Extracellular vesicles derived from plasmodium-infected red blood cells alleviate cerebral malaria in plasmodium berghei ANKA-infected C57BL/6J mice.

RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. To mitigate the risk of cerebral malaria (CM) among children under the age of 5, it is imperative to develop new vaccines. EVs are potential vaccine candidates as they obtain the ability of brain-targeted delivery and transfer plasmodium antigens and immunomodulators during infections. This study extracted EVs from BALB/c mice infected with Plasmodium yoelii 17XNL (P.y17XNL). C57BL/6J mice were intravenously immunized with EVs (EV-I.V. + CM group) or subcutaneously vaccinated with the combination of EVs and CpG ODN-1826 (EV + CPG ODN-S.C. + CM group) on days 0 and 20, followed by infection with Plasmodium berghei ANKA (P.bANKA) on day 20 post-second immunization. We monitored Parasitemia and survival rate. The integrity of the Blood-brain barrier (BBB) was examined using Evans blue staining.The levels of cytokines and adhesion molecules were evaluated using Luminex, RT-qPCR, and WB. Brain pathology was evaluated by hematoxylin and eosin and immunohistochemical staining. The serum levels of IgG, IgG1, and IgG2a were analyzed by enzyme-linked immunosorbent assay. Compared with those in the P.bANKA-infected group, parasitemia increased slowly, death was delayed (day 10 post-infection), and the survival rate reached 75 %-83.3 % in the EV-I.V. + ECM and EV + CPG ODN-S.C. + ECM groups. Meanwhile, compared with the EV + CPG ODN-S.C. + ECM group, although parasitemia was almost the same, the survival rate increased in the EV-I.V. + ECM group.Additionally, EVs immunization markedly downregulated inflammatory responses in the spleen and brain and ameliorated brain pathological changes, including BBB disruption and infected red blood cell (iRBC) sequestration. Furthermore, the EVs immunization group exhibited enhanced antibody responses (upregulation of IgG1 and IgG2a production) compared to the normal control group. EV immunization exerted protective effects, improving the integrity of the BBB, downregulating inflammation response of brain tissue, result in reduces the incidence of CM. The protective effects were determined by immunological pathways and brain targets elicited by EVs. Intravenous immunization exhibited better performance than subcutaneous immunization, which perhaps correlated with EVs, which can naturally cross BBB to play a better role in brain protection.

Essential Oil of Matricaria chamomilla Alleviate Psoriatic-Like Skin Inflammation by Inhibiting PI3K/Akt/mTOR and p38MAPK Signaling Pathway.

Background: The traditional Matricaria chamomilla L. has been used to treat dermatitis for thousands of years. Due to emerging trends in alternative medicine, patients prefer natural remedies to relieve their symptoms. Therefore, finding safe and effective plant medicines for topical applications on the skin is an important treatment strategy for dermatologists. German chamomile (Matricaria chamomilla L.) from the Compositae family is a famous medicinal plant, often known as the "star of medicinal species."However, the function of Matricaria chamomilla essential oil on skin inflammation has not been thoroughly examined in earlier research. Methods: GC-MS analyzed the components of MCEO, and this study explored the anti-inflammation effects of MCEO on psoriasis with network pharmacological pathway prediction. Following this, we used clinical samples of psoriasis patients to confirm the secretory characteristic of relative inflammatory markers. The therapeutic effect of MCEO on skin inflammation was detected by examination of human keratinocytes HaCaT. At the same time, we prepared imiquimod-induced psoriatic-like skin inflammation in mice to investigate thoroughly the potential inhibition functions of MCEO on psoriatic skin injury and inflammation. Results: MCEO significantly reduced interleukin-22/tumor necrosis factor α/lipopolysaccharide-stimulated elevation of HaCaT cell inflammation, which was correlated with downregulating PI3K/Akt/mTOR and p38MAPK pathways activation mediated by MCEO in HaCaT cells treated with IL-22/TNF-α/LPS. Skin inflammation was evaluated based on the PASI score, HE staining, and relative inflammatory cytokine levels. The results showed that MCEO could significantly contribute to inflammatory skin disease treatment. Conclusion: MCEO inhibited inflammation in HaCaT keratinocytes induced by IL-22/TNF-α/LPS, the potential mechanisms associated with inhibiting excessive activation and crosstalk between PI3K/Akt/mTOR and p38MAPK pathways. MCEO ameliorated skin injury in IMQ-induced psoriatic-like skin inflammation of mice by downregulating the levels of inflammatory cytokines but not IL-17A. Thus, anti-inflammatory plant drugs with different targets with combined applications were a potential therapeutic strategy in psoriasis.

Engineered elastin-like polypeptide-based hydrogel delivering chemotherapeutics and PD-L1 antibodies for potentiated cancer immunotherapy.

Immune checkpoint inhibitors (ICIs) have effectively eradicated advanced tumors by inducing durable and systematic antitumor immune responses. However, when used as a standalone treatment, ICIs typically exhibit a low response rate in many cancers. In this study, we engineered an in situ-formed gel depot using elastin-like polypeptides (ELPs) to efficiently deliver PD-L1 antibodies (aPD-L1) and gemcitabine (GEM) for enhanced immunotherapy in melanoma. Sustainably released chemotherapeutics from gel depots could kill melanoma cells and promote PD-L1 upregulation in tumor cells. Moreover, aPD-L1/GEM-encapsulated ELP hydrogel promoted a 3.0-fold increase of tumor-infiltrated CD8+ T cells and 60% Tregs depletion compared with PBS group, eliciting a robust antitumor immune response for immunotherapy in melanoma mouse models. This research highlights the promising potential of ELP-based hydrogels in delivering ICIs and chemotherapeutic agents for potentiated cancer immunotherapy.

Exosome-derived long noncoding RNAs: Mediators of host-Plasmodium parasite communication.

Overcoming challenges associated with malaria eradication proves to be a formidable task due to the complicated life cycle exhibited by the malaria parasite and the lack of safe and enduring vaccines against malaria. Investigating the interplay between Plasmodium parasites and their mammalian hosts is crucial for the development of novel vaccines. Long noncoding RNAs (lncRNAs) derived from Plasmodium parasites or host cells have emerged as potential signaling molecules involved in the trafficking of proteins, RNA (mRNAs, miRNAs, and ncRNAs), and DNA. These lncRNAs facilitate the interaction between hosts and parasites, impacting normal physiology or pathology in malaria-infected individuals. Moreover, they possess the capacity to regulate immune responses and associated signaling pathways, thus potentially influencing chromatin organization, epigenetic modifications, mRNA processing, splicing, and translation. However, the functional role of exosomal lncRNAs in malaria remains poorly understood. This review offers a comprehensive analysis of lncRNA and exosomal lncRNA profiles during malaria infection. It presents an overview of recent progress in elucidating the involvement of exosomal lncRNAs in host-parasite interactions. Additionally, potential exosomal lncRNAs linked to the domains of innate and adaptive immunity in the context of malaria are proposed. These findings may contribute to the discovery of new diagnostic and therapeutic strategies for malaria. Furthermore, the need for additional research was highlighted that aimed to elucidate the mechanisms underlying lncRNA transportation into host cells and their targeting of specific genes to regulate the host's immune response. This knowledge gap presents an opportunity for future investigations, offering innovative approaches to enhance malarial control. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Small Molecule-RNA Interactions RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.

Extracellular Vesicles Derived from Plasmodium-infected Hosts as Stimuli of "Trained" Innate Immunity.

Although the burden of malaria has been successfully controlled globally, this disease remains a major public health issue. To date, neither existing drugs nor vaccines against malaria are sufficient in eliminating malaria worldwide. To achieve the eradication of malaria by 2040, effective interventions targeting all Plasmodium species are urgently needed. As the cornerstone of vaccine design, immune memory serves a significant role in the host's defense against Plasmodium infections. It has long been considered that innate immunity is non-specific and lacks immunologic memory. However, emerging evidence has suggested that innate immunity can be trained following exposure of the body to infectious agents, such as Plasmodium or its products, which, in turn, promotes the onset of a type of memory in innate immune cells. The above "trained" innate immune cells, whose phenotype is modified in response to epigenetic modifications, metabolic recombination, or cytokine secretion, exhibit differential pathophysiology after the exposure of the body to a pathogen. In addition, Plasmodium-infected red blood cells and other host cells can secrete exosomes that contain conserved parasite-specific information, such as proteins, RNA, non-coding RNA molecules, and nucleic acids. These molecules can act as stimuli for promoting the establishment of "trained" innate immunity against malaria, thereby altering the onset and progression of the parasitic disease. A deeper understanding of the role of exosomes in the development of "trained" innate immunity during Plasmodium infection could provide novel therapeutic and prevention strategies against malaria infections.

High-Flux Ultrafiltration Membranes Combining Artificial Water Channels and Covalent Organic Frameworks.

Artificial water channels (AWCs) have been well investigated, and the imidazole-quartet water channel is one of the representative channels. In this work, covalent organic frameworks (COFs) composite membranes were fabricated through assembling COF layers and imidazole-quartet water channel. The membranes were synthesized by interfacial polymerization and self-assembly process, using polyacrylonitrile (PAN) ultrafiltration substrates with artificial water channels (HC6H) as modifiers. Effective combination of COF layers and imidazole-quartet water channels provide the membrane with excellent performance. The as-prepared membrane exhibits a water permeance above 271.7 L·m−2·h−1·bar−1, and high rejection rate (>99.5%) for CR. The results indicated that the composite structure based on AWCs and COFs may provide a new idea for the development of high-performance membranes for dye separation.

A systematic review and meta-analysis on the effects of the ultra-pulse CO2 fractional laser in the treatment of depressed acne scars.

BACKGROUND: Acne is a chronic inflammatory disease that occurs in the sebaceous glands of the hair follicles. Depressed acne scars, also known as depressed scars, remain after recovery. Clinical treatments of depressed scars include chemical peels, surgical treatments, radio frequency treatments, and laser treatments. Ultra-pulse carbon dioxide (CO2) fractional laser treatment has become the main method for treating depressed scars in recent years, but there are no systematic reports on the effectiveness and safety of this treatment. METHODS: English databases, including PubMed, Embase, and Ovid-Medline, were searched to retrieve relevant articles. The search period ran from the establishment of the databases to April 2021. The search terms included CO2 lattice laser, depressed acne scars, depressed scars, and effectiveness. RESULTS: A total of 6 articles comprising 467 patients with depressed acne scars were included in the meta-analysis. The results showed that patients treated with ultra-pulsed CO2 fractionated laser scored higher in skin smoothness compared to other methods [standard mean difference (SMD) =0.49, 95% confidence interval (CI): 0.13-0.84; P=0.008], and significantly higher total skin lesion scores (SMD =0.35, 95% CI: -0.00 to 0.70; P=0.05). DISCUSSION: A total of 6 articles were included in this study on the clinical efficacy of the ultra-pulse CO2 fractional laser in the treatment of depressed acne scars. The study found that compared to other treatments, this laser had a better curative effect in terms of the effective rate and patient skin smoothness score.

The Anti-Inflammatory and Anti-Pruritus Mechanisms of Huanglian Jiedu Decoction in the Treatment of Atopic Dermatitis.

Atopic dermatitis (AD) is a common chronic skin disease driven by a T-cell-mediated immune response, with inflammation and pruritus being its main clinical manifestations. Huanglian Jiedu decoction (HLJDT), which is an ancient Chinese medicine herbal formula derived from Wai-Tai-Mi-Yao, is a potentially effective treatment for AD. We aimed to clarify the anti-inflammatory and anti-pruritus mechanisms of HLJDT in AD treatment. We performed immunohistochemistry, Western blotting, reverse transcriptase-polymerase chain reaction, Luminex-based direct multiplex immunoassay, enzyme-linked immunosorbent assays, and flow cytometry to address the abovementioned aims. HLJDT significantly reduced clinical symptoms and ear swelling in AD-like mice by inhibiting the production of cytokines [histamine, interleukin (IL)-3, IL-4, IL-5, IL-13, IL-17A, IL-31, and IL-33], substance P (SP), transient receptor potential cation channel subfamily V member 1 (TRPV-1), and gastrin-releasing peptide (GRP). Additionally, HLJDT significantly suppressed the protein expression levels and positive cell percentage of CD28, CD80, CD86, CD207, CD326, MHCII, and OX40 in the lymphoid nodes. Moreover, HLJDT significantly suppressed mRNA and protein expression of tyrosine-protein kinase (JAK1), histamine H4 receptor, and IL-4Rα, as well as the protein expression of GRP, SP, and TRPV-1 in the root ganglion. Our findings indicate that HLJDT can treat AD by regulating the antigen presentation function of dendritic cells, weakening T-lymphocyte activation, and subsequently exerting anti-inflammatory and anti-pruritus effects.

Study on the Molecular Basis of Huanglian Jiedu Decoction Against Atopic Dermatitis Integrating Chemistry, Biochemistry, and Metabolomics Strategies.

Atopic dermatitis (AD) is a common chronic relapsing skin inflammation, which severely affect the quality of life of patients. Inhibiting itching and enhancing immunity to mitigate scratching are key elements in the fight against AD. Huanglian Jiedu decoction (HLJDD) has multiple pharmacological effects in the treatment of AD. However, the effective ingredients and underlying molecular mechanisms have not yet been fully explored. Thus, this study integrates chemistry, biochemistry, and metabolomics strategies to evaluate the active substance basis of HLJDD against AD. First, HLJDD was split to five fractions (CPF, 40AEF, 90AEF, PEF and WEF) and 72 chemical components were identified. NSD (Non-similarity degree) among the different fractions showed significant chemical differences (>81%). Interleukin IL-13, IL-17A, IL-3, IL-31, IL-33, IL4, IL-5, TSLP, IgE, and histamine in the serum, and IL-4Rα, JAK1, and HRH4 levels in skin, participating in inhibiting itching and regulating immunity signaling, were found to be restored to varying degrees in AD treating with HLJDD and its fractions, especially 40AEF and CPF. Untargeted metabolomics analysis demonstrated that forty metabolites were differential metabolites in plasma between the HLJDD-treated group and the AD group, involving in histidine metabolism, arginine biosynthesis, pyrimidine metabolism, and so on. Further, targeted metabolomics analysis revealed that eleven differential metabolites, associating with physiological and biochemical indices, were significant improved in the HLJDD and its fractions groups. In conclusion, HLJDD exhibited anti-AD effects by inhibiting itching and enhancing immunity, which in turn regulating the levels of relative metabolites, and CPF and 40AEF were considered the most important components of HLJDD.

Profiling transcriptomic changes and signaling pathways in atopic dermatitis by integrative analyses on multiple databases.

Atopic dermatitis (AD) is a condition driven by T cell-mediated immune response. Targeted therapy of AD is challenging due to its complex pathogenesis. In the current study, by analyzing multiple expression and network datasets, we aimed at: (1) identifying important transcriptomic signatures/profiles for AD to seek potential therapeutic targets and (2) discovering key regulators in the pathogenesis of AD. Our differentially expressed gene (DEG) analysis revealed multiple genes involved in immune response and dermal structural integrity. Functional enrichment analyses suggested that signaling pathways involved in epidermal barrier and inflammation and immunity are overrepresented in lesional AD. Protein-protein interaction (PPI) network and causal interactions analyses highlighted the roles of regulators of epidermal integrity and immune response in the pathogenesis of AD. Prominently, a negative regulator of the B-cell receptor-mediated immune response, PKCß, has been suggested in the predicted pathogenesis model for AD, implying B cell-mediated immune response may play an equally important role as that of the T cell-mediated immune response in AD. A further search in a perturbagen database has identified small molecular drugs that may alter expression profiles of key regulators in the pathogenesis of AD. In this study, we propose a systemic multi-omics strategy incorporating multiple analyses on various datasets of transcriptomes, diseases, and pharmacology. Such integrative analyses will effectively advance our understanding on the pathogenesis and treatment of AD.

Gut-Brain-Skin Axis in Psoriasis: A Review.

INTRODUCTION: Psoriasis is a common skin disease, with chronic inflammation and a complex etiology. It has long been recognized that chronic skin conditions and mental health disorders are often co-morbid. Thus, the concept of the gut-brain-skin axis emphasized in mental health disorders may also regulate the health of skin. RESULTS: The gut microbiota has been found to be the bridge between the immune system and nervous system. By leveraging clinical cases and animal models of psoriasis, an important communication pathway has been identified along the gut-brain-skin axis that is associated with the modulation of neurotransmitters from the microbiota. Furthermore, mammalian neurotransmitters, including dopamine, serotonin, or γ-aminobutyric acid (GABA), can be produced and/or consumed by several types of bacteria. Other studies suggest that manipulating these neurotransmitters by bacteria may have an effect on host physiology, and the levels of neurotransmitter can be altered by microbiota-based interventions. CONCLUSIONS: Nonetheless, it is unknown whether or not the manipulation of neurotransmitter levels by bacteria can affect the occurrence and development of psoriasis. Notably, preliminary experiments found that oral consumption of probiotics improves the clinical symptoms in patients with psoriasis, perhaps correlated with the gut microbiome-mediated crosstalk between the immune system and the nervous system by secreting neurotransmitters in psoriasis. In this review, the communication along the gut-brain-skin axis is discussed.

Ginsenoside compound K ameliorates imiquimod-induced psoriasis-like dermatitis through inhibiting REG3A/RegIIIγ expression in keratinocytes.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation. Ginsenoside compound K (CK), a bioactive metabolite of ginseng, modulates various skin disorders with an impact on keratinocyte biology. However, the effect of Ginsenoside CK in psoriasis has not been explored. OBJECTIVE: Our aim was to investigate whether ginsenoside CK could affect the homeostasis of keratinocytes and their expression of psoriasis-associated antimicrobial protein regenerating islet-derived protein 3-alpha (REG3A) and its murine ortholog RegIIIγ. We further explored the therapeutic potential of ginsenoside CK in imiquimod (IMQ)-induced psoriasis-like dermatitis. METHODS: The effects of ginsenoside CK in cell growth and apoptosis of human keratinocytes were measured by MTT assay and flow cytometry, respectively. Bax levels were evaluated by Western blot in HaCaT cells following ginsenoside CK stimulation. REG3A levels were assessed by RT-PCR and Western blot in human keratinocytes following interleukin (IL)-36γ and ginsenoside CK co-simulation. Utilizing IMQ-induced psoriasis mouse model, the therapeutic effects of 0.1% and 1% ginsenoside CK cream were assessed by skin thicknesses and histological examinations, and RegIIIγ level in the lesional skin was detected by Western blot and immunofluorescence. RESULTS: Ginsenoside CK prohibited human keratinocyte proliferation but did not affect their apoptosis. Moreover, it inhibited IL-36γ-induced REG3A expression in HaCaT cells. Ginsenoside CK alleviated imiquimod-induced psoriasis-like hyperkeratosis and reduced RegIIIγ expression in the keratinocytes from lesional skin. CONCLUSION: Ginsenoside CK ameliorated IMQ-induced psoriasis-like dermatitis possibly through inhibiting REG3A/RegIIIγ expression in keratinocytes, which highlighted a therapeutic potential of ginsenoside CK in psoriasis.

Silencing KRT16 inhibits keratinocyte proliferation and VEGF secretion in psoriasis via inhibition of ERK signaling pathway.

Psoriasis is a multisystem disease affecting about 2% of the population, while keratin16 (KRT16) has been reported to participate in psoriasis. However, the specific mechanism of KRT16 in psoriasis was inadequately investigated. The objective of the study was to elucidate the mechanism by which siRNA-mediated silencing of KRT16 affects keratinocyte proliferation and vascular endothelial growth factor (VEGF) secretion in psoriasis through the extracellular signal-related kinase (ERK) signaling pathway. Psoriasis-related core gene KRT16 was screened out. Then, the expression of KRT16, VEGF, and ERK signaling pathway-related genes was detected in psoriatic patients. To further investigate the mechanism of KRT16, keratinocytes in psoriatic patients were treated with KRT16 siRNA or/and ERK inhibitor (PD98059) to detect the changes in related gene expression and cell survival. KRT16 was involved in psoriasis development. The expression levels of KRT16, p-ERK1/2, and VEGF in lesion tissues are significantly elevated. Keratinocytes treated with KRT16-siRNA and KRT16-siRNA + PD98059 exhibited reduced KRT16, p-ERK1/2, and VEGF expression. The cell survival rate in cells treated with KRT16-siRNA, PD98059, and KRT16-siRNA + PD98059 reduced significantly. These findings indicate that silencing KRT16 inhibits keratinocyte proliferation and VEGF secretion in psoriasis via inhibition of ERK signaling pathway, which provides a basic theory in the treatment of psoriasis.

[Expression of Th17/Treg cell in patients with psoriasis arthritis and its clinical significance].

OBJECTIVE: To investigate the change of Th17/Treg cell in patients with psoriasis arthritis (PA) and its clinical significance. METHODS: The levels of IL-17 and TGF-ß1 were measured by enzyme-linked immunosorbent assay(ELISA) in PA patients (n=35) and healthy controls(n=30). The frequencies of Th17 and Treg in the peripheral blood were detected by flow cytometry. RESULTS: Compared with the healthy controls, Th17/Treg in peripheral blood were significantly increased (p<0.05), Th17-related cytokine IL-17 significantly increased (p<0.05), and TGF-ß1 significantly decreased (p<0.05) in the PA patients. CONCLUSION: Th17/Treg cell and the related cytokines IL-17 and TGF-ß1 may be involved in the pathogenesis of PA.

Preparation and anti-inflammatory activity of triptolide ethosomes in an erythema model.

CONTEXT: The aim of this work was to evaluate the suitability of ethosomes as carriers for the topical application of triptolide in a rat model of erythema. OBJECTIVE: We determined the optimal conditions for preparing ethosomes, and we measured their vesicle size by a laser particle-size analyzer and the efficiency of entrapment of triptolide by ultracentrifugation. METHODS: The in vitro percutaneous permeation of triptolide-loaded ethosomes was investigated by measuring diffusion across a sample of rat skin. To explore the transdermal delivery in vivo, we used a model in which erythema was induced in rats by methyl nicotinate and determined the change in erythema index caused by the anti-inflammatory activity of triptolide by a reflection spectrophotometer. RESULTS: The optimal conditions for preparing triptolide ethosomes consisted of ultrasonication of 45% (v/v) ethanol and 2% (w/v) DPPC for 5 minutes, which produced an average vesicle size of 51.4 nm and an entrapment efficiency of 98%. This ethosomal formulation of triptolide caused the greatest in vitro 24-hour accumulation of triptolide (83.7%) with no permeation time delay, and it reduced erythema in vivo more rapidly and more completely than other formulations. CONCLUSIONS: Ethosomes might be a promising carrier that would enable the beneficial properties of triptolide to be safely delivered in a topical formulation.

[Effect of Huangbai Liquid on expression of human beta-defensin-2 mRNA in skin lesions of patients with recurrent genital herpes].

OBJECTIVE: To investigate the expression of human beta-defensin-2 (HBD-2) mRNA in skin lesions of patients with recurrent genital herpes (RGH) and the effect of Huangbai Liquid (HL) on it. METHODS: Twenty-seven patients were randomly assigned to 2 groups, the HL group (n = 14) treated with HL and the famciclovir group (n = 13) with famciclovir. HBD-2 expression of patients were detected before and after the treatment and compared with that of 10 healthy subjects. RESULTS: HBD-2 expression was found in the skin lesions of both the healthy persons and the RGH patients before treatment. It is higher significantly in the HL group than in the famciclovir group after treatment. CONCLUSION: HL was suitable for treatment of RGH since it could improve immune function of RGH patients and keep a rather higher concentration of HBD-2 expression in local skin lesions.