given to solid tumors has remained at a median of 0.7% of the injected dose. Most nanoparticles are trapped in a mononuclear phagocyte system (MPS), of which 85% are Kupffer cells. In our study, threshold doses of bovine serum albumin (BSA) nanoparticles were investigated for the uptake of Kupffer cells in vitro and in vivo. The antitumor effect and safety of albumin-bound paclitaxel (ABP) were improved by using threshold doses of BSA nanoparticles. We found a threshold dose of 20,000 nanoparticles per macrophage uptake in vitro and a saturation dose of 0.3 trillion nanoparticles in tumor-bearing mice. In vivo efficacy and safety evaluations demonstrated that the threshold doses of blank BSA nanoparticles could significantly improve the efficacy and safety of ABP against tumors compared with ABP alone. In this study, the delivery efficiency of ABP was improved by using blank nanoparticles to saturate Kupffer cells, which provided a new approach to studying the Kupffer cell saturation threshold and thus a new scheme for improving the curative effect of ABP.

Immune cells in the epithelial immune microenvironment of psoriasis: emerging therapeutic targets.

Psoriasis is a chronic autoimmune inflammatory disease characterized by erroneous metabolism of keratinocytes. The development of psoriasis is closely related to abnormal activation and disorders of the immune system. Dysregulated skin protective mechanisms can activate inflammatory pathways within the epithelial immune microenvironment (EIME), leading to the development of autoimmune-related and inflammatory skin diseases. In this review, we initially emphasized the pathogenesis of psoriasis, paying particular attention to the interactions between the abnormal activation of immune cells and the production of cytokines in psoriasis. Subsequently, we delved into the significance of the interactions between EIME and immune cells in the emergence of psoriasis. A thorough understanding of these immune processes is crucial to the development of targeted therapies for psoriasis. Finally, we discussed the potential novel targeted therapies aimed at modulating the EIME in psoriasis. This comprehensive examination sheds light on the intricate underlying immune mechanisms and provides insights into potential therapeutic avenues of immune-mediated inflammatory diseases.