Systematic Structural Modification of Squaraine Dye for Near-Infrared Window One and Two Multiplexed In Vivo Imaging and Photothermal Therapy.

Due to the wide application of reporter gene-related visible/NIR-I bioluminescent imaging, multiplexed fluorescence imaging across visible/NIR-I/NIR-II has excellent potential in biomedical research. However, in vivo multiplexed imaging applications across those regions have rarely been reported due to the lack of proper fluorophores. Herein, nine squaraine dyes, which exhibit diverse adsorption and emission wavelengths, were synthesized. Among them, water-soluble SQ 710-5k and SQ 905 were found to have significant absorption differences, which allowed the tumor and lymph nodes to be identified. Then, for the first time, six-channel multiplexed fluorescence imaging across visible/NIR-I/II was achieved by coordination with reporter gene-related bioluminescent phosphors. Additional research revealed that SQ 710-5k exhibited higher-quality blood vessels and tumor imaging in NIR-II. H-aggregates SQ 905 demonstrated a high photothermal conversion efficiency for photothermal therapy. This study proposed an approach to creating small molecular dyes that coordinate with reporter gene-related bioluminescent phosphors for six-color fluorescence imaging.

Otitis media with effusion in preschool children with adenoid hypertrophy: Risk factors and nursing care.

AIM: To evaluate the influencing factors of otitis media with effusion (OME) in children with adenoid hypertrophy and to provide evidence for clinical treatment and care of children with adenoid hypertrophy. DESIGN: A retrospective study. METHODS: Preschool children with adenoid hypertrophy treated in our hospital from 1 January 2021 to 30 July 2022 were included. We analysed the characteristics of OME and non-OME children with adenoid hypertrophy. Pearson correlation analysis and logistic regression analysis were performed to evaluate the risk factors for OME in children with adenoid hypertrophy. CONCLUSION: A total of 166 children with adenoid hypertrophy were included; the incidence of OME in children with adenoid hypertrophy was 34.94%. The incidence of OME decreased significantly with the increase in age (p = 0.014). Logistic regression analysis showed that age < 3 years (OR = 3.149, 95%CI: 2.812-3.807) and duration of adenoid hypertrophy ≥12 months (OR = 2.326, 95%CI: 2.066-2.612) were the risk factors of OME in children with adenoid hypertrophy (all p < 0.05). PATIENT CONTRIBUTION: The incidence of adenoid hypertrophy with OME is high in preschool children, and it is related to the age and duration of adenoid hypertrophy.

Effects of SARS-CoV-2 vaccine (Vero cells) on disease activity in patients with inflammatory bowel disease in China: a multicenter study.

AIMS: To evaluate the impact of SARS-CoV-2 vaccine on IBD activity. METHODS: Adult IBD patients from five large IBD centers in China were enrolled and followed up for 6 months. Patients were divided into vaccinated and unvaccinated groups according to vaccination status. Demographic and clinical data were collected. RESULTS: A total of 280 individuals (213 UC and 67 CD patients) were enrolled in the study. The unvaccinated and vaccinated groups of UC patients were comparable for basic characteristics, including age (t = - 0.8, p = 0.425), sex (χ2 = 0.980, p = 0.322), course of disease (z = - 0.513, p = 0.608), surgical conditions (χ2 = 1.042, p = 0.838), disease extent (χ2 = 4.853, p = 0.088), or baseline drug therapy (χ2 = 7.784, p = 0.064). In the subgroup of UC patients, there was no association between vaccination and disease activities, according to the medium disease activity scores for two groups: unvaccinated patients having scores (IQR) 1(2.75), 1(2), 1(2), and 1(2) at baseline, 1, 3, and 6 months, respectively, whereas vaccinated patients having scores (IQR) 1(2), 1(2), 1(2), and 1(2). Similar conclusions were also derived in the subgroup of CD patients. There were also no statistically significant differences in age (t = - 1.48, p = 0.144), sex (χ2 = 0.003, p = 0.957), course of disease (z = - 0.074, p = 0.941), surgical conditions (χ2 = 0.613, p = 0.594), localization (χ2 = 6.261, p = 0.199), or baseline drug therapy (χ2 = 5.881, p = 0.114) between 2 groups of CD patients. The medium disease activity scores (IQR) of the unvaccinated group at baseline, 1, 3, and 6 months were 1(4), 1(3), 1(3), and 1(3), respectively, whereas those of vaccinated group were 2.5(3.75), 2.5(3.75), 3(2), and 2(2), respectively. Overall, very few participants in this study described worsening IBD disease activity requiring a change or addition of medication. CONCLUSIONS: SARS-CoV-2 vaccine has no adverse effect on disease activity in IBD population. IBD patients should be recommended to receive SARS-CoV-2 vaccine in time.

Exosomes Derived from Baicalin-Pretreated Mesenchymal Stem Cells Alleviate Hepatocyte Ferroptosis after Acute Liver Injury via the Keap1-NRF2 Pathway.

Acute liver injury (ALI) is characterized as a severe metabolic dysfunction caused by extensive damage to liver cells. Ferroptosis is a type of cell death dependent on iron and oxidative stress, which differs from classical cell death, such as apoptosis and necrosis. Ferroptosis has unique morphological features, which mainly include mitochondrial dissolution and mitochondrial outline reduction. Furthermore, the intracellular accumulation of lipid peroxides directly affects the occurrence of ferroptosis. Baicalin, the main compound isolated from Scutellaria baicalensis, has anti-inflammatory and antioxidative effects. Recently, exosomes derived from preconditioned mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases including ALI. This study investigates the ability of exosomes derived from baicalin-pretreated MSCs (Ba-Exo) to promote liver function recovery in mice with ALI compared with those without pretreatment. Through in vivo and in vitro experiments, this study demonstrates for the first time that Ba-Exo greatly attenuates D-galactosamine and lipopolysaccharide (D-GaIN/LPS)-induced liver damage and inhibits reactive oxygen species (ROS) production and lipid peroxide-induced ferroptosis. Moreover, P62 was significantly upregulated in Ba-Exo, whereas its downregulation in Ba-Exo counteracted the beneficial effect of Ba-Exo. P62 regulates hepatocyte ferroptosis by activating the Keap1-NRF2 pathway. The beneficial effect of Ba-Exo in inhibiting ferroptosis was also attenuated after the NRF2 pathway was inhibited. Therefore, baicalin pretreatment is an effective and promising approach to optimize the therapeutic efficacy of MSC-derived exosomes in ALI.

A Novel Bifunctional Fusion Protein, Vunakizumab-IL22, for Protection Against Pulmonary Immune Injury Caused by Influenza Virus.

Influenza A virus infection is usually associated with acute lung injury, which is typically characterized by tracheal mucosal barrier damage and an interleukin 17A (IL-17A)-mediated inflammatory response in lung tissues. Although targeting IL-17A has been proven to be beneficial for attenuating inflammation around lung cells, it still has a limited effect on pulmonary tissue recovery after influenza A virus infection. In this research, interleukin 22 (IL-22), a cytokine involved in the repair of the pulmonary mucosal barrier, was fused to the C-terminus of the anti-IL-17A antibody vunakizumab to endow the antibody with a tissue recovery function. The vunakizumab-IL22 (vmab-IL-22) fusion protein exhibits favorable stability and retains the biological activities of both the anti-IL-17A antibody and IL-22 in vitro. Mice infected with lethal H1N1 influenza A virus and treated with vmab-mIL22 showed attenuation of lung index scores and edema when compared to those of mice treated with saline or vmab or mIL22 alone. Our results also illustrate that vmab-mIL22 triggers the upregulation of MUC2 and ZO1, as well as the modulation of cytokines such as IL-1ß, HMGB1 and IL-10, indicating the recovery of pulmonary goblet cells and the suppression of excessive inflammation in mice after influenza A virus infection. Moreover, transcriptome profiling analysis suggest the downregulation of fibrosis-related genes and signaling pathways, including genes related to focal adhesion, the inflammatory response pathway, the TGF-ß signaling pathway and lung fibrosis upon vmab-mIL22 treatment, which indicates that the probable mechanism of vmab-mIL22 in ameliorating H1N1 influenza A-induced lung injury. Our results reveal that the bifunctional fusion protein vmab-mIL22 can trigger potent therapeutic effects in H1N1-infected mice by enhancing lung tissue recovery and inhibiting pulmonary inflammation, which highlights a potential approach for treating influenza A virus infection by targeting IL-17A and IL-22 simultaneously.

Cinnamtannin D1 attenuates autoimmune arthritis by regulating the balance of Th17 and treg cells through inhibition of aryl hydrocarbon receptor expression.

The suppression of the abnormal systemic immune response constitutes a primary strategy for treatment of rheumatoid arthritis (RA); toward this end, the identification of natural compounds with immunosuppressive activity represents a promising strategy for RA drug discovery. Cinnamtannin D1 (CTD-1), a polyphenolic compound isolated from Cinnamomum tamala, was previously reported to possess good immunosuppressive activity. However, the beneficial effect of CTD-1 on RA is currently unknown. The aim of this study was to evaluate the anti-arthritic effect of CTD-1 in collagen-induced arthritis (CIA) mice and clarify the underlying mechanisms. CTD-1 treatment significantly alleviated the severity of CIA mice, affording reduced clinical scores and paw swelling, along with reduced inflammatory cell infiltration and cartilage damage in the joints; in addition, the serum levels of IL-17, IL-6, and IL-1ß were decreased whereas those of TGF-ß and IL-10 were increased. CTD-1-treated mice exhibited lower frequency of Th17 cells and higher frequency of Treg cells compared to those in untreated mice, indicating that the balance of Th17/Treg cells may serve as the target for CTD-1. Consistent with this, in ex vivo assays, CTD-1 inhibited Th17 cell differentiation through the downregulation of phospho-STAT3/RORγt, whereas it promoted Treg differentiation by upregulating phospho-STAT5/Foxp3 in response to the stimulation of collagen type II. Moreover, in an in vitro naïve CD4+ T cell differentiation assay, CTD-1 directly inhibited Th17 cell differentiation and promoted Treg differentiation, suggesting that CTD-1 regulated the balance of Th17 and Treg cells to inhibit excessive immune response. Furthermore, the regulation effect of CTD-1 on Th17 and Treg cells was dependent on Ahr expression, as this effect was abolished when Ahr was knocked down and was impaired when Ahr was overexpressed. Together, our results indicated that CTD-1 treatment benefits CIA mice by regulating Th17 and Treg differentiation through the inhibition of AHR expression, and suggested a potential application of CTD-1 toward RA treatment.

The Hydroxyl at Position C1 of Genipin Is the Active Inhibitory Group that Affects Mitochondrial Uncoupling Protein 2 in Panc-1 Cells.

Genipin (GNP) effectively inhibits uncoupling protein 2 (UCP2), which regulates the leakage of protons across the inner mitochondrial membrane. UCP2 inhibition may induce pancreatic adenocarcinoma cell death by increasing reactive oxygen species (ROS) levels. In this study, the hydroxyls at positions C10 (10-OH) and C1 (1-OH) of GNP were hypothesized to be the active groups that cause these inhibitory effects. Four GNP derivatives in which the hydroxyl at position C10 or C1 was replaced with other chemical groups were synthesized and isolated. Differences in the inhibitory effects of GNP and its four derivatives on pancreatic carcinoma cell (Panc-1) proliferation were assessed. The effects of GNP and its derivatives on apoptosis, UCP2 inhibition and ROS production were also studied to explore the relationship between GNP's activity and its structure. The derivatives with 1-OH substitutions, geniposide (1-GNP1) and 1-ethyl-genipin (1-GNP2) lacked cytotoxic effects, while the other derivatives that retained 1-OH, 10-piv-genipin (10-GNP1) and 10-acetic acid-genipin (10-GNP2) exerted biological effects similar to those of GNP, even in the absence of 10-OH. Thus, 1-OH is the key functional group in the structure of GNP that is responsible for GNP's apoptotic effects. These cytotoxic effects involve the induction of Panc-1 cell apoptosis through UCP2 inhibition and subsequent ROS production.

Alterations in gene expression during sexual differentiation in androgen receptor knockout mice induced by environmental endocrine disruptors.

In the present study, we aimed to explore the effect of environmental endocrine disruptors (EEDs) on sexual differentiation in androgen receptor (AR)-/-, AR+/- and AR+/+ male mice. By using a Cre-loxP conditional knockout strategy, we generated AR knockout mice. By mating flox-AR female mice with AR-Cre male mice, the offspring male mice which were produced were examined. Mice not subjected to any type of intervention were used as the controls. Furthermore, male mice of different genotypes were selected and further divided into subgroups as follows: the control group, bisphenol A (BPA) group and the dibutyl phthalate [corrected] (DBP) group. The expression of the Wilms tumor 1 (WT1), lutropin/choriogonadotropin receptor (LHR), 17-ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3) and steroid-5-alpha-reductase, alpha polypeptide 2 (SRD5A2) genes was determined by RT-qPCR and western blot analysis. There was no statistically significant difference in the weight of the mice between the control group and the knockout group (P>0.05). The results revealed that, compared with the control group, in the knockout group, anogenital distance was shortened, and testicular weight and testosterone levels were decreased; estradiol levels were elevated; the differences were statistically significant (P<0.05). In the group of AR+/- male mice exposed to 100 mg/l EEDs, hypospadias was successfully induced, suggesting that EEDs are involved in the embryonic stage of sexual development in male mice. The quantitative detection of WT1, LHR, 17ßHSD3 and SRD5A2 gene expression by RT-qPCR and western blot analysis indicated that these genes were significantly downregulated in the mice in the BPA group. In conclusion, exposure to EEDs induces hypospadias in heterozygous and wild-type male mice offspring during sexual differentiation, but has no effect on homozygous offspring. Therefore, EEDs play an important role during the third stage of sexual differentiation.