TRPV3-activated PARP1/AIFM1/MIF axis through oxidative stress contributes to atopic dermatitis.

TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function mutations in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. Herein, we showed that gain-of-function mutation or pharmacological activation of TRPV3 resulted in PARP1/AIFM1/MIF axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging reactive oxygen species or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis (AD), while inhibiting PARP1 largely alleviated the MC903-induced dermatitis. Additionally, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of AD. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/MIF axis is a critical contributor to the pathogenesis of Olmsted syndrome and AD, suggesting that modulating the PARP1/AIFM1/MIF axis is a promising therapy for these conditions.

A cavity induced mode hybridization plasmonic sensor for portable detection of exosomes.

Exosomes have been considered as promising biomarkers for cancer diagnosis due to their abundant information from originating cells. However, sensitive and reliable detection of exosomes is still facing technically challenges due to the lack of a sensing platform with high sensitivity and reproducibility. To address the challenges, here we propose a portable surface plasmon resonance (SPR) sensing of exosomes with a three-layer Au mirror/SiO2 spacer/Au nanohole sensor, fabricated by an economical polystyrene nanosphere self-assembly method. The SiO2 spacer can act as an optical cavity and induce mode hybridization, leading to excellent optimization of both sensitivity and full width at half maximum compared with normal single layer Au nanohole sensors. When modified with CD63 or EpCAM aptamers, a detection of limit (LOD) of as low as 600 particles/µL was achieved. The sensors showed good capability to distinguish between non-tumor derived L02 exosomes and tumor derived HepG2 exosomes. Additionally, high reproducibility was also achieved in detection of artificial serum samples with RSD as low as 2%, making it feasible for clinical applications. This mode hybridization plasmonic sensor provides an effective approach to optimize the detection sensitivity of exosomes, pushing SPR sensing one step further towards cancer diagnosis.

Serine/Arginine-Rich Splicing Factor 7 Knockdown Inhibits Aerobic Glycolysis and Growth in HepG2 Cells by Regulating PKM2 Expression.

Serine/arginine-rich splicing factors (SRSFs), part of the serine/arginine-rich (SR) protein family, play a crucial role in precursor RNA splicing. Abnormal expression of SRSFs in tumors can disrupt normal RNA splicing, contributing to tumor progression. Notably, SRSF7 has been found to be upregulated in hepatocellular carcinoma (HCC), yet its specific role and molecular mechanisms in HCC pathogenesis are not fully understood. We investigated the expression and prognostic significance of SRSF7 in HCC using bioinformatics database analysis. In HepG2 cells, the expressions of SRSF7 and glycolytic enzymes were analyzed using qRT-PCR, and Western blot. Glucose uptake and lactate production were quantified using relevant reagent kits. Additionally, cell proliferation, clonogenicity, invasion, and apoptosis were evaluated using MTS assay, clonal formation assay, Transwell assay, and mitochondrial membrane potential assay, respectively. This study demonstrated significant overexpression of SRSF7 in HCC tissue, correlating with poor prognosis. Knockdown of SRSF7 in HepG2 cells resulted in inhibited proliferation, clonogenicity, and invasion, while apoptosis was enhanced. This knockdown also decreased glucose uptake and lactate production, along with a reduction in the expression of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). Furthermore, SRSF7 downregulation increased the pyruvate kinase muscle 1 (PKM1)/PKM2 ratio. The glycolytic boost due to PKM2 overexpression partially counteracted the effects of SRSF7 silencing on HepG2 cell growth. The knockdown of SRSF7 impairs aerobic glycolysis and growth in HepG2 cells by downregulating PKM2 expression.

Comprehensive analysis of phenotypes and transcriptome characteristics reveal the best atopic dermatitis mouse model induced by MC903.

BACKGROUND: Although several mouse models of exogenous-agent-induced atopic dermatitis (AD) are currently available, the lack of certainty regarding their similarity with human AD has limited their scientific value. Thus, comprehensive evaluation of the characteristics of mouse models and their similarity with human AD is essential. OBJECTIVE: To compare six different exogenous-agent-induced AD mouse models and find out the optimum models for study. METHODS: Female BALB/c mice underwent induction of AD-like dermatitis by MC903 alone or in combination with ovalbumin (OVA), dinitrofluorobenzene (DNFB) alone or in combination with OVA, OVA alone, or Staphylococcus aureus. Gross phenotype, total immunoglobulin E (IgE) level, histopathological manifestations, and skin lesion transcriptome were analyzed, and metagenomic sequencing of the gut microbiome was performed. RESULTS: The DNFB plus OVA model showed the highest disease severity, while the OVA model showed the lowest severity. The MC903 and MC903 plus OVA models showed high expression of T-helper (Th)2- and Th17-related genes; the DNFB and DNFB plus OVA models showed upregulation of Th1-, Th2-, and Th17-related genes; while the S. aureus inoculation model showed more enhanced Th1 and Th17 immune responses. In contrast to the other models, the OVA-induced model showed the lowest expression levels of inflammation-related genes, while the MC903 model shared the largest overlap with human AD profiles. The intestinal microbiota of all groups showed significant differences after modeling. CONCLUSION: Each AD mouse model exhibited different characteristics. The MC903 model was the best to recapitulate most features of human AD among these exogenous-agent-induced AD models.

Senescent fibroblasts and innate immune cell activation might play a role in the pathogenesis of elderly atopic dermatitis.

BACKGROUND: Elderly atopic dermatitis (AD) is a subtype of AD defined by age (≥ 60 years). The molecular characteristics of elderly AD remain to be clarified. OBJECTIVE: We sought to characterize the molecular features of skin lesions and peripheral blood mononuclear cells (PBMCs) in patients with AD across different age, focusing on elderly AD. METHODS: Skin and PBMCs samples were used for RNA sequencing. Analysis of differentially expressed genes and gene set variation analysis were performed. Immunofluorescence staining, quantitative real-time PCR (qRT-PCR), flow cytometry and transwell assay were used for validation. RESULTS: Compared with healthy controls, the skin transcriptome of AD patients showed common signatures of AD, like barrier dysfunction and enhanced Th1/Th2/Th17 immune pathways. In PBMCs, the expression of Th1/Th2 response genes was more remarkable in adult AD, while expression of Th17-related genes was significantly higher in childhood AD. The gene modules associated with natural killer (NK) cells were downregulated in elderly AD. In skin lesions, elderly AD exhibited enrichment of macrophages, fibroblasts and senescence-associated secretory phenotype (SASP) related genes. The correlation among fibroblasts, SASP and innate immune cells were revealed by the co-localization of fibroblasts, macrophages and NK cells in the lesions across different age groups. Fibroblasts under inflammation or senescence could induce stronger chemotaxis of macrophages and NK cells. CONCLUSION: We identified the molecular phenotypes of skin lesions and PBMCs in elderly AD individuals. Fibroblasts, innate immune cells, and SASP might play important roles in the pathogenesis of elderly AD.

Chemo-photodynamic antitumour therapy based on Er-doped upconversion nanoparticles coated with hypocrellin B and MnO2.

An antitumour chemo-photodynamic therapy nanoplatform was constructed based on phospholipid-coated NaYF4: Yb/Er upconversion nanoparticles (UCNPs). In this work, the amphiphilic block copolymer DSPE-PEG2000 was combined with the surface ligand oleic acid of the UCNPs through hydrophobic interaction to form liposomes with a dense hydrophobic layer in which the photosensitizer hypocrellin B (HB) was assembled. The coated HB formed J-aggregates, which caused a large redshift in the absorption spectrum and improved the quantum efficiency of energy transfer. Furthermore, MnO2 nanosheets grew in-situ on the liposomes through OMn coordination. Therefore, a multifunctional tumour microenvironment (TME)-responsive theranostic nanoplatform integrating photodynamic therapy (PDT) and chemodynamic therapy (CDT) was successfully developed. The results showed that this NIR-mediated chemo-photodynamic therapy nanoplatform was highly efficient for oncotherapy.

Distribution, mobilization, risk assessment and source identification of heavy metals and nutrients in surface sediments of three urban-rural rivers after long-term water pollution treatment.

Sediments are critical pollution carriers in urban-rural rivers, which can threaten the water quality of the river and downstream lakes for a long time. However, it is still not clear whether conventional water pollution treatments could abate sediment pollution or not. In this study, heavy metals (HMs) and nutrient salts in the surface sediments and overlying water were investigated after decades' water pollution treatment in three urban-rural rivers. HM speciation was determined by the sequential extraction; diffusion fluxes were estimated using Fick's first law; HM ecological risk and nutrient pollution were evaluated; and pollution sources were identified by statistical analysis and GIS. The results showed that the HMs and nutrients were extremely serious in the urban regions. The accumulation level of Pb, Cu and Cd in the sediments of the three rivers were all much higher than the soil background value, and the labile fractions accounted for high proportions (57 % for Pb, 55 % for Cu and 43 % for Cd), which could be easily eluate from the sediments and caused hazards to the aquatic environment. The sediment diffusion fluxes of HMs and ammonia nitrogen were mostly positive, which indicated these sites currently released these pollutants from sediment to overlying water. Cd, Pb, Cu and Cr may mainly originate from industrial discharge and domestic sewage, while Cr was also greatly affected by crustal weathering; nutrient pollution may originate from agricultural activities and domestic sewage. Our study demonstrated that after decades' conventional water treatment in these rivers, the sediment pollution was still in a serious level with high ecological risk, and Cd was the dominant pollutant. At present, the external point source pollution has been effectively controlled, thus, the in-depth understanding of the sediment pollution characteristics after long-term water treatment could provide a scientific basis for the accurate elimination of river pollution.

Biosynthesis and Anticancer Activity of Genistein Glycoside Derivatives.

As a beneficial natural flavonoid, genistein has demonstrated a wide range of biological functions via regulating a number of targets and signaling pathways, such as anti-cancer, antioxidant, antibacterial, antiinflammatory, antifungal, antiviral, iron chelation, anti-obesity, anti-diabetes, and anti-hypertension. PubMed/Medline and Web of Science were searched using appropriate keywords until the end of December 2023. Despite its many potential benefits, genistein's clinical application is limited by low hydrophilicity, poor solubility, and suboptimal bioavailability due to its structure. These challenges can be addressed through the conversion of genistein into glycosides. Glycosylation of active small molecules may enhance their solubility, stability, and biological activity. In recent years, extensive research has been conducted on the synthesis, properties, and anticancer activity of glycoconjugates. Previous reviews were devoted to discussing the biological activities of genistin, with a little summary of the biosynthesis and the structure-activity relationship for their anticancer activity of genistein glycoside derivatives. Therefore, we summarized recent advances in the biosynthesis of genistein glycosylation and discussed the antitumor activities of genistein glycoside derivatives in a structure-activity relationship, which may provide important information for further development of genistein derivatives.

Effects and mechanisms of polycyclic aromatic hydrocarbons in inflammatory skin diseases.

Polycyclic aromatic hydrocarbons (PAHs) are hydrocarbons characterized by the presence of multiple benzene rings. They are ubiquitously found in the natural environment, especially in environmental pollutants, including atmospheric particulate matter, cigarette smoke, barbecue smoke, among others. PAHs can influence human health through several mechanisms, including the aryl hydrocarbon receptor (AhR) pathway, oxidative stress pathway, and epigenetic pathway. In recent years, the impact of PAHs on inflammatory skin diseases has garnered significant attention, yet many of their underlying mechanisms remain poorly understood. We conducted a comprehensive review of articles focusing on the link between PAHs and several inflammatory skin diseases, including psoriasis, atopic dermatitis, lupus erythematosus, and acne. This review summarizes the effects and mechanisms of PAHs in these diseases and discusses the prospects and potential therapeutic implications of PAHs for inflammatory skin diseases.

Environmental exposure to polycyclic aromatic hydrocarbons: An underestimated risk factor for systemic lupus erythematosus onset and progression.

OBJECTIVE: To investigate the link between systemic lupus erythematosus (SLE) incidence and exposure to environmental polycyclic aromatic hydrocarbons (PAH). METHODS: A case-control study (ChiCTR2000038187) involving 316 SLE patients and 851 healthy controls (HCs) was executed. Environmental exposure was assessed via a questionnaire, stratified by gender and age (females <35 and ≥35 years, males). Blood samples collected from 89 HCs, 85 inactive, and 95 active SLE patients were used to measure serum benzo[a]pyrene diol epoxide -albumin (BPDE-Alb) adducts and PAH concentrations, indicating long-term and short-term exposure respectively. Intergroup comparisons and statistical analyses were conducted using R version 4.3.1. RESULTS: Diverse patterns were found in how environmental factors affect SLE onset across different demographics. Lifestyle exposure factors were found to be a stronger determinant of SLE onset than occupational exposure factors in women under 35. Indoor air pollution had a significant impact on SLE incidence, potentially comparable to outdoor air pollution. Lifestyle-related PAH exposure had a greater impact on SLE than occupational PAH exposure. PAH exposure levels progressively increase from HCs to inactive and active SLE patients. Active SLE patients show markedly higher BPDE-Alb levels than HCs. CONCLUSIONS: Environmental PAH, particularly lifestyle-related, are significant, yet under-recognized, risk factors for SLE. STATEMENT OF ENVIRONMENTAL IMPLICATION: We examined the relationship between exposure to environmental polycyclic aromatic hydrocarbons (PAH) and the incidence of systemic lupus erythematosus (SLE). PAH, prevalent in sources such as cigarette smoke, air pollution, and charred food, pose significant health hazards. This study is the first to investigate specific PAH exposure levels in SLE patients. We determined actual PAH exposure levels in both SLE patients and healthy individuals and indicated that long-term PAH exposure biomarker is more reliable for evaluating exposure in non-occupationally exposed groups like SLE, compared to short-term markers. These findings provide valuable insights for future research on similar non-occupationally exposed populations.

Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain.

Bilirubin is mainly generated from the breakdown of heme when red blood cells reach the end of their lifespan. Accumulation of bilirubin in human body usually leads to various disorders, including jaundice and liver disease. Bilirubin is conjugated in hepatocytes and excreted to bile duct via the ATP-binding cassette transporter ABCC2, dysfunction of which would lead to Dubin-Johnson syndrome. Here we determine the structures of ABCC2 in the apo, substrate-bound and ATP/ADP-bound forms using the cryo-electron microscopy, exhibiting a full transporter with a regulatory (R) domain inserted between the two half modules. Combined with substrate-stimulated ATPase and transport activity assays, structural analysis enables us to figure out transport cycle of ABCC2 with the R domain adopting various conformations. At the rest state, the R domain binding to the translocation cavity functions as an affinity filter that allows the substrates of high affinity to be transported in priority. Upon substrate binding, the R domain is expelled from the cavity and docks to the lateral of transmembrane domain following ATP hydrolysis. Our findings provide structural insights into a transport mechanism of ABC transporters finely tuned by the R domain.

Study on the improvement of complexation efficiency and anti-digestibility of phenolic acids based on electrospun starch fibers.

Phenolic acids can be encapsulated by starch electrospun fibers, and the structural and functional properties of the electrospun fiber are affected by the chemical structure of phenolic acid. In this study, five phenolic acids (protocatechuic acid (PA), p-hydroxybenzoic acid (PHBA), p-coumaric acid (PCA), ferulic acid (FA), and caffeic acid (CA)) were chosen to prepare electrospun fibers with high amylose corn starch (HACS) at different voltages. Morphology and complexation efficiency results revealed that the electrospun fibers prepared at 21.0 kV were smooth and continuous with high encapsulation efficiency (EE) and loading efficiency (LE). The chemical structure of phenolic acid played an important role in the structure and properties of electrospun fibers by influencing the complexation of HACS with phenolic acids and the inhibitory effect of amylase. As a result, electrospun fibers containing HACS-CA inclusion complex had higher relative crystallinity (25.47 %), higher thermal degradation temperatures (356.17 °C), and the strongest resistance to digestion (starch digestive ratio = 22.98 %). It is evident that electrospun fibers containing HACS-phenolic acid inclusion complexes not only achieve high phenolic acid complexation efficiency, but also resist the effects of the gastric and small intestinal environment on phenolic acids, thereby improving the bioaccessibility of phenolic acids.

Propionate alleviates itch in murine models of atopic dermatitis by modulating sensory TRP channels of dorsal root ganglion.

BACKGROUND: Itch is the most common symptom of atopic dermatitis (AD) and significantly decreases the quality of life. Skin microbiome is involved in AD pathogenesis, whereas its role in the regulation of itch remains elusive. In this study, we aimed to investigate the effects of skin microbial metabolite propionate on acute and chronic pruritus and to explore the mechanism. METHODS: Using various mouse models of itch, the roles of propionate were explored by behavioral tests and histopathology/immunofluorescent analysis. Primary-cultured dorsal root ganglion neurons and HEK293 cells expressing recombinant human TRP channels were utilized for in vitro calcium imaging/in vivo miniature two-photon imaging in combination with electrophysiology and molecular docking approaches for investigation of the mechanism. RESULTS: Propionate significantly alleviated itch and alloknesis in various mouse models of pruritus and AD and decreased the density of intraepidermal nerve fibers. Propionate reduced the responsiveness of dorsal root ganglion neurons to pruritogens in vitro, attenuated the hyper-excitability in sensory neurons in MC903-induced AD model, and inhibited capsaicin-evoked hTRPV1 currents (IC50 = 20.08 ± 1.11 µM) via interacting with the vanilloid binding site. Propionate also decreased the secretion of calcitonin gene-related peptide by nerves in MC903-induced AD mouse model, which further attenuated itch and skin inflammation. CONCLUSION: Our study revealed a protective effect of propionate against persistent itch through direct modulation of sensory TRP channels and neuropeptide production in neurons. Regulation of itch via the skin microbiome might be a novel strategy for the treatment of AD.

Advances in ß-Diketocyclisation of Curcumin Derivatives and their Antitumor Activity.

Curcumin, derived from the popular spice turmeric, is a pharmacologically active polyphenol. Curcumin's therapeutic activity has been extensively studied in recent decades, with reports implicating curcumin in many biological activities, particularly, its significant anticancer activity. However, its potential as an oral administration product is hampered by poor bioavailability, which is associated with a variety of factors, including low water solubility, poor intestinal permeability, instability, and degradation at alkaline pH. To improve its bioavailability, modifying ß-diketone curcumin with heterocycles, such as pyrazole, isoxazole and triazole is a powerful strategy. Derivatives are synthesized while maintaining the basic skeleton of curcumin. The ß-diketone cyclized curcumin derivatives are regulators of multiple molecular targets, which play vital roles in a variety of cellular pathways. In some literatures, structurally modified curcumin derivatives have been compared with curcumin, and the former has enhanced biological activity, improved water solubility and stability. Therefore, the scope of this review is to report the most recently synthesized heterocyclic derivatives and to classify them according to their chemical structures. Several of the most important and effective compounds are reviewed by introducing different active groups into the ß-diketone position to achieve better therapeutic efficacy and bioavailability.

Screening of heat stress-related biomarkers in chicken serum through label-free quantitative proteomics.

Heat stress (HS) can result in sudden death and is one of the most stressful and costly events in chicken. Currently, biomarkers used clinically to detect heat stress state in chickens are not optimal, especially for living ones. Analysis of changes in serum proteins of heat-stressed chickens can help to identify some novel convenient biomarkers for this. Twenty-four chickens were exposed to HS at 42°C ± 1°C with a relative humidity of 65% for continuous 5 h in a single day, and 10 birds were used as controls (Con). During HS, 15 dead chickens were categorized as heat stress death group (HSD), and 9 surviving ones served as heat stress survivor group (HSS). Label-free quantitative proteomics (LFQP) was used to analyze differentially expressed proteins (DEPs) in serum of tested animals. Candidate proteins associated with HS were validated by enzyme-linked immunosorbent assay (ELISA). Diagnostic value of candidate biomarkers was assessed using receiver operating characteristic (ROC) curve analysis. Source of the selected proteins was analyzed in liver tissues with immunohistochemistry and in cell culture supernatant of primary chicken hepatocytes (PCH) using ELISA. In this study, compared to Con, LFQP identified 123 and 53 significantly different serum proteins in HSD and HSS, respectively. Bioinformatics analysis showed that XDH, POSTN, and HSP90 were potential HS biomarkers in tested chickens, which was similar with results from serum ELISAs and immunohistochemistry in liver tissues. The ROC values of 0.793, 0.752, and 0.779 for XDH, POSTN, and HSP90, respectively, permitted the distinction of heat-stressed chickens from the control. Levels of 3 proteins above in the cell culture supernatant of PCH showed an increasing trend as HS time increased. Therefore, considering that mean concentration of POSTN in serum was higher than that of HSP90, XDH, and POSTN may be optimal biomarkers in serum for detecting HS level in chickens, and mainly secreted from hepatocytes. The former indicates that heat-stressed chickens are in a damaged state, and the latter implies that chickens can repair heat stress damage.

Experimental investigation on the aero-optical effects of supersonic gas films with various cooling fluids.

Despite the fact that a supersonic cooling gas film can efficiently insulate aerodynamic heating, its interaction with the mainstream generates a sophisticated flow structure which may cause significant aero-optical ramifications. This study aims to analyze the fluid structure and wavefront distortion of supersonic gas film when subjected to varying nozzle pressure ratios (NPR) by employing two distinct cooling refrigerants, namely C O 2 and air. Within the NPR range of 0 to 2, a linear relationship exists between the wavefront distortion of both C O 2 and air films, while the C O 2 film exhibits higher wavefront distortion than the air. Additionally, the influence of condensation on the discrepancies in aero-optical effects of the two refrigerants is discussed.

Attenuation of allergen-specific immunotherapy for atopic dermatitis by ectopic colonization of Brevundimonas vesicularis in the intestine.

Allergen-specific immunotherapy (AIT) has shown beneficial effects against atopic dermatitis (AD); however, the mechanisms and parameters underlying the efficacy of AIT remain unclear. Here, we report that the community structure and function of the oral and gut microbiota are changed in patients with AD undergoing AIT. Transplantation of fecal microbiota from patients who respond well to AIT improves AD-like dermatitis in mice. The abundance of Brevundimonas vesicularis in the gut of AD patients has been found to be positively correlated with disease severity and is decreased following AIT. Furthermore, we find that B. vesicularis from the oral cavity might ectopically colonize the gut of AD patients. In AD model mice, meanwhile, B. vesicularis promotes the skewing of the Treg/Th17 balance toward Th17 polarization and attenuates the efficacy of ovalbumin-specific immunotherapy. Our findings provide potential strategies for the optimization of AIT for AD via the modulation of the gut microbiota.

Ph3P/ICH2CH2I-promoted reductive deoxygenation of alcohols.

Owing to the ubiquity of the hydroxyl group, reductive deoxygenation of alcohols has become an active research area. The classic Barton-McCombie reaction suffers from a tedious two-step procedure. New efficient methods have been developed, but they have some limitations, such as a narrow substrate scope and the use of moisture-sensitive Lewis acids. In this work, we describe the Ph3P/ICH2CH2I-promoted reductive deoxygenation of alcohols with NaBH4. The process is applicable to benzyl, allyl and propargyl alcohols, and also to primary and secondary alcohols, demonstrating a wide substrate scope and a good level of functional group tolerance. This protocol features convenient operation and low cost of all reagents.