Effects and potential mechanisms of Saposhnikovia divaricata (Turcz.) Schischk. On type I allergy and pseudoallergic reactions in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence of allergic disease is constantly increasing, but its pathogenesis is not fully understood. Saposhnikovia divaricata (SD), called 'Fangfeng' in China, not only can be used for antipyretic, analgesic and anti-inflammatory as a traditional Chinese medicine, but also as an active ingredient in about 8% prescriptions. However, its effects on type I allergy and pseudoallergy have not been clarified. AIM OF THE STUDY: To explore the treatment and potential mechanisms of SD and its major bioactive component Prim-O-glucosylcimifugin (POG) on type I allergy and pseudoallergy in vitro and in vivo. MATERIALS AND METHODS: The inhibitory effect of SD decoction and POG on type I allergy and its possible mechanism were evaluated by using RBL-2H3 cells model in vitro and the passive cutaneous anaphylaxis (PCA) mouse model in vivo. The cell degranulation of RBL-2H3 cells induced by DNP-IgE/DNP-BSA and Compound 48/80 (C48/80) was investigated, and the molecules of degranulation related signaling pathway was further detected by qRT-PCR and Western Blot analysis. Meanwhile, therapeutic effect of SD Decoction and POG were evaluated using PCA models in vivo. The molecular docking technology was conducted to explore the potential mechanisms. RESULTS: In cells model induced by DNP-IgE/DNP-BSA, the release rate of ß-Hex in high dose of SD and POG groups were 43.79% and 57.01%, and the release amount of HA in high dose of SD and POG groups were 26.19 ng/mL and 24.20 ng/mL. They were significantly lower than that in the model group. Besides, SD decoction and POG could significantly inhibit intracellular Ca2+ increasing and cell apoptosis. But there is no obvious effect on cells degranulation induced by C48/80. The molecular docking results showed that 5-O-Methylvisamioside and POG could bind with FcεRI α with stronger binding ability, but weak binding ability to Mrgprx2. Moreover, qPCR and Western blot analyses indicated that SD could down-regulate Lyn/Syk/PLCγ, MAPK and PI3K/AKT/NF-κB signal pathway to inhibit IgE-dependent cell degranulation. In mice PCA model, both SD and POG could dose-dependently attenuate the Evans Blue extravasation, paw and ear swelling induced by DNP-IgE/DNP-BSA, but no significant inhibition under the PCA models induced by C48/80. CONCLUSION: In conclusion, SD is effective for the therapeutic of type I allergies, suggesting that SD is a potential candidate for the treatment of type I allergy, and the underlying mechanism of these effects needs to be further studied.

Inhibitors of stimulator of interferon genes from 2019 to July 2022: An overview of the structure and bioactivity.

Stimulator of interferon genes (STING) plays a vital role in the human innate immune system. Aberrant expression of STING has been proven to be associated with several diseases, such as STING-associated vasculopathy with onset in infancy, Aicardi-Goutieres syndrome, and systemic lupus erythematosus. Therefore, inhibition of the STING signaling pathway can also be expected to provide effective therapeutic strategies for treating specific inflammatory and autoimmune diseases. However, the development of STING inhibitors is still in its infancy. There is still a need for additional efforts toward the discovery of new skeletons and more potent lead compounds for STING inhibition to meet clinical demand. In this review, we provide a summary of STING inhibitors, classified by different structural skeletons, reported in patents published from 2019 to July 2022. In addition, we also focus on the STING inhibitors, representative structures, biological activity, and mechanisms of action.

NKRF in Cardiac Fibroblasts Protects against Cardiac Remodeling Post-Myocardial Infarction via Human Antigen R.

Myocardial infarction (MI) remains the leading cause of death worldwide. Cardiac fibroblasts (CFs) are abundant in the heart and are responsible for cardiac repair post-MI. NF-κB-repressing factor (NKRF) plays a significant role in the transcriptional inhibition of various specific genes. However, the NKRF action mechanism in CFs remains unclear in cardiac repair post-MI. This study investigates the NKRF mechanism in cardiac remodeling and dysfunction post-MI by establishing a CF-specific NKRF-knockout (NKRF-CKO) mouse model. NKRF expression is downregulated in CFs in response to pathological cardiac remodeling in vivo and TNF-α in vitro. NKRF-CKO mice demonstrate worse cardiac function and survival and increased infarct size, heart weight, and MMP2 and MMP9 expression post-MI compared with littermates. NKRF inhibits CF migration and invasion in vitro by downregulating MMP2 and MMP9 expression. Mechanistically, NKRF inhibits human antigen R (HuR) transcription by binding to the classical negative regulatory element within the HuR promoter via an NF-κB-dependent mechanism. This decreases HuR-targeted Mmp2 and Mmp9 mRNA stability. This study suggests that NKRF is a therapeutic target for pathological cardiac remodeling.

Identifying the common elements of psychological and psychosocial interventions for preventing postpartum depression: Application of the distillation and matching model to 37 winning protocols from 36 intervention studies.

AIM: Postpartum depression is prevalent worldwide and seriously endangers maternal and child health. Previous studies have demonstrated the effectiveness of psychological and psychosocial intervention programmes in preventing postpartum depression. However, the literature offers limited practice guidance. Therefore, this study aimed to deeply analyse prior findings to gather rich evidence-based information on this topic. METHODS: Using the distillation and matching model, we conducted a systematic review of psychological and psychosocial interventions used to effectively prevent postpartum depression. Four researchers trained in coding system independently read eligible studies and identified reliable (Cohen's kappa >0.40) and frequently occurring (frequency ≥3 winning study groups) practice elements. RESULTS: Our review included 36 studies containing 37 winning study groups. Fourteen practice elements were identified and subsequently divided into six categories: postpartum practical problems-related, social support-related, interpersonal psychotherapy-related, cognitive behavioural therapy-related, labour trauma-related and non-specific techniques. The most common practice elements were baby care skills and mother-infant bonding/interaction enhancement. Inter-rater reliability averaged 0.86, ranging from 0.48 to 1. CONCLUSION: The practice elements identified in this study provide rich evidence-based information that can guide clinical practitioners in selecting or developing effective, realistically available intervention programmes.

Vascular wall microenvironment: exosomes secreted by adventitial fibroblasts induced vascular calcification.

Vascular calcification often occurs in patients with chronic renal failure (CRF), which significantly increases the incidence of cardiovascular events in CRF patients. Our previous studies identified the crosstalk between the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and the paracrine effect of VSMCs, which regulate the calcification of VSMCs. Herein, we aim to investigate the effects of exosomes secreted by high phosphorus (HPi) -induced adventitial fibroblasts (AFs) on the calcification of VSMCs and the underlying mechanism, which will further elucidate the important role of AFs in high phosphorus vascular wall microenvironment. The conditioned medium of HPi-induced AFs promotes the calcification of VSMCs, which is partially abrogated by GW4869, a blocker of exosomes biogenesis or release. Exosomes secreted by high phosphorus-induced AFs (AFsHPi-Exos) show similar effects on VSMCs. miR-21-5p is enriched in AFsHPi-Exos, and miR-21-5p enhances osteoblast-like differentiation of VSMCs by downregulating cysteine-rich motor neuron 1 (Crim1) expression. AFsHPi-Exos and exosomes secreted by AFs with overexpression of miR-21-5p (AFsmiR21M-Exos) significantly accelerate vascular calcification in CRF mice. In general, AFsHPi-Exos promote the calcification of VSMCs and vascular calcification by delivering miR-21-5p to VSMCs and subsequently inhibiting the expression of Crim1. Combined with our previous studies, the present experiment supports the theory of vascular wall microenvironment.

Angiogenesis modulated by CD93 and its natural ligands IGFBP7 and MMRN2: a new target to facilitate solid tumor therapy by vasculature normalization.

The tumor vasculature was different from the normal vasculature in both function and morphology, which caused hypoxia in the tumor microenvironment (TME). Previous anti-angiogenesis therapy had led to a modest improvement in cancer immunotherapy. However, antiangiogenic therapy only benefitted a few patients and caused many side effects. Therefore, there was still a need to develop a new approach to affect tumor vasculature formation. The CD93 receptor expressed on the surface of vascular endothelial cells (ECs) and its natural ligands, MMRN2 and IGFBP7, were now considered potential targets in the antiangiogenic treatment because recent studies had reported that anti-CD93 could normalize the tumor vasculature without impacting normal blood vessels. Here, we reviewed recent studies on the role of CD93, IGFBP7, and MMRN2 in angiogenesis. We focused on revealing the interaction between IGFBP7-CD93 and MMRN2-CD93 and the signaling cascaded impacted by CD93, IGFBP7, and MMRN2 during the angiogenesis process. We also reviewed retrospective studies on CD93, IGFBP7, and MMRN2 expression and their relationship with clinical factors. In conclusion, CD93 was a promising target for normalizing the tumor vasculature.

Emotion regulation of social pain: double dissociation of lateral prefrontal cortices supporting reappraisal and distraction.

The dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) are both crucial regions involved in voluntary emotion regulation. However, it remains unclear whether the two regions show functional specificity for reappraisal and distraction. This study employed transcranial magnetic stimulation (TMS) to explore, in a real social interactive scenario, whether different lateral prefrontal regions play relatively specific roles in downregulating social pain via reappraisal and distraction. Participants initially took part in a social interactive game, followed by receiving either active (the DLPFC- or VLPFC-activated group, n = 100 per group) or control (the vertex-activated group, n = 100) TMS session. They were then instructed to use both distraction and reappraisal strategies to downregulate any negative emotions evoked by the social evaluation given by their peers who interacted with them previously. Results demonstrated that the TMS-activated DLPFC has a greater beneficial effect during distraction, whereas the activated VLPFC has a greater beneficial effect during reappraisal. This result investigated the direct experience of social pain and extended previous findings on empathy-related responses to affective pictures while also controlling for confounding factors such as empathic concern. Therefore, we are now confident in the double dissociation proposal of the DLPFC and VLPFC in distraction and reappraisal.

Alternative splicing of its 5' UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies.

Aberrant skipping of coding exons in CD19 and CD22 compromises responses to immunotherapy for B-cell malignancies. Here, we show that the MS4A1 gene encoding human CD20 also produces several mRNA isoforms with distinct 5' untranslated regions (5'-UTR). Four variants (V1-4) were detectable by RNA-seq in distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant by far. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform was found to contain upstream open reading frames (uORFs) and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching Morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, while V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in vitro CD20-directed CAR T cells were able to kill both V3- and V1-expressing cells, but the bispecific T cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on four post-mosunetuzumab follicular lymphoma relapses and discovered that in two of them downregulation of CD20 was accompanied by the V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.

Low Prognostic Nutritional Index is Common and Associated with Poor Outcomes Following Curative-intent Resection for Gastro-entero-pancreatic Neuroendocrine Tumors.

INTRODUCTION: To investigate the impact of prognostic nutritional index (PNI) on short- and long-term outcomes of patients who underwent curative-intent resection for gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). METHODS: Patients with GET-NETs who underwent curative-intent resection were identified from a multi-center database. The prognostic impact of clinicopathological factors including PNI on post-operative outcomes were evaluated. A novel nomogram was developed and externally validated. RESULTS: A total of 2,099 patients with GEP-NETs were included in the training cohort; 255 patients were in the external validation cohort. Median PNI (n=973) was 47.4 (IQR 43.1-52.4). At the time of presentation, 1,299 (61.9%) patients presented with some type of clinical symptom. Low-PNI (≤ 42.2) was associated with gastrointestinal symptoms, as well as nodal metastasis and distant metastasis (all p<0.05). Patients with a low PNI had a higher incidence of severe (≥ Clavien-Dindo grade IIIa: low PNI 24.9% vs. high PNI 15.4%, p=0.001) and multiple (≥ 3 types of complications: low PNI 14.5% vs. high PNI 9.2%, p=0.024) complications, as well as a worse overall survival (OS)(5-year OS, low PNI 73.7% vs. high PNI 88.5%, p<0.001), and RFS (5-year RFS, low PNI 68.5% vs. high PNI 79.8%, p=0.008) versus patients with high PNI (>42.2). A nomogram based on PNI, tumor grade and metastatic disease demonstrated excellent discrimination and calibration to predict OS in both the training (C-index 0.748) and two external validation (C-index 0.827, 0.745) cohorts. CONCLUSIONS: Low PNI was common and associated with worse short- and long-term outcomes among patients with GEP-NETs.

Targeting biophysical microenvironment for improved treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is responsible for high disability rates, high death rates, and significant cost to health systems. Growing evidence in recent decades shows significant biophysical microenvironment changes in COPD, impacting lung tissues, cells, and treatment response. Furthermore, such biophysical changes have shown great potential as novel targets for improved therapeutic strategy of COPD, where both pharmacological and non-pharmacological therapies focusing on repairing the biophysical microenvironment of the lung have emerged. We present the first comprehensive review of four distinct biophysical hallmarks [i.e., extracellular matrix (ECM) microarchitecture, stiffness, fluid shear stress, and mechanical stretch] in COPD, the possible involvement of pathological changes, possible effects, and correlated in vitro models and sum up the emerging COPD treatments targeting these biophysical hallmarks.

Precise fermentation coupling with simultaneous separation strategy enables highly efficient and economical sophorolipids production.

Sophorolipids (SLs) represent highly promising biosurfactants. However, its widespread production and application encounter obstacles due to the significant costs involved. Here, an intelligent and precise regulation strategy was elucidated for the fermentation process coupled with in-situ separation production mode, to achieve cost-effective SLs production. Firstly, a mechanism-assisted data-driven model was constructed for "on-demand feeding of cells". Moreover, a strategy of step-wise oxygen supply regulation based on the demand for cell metabolic capacity was developed, which accomplished "on-demand oxygen supply of cells", to optimize the control of energy consumption. Finally, a systematic approach was implemented by integrating a semi-continuous fermentation mode with in-situ separation technology for SLs production. This strategy enhanced SLs productivity and yield, reaching 2.30 g/L/h and 0.57 g/g, respectively. These values represented a 40.2% and 18.7% increase compared to fed-batch fermentation. Moreover, the concentration of crude SLs after separation reached 793.12 g/L, facilitating downstream separation and purification processes.

Point-of-care ultrasound for monitoring catheter tip location during umbilical vein catheterization in neonates: a prospective study.

Background: Point-of-care ultrasound (POCUS) can guide umbilical vein catheter placement in real time and monitor catheter tip position, allowing avoidance of severe complications due to catheter malposition. This study aims to explore the effectiveness of POCUS in guiding venous catheter insertion and monitoring complications. Methods: Sixty-eight neonates with ultrasound-guided venous catheter insertion at the Neonatal Department of Dongguan Children's Hospital between December 2020 and February 2022 were included. POCUS was applied to monitor catheter tip location daily until catheter removal. A displacement range exceeding the intersection of the inferior vena cava and right atrium by ±0.5 cm was considered misalignment. Results: Sixty-four neonates had a displaced catheter tip (94.1%, 64/68), with a median displacement distance of 0.4 cm (minimum -0.2 cm, maximum 1.2 cm). Ten neonates had a misalignment (14.7%, 10/68) caused by displacement. Displacement usually occurs within 2-4 days after placement, with displacement rates of 94.1% (64/68), 90.6% (58/64), and 98.3% (59/60) on days 2, 3, and 4, respectively, and could still occur on day 9 post-placement. In addition, misalignment mainly occurs on the second day after placement. During the monitoring process, 58 neonates had catheter tip displacement ≥2 times, resulting in 252 displacement and 22 misalignment incidents. Among them, the catheter tip migrated outward from the inferior vena cava seven times, all of which were removed in time. Ultrasound was used for positioning 486 times, and x-ray was indirectly avoided 486 times. Conclusion: The catheter tip is prone to displacement and misalignment after umbilical vein catheterization, which most commonly occurs on days 2-4. POCUS is recommended for daily monitoring of the tip location during umbilical vein catheterization until catheter removal.

Association of serum lipids with inflammatory bowel disease: a systematic review and meta-analysis.

Background: Serum lipid levels seem to be abnormal in Inflammatory bowel disease (IBD). However, the specific manifestation of abnormal serum lipid levels in IBD are heterogeneous among studies and have not been sufficiently determined yet. Methods: PubMed, EMBASE, and Cochrane Library databases were searched. Serum lipid levels were compared between IBD patients and Health individuals, Crohn's (CD) and ulcerative colitis (UC), active and inactive, mild and non-mild patients, respectively. Meta-analyses were performed by using a random-effect model. Weight mean difference (WMD) with 95% confidence intervals (CIs) were calculated. Results: Overall, 53 studies were included. Compared with healthy controls, IBD patients had significantly lower TC (WMD = -0.506, 95%CI = -0.674 to -0.338, p < 0.001), HDL-c (WMD = -0.122, 95%CI = -0.205 to -0.039, p = 0.004), and LDL-c (WMD = -0.371, 95%CI = -0.547 to -0.194, p < 0.001) levels. CD groups had a significantly lower TC (WMD = -0.349, 95%CI = -0.528 to -0.170, p < 0.0001) level as compared to UC groups. Active IBD and non-mild UC groups had significantly lower TC (WMD = -0.454, 95%CI = -0.722 to -0.187, p = 0.001) (WMD =0.462, 95%CI = 0.176 to 0.748, p = 0.002) and LDL-c (WMD = -0.225, 95%CI = -0.445 to -0.005, p = 0.045) (WMD =0.346, 95%CI = 0.084-0.609, p = 0.010) levels as compared to inactive IBD and mild UC groups, respectively. Conclusion: The overall level of serum lipids in IBD patients is lower than that of healthy individuals and is negatively associated with disease severity. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022383885.

Association of regulatory T cells with renal outcomes in patients with proliferative lupus nephritis.

BACKGROUND: Despite progress in the diagnosis and treatment of proliferative lupus nephritis (PLN), the prognosis remains unfavorable. Previous investigations have suggested that the deficiency of regulatory T cells (Tregs) is involved in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). But the prognostic value of Tregs in PLN remains controversial. This study aimed to investigate the association of Tregs with renal outcomes in patients with PLN. METHODS: The baseline and follow-up data of patients with biopsy-proven PLN were collected in this study. All patients were divided into two groups according to whether the renal endpoint event occurred. Clinicopathologic features and therapeutic responses were compared between the two groups. Cox regression analyses curve fitting and threshold effect analysis were implemented to investigate the relationship between Tregs level and the long-term renal outcomes. The renal endpoint was defined as end-stage kidney disease (ESKD) or doubling the SCr value. RESULTS: A total of 405 PLN patients were included. After a follow-up of 71.53 (53.13-97.47) months, 42 (10.4%) patients reached the renal endpoint. The Treg cell counts (16/µL) in the renal endpoint group were significantly decreased than that in the non-renal endpoint group (p < 0.001). Univariate and multivariate Cox regression analyses showed that the high level of Tregs was an independent protective factor for the long-term renal prognosis of PLN. Smooth curve fitting of the generalized additive mixed model analysis indicated that the risk of renal endpoint first decreased with Tregs and then slightly increased along with Treg cell levels. The segmented linear model revealed that when Treg cell counts <46/µL, the risk of renal endpoint decreased by 6.8% for every 1 µL increase in Treg levels (p = 0.0029). CONCLUSION: Treg cell counts are closely related to the long-term renal outcomes of patients with PLN, and increasing Treg cell levels may play an important role in improving the prognosis of the kidney, but there may be a turning point (i.e., threshold effect) at the Treg cell counts that leads to directional changes in the renal outcomes.

Neural signals-based respiratory motion tracking: a proof-of-concept study.

Objective.Respiratory motion tracking techniques can provide optimal treatment accuracy for thoracoabdominal radiotherapy and robotic surgery. However, conventional imaging-based respiratory motion tracking techniques are time-lagged owing to the system latency of medical linear accelerators and surgical robots. This study aims to investigate the precursor time of respiratory-related neural signals and analyze the potential of neural signals-based respiratory motion tracking.Approach.The neural signals and respiratory motion from eighteen healthy volunteers were acquired simultaneously using a 256-channel scalp electroencephalography (EEG) system. The neural signals were preprocessed using the MNE python package to extract respiratory-related EEG neural signals. Cross-correlation analysis was performed to assess the precursor time and cross-correlation coefficient between respiratory-related EEG neural signals and respiratory motion.Main results.Respiratory-related neural signals that precede the emergence of respiratory motion are detectable via non-invasive EEG. On average, the precursor time of respiratory-related EEG neural signals was 0.68 s. The representative cross-correlation coefficients between EEG neural signals and respiratory motion of the eighteen healthy subjects varied from 0.22 to 0.87.Significance.Our findings suggest that neural signals have the potential to compensate for the system latency of medical linear accelerators and surgical robots. This indicates that neural signals-based respiratory motion tracking is a potential promising solution to respiratory motion and could be useful in thoracoabdominal radiotherapy and robotic surgery.

A 3D tetrathiafulvalene-based metal-organic framework with intramolecular charge transfer for efficient near-infrared photothermal conversion.

The selection of metal centers can endow donor-metal-accepter (D-M-A) type MOFs with progressive framework dimensions. 3D Cd-based MOFs with intramolecular charge transfer caused by D-M-A exhibit a satisfactory photothermal conversion efficiency of 35.7%, with the temperature rapidly rising from 25 °C to 201 °C in 7 s under 808 nm laser irradiation.

An analysis of the relationship between donor and recipient biomarkers and kidney graft function, dysfunction, and rejection.

BACKGROUND: The study aimed to find predictive biomarkers to evaluate donor kidney function to predict graft dysfunction as well as to assess an early signs of acute graft rejection. METHOD: Twenty-seven deceased donors and 54 recipients who underwent a successful kidney transplantation were enrolled in the study. An assessment was made in serum and urine from donors and recipients to measure the following biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase 2 (TIMP-2) and urinary N-acetyl-b-D-glucosaminidase (uNAG). These biomarkers were used to establish a model for predicting a reduced graft function (RGF) classified as either a delayed or slow graft function. RESULT: Our analysis suggest that out of four tested biomarkers, the serum TIMP-2 and uNAG levels of the donors had a predictive value for RGF; the area under the receiver operating characteristic curves (AUROC) of serum TIMP-2 and uNAG were 0.714 and 0.779, respectively. The combined best fitting prediction model of serum TIMP-2, uNAG, and creatinine levels was better in predicting RGF than the serum creatinine level alone. In addition, the recipient serum TIMP-2 level on the third day post-transplantation (D3) was associated with the estimated glomerular filtration rate (eGFR) on the seventh day post-transplantation (D7; OR 1.119, 95% CI 1.016-1.233, p = 0.022). Furthermore, the ROC curve value revealed that the AUROC of TIMP-2 on D3 was 0.99 (95% CI 0.97-1, p < 0.001), and this was the best predictive value of the renal function on D7. CONCLUSIONS: Donor serum TIMP-2 and uNAG levels are useful predictive biomarkers because they can provide the donor-based prediction for RGF.