Recent advances in the epithelial barrier theory.

The epithelial barrier theory links the recent rise in chronic non-communicable diseases, notably autoimmune and allergic disorders, to environmental agents disrupting the epithelial barrier. Global pollution and environmental toxic agent exposure have worsened over six decades because of uncontrolled growth, modernization, and industrialization, affecting human health. Introducing new chemicals without any reasonable control of their health effects through these years has led to documented adverse effects, especially on the skin and mucosal epithelial barriers. These substances, such as particulate matter, detergents, surfactants, food emulsifiers, micro- and nano-plastics, diesel exhaust, cigarette smoke, and ozone, have been shown to compromise the epithelial barrier integrity. This disruption is linked to the opening of the tight-junction barriers, inflammation, cell death, oxidative stress, and metabolic regulation. Consideration must be given to the interplay of toxic substances, underlying inflammatory diseases, and medications, especially in affected tissues. This review article discusses the detrimental effect of environmental barrier-damaging compounds on human health and involves cellular and molecular mechanisms.

Regulation of immune response genes in the skin of allergic and clinically tolerant individuals exposed to p-phenylenediamine.

BACKGROUND: p-Phenylenediamine (PPD) is a potent contact allergen found in many hair colour products. However, not all individuals develop allergic contact dermatitis (ACD) although they are regularly exposed to PPD. It is unclear whether these asymptomatic individuals are true non-responders to PPD or whether they mount a response to PPD without showing any symptoms. METHODS: Skin biopsies were collected from 11 asymptomatic hairdressers regularly exposed to PPD and from 10 individuals with known ACD on day 4 after patch testing with 1% PPD in petrolatum and petrolatum exclusively as control. RNA sequencing and confocal microscopy were performed. RESULTS: T cell activation, inflammation and apoptosis pathways were up-regulated by PPD in both asymptomatic and allergic individuals. Compared to asymptomatic individuals with a negative patch test, individuals with a strong reaction to PPD strongly up-regulated both pro- and anti-inflammatory cytokines genes. Interestingly, PPD treatment induced significant up-regulation of several genes for chemokines, classical type 2 dendritic cell markers and regulatory T cell markers in both asymptomatic and allergic individuals. In addition, apoptosis signalling pathway was activated in both non-responders and allergic individuals. CONCLUSION: This study demonstrates that there are no true non-responders to PPD but that the immune response elicited by PPD differs between individuals and can lead to either tolerance, subclinical inflammation or allergy.

Household laundry detergents disrupt barrier integrity and induce inflammation in mouse and human skin.

BACKGROUND: Epithelial barrier impairment is associated with many skin and mucosal inflammatory disorders. Laundry detergents have been demonstrated to affect epithelial barrier function in vitro using air-liquid interface cultures of human epithelial cells. METHODS: Back skin of C57BL/6 mice was treated with two household laundry detergents at several dilutions. Barrier function was assessed by electric impedance spectroscopy (EIS) and transepidermal water loss (TEWL) measurements after the 4 h of treatments with detergents. RNA sequencing (RNA-seq) and targeted multiplex proteomics analyses in skin biopsy samples were performed. The 6-h treatment effect of laundry detergent and sodium dodecyl sulfate (SDS) was investigated on ex vivo human skin. RESULTS: Detergent-treated skin showed a significant EIS reduction and TEWL increase compared to untreated skin, with a relatively higher sensitivity and dose-response in EIS. The RNA-seq showed the reduction of the expression of several genes essential for skin barrier integrity, such as tight junctions and adherens junction proteins. In contrast, keratinization, lipid metabolic processes, and epidermal cell differentiation were upregulated. Proteomics analysis showed that the detergents treatment generally downregulated cell adhesion-related proteins, such as epithelial cell adhesion molecule and contactin-1, and upregulated proinflammatory proteins, such as interleukin 6 and interleukin 1 beta. Both detergent and SDS led to a significant decrease in EIS values in the ex vivo human skin model. CONCLUSION: The present study demonstrated that laundry detergents and its main component, SDS impaired the epidermal barrier in vivo and ex vivo human skin. Daily detergent exposure may cause skin barrier disruption and may contribute to the development of atopic diseases.

The epithelial barrier: The gateway to allergic, autoimmune, and metabolic diseases and chronic neuropsychiatric conditions.

Since the 1960 s, our health has been compromised by exposure to over 350,000 newly introduced toxic substances, contributing to the current pandemic in allergic, autoimmune and metabolic diseases. The "Epithelial Barrier Theory" postulates that these diseases are exacerbated by persistent periepithelial inflammation (epithelitis) triggered by exposure to a wide range of epithelial barrier-damaging substances as well as genetic susceptibility. The epithelial barrier serves as the body's primary physical, chemical, and immunological barrier against external stimuli. A leaky epithelial barrier facilitates the translocation of the microbiome from the surface of the afflicted tissues to interepithelial and even deeper subepithelial locations. In turn, opportunistic bacterial colonization, microbiota dysbiosis, local inflammation and impaired tissue regeneration and remodelling follow. Migration of inflammatory cells to susceptible tissues contributes to damage and inflammation, initiating and aggravating many chronic inflammatory diseases. The objective of this review is to highlight and evaluate recent studies on epithelial physiology and its role in the pathogenesis of chronic diseases in light of the epithelial barrier theory.

Disrupted epithelial permeability as a predictor of severe COVID-19 development.

BACKGROUND: An impaired epithelial barrier integrity in the gastrointestinal tract is important to the pathogenesis of many inflammatory diseases. Accordingly, we assessed the potential of biomarkers of epithelial barrier dysfunction as predictive of severe COVID-19. METHODS: Levels of bacterial DNA and zonulin family peptides (ZFP) as markers of bacterial translocation and intestinal permeability and a total of 180 immune and inflammatory proteins were analyzed from the sera of 328 COVID-19 patients and 49 healthy controls. RESULTS: Significantly high levels of circulating bacterial DNA were detected in severe COVID-19 cases. In mild COVID-19 cases, serum bacterial DNA levels were significantly lower than in healthy controls suggesting epithelial barrier tightness as a predictor of a mild disease course. COVID-19 patients were characterized by significantly elevated levels of circulating ZFP. We identified 36 proteins as potential early biomarkers of COVID-19, and six of them (AREG, AXIN1, CLEC4C, CXCL10, CXCL11, and TRANCE) correlated strongly with bacterial translocation and can be used to predict and discriminate severe cases from healthy controls and mild cases (area under the curve (AUC): 1 and 0.88, respectively). Proteomic analysis of the serum of 21 patients with moderate disease at admission which progressed to severe disease revealed 10 proteins associated with disease progression and mortality (AUC: 0.88), including CLEC7A, EIF4EBP1, TRANCE, CXCL10, HGF, KRT19, LAMP3, CKAP4, CXADR, and ITGB6. CONCLUSION: Our results demonstrate that biomarkers of intact or defective epithelial barriers are associated with disease severity and can provide early information on the prediction at the time of hospital admission.

The epithelial barrier theory: Development and exacerbation of allergic and other chronic inflammatory diseases.

It is now longer than half a century, humans, animals, and nature of the world are under the influence of exposure to many newly introduced noxious substances. These exposures are nowadays pushing the borders to be considered as the causative or exacerbating factors for many chronic disorders including allergic, autoimmune/inflammatory, and metabolic diseases. The epithelial linings serve as the outermost body's primary physical, chemical, and immunological barriers against external stimuli. The "epithelial barrier theory" hypothesizes that these diseases are aggravated by an ongoing periepithelial inflammation triggered by exposure to a wide range of epithelial barrier-damaging insults that lead to "epithelitis" and the release of alarmins. A leaky epithelial barrier enables the microbiome's translocation from the periphery to interepithelial and even deeper subepithelial areas together with allergens, toxins, and pollutants. Thereafter, microbial dysbiosis, characterized by colonization of opportunistic pathogen bacteria and loss of the number and biodiversity of commensal bacteria take place. Local inflammation, impaired tissue regeneration, and remodeling characterize the disease. The infiltration of inflammatory cells to affected tissues shows an effort to expulse the tissue invading bacteria, allergens, toxins, and pollutants away from the deep tissues to the surface, representing the "expulsion response." Cells that migrate to other organs from the inflammatory foci may play roles in the exacerbation of various inflammatory diseases in distant organs. The purpose of this review is to highlight and appraise recent opinions and findings on epithelial physiology and its role in the pathogenesis of chronic diseases in view of the epithelial barrier theory.

Parasite-host network analysis provides insights into the evolution of two mistletoe lineages (Loranthaceae and Santalaceae).

Mistletoes are ecologically important parasitic plants, with > 1600 species from five lineages worldwide. Mistletoe lineages exhibit distinct patterns of species diversification and host specificity, however, the mechanisms underlying these differences are poorly understood. In this study, we analysed a comprehensive parasite-host network, including 280 host species from 60 families and 22 mistletoe species from two lineages (Santalaceae and Loranthaceae) in Xishuangbanna, located in a biodiversity hotspot of tropical Asia. We identified the factors that predict the infection strength of mistletoes. We also detected host specificity and the phylogenetic signal of mistletoes and their hosts. We found that this interaction network could be largely explained by a model based on the relative abundance of species. Host infection was positively correlated with diameter at breast height and tree coverage, but negatively correlated with wood density. Overall, closely related mistletoe species tend to interact more often with similar hosts. However, the two lineages showed a significantly different network pattern. Rates of host generality were higher in Loranthaceae than in Santalaceae, although neither lineage showed phylogenetic signal for host generality. This study demonstrates that the neutral interaction hypothesis provides suitable predictions of the mistletoe-host interaction network, and mistletoe species show significant phylogenetic signals for their hosts. Our findings also indicate that high species diversification in Loranthaceae may be explained by high rates of host generality and the evolutionary history shared by Loranthaceae species with diverse host plants in the tropics.

High outcrossing rates in a self-compatible and highly aggregated host-generalist mistletoe.

Plants have evolved various strategies to avoid inbreeding, but the mass flowering displayed by many plants predisposes them to within-plant pollen movements and self-pollination. Mistletoes often aggregate at multiple spatial scales. Their bird pollinators often visit several flowers of the same individual and of others on the same host tree. We hypothesized that hermaphroditic mistletoes have self-incompatibility mechanisms that reduce or prevent selfing. Whether their spatial distribution, affected by host specificity, host distribution, and the behaviour of seed dispersers, influences their mating system and population genetic structure remains unclear. We studied how mating system and spatial distribution affect genetic structure in four populations of the host-generalist mistletoe Dendrophthoe pentandra in southwestern China using microsatellite markers and progeny arrays. We also characterized the fine-scale spatial genetic structure among 166 mistletoes from four host trees in one population. Prevalence and intensity of infection both appeared to vary among host species, strongly affecting the degree of aggregation. Host tree size had a strong effect on infection intensity. Surprisingly, manual pollination experiments indicated that D. pentandra is self-compatible, but genetic analyses revealed that outcrossing rates were higher than expected in all four populations (MLTR tm 0.83-1.20, Bayesian tm 0.772-0.952). Spatial genetic structure was associated with distance between host trees but not at shorter scales (within hosts). Our results demonstrate that the combination of bird pollination, bird-mediated seed dispersal, and post-dispersal processes result in outcrossing and maintain relatively high diversity in the presence of biparental inbreeding, despite very high local densities and possible self-compatibility.

Celastrol Targets Cullin-Associated and Neddylation-Dissociated 1 to Prevent Fibroblast-Myofibroblast Transformation against Pulmonary Fibrosis.

Celastrol (CEL), a pentacyclic triterpene compound, has been proven to have a definite antipulmonary fibrosis effect. However, its direct targets for antipulmonary fibrosis remain unknown. In this study, we designed and synthesized a series of celastrol-based probes to identify the direct targets in human pulmonary fibroblasts using an activity-based protein profiling strategy. Among many fished targets, we identified a key protein, cullin-associated and neddylation-dissociated 1 (CAND1), which was involved in fibroblast-myofibroblast transformation (FMT). More importantly, we found that the inhibitory effect of celastrol on FMT is dependent on CAND1, through improving the interactions between CAND1 and Cullin1 to promote the activity of Skp1/Cullin1/F-box ubiquitin ligases. In silico studies and cysteine mutation experiments further demonstrated that Cys264 of CAND1 is the site for conjugation of celastrol. This reveals a new mechanism of celastrol against pulmonary fibrosis and may provide a novel therapeutic option for antipulmonary fibrosis.

Allosteric inhibition reveals SHP2-mediated tumor immunosuppression in colon cancer by single-cell transcriptomics.

Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68+ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.

Nintedanib exerts anti-pulmonary fibrosis activity via inhibiting TANK-binding kinase 1 (TBK1) phosphorylation.

Since triple angiokinase inhibitor could not fully explain the anti-pulmonary fibrosis activity of nintedanib (NDNB), the chemoproteomic strategy was performed to identify TANK-binding kinase 1 (TBK1) as the key target of NDNB in human pulmonary fibroblasts (HPFs). Functionally, NDNB exerts anti-fibrosis activity through impairing the p-TBK1-mediated Yes-associated protein (YAP)/transcriptional cofactor with PDZ-binding motif (TAZ) nuclear translocation.

Erratum: The effects of systematic psychological nursing on the sleep quality of schizophrenic patients with sleep disorders.

[This corrects the article on p. 7263 in vol. 13, PMID: 34306491.].

Deciphering the mechanism of Fang-Ji-Di-Huang-Decoction in ameliorating psoriasis-like skin inflammation via the inhibition of IL-23/Th17 cell axis.

ETHNOPHARMACOLOGICAL RELEVANCE: In the theory of traditional Chinese medicine (TCM), the etiology of psoriasis is assigned to damp-heat internal depression, blood poisoning, Yin deficiency and loss of nourishment. Fang-Ji-Di-Huang-Decoction (FJDH), a well-known Chinese traditional formula, is recorded in Synopsis of the Golden Chamber (in the Eastern Han Dynasty). This decoction is composed of dried roots of Rehmannia glutinosa (Gaertn.) DC., dried roots of Stephania tetrandra S. Moore, roots of Saposhnikovia divaricata (Turcz.) Schischk., dried twigs of Cinnamomum cassia (L.) J. Presl and dry roots and rhizomes of Glycyrrhiza uralensis Fisch. FJDH has the function of clearing heat, removing dampness, and nourishing blood. Therefore, in modern medical theory, FJDH can regulate the infiltration of inflammatory cells and the secretion of inflammatory cytokines in the process of psoriasis. AIM OF THE STUDY: This study evaluated whether FJDH treated psoriasis and its specific mechanism for the efficacy in mice. At the same time, it clarified s what important role of the copperware played s in the curative effect of FJDH. METHODS AND MATERIALS: We used imiquimod (IMQ) to induce psoriasis-like skin inflammation in mice. Mice were treated with imiquimod for one week, and FJDH was given by intragastric administration one week in advance. Record the weight change and psoriasis Area and Severity Index (PASI) score of the mouse during the whole process to assess the severity of psoriasis were recored mouse. Hematoxylin-eosin staining was used to evaluate skin tissue structure change. Immunohistochemistry was performed to observe the expressions of Ki67 and proliferating cell nuclear antigen (PCNA) in skin tissue. In order to further explore the mechanism of FJDH in the treatment of psoriasis, we used network pharmacology to predict the therapeutic target. TCMSP and Uniprot were used to collect compounds and genes of FJDH. Genecards was used for obtaining genes of psoriasis. String was used to analyze the relationship between genes. Metascape was used for gene enrichment and pathway prediction. Using molecular biological detection methods, we verified whether FJDH could regulate Interleukin 17 signaling pathway and T helper cell 17 (Th17) cell differentiation. Flow cytometry was used to detect Th17 cell differentiation in mouse spleen. Quantitative Real-time PCR was used to detect mRNA expression of IL-17 signaling pathway-related inflammatory factors in mouse skin tissues. UPLC-Triple TOF-MS/MS and Phenol-Sulphate colorimetry were used to explore the main components of FJDH, and further elaborate the mechanism of FJDH in the treatment of psoriasis. RESULTS: FJDH with copper was found to improve psoriasis-related pathological symptoms in a dose-dependent manner, possibly by inhibiting IL-23/Th17 cell axis and reducing inflammatory cytokines such as IL-17A, IL-17F, IL-22 and TNF-α. Furthermore, R. glutinosa polysaccharide in FJDH was the main substance that exerted the drug effect and it work by forming a complex with copper. Experimental data proved that Rehmannia glutinosa polysaccharide and copper complex had the same pharmacological activity and therapeutic effect as FJDH. CONCLUSIONS: FJDH may attenulated imiquimod-induced psoriasis-like skin inflammation in mice by inhibiting IL-23/Th17 cell axis. The material basis for the therapeutic effect may be the formation of complexes between the polysaccharides of R. glutinosa and copper in FJDH to produce the effect. These findings suggest that FJDH can be used as an effective Chinese medicine to treat psoriasis.

The effects of systematic psychological nursing on the sleep quality of schizophrenic patients with sleep disorders.

OBJECTIVE: This study was designed to explore the effects of systematic psychological nursing (SPN) on the sleep quality of schizophrenic patients with sleep disorders. METHODS: A total of 101 schizophrenic patients with sleep disorders were divided into the control group (50 patients who underwent routine nursing) and the observation group (51 patients who underwent SPN, including health education, psychological nursing, cognitive intervention, reasonable entertainment, and family and social support). One month after the nursing, the sleep quality (the Pittsburgh Sleep Quality Index (PSQI) scores), the improvement in the patients' schizophrenic symptoms (their Positive and Negative Syndrome Scale (PANSS) scores), their sense of self-esteem (their Self-Esteem Scale (SES) scores), their medication compliance (their Morisky Medication Adherence Scale (MMAS) scores), their self-efficacy (their Strategies Used by People to Promote Health (SUPPH) scores), and their quality of life (Generic Quality of Life Inventory (GQOLI)-74 scores) were compared between the two groups. RESULTS: After the nursing, the PSQI and PANSS scores in the two groups were decreased, and lower scores were seen in the observation group (both P<0.05). However, there were opposite trends in the SES, MMAS, GQOLI-74, and SUPPH scores (all P<0.05). CONCLUSION: SPN can effectively improve the schizophrenia symptoms and the sleep quality, enhance the sense of self-esteem, and improve the medication compliance, self-efficacy, and quality of life in schizophrenic patients with sleep disorders. Therefore, SPN is worthy of clinical application.

The complete chloroplast genome of Scurrula chingii (W.C. Cheng) H.S. Kiu (Loranthaceae), a hemiparasitic shrub.

Scurrula chingii (W.C. Cheng) H.S. Kiu is a stem hemiparasite of the genus Scurrula in the family Loranthaceae distributed in southwest China and northern Vietnam. Here, we report and characterize the complete plastid genome sequence of S. chingii to provide genomic resources useful for the phylogenetic studies of Santalales. The plastome of S. chingii is 122,764 bp in length, consisted of a large single-copy region (70,726 bp), a small single-copy region (6,091 bp), and a pair of inverted repeat regions (22,974 bp). The GC content of the whole plastome is 37.2%. It contains 109 genes, including 69 CDS (protein-coding genes), eight rRNAs, and 32 tRNAs. The alignment of 14 species complete chloroplast genomes of Loranthaceae was implemented and a phylogenetic tree was constructed using maximum-likelihood (ML) method, which revealed that S. chingii clustered with Scurrula parasitica and Taxillus thibetensis as a monophyletic group.

Harnessing affinity-based protein profiling to reveal a novel target of nintedanib.

Nintedanib (BIBF1120), a triple angiokinase inhibitor, was first approved for idiopathic pulmonary fibrosis (IPF) therapy and is also efficacious for lung carcinoma, and interstitial lung diseases, far beyond its inhibition of VEGFR/PDGFR/FGFR. We identified tripeptidyl-peptidase 1 (TPP1) as one of the direct targets of nintedanib employing the affinity-based protein profiling (AfBPP) technique. This may be a new mechanism for nintedanib's role different from tyrosine kinase inhibition.

Andrographolide potentiates PD-1 blockade immunotherapy by inhibiting COX2-mediated PGE2 release.

Cancer immunotherapy has now become a first line therapy for several kinds of tumors. However, the clinical performance of immnuocheckpoint blockade therapy is usually limited by low response rate or side effects including cytokine storm. Andrographolide, a natural diterpenoid from Andrographis paniculata, has been used in Asia for treatment of bronchitis, paristhmitis and bacillary dysentery for its unique anti-inflammatory effect. However, its effect on anti-tumor immunity remains elusive. In this study, we found that andrographolide in combination with anti-PD-1 antibody showed a higher therapeutic benefit than individual therapy in murine xenograft model of CT26 colon cancer. Consequently, andrographolide and anti-PD-1 antibody co-treatment boosted the function of CD4+ and CD8+ T cells evidenced by considerable tissue infiltration, elevated IFN-γ secretion and enhanced expression of cytotoxic T-cell related molecules including FasL, perforin and Granzyme B, which significantly decreases the tumor load. Mechanistically, andrographolide treatment inhibited COX2 activity and PGE2 release both in vivo and in vitro, which augments anti-tumor efficiency of anti-PD-1 therapy. Finally, we confirmed that COX2 level in human colon cancer sample positively correlated with tumor-promoting factors. Our study here provides a potential combination strategy for immunotherapy against colorectal cancer.

Loss of hnRNP A1 in murine skeletal muscle exacerbates high-fat diet-induced onset of insulin resistance and hepatic steatosis.

Impairment of glucose (Glu) uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions. The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis. Our results showed that conditional deletion of hnRNP A1 in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet (HFD). Conditional knockout mice fed a HFD showed exacerbated obesity, insulin resistance, and hepatic steatosis. In vitro interference of hnRNP A1 in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake, whereas hnRNP A1 overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin. The expression and stability of glycogen synthase (gys1) mRNA were also decreased in the absence of hnRNP A1. Mechanistically, hnRNP A1 interacted with gys1 and stabilized its mRNA, thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue. Taken together, our findings are the first to show that reduced expression of hnRNP A1 in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.