Meteorin-like protein/METRNL/Interleukin-41 ameliorates atopic dermatitis-like inflammation.

BACKGROUND: Meteorin-like protein (METRNL)/Interleukin-41 (IL-41) is a novel immune-secreted cytokine/myokine involved in several inflammatory diseases. However, how METRNL exerts its regulatory properties on skin inflammation remains elusive. This study aims to elucidate the functionality and regulatory mechanism of METRNL in atopic dermatitis (AD). METHODS: METRNL levels were determined in skin and serum samples from patients with AD and subsequently verified in the vitamin D3 analogue MC903-induced AD-like mice model. The cellular target of METRNL activity was identified by multiplex immunostaining, single-cell RNA-seq and RNA-seq. RESULTS: METRNL was significantly upregulated in lesions and serum of patients with dermatitis compared to healthy controls (p <.05). Following repeated MC903 exposure, AD model mice displayed elevated levels of METRNL in both ears and serum. Administration of recombinant murine METRNL protein (rmMETRNL) ameliorated allergic skin inflammation and hallmarks of AD in mice, whereas blocking of METRNL signaling led to the opposite. METRNL enhanced ß-Catenin activation, limited the expression of Th2-related molecules that attract the accumulation of Arginase-1 (Arg1)hi macrophages, dendritic cells, and activated mast cells. CONCLUSIONS: METRNL can bind to KIT receptor and subsequently alleviate the allergic inflammation of AD by inhibiting the expansion of immune cells, and downregulating inflammatory gene expression by regulating the level of active WNT pathway molecule ß-Catenin.

Dark under the Lamp: Neglected Biological Pollutants in the Environment Are Closely Linked to Lung Cancer.

Environmental pollutants are closely linked to lung cancer. The different types of environmental pollutants can be classified as chemical, physical, and biological. The roles of common chemical and physical pollutants such as PM2.5, smoking, radon, asbestos, and formaldehyde in lung cancer have been extensively studied. Notably, the worldwide COVID-19 pandemic raised awareness of the strong link between biological pollution and human health. Allergens such as house dust mites and pollen, as well as bacteria and viruses, are common biological pollutants. A few biological pollutants have been reported to promote lung cancer via inducing inflammatory cytokines secretion, such as IL-1ß, IL-6, and TGF-ß, as well as suppressing immunosurveillance by upregulating regulatory T (Treg) cells while dampening the function of CD8+ T cells and dendritic cells. However, the correlation between common biological hazards, such as SARS-CoV-2, human immunodeficiency viruses, Helicobacter pylori, and house dust mites, and lung cancer is not fully elucidated, and the underlying mechanisms are still unclear. Moreover, the majority of studies that have been performed in lung cancer and biological carcinogens were not based on the perspective of biological pollutants, which has challenged the systematicity and coherence in the field of biological pollutants in lung cancer. Here, in addition to reviewing the recent progress made in investigating the roles of allergens, viruses, and bacteria in lung cancer, we summarized the potential mechanisms underlying biological pollutants in lung cancer. Our narrative review can shed light on understanding the significance of biological pollutants in lung cancer, as well as inspire and broaden research ideas on lung cancer etiology.

Immune modulation by rural exposures and allergy protection.

BACKGROUND: Growing up on traditional farms protects children from the development of asthma and allergies. However, we have identified distinct asthma-protective factors, such as poultry exposure. This study aims to examine the biological effect of rural exposure in China. METHODS: We recruited 67 rural children (7.4 ± 0.9 years) and 79 urban children (6.8 ± 0.6 years). Depending on the personal history of exposure to domestic poultry (DP), rural children were further divided into those with DP exposure (DP+ , n = 30) and those without (DP- , n = 37). Blood samples were collected to assess differential cell counts and expression of immune-related genes. Dust samples were collected from poultry stables inside rural households. In vivo activities of nasal administration of DP dust extracts were tested in an ovalbumin-induced asthma model. RESULTS: There was a stepwise increase in the percentage of eosinophils (%) from rural DP+ children (median = 1.65, IQR = [1.28, 3.75]) to rural DP- children (3.40, [1.70, 6.50]; DP+ vs. DP- , p = .087) and to the highest of their urban counterparts (4.00, [2.00, 7.25]; urban vs. DP+ , p = .017). Similarly, rural children exhibited reduced mRNA expression of immune markers, both at baseline and following lipopolysaccharide (LPS) stimulation. Whereas LPS stimulation induced increased secretion of Th1 and proinflammatory cytokines in rural DP+ children compared to rural DP- children and urban children. Bronchoalveolar lavage of mice with intranasal instillation of dust extracts from DP household showed a significant decrease in eosinophils as compared to those of control mice (p < .05). Furthermore, DP dust strongly inhibited gene expression of Th2 signature cytokines and induced IL-17 expression in the murine asthma model. CONCLUSIONS: Immune responses of rural children were dampened compared to urban children and those exposed to DP had further downregulated immune responsiveness. DP dust extracts ameliorated Th2-driven allergic airway inflammation in mice. Determining active protective components in the rural environment may provide directions for the development of primary prevention of asthma.

Agree to disagree: The contradiction between IL-18 and IL-37 reveals shared targets in cancer.

IL-37 is a newly discovered member of the IL-1 cytokine family which plays an important role in regulating inflammation and maintaining physiological homeostasis. IL-37 showed a close relationship with IL-18, another key cytokine in inflammation regulation and cancer development. IL-37 affects the function of IL-18 either by binding to IL-18Rα, a key subunit of both IL-37 and IL-18 receptor, or by drastically neutralizing the IL-18 protein expression of IL-18 binding protein, an important natural inhibitory molecule of IL-18. Moreover, as another subunit receptor of IL-37, IL-1R8 can suppress IL-18Rα expression, functioning as a surveillance mechanism to prevent overactivation of both IL-18 and IL-37 signaling pathways. While IL-18 and IL-37 share the same receptor subunit, IL-18 would in turn interfere with IL-37 signal transduction by binding to IL-18Rα. It is also reported that IL-18 and IL-37 demonstrated opposing effects in a variety of cancers, such as glioblastoma, lung cancer, leukemia, and hepatocellular cancer. Although the mutual regulation of IL-18 and IL-37 and their diametrically opposed effects in cancers has been reported, IL-18 has not been taken into consideration when interpreting clinical findings and conducting mechanism investigations related to IL-37 in cancer. We aim to review the recent progress in IL-18 and IL-37 research in cancer and summarize the correlation between IL-18 and IL-37 in cancer based on their expression level and underlying mechanisms, which would provide new insights into elucidating the conflicting roles of IL-18 and IL-37 in cancer and bring new ideas for translational research related to IL-18 and IL-37.

Adjuvant activities of immunostimulating natural products: Astragalus membranaceus (Fisch.) Bge. and Coriolus versicolor in BNT162b2 vaccination against COVID-19 infection.

The global pandemic of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been developing all over the world for more than 3 years. In late 2020, several variants of concern of SARS-CoV-2 virus emerged, with increased viral fitness and transmissibility by mutations of the spike proteins of the viral particle, denting hopes of the use of early-generation vaccines for a widespread protective immunity against viral infection. The use of adjuvants may enhance the immune responses of the conventional application of the COVID-19 vaccine. We have shown that the water extract of 2 ß-glucan-enriched immunostimulating natural products, Astragalus membranaceus (Fisch.) Bge. (AM) and Coriolus versicolor (CV), could induce innate immunity-related cytokines from human monocytes (CCL5, interleukin [IL]-6, IL-10, and tumor necrosis factor α) and monocyte-derived dendritic cells (IL-1ß, IL-10, IL-12, and tumor necrosis factor α). Using BALB/c mice, orally administrated AM and CV (1,384 and 742 mg/kg/d) for 4 d after vaccination, respectively, could enhance (1) the immunoglobulin G binding activities of BNT162b2 vaccination against ancestral and Delta SARS-CoV-2 spike proteins by 5.8- and 4.3-fold, respectively; (2) the immunoglobulin G3 subclass production of BNT162b2 vaccination against ancestral and variant SARS-CoV-2 spike proteins; and (3) the in vitro antibody-neutralizing activities of BNT162b2 vaccinated mice. In conclusion, combining AM and CV was effective in acting as an oral adjuvant with the messenger RNA vaccine BNT162b2 to improve the antigen binding activities against SARS-CoV-2 ancestral and variant SARS-CoV-2 spike proteins, probably via trained immunity of macrophages and dendritic cells.

Immunoregulatory and Anti-cancer Activities of Combination Treatment of Novel Four-Herb Formula and Doxorubicin in 4T1-Breast Cancer Bearing Mice.

OBJECTIVE: To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula (4HF) and doxorubicin in triple-negative breast cancer (TNBC). METHODS: Murine-derived triple-negative mammary carcinoma cell line, 4T1 cells, was cultured and inoculated into mouse mammary glands. Sixty-six mice were randomly assigned into 6 groups (n=11 in ench): naïve, control, LD 4HF (low dose 4HF), HD 4HF (high dose 4HF), LD 4HF + D (low dose and doxorubicin), and D (doxorubicin). Apart from the naïve group, each mouse received subcutaneous inoculation with 5 × 105 4T1 cells resuspended in 100 µL of normal saline in the mammary fat pads. Starting from the day of tumor cell inoculation, tumors were grown for 6 days. The LD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF, respectively. The LD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin (5 mg/kg). The D group received weekly intraperitoneal injections of doxorubicin (5 mg/kg). The treatment naïve mice received daily oral gavage of 0.2 mL double distilled water and 0.1 mL normal saline via intraperitoneal injection once a week. The control group received daily oral gavage of 0.2 mL double-distilled water. The treatment period was 30 days. At the end of treatment, mice organs were harvested to analyze immunological activities via immunophenotyping, gene and multiplex analysis, histological staining, and gut microbiota analysis. RESULTS: Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens (P<0.05), altered the hypoxia and overall immune lymphocyte landscape, and manipulated gut microbiota to favor the anti-tumor immunological activities. Moreover, immunosuppressive genes, cytokines, and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated (P<0.05). 4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective in activating the anti-tumor immune response (P<0.05). CONCLUSION: The above results provide evidence for evaluating the immune regulating mechanisms of 4HF in breast cancer and support its clinical significance in its potential as an adjunctive therapeutic agent or immune supplement.

Effects of increasing light versus moderate-to-vigorous physical activity on cardiometabolic health in Chinese adults with obesity.

Increasing daily physical activity (PA) is a practical way to decrease the risk of cardiometabolic diseases, while the studies on exercise intensity remain limited. The purpose of the present study was to compare the effects of increasing light PA (LPA) or moderate-to-vigorous PA (MVPA) for 12 weeks on cardiometabolic markers in Chinese adults with obesity. Fifty-three adults were randomly assigned to the 1) control group, 2) LPA group, and 3) MVPA group in free-living settings. The intervention effects on body composition, cardiorespiratory fitness, and cardiometabolic biomarkers were analysed using a generalized estimated equation model adjusted for baseline values and potential confounders. Compared with the control group, the MVPA group showed improvements in body composition, lipids, C-peptide, monocyte chemoattractant protein-1 (MCP-1), interleukin-8, leptin, and E-selectin. A favourable change in triglycerides and E-selectin were observed in the LPA group when compared to the control group. Lastly, improvements in waist circumference, C-reactive protein, and MCP-1 were observed in the MVPA group when compared to those in the LPA group. Although increasing both LPA and MVPA improved certain cardiometabolic biomarkers, the latter may have more benefits. These findings imply that MVPA may reduce cardiometabolic disease risk more effectively than LPA, especially in Chinese adults with obesity.

Elevation of Metrnß and Its Association with Disease Activity in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an auto-immune disease, the pathogenesis of which remains to be fully addressed. Metrnß is a novel cytokine involved in the pathogenesis of inflammatory disease, but its regulatory roles in SLE are unclear. We aimed to comprehensively investigate the clinical value of Metrnß in SLE. A massive elevation of circulating Metrnß levels was observed in SLE, and patients with an active phase displayed higher Metrnß concentrations than those with inactive phases. Additionally, we found that Metrnß expression was positively correlated with clinical indicators of SLE. Longitudinal cytokine and chemokine profiles revealed a disturbed immune response in SLE, with high activity profiles displayed severe pathogenic inflammation, and a positive correlation of the serum Metrnß with CXCL9, IL10, IL18 and IL1RA was observed as well. Moreover, Metrnß expressions exhibited an inverse correlation with Treg and B10. Of note, a significant decrease of ILC2 was found in SLE, and there was a negative correlation of Metrnß with ILC2 as well. Further ROC analysis showed that the area under the curve (AUC) for Metrnß was 0.8250 (95% CI: 0.7379-0.9121), with a cutoff value of 1131 pg/mL to effectively distinguish SLE patients from healthy controls. Our study herein demonstrated for the first time that Metrnß values were increased and were immunologically correlated with SLE activity, which could be utilized as an alternative biomarker for the early identification and predicting of the immuno-response of SLE.

Natural-Product-Derived Adjunctive Treatments to Conventional Therapy and Their Immunoregulatory Activities in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an invasive and persistent subtype of breast cancer that is likely to be resistant to conventional treatments. The rise in immunotherapy has created new modalities to treat cancer, but due to high costs and unreliable efficacy, adjunctive and complementary treatments have sparked interest in enhancing the efficacy of currently available treatments. Natural products, which are bioactive compounds derived from natural sources, have historically been used to treat or ameliorate inflammatory diseases and symptoms. As TNBC patients have shown little to no response to immunotherapy, the potential of natural products as candidates for adjuvant immunotherapy is being explored, as well as their immunomodulatory effects on cancer. Due to the complexity of TNBC and the ever-changing tumor microenvironment, there are challenges in determining the feasibility of using natural products to enhance the efficacy or counteract the toxicity of conventional treatments. In view of technological advances in molecular docking, pharmaceutical networking, and new drug delivery systems, natural products show promise as potential candidates in adjunctive therapy. In this article, we summarize the mechanisms of action of selected natural-product-based bioactive compounds and analyze their roles and applications in combination treatments and immune regulation.

Creating a Vaccine-like Supplement against Respiratory Infection Using Recombinant Bacillus subtilis Spores Expressing SARS-CoV-2 Spike Protein with Natural Products.

Vaccination is the most effective method of combating COVID-19 infection, but people with a psychological fear of needles and side effects are hesitant to receive the current vaccination, and alternative delivery methods may help. Bacillus subtilis, a harmless intestinal commensal, has recently earned a strong reputation as a vaccine production host and delivery vector, with advantages such as low cost, safety for human consumption, and straightforward oral administration. In this study, we have succeeded generating "S spores" by engineering B. subtilis with spore coat proteins resembling the spike (S) protein of the ancestral SARS-CoV-2 coronavirus. With the addition of two immunostimulating natural products as adjuvants, namely Astragalus membranaceus (Fisch.) Bge (AM) and Coriolus versicolor (CV), oral administration of S spores could elicit mild immune responses against COVID-19 infection without toxicity. Mucosal IgA against the S protein was enhanced by co-feeding with AM and CV in an S spores-inoculated mouse model. Faster and stronger IgG responses against the S protein were observed when the mice were fed with S spores prior to vaccination with the commercial COVID-19 vaccine CoronaVac. In vitro studies demonstrated that AM, CV, and B. subtilis spores could dose-dependently activate both macrophages and dendritic cells by secreting innate immunity-related IL-1ß, IL-6, and TNF-α, and some other proinflammatory chemokines and cytokines. In conclusion, the combination of S spores with AM and CV may be helpful in developing a vaccine-like supplement against respiratory infection.

Characterization of upper airway microbiome across severity of COVID-19 during hospitalization and treatment.

Longitudinal studies on upper respiratory tract microbiome in coronavirus disease 2019 (COVID-19) without potential confounders such as antimicrobial therapy are limited. The objective of this study is to assess for longitudinal changes in the upper respiratory microbiome, its association with disease severity, and potential confounders in adult hospitalized patients with COVID-19. Serial nasopharyngeal and throat swabs (NPSTSs) were taken for 16S rRNA gene amplicon sequencing from adults hospitalized for COVID-19. Alpha and beta diversity was assessed between different groups. Principal coordinate analysis was used to assess beta diversity between groups. Linear discriminant analysis was used to identify discriminative bacterial taxa in NPSTS taken early during hospitalization on need for intensive care unit (ICU) admission. A total of 314 NPSTS samples from 197 subjects (asymptomatic = 14, mild/moderate = 106, and severe/critical = 51 patients with COVID-19; non-COVID-19 mechanically ventilated ICU patients = 11; and healthy volunteers = 15) were sequenced. Among all covariates, antibiotic treatment had the largest effect on upper airway microbiota. When samples taken after antibiotics were excluded, alpha diversity (Shannon, Simpson, richness, and evenness) was similar across severity of COVID-19, whereas beta diversity (weighted GUniFrac and Bray-Curtis distance) remained different. Thirteen bacterial genera from NPSTS taken within the first week of hospitalization were associated with a need for ICU admission (area under the receiver operating characteristic curve, 0.96; 95% CI, 0.91-0.99). Longitudinal analysis showed that the upper respiratory microbiota alpha and beta diversity was unchanged during hospitalization in the absence of antimicrobial therapy.

Mechanistic insights into the anti-tumor and anti-metastatic effects of Patrinia villosa aqueous extract in colon cancer via modulation of TGF-ß R1-smad2/3-E-cadherin and FAK-RhoA-cofilin pathways.

BACKGROUND: Patrinia villosa, a traditional medicinal herb commonly used for treating intestinal-related diseases, has been commonly prescribed by Chinese medicine practitioners as a key component herb to treat colon cancer, although its anti-tumor effect and mechanisms of action have not been fully elucidated. HYPOTHESIS/PURPOSE: This study aimed to investigate the anti-tumor and anti-metastatic effects of Patrinia villosa aqueous extract (PVW), and its underlying mechanisms. METHOD: The chemical profile of PVW was analysed by high-performance liquid chromatography with photodiode-array detection (HPLC-DAD) method. Cell-based functional assays MTT, BrdU, scratch, and transwell were conducted to evaluate the effects of PVW on human colon cancer HCT116 and murine colon26-luc cells, assessing cytotoxicity, cell proliferation, motility, and migration, respectively. Western blotting was performed to assess the effect of PVW on the expression of key intracellular signaling proteins. In vivo studies were conducted using zebrafish embryos and tumor-bearing mice to evaluate the anti-tumor, anti-angiogenesis, and anti-metastatic effects of PVW in colon cancer. RESULTS: Five chemical markers were identified and quantified in PVW. PVW exhibited significant cytotoxicity and anti-proliferative activity, as well as inhibitory effects on cell motility and migration in both HCT116 and colon 26-luc cancer cells via modulating protein expressions of TGF-ß R1, smad2/3, snail, E-cadherin, FAK, RhoA, and cofilin. PVW (0.01-0.1 mg/ml) could significantly decrease the length of subintestinal vessels of zebrafish embryos through decreasing mRNA expressions of FLT1, FLT4, KDRL, VEGFaa, VEGFc, and Tie1. PVW (> 0.05 mg/ml) also significantly suppressed colon cancer cells migration in the zebrafish embryos. Furthermore, oral administration of PVW (1.6 g/kg) significantly inhibited tumor growth by decreasing the expressions of tumor activation marker Ki-67 and CD 31 in tumor tissues of HCT116 tumor-bearing mice. PVW could also significantly inhibit lung metastasis in colon 26-luc tumor-bearing mice by modulating their tumor microenvironment, including immune cells populations (T cells and MDSCs), levels of cytokines (IL-2, IL-12, and IFN-γ), as well as increasing the relative abundance of gut microbiota. CONCLUSION: This study revealed for the first time the anti-tumor and anti-metastatic effects of PVW through regulation of TGF-ß-smad2/3-E-cadherin, and FAK-cofilin pathways in colon cancer. These findings provide scientific evidence to support the clinical use of P. villosa in patients with colon cancer.

Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma.

Neutrophils are dynamic with their phenotype and function shaped by the microenvironment, such as the N1 antitumor and N2 pro-tumor states within the tumor microenvironment (TME), but its regulation remains undefined. Here we examine TGF-ß1/Smad3 signaling in tumor-associated neutrophils (TANs) in non-small cell lung carcinoma (NSCLC) patients. Smad3 activation in N2 TANs is negatively correlate with the N1 population and patient survival. In experimental lung carcinoma, TANs switch from a predominant N2 state in wild-type mice to an N1 state in Smad3-KO mice which associate with enhanced neutrophil infiltration and tumor regression. Neutrophil depletion abrogates the N1 anticancer phenotype in Smad3-KO mice, while adoptive transfer of Smad3-KO neutrophils reproduces this protective effect in wild-type mice. Single-cell analysis uncovers a TAN subset showing a mature N1 phenotype in Smad3-KO TME, whereas wild-type TANs mainly retain an immature N2 state due to Smad3. Mechanistically, TME-induced Smad3 target genes related to cell fate determination to preserve the N2 state of TAN. Importantly, genetic deletion and pharmaceutical inhibition of Smad3 enhance the anticancer capacity of neutrophils against NSCLC via promoting their N1 maturation. Thus, our work suggests that Smad3 signaling in neutrophils may represent a therapeutic target for cancer immunotherapy.

Characterization of METRNß as a novel biomarker of Coronavirus disease 2019 severity and prognosis.

Introduction: Coronavirus disease 2019 (COVID-19) is increasing worldwide, with complications due to frequent viral mutations, an intricate pathophysiology, and variable host immune responses. Biomarkers with predictive and prognostic value are crucial but lacking. Methods: Serum samples from authentic and D614G variant (non-Omicron), and Omicron-SARS-CoV-2 infected patients were collected for METRNß detection and longitudinal cytokine/chemokine analysis. Correlation analyses were performed to compare the relationships between serum METRNß levels and cytokines/chemokines, laboratory parameters, and disease severity. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves were used to evaluate the predictive value of METRNß in COVID-19. Results: The serum level of METRNß was highly elevated in non-Omicron-SARS-CoV-2 infected patients compared to healthy individuals, and the non-survivor displayed higher METRNß levels than survivors among the critical ones. METRNß concentration showed positive correlation with viral load in NAPS. ROC curve showed that a baseline METRNß level of 1886.89 pg/ml distinguished COVID-19 patients from non-infected individuals with an AUC of 0.830. Longitudinal analysis of cytokine/chemokine profiles revealed a positive correlation between METRNß and pro-inflammatory cytokines such as IL6, and an inverse correlation with soluble CD40L (sCD40L). Higher METRNß was associated with increased mortality. These findings were validated in a second and third cohort of COVID-19 patients identified in a subsequent wave. Discussion: Our study uncovered the precise role of METRNß in predicting the severity of COVID-19, thus providing a scientific basis for further evaluation of the role of METRNß in triage therapeutic strategies.

An efficient approach to estimate the risk of coronary artery disease for people living with HIV using machine-learning-based retinal image analysis.

BACKGROUND: People living with HIV (PLWH) have increased risks of non-communicable diseases, especially cardiovascular diseases. Current HIV clinical management guidelines recommend regular cardiovascular risk screening, but the risk equation models are not specific for PLWH. Better tools are needed to assess cardiovascular risk among PLWH accurately. METHODS: We performed a prospective study to determine the performance of automatic retinal image analysis in assessing coronary artery disease (CAD) in PLWH. We enrolled PLWH with ≥1 cardiovascular risk factor. All participants had computerized tomography (CT) coronary angiogram and digital fundus photographs. The primary outcome was coronary atherosclerosis; secondary outcomes included obstructive CAD. In addition, we compared the performances of three models (traditional cardiovascular risk factors alone; retinal characteristics alone; and both traditional and retinal characteristics) by comparing the area under the curve (AUC) of receiver operating characteristic curves. RESULTS: Among the 115 participants included in the analyses, with a mean age of 54 years, 89% were male, 95% had undetectable HIV RNA, 45% had hypertension, 40% had diabetes, 45% had dyslipidemia, and 55% had obesity, 71 (61.7%) had coronary atherosclerosis, and 23 (20.0%) had obstructive CAD. The machine-learning models, including retinal characteristics with and without traditional cardiovascular risk factors, had AUC of 0.987 and 0.979, respectively and had significantly better performance than the model including traditional cardiovascular risk factors alone (AUC 0.746) in assessing coronary artery disease atherosclerosis. The sensitivity and specificity for risk of coronary atherosclerosis in the combined model were 93.0% and 93.2%, respectively. For the assessment of obstructive CAD, models using retinal characteristics alone (AUC 0.986) or in combination with traditional risk factors (AUC 0.991) performed significantly better than traditional risk factors alone (AUC 0.777). The sensitivity and specificity for risk of obstructive CAD in the combined model were 95.7% and 97.8%, respectively. CONCLUSION: In this cohort of Asian PLWH at risk of cardiovascular diseases, retinal characteristics, either alone or combined with traditional risk factors, had superior performance in assessing coronary atherosclerosis and obstructive CAD. SUMMARY: People living with HIV in an Asian cohort with risk factors for cardiovascular disease had a high prevalence of coronary artery disease (CAD). A machine-learning-based retinal image analysis could increase the accuracy in assessing the risk of coronary atherosclerosis and obstructive CAD.

The Application of Adipose Tissue-Derived Mesenchymal Stem Cells (ADMSCs) and a Twin-Herb Formula to the Rodent Wound Healing Model: Use Alone or Together?

Our previous study reported that mesenchymal stem cells (MSCs) accelerated the wound healing process through anti-inflammatory, anti-apoptotic, and pro-angiogenetic effects in a rodent skin excision model. NF3 is a twin-herb formula, which presents similar effects in promoting wound healing. Research focusing on the interaction of MSCs and Chinese medicine is limited. In this study, we applied MSCs and the twin-herb formula to the wound healing model and investigated their interactions. Wound healing was improved in all treatment groups (MSCs only, NF3 only, and MSCs + NF3). The combined therapy further enhanced the effect: more GFP-labelled ADMSCs, collagen I and collagen III expression, Sox9 positive cells, and CD31 positive cells, along with less ED-1 positive cells, were detected; the expressions of proinflammatory cytokine IL-6 and TNF-α were downregulated; and the expression of anti-inflammatory cytokine IL-10 was upregulated. In vitro, NF3 promoted the cell viability and proliferation ability of MSCs, and a higher concentration of protein was detected in the NF3-treated supernatant. A proteomic analysis showed there were 15 and 22 proteins in the supernatants of normal ADMSCs and NF3-treated ADMSCs, respectively. After PCR validation, the expressions of 11 related genes were upregulated. The results of a western blot suggested that the TGFß/Smad and Wnt pathways were related to the therapeutic effects of the combined treatment. Our study suggests for the first time that NF3 enhanced the therapeutic effect of MSCs in the wound healing model and the TGFß/Smad and Wnt pathways were related to the procedure.

Hyaluronic acid association with bacterial, fungal and viral infections: Can hyaluronic acid be used as an antimicrobial polymer for biomedical and pharmaceutical applications?

The relationships between hyaluronic acid (HA) and pathological microorganisms incite new understandings on microbial infection, tissue penetration, disease progression and lastly, potential treatments. These understandings are important for the advancement of next generation antimicrobial therapeutical strategies for the control of healthcare-associated infections. Herein, this review will focus on the interplay between HA, bacteria, fungi, and viruses. This review will also comprehensively detail and discuss the antimicrobial activity displayed by various HA molecular weights for a variety of biomedical and pharmaceutical applications, including microbiology, pharmaceutics, and tissue engineering.

The Sequential Use of Extracorporeal Cytokine Removal Devices in an Adolescent With COVID-19 Receiving Continuous Renal Replacement Therapy.

A 14-year-old male developed multisystem inflammatory syndrome in children (MIS-C) after acquiring the SARS-CoV-2 infection. He deteriorated rapidly requiring inotropic and ventilatory support as well as continuous renal replacement therapy (CRRT) due to rhabdomyolysis-associated acute kidney injury. A hemoadsoprtion column Cytosorb® was first incorporated into the CRRT circuit for myoglobin and cytokines removal, which was followed by sequential use of another type of cytokine-removing hemofilter (Oxiris®) (altogether 100 hours of extracorporeal blood purification [EBP] therapy). There was no major complication related to the EBP therapy. Cytokine profile revealed a marked reduction of levels of several cytokines including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and IL-10 after the EBP therapy. It was noted that both pro-inflammatory and anti-inflammatory cytokines were removed, and the removal efficacy varied between different devices. His condition improved and the serum ferritin, C-reactive protein, and procalcitonin levels also dropped gradually, which correlated well with his clinical progress and the trend of cytokine levels. Our case demonstrated that extracorporeal cytokine removal can be safely applied in children with MIS-C and can be considered as adjunctive therapy in selected patients with critically ill conditions.

The Extracts of Dendrobium Alleviate Dry Eye Disease in Rat Model by Regulating Aquaporin Expression and MAPKs/NF-κB Signalling.

Dry eye is one of the most common ocular surface diseases caused by tear film instability and ocular surface damage due to an abnormal quality or quantity of tears. Inflammatory factors can initiate relevant transduction signalling pathways and trigger the inflammatory cascade response, resulting in ocular surface inflammation. It has been shown that the active ingredients in Dendrobium, such as polysaccharides, alkaloids and phenols, have anti-inflammatory, anti-tumour and immunity-boosting effects, and Dendrobium officinale extract can improve glandular secretion function, increase salivary secretion and increase the expression level of water channel protein in salivary glands in patients with dry eye syndromes. We investigated the in vitro cytoprotective effect of Dendrobium extracts in sodium chloride induced hyperosmotic conditions in human cornea keratocytes (HKs). Results showed that Dendrobium officinale Kimura et Migo water extract (DOW) and Dendrobium loddigesii Rolfe water extract (DLW) could upregulate the expression of aquaporins (AQP)5 protein, thus exerting a repairing effect by promoting cell migration. Furthermore, oral administration of DOW and DLW enhanced tear production in rats and exerted a protective effect on ocular surface damage. DOW and DLW could upregulate the expression of AQP5 and mucin (muc)5ac proteins in the lacrimal gland and reduce the inflammatory response. DOW and DLW inhibited the activation of the corresponding mitogen-activated protein kinases (MAPK) and NF-KB pathway, thereby playing a role in improving dry eye symptoms. This study provides a new perspective on dry eye treatment, and DOW and DLW may be potential therapeutic agents for dry eye.

A prospective study comparing the inflammation-related cytokine and chemokine profile from the day of blastocyst transfer to 7 weeks of gestation between pregnancies that did or did not result in a miscarriage.

The dynamics of maternal immunomodulation is essential in early pregnancy. In our previous study, successful implantation is characterized by a transient increase of pro-inflammatory cytokines followed by a switch to an anti-inflammatory state in peripheral blood around 3-6 days after embryo transfer (ET). In this study, we aimed to extend the time points to compare the cytokine and chemokine profiles between women who did or did not subsequently miscarry. We utilized precisely timed serum samples on the day of ET and 3, 6, 9, 16, 23 and 30 days after ET in women undergoing single blastocyst transfer. Our analysis revealed a significant alteration in cytokine profile after day ET+ 9 between the two groups. Regarding pro-inflammatory cytokine profile, there was a significant increase in IL-17 on days ET+ 16, + 23, and + 30 (50.60 ± 9.97 vs 37.09 ± 3.25, 53.20 ± 8.13 vs 36.51 ± 3.34, 57.06 ± 8.83 vs 33.04 ± 3.11 pg/mL), TNF-α on days ET+ 23 and + 30 (73.90 ± 12.42 vs 50.73 ± 3.55, 74.16 ± 12.46 vs 46.59 ± 3.21 pg/mL), IFN-γ on day ET+ 30 (69.52 ± 13.19 vs 42.28 ± 7.76 pg/mL) in women who miscarried compared to women who had a live birth. In contrast, the concentrations of anti-inflammatory cytokines IL-10 on days ET+ 23 and + 30 (26.23 ± 2.11 vs 38.30 ± 4.64, 23.77 ± 2.06 vs 39.16 ± 4.99 pg/mL) and TGF-ß1 on day ET+ 30 (20.30 ± 1.25 vs 23.81 ± 0.88 ng/mL) were significantly decreased in women who miscarried compared to women who had a live birth. While for the chemokine profile, there was no significant alteration observed between the two groups across all the time points. These findings suggest that a sustained anti-inflammatory milieu is concomitant with the maintenance of early pregnancy, while the remarkable pro-inflammatory shift as early as day ET+ 16 in women who subsequently miscarried was observed before the diagnosis of miscarriage.