5-HT7R enhances neuroimmune resilience and alleviates meningitis by promoting CCR5 ubiquitination.

INTRODUCTION: Excessive immune activation induces tissue damage during infection. Compared to external strategies to reconstruct immune homeostasis, host balancing ways remain largely unclear. OBJECTIVES: Here we found a neuroimmune way that prevents infection-induced tissue damage. METHODS: By FACS and histopathology analysis of brain Streptococcus pneumonia meningitis infection model and behavioral testing. Western blot, co-immunoprecipitation, and ubiquitination analyze the Fluoxetine initiate 5-HT7R-STUB1-CCR5 K48-linked ubiquitination degradation. RESULTS: Fluoxetine, a selective serotonin reuptake inhibitor, or the agonist of serotonin receptor 5-HT7R, protects mice from meningitis by inhibiting CCR5-mediated excessive immune response and tissue damage. Mechanistically, the Fluoxetine-5-HT7R axis induces proteasome-dependent degradation of CCR5 via mTOR signaling, and then recruits STUB1, an E3 ubiquitin ligase, to initiate K48-linked polyubiquitination of CCR5 at K138 and K322, promotes its proteasomal degradation. STUB1 deficiency blocks 5-HT7R-mediated CCR5 degradation. CONCLUSION: Our results reveal a neuroimmune pathway that balances anti-infection immunity via happiness neurotransmitter receptor and suggest the 5-HT7R-CCR5 axis as a potential target to promote neuroimmune resilience.

Ultrasound-guided acupotomy for trigger finger: a systematic review and meta-analysis.

BACKGROUND: Trigger finger is a common condition in the hand, and ultrasound-guided acupotomy for trigger finger has been widely used in recent years. PURPOSE: This study aims to investigate the efficacy and safety of ultrasound-guided acupotomy for trigger finger. METHODS: We searched for relevant studies in the Cochrane Library, China National Knowledge Infrastructure (CNKI), Embase, PubMed, Chinese Biomedical Literature Database (CBM), Wanfang Data, and other resources from their inception to January 2023. Randomized controlled trials of ultrasound-guided acupotomy for trigger finger were included. The meta-analysis was carried out using Review Manager 5.4 and Stata 15.1. RESULTS: Overall, 15 studies with 988 patients were included. The experimental group was treated with ultrasound-guided acupotomy, and the Control group received traditional acupotomy, traditional operation or injection of medication. Meta-analysis showed that the overall clinical effectiveness (OR = 4.83; 95% CI 2.49-9.37; I2 = 73.1%; P < 0.001) in the experimental group was significantly better than that of the control group. And the Visual Analogue Scale (VAS) score (WMD = - 1; 95% CI - 1.24, - 0.76; I2 = 99%; P < 0.001), the QuinneII classification (WMD = - 0.84; 95% CI - 1.28, - 0.39; I2 = 99.1%, P < 0.001), the incidence of complications (RR = 0.26; 95% CI 0.11, 0.63; I2 = 0%, P = 0.003), and the recurrence rate (RR = 0.14; 95% CI 0.03, 0.74; I2 = 0%; P = 0.021) were significantly lower in the experimental group. CONCLUSION: Our systematic review and meta-analysis can prove the effectiveness and safety of ultrasound-guided acupotomy in the treatment of trigger finger, but this still needs to be verified by a clinical standard large sample test.

HSF4 Transcriptionally Activates Autophagy by Regulating ATG9a During Lens Terminal Differentiation.

Purpose: HSF4 mutations are responsible for congenital cataract formation. Dysfunction of HSF4 leads to defects in lens terminal differentiation. We aimed to study the mechanism of how HSF4 promotes organelle degradation during lens differentiation. Methods: HSF4del42 mutant mice that developed congenital cataracts were employed. The organelle degradation and autophagic function in lens fibers were detected by immunofluorescence and Immunoblotting. Transcriptome analysis was performed to investigate the differentially expressed genes in HSF4del42 lenses, whereas luciferase report assay and ChIP assay were used to confirm the directly transcriptional regulation of ATG9a by HSF4. Results: HSF4del42 mice displayed delayed organelle clearance and impaired autophagic degradation function in lens fibers. Activation of autophagy by rapamycin ameliorated the defects in organelle clearance in HSF4del42 lenses ex vivo and in vivo. Depletion of HSF4 attenuated autophagic flux by disrupting autophagosome biogenesis and maturation in lens epithelial cells. HSF4 directly transcriptionally activated the core autophagy protein ATG9a. Instead of the canonical ATG9a isoform, the ATG9a-X2 isoform was predominantly expressed in the lens and alleviated autophagic defects in HSF4 KO lens epithelial cells. The ATG9a-X2 protein displayed a short half-life, and rapamycin treatment restored its levels in HSF4 KO lens epithelial cells and HSF4del42 lenses. Conclusions: Our findings demonstrate that HSF4 facilitates organelle degradation probably by transcriptionally activating autophagy during lens terminal differentiation. We first report the involvement of HSF4 in autophagy and the tissue specific splicing of ATG9a. Our study indicates that autophagy activation is a possible therapeutic strategy for HSF4-related congenital cataracts.

Retinitis pigmentosa 2 pathogenic mutants degrade through BAG6/HUWE1 complex.

Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease which is the major cause of vision loss. X-linked RP patients account for 5%-15% of all inherited RP cases and mutations in RP2 (Retinitis pigmentosa 2) were responsible for about 20% X-linked RP families. A majority of RP2 pathogenic mutations displayed a vulnerable protein stability and degraded rapidly through ubiquitin-proteasome system (UPS). Though the RP2 protein could be readily recovered by proteasome inhibitors, e.g., MG132, their applications for RP2-related RP therapy were limited by their nonspecific characterization. In the present study, we aimed to identify UPS-related factors, such as E3 ligases, which are specifically involved in degradation of RP2 pathogenic mutants. We identified several E3 ligases, such as HUWE1, and the co-chaperon BAG6 specifically interacting with RP2 pathogenic mutants. Knockdown of HUWE1 and BAG6 could partially rescue the reduced protein levels of RP2 mutants. BAG6 is required for recruitment of HUWE1 to ubiquitinate RP2 mutants at the K268 site. The HUWE1 inhibitor BI8622 could restore the levels of RP2 mutant and then the binding to its partner ARL3 in retina cell lines. This study revealed the details of UPS-related degradation of RP2 mutants and possibly provided a potential treatment for RP2-related RP.

Controlling Nutritional Status Score Before Receiving Treatment as a Prognostic Indicator for Patients With Urothelial Cancer: An Exploration Evaluation Methods.

INTRODUCTION: This meta-analysis aims to assess whether the Controlling nutritional status (CONUT) score before treatment can be an independent predictor of the prognosis of patients with urothelial cancer (UC). METHODS: The system searches Web of Science, PubMed, MEDLINE, China National Knowledge Infrastructure (CNKI), and Cochrane Library, and the search time is up to April 2021. Use STATA 16.0 and Engauge Digitizer 4.1 software for data processing and statistical analysis. RESULTS: A total of 8 studies were included in this meta-analysis. The meta-analysis results show that compared with the low CONUT group, the high CONUT group has worse over survival (OS) [HR=1.58, 95%CI (1.34, 1.86), P=0.001], cancer-specific survival (CSS) [HR=2.03, 95%CI (1.25-3.29), P=0.04] and recurrence-free survival (RFS) [HR=1.97, 95%CI (1.15, 3.40), P=0.014]; for progression-free survival (PFS), or disease-free survival (DFS), the difference between the two groups was not statistically significant [HR=2.30, 95%CI (0.72, 7.32), P=0.158]. According to different carcinoma types, cut-off value, and region, subgroup analysis of OS was performed, and similar results were obtained. CONCLUSIONS: Based on current evidence, this meta-analysis proves that the CONUT score of UC patients before treatment is an independent prognostic predictor. It performs well on OS, CSS, and RFS, but the conclusions on DFS/PFS need to be treated with caution. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021251890, identifier CRD42021251890.

Deficiency of heat shock factor 4 promotes lens epithelial cell senescence through upregulating p21cip1 expression.

Genetic mutations in heat shock factor 4 (Hsf4) is associated with both congenital and age-related cataracts. Hsf4 regulates lens development through its ability to both activate and inhibit transcription. Previous studies suggested Hsf4 is involved in modulating cellular senescence depending on p21cip1 and p27 kip1 expression in MEF cells. Here, we found that Hsf4 acts as a suppressor of p21cip1 expression and plays an anti-senescence role during lens development. Knocking out Hsf4 facilitated UVB-induced cellular senescence in mouse lens epithelial cells (mLECs). p21cip1 was upregulated at both the mRNA and protein levels in HSF4-/- mLECs under control and UVB-treated conditions, and knockdown of p21cip1 by siRNA alleviated UVB-induced cellular senescence. HSF4 directly bound to the p21cip1 promoter and increased H3K27m3 levels at the p21cip1 proximal promoter region by recruiting the methyltransferase EZH2. In animal models, p21cip1 was gradually upregulated in wild-type mouse lenses with increasing age, while Hsf4 levels decreased. We generated a Hsf4 mutant mice line (Hsf4del-42) which displayed obvious congenital cataract phenotype. The expression of p21cip1 and senescence-associated cytokines were induced in the cataractous lenses of Hsf4del-42 mice. H3K27m3 and EZH2 levels decreased in p21cip1 promoters in the lenses of Hsf4del-42 mice. The SA-ß-Gal activities were positive in lens epithelia of aged Hsf4null zebrafish compared to wild-type lenses. p21cip1 and senescence-associated cytokines levels were also upregulated in lenses of Hsf4null zebrafish. Accordingly, we propose that HSF4 plays a protective role in lens epithelial cells against cellular senescence during lens development and aging, partly by fine-tuning p21cip1 expression.

Comparison of Posterior Retroperitoneoscopic Adrenalectomy Versus Lateral Transperitoneal Laparoscopic Adrenalectomy for Adrenal Tumors: A Systematic Review and Meta-Analysis.

OBJECTIVE: To discuss the differences in the effectiveness and security for adrenal tumors by posterior retroperitoneoscopic adrenalectomy (PRA) and lateral transperitoneal laparoscopic adrenalectomy (LTA). METHODS: We systematically searched PubMed, Embase, Scopus database and Cochrane Library, and the date was from above database establishment to November 2020. Stata 16 was used for calculation and statistical analyses. RESULTS: Nine studies involving eight hundred patients were included. The following differences were observed in favor of PRA vs LTA: less operative time (MD: -22.5; 95% CI -32.57 to -12.45; P=0.000), Fewer estimated blood loss (MD: -15.17; 95% CI -26.63 to -3.72; P=0.009), lower intensity of postoperative pain (MD: -0.56; 95% CI, -1.05 to -0.07; P=0.026), shorter length of hospital stay (MD: -1.15; 95% CI -1.94 to -0.36; P=0.04). No differences were shown in conversion rate (OR 2.07; 95%CI 0.71 to 6.03; P=0.181) and complications (OR 0.85;95% CI 0.46 to 1.56; P=0.597). CONCLUSIONS: Posterior retroperitoneoscopic adrenalectomy was clinically superior to lateral transperitoneal laparoscopic adrenalectomy for adrenal tumors in operative time, estimated blood loss, length of hospital stay, and postoperative pain. Only in term of conversion rate and complications, both were similar.

Construction of sustainable and multifunctional polyester fabrics via an efficiently and eco-friendly spray-drying layer-by-layer strategy.

Polyester fabric (PET fabric) has aroused widespread attention from people thanks to the advantages of smooth feel, easy washing, quick-drying, high strength, and chemical resistance. However, PET fabric's wide application has been limited by its hydrophobicity, poor resistance to bacterial contamination, and static accumulation. Herein, a super-hydrophilic PET fabric was achieved via a spray-drying layer-by-layer self-assembly method for comfortable garment manufacturing. The as-prepared PET fabric exhibited good superhydrophilicity, excellent antistatic property, and durable antibacterial performance. Moreover, the water contact angle of the treated fabric decreased to 0° from 121° of the original PET fabric, and the capillary height also increased from 7.1 cm to 21.4 cm. Besides, the treated fabric showed a durable antibacterial rate of 99.5% against both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) after ten standard washing cycles. The prepared fabric was also identified with good cytocompatibility, making it a good material for garments in real life. Promisingly, this novel approach can be easily integrated into the finishing of textiles and is expected to be applied to various substrates with superhydrophilic and antibacterial properties.

Knockout of DNase1l1l abrogates lens denucleation process and causes cataract in zebrafish.

Removal of nuclei in lens fiber cells is required for organelle-free zone (OFZ) formation during lens development. Defect in degradation of nuclear DNA leads to cataract formation. DNase2ß degrades nuclear DNA of lens fiber cells during lens differentiation in mouse. Hsf4 is the principal heat shock transcription factor in lens and facilitates the lens differentiation. Knockout of Hsf4 in mouse and zebrafish resulted in lens developmental defect that was characterized by retaining of nuclei in lens fiber cells. In previous in vitro studies, we found that Hsf4 promoted DNase2ß expression in human and mouse lens epithelial cells. In this study, it was found that, instead of DNase2ß, DNase1l1l is uniquely expressed in zebrafish lens and was absent in Hsf4-/- zebrafish lens. Using CRISPR-Cas9 technology, a DNase1l1l knockout zebrafish line was constructed, which developed cataract. Deletion of DNase1l1l totally abrogated lens primary and secondary fiber cell denucleation process, whereas had little effect on the clearance of other organelles. The transcriptional regulation of DNase1l1l was dramatically impaired in Hsf4-/- zebrafish lens. Rescue of DNase1l1l mRNA into Hsf4-/- zebrafish embryos alleviated its defect in lens fiber cell denucleation. Our results in vivo demonstrated that DNase1l1l is the primary DNase responsible for nuclear DNA degradation in lens fiber cells, and Hsf4 can transcriptionally activate DNase1l1l expression in zebrafish.

Effective adsorption of diclofenac sodium from neutral aqueous solution by low-cost lignite activated cokes.

Activated cokes have attracted great interest inwater treatment to remove organic pollutants due to their low cost and specific textural properties. In this study, adsorptive removal of diclofenac sodium (DCF) from neutral aqueous solution by available lignite activated cokes (LACs) was reported for the first time. Diclofenac sodium could be quickly removed from aqueous solution by LAC-2, with the maximum Langmuir adsorption capacity qm of 224 mg/g at pH 6.5. Characterization results (including scanning electron microscopy, transmission electron microscopy, elemental analyses, Boehm titrations, N2 adsorption-desorption isotherms and Fourier transform infrared spectroscopy) and a series of adsorption kinetics, adsorption isotherms model studies revealed that high porosity with developed macro- and micropore structures on LAC-2, as well as high content of phenolic groups, could obviously enhance the DCF adsorption capacity and rate. Moreover, LAC-2 showed high affinity towards DCF at low concentrations, as well as good reusability after three adsorption-desorption cycles. pH effect studies revealed that hydrogen-bonding interaction plays an important role during adsorption, accompanied with certain contribution from electrostatic interaction and π-π interaction. This study indicates the promising potential of LAC-2 as an efficient, low-cost and recyclable material for DCF removal from water bodies.

Heat shock factor 4 regulates lysosome activity by modulating the αB-crystallin-ATP6V1A-mTOR complex in ocular lens.

BACKGROUND: Germline mutations in heat shock factor 4 (HSF4) cause congenital cataracts. Previously, we have shown that HSF4 is involved in regulating lysosomal pH in mouse lens epithelial cell in vitro. However, the underlying mechanism remains unclear. METHODS: HSF4-deficient mouse lens epithelial cell lines and zebrafish were used in this study. Immunoblotting and quantitative RT-PCR were used for expression analysis. The protein-protein interactions were tested with GST-pull downs. The lysosomes were fractioned by ultracentrifugation. RESULTS: HSF4 deficiency or knock down of αB-crystallin elevates lysosomal pH and increases the ubiquitination and degradation of ATP6V1A by the proteasome. αB-crystallin localizes partially in the lysosome and interacts solely with the ATP6V1A protein of the V1 complex of V-ATPase. Furthermore, αB-crystallin can co-precipitate with mTORC1 and ATP6V1A in GST pull down assays. Inhibition of mTORC1 by rapamycin or siRNA can lead to dissociation of αB-crystallin from the ATP6V1A and mTORC1complex, shortening the half-life of ATP6V1A and increasing the lysosomal pH. Mutation of ATP6V1A/S441A (the predicted mTOR phosphorylation site) reduces its association with αB-crystallin. In the zebrafish model, HSF4 deficiency reduces αB-crystallin expression and elevates the lysosomal pH in lens tissues. CONCLUSION: HSF4 regulates lysosomal acidification by controlling the association of αB-crystallin with ATP6V1A and mTOR and regulating ATP6V1A protein stabilization. GENERAL SIGNIFICANCE: This study uncovers a novel function of αB-crystallin, demonstrating that αB-crystallin can regulate lysosomal ATP6V1A protein stabilization by complexing to ATP6V1A and mTOR. This highlights a novel mechanism by which HSF4 regulates the proteolytic process of organelles during lens development.

A novel RP2 missense mutation Q158P identified in an X-linked retinitis pigmentosa family impaired RP2 protein stability.

Retinitis pigmentosa (RP) is the most common form of inherited retinal degenerative diseases. X-linked RP accounts for nearly 15% of all RP cases. In this study, we identified a novel RP2 missense mutation Q158P in a Chinese XLRP family. The RP2 Q158P mutation located in the RP2 TBCC domain and obviously destabilized RP2 protein in ARPE-19 cells. The proteasome inhibitor MG132 could restore the RP2 Q158P protein levels. Meanwhile, lower doses of bortezomib and carfilzomib, another two proteasome inhibitors that have been approved in multiple myeloma clinical therapy, also could rescue the RP2 Q158P protein levels. The ubiquitination of RP2 Q158P protein obviously increased when compared with wild type RP2 protein. Our findings broadened the spectrum of RP2 mutations and may contribute a better understanding of the molecular mechanism of XLRP.

Local Cooling as a Step of Treatment for Tissue Ischemia Caused by Hyaluronic Acid Injection-induced Embolism-A Report of 9 Cases.

Hyaluronic acid injection is 1 of the most popular procedures in facial rejuvenation and augmentation. It is widely popular in the cosmetic surgery due to several advantages, which include rapid effect, minimal injury, and a short postoperative recovery period. With continuous increase in hyaluronic acid injections, many cases of hyaluronic acid injection-induced embolism have been reported. At present, methods for early treatment of hyaluronic acid injection-induced embolism include local injection of hyaluronidase, topical application of nitroglycerin ointment, massage, hot compression, and intravenous injections of antibiotics and hormones. Although early warm massage may facilitate hyaluronic acid degradation by hyaluronidase, local application of heat will also increase metabolic rate in the tissue, thereby reducing the ischemic tolerance of the tissue. Therefore, in this study, warm massage was limited to the first 30 minutes after hyaluronidase injection and was followed by local cooling using a gauze pad soaked with antibiotic saline solution. Excellent therapeutic effects were achieved with this approach. The methods of treatment for tissue ischemia caused by hyaluronic acid injection-induced embolism and clinical cases are introduced in the article.

[Design and application of a new type minor smoke warming moxibustion cup].

OBJECTIVE: To design a new type minor smoke warming moxibustion cup for convenient use of both the physicians and the patients. METHODS: The double-deck minor smoke warming moxibustion cup is fixed on the part receiving moxibustion by vacuum adsorption; the filtration device on the upper can filtrate and adsorb the harmful substance in the moxa-smoke, and the device with a double-temperature control on the lower can sensitively regulate the moxibustion temperature. RESULTS: This new type minor smoke warming moxibustion cup has the advantages of minor smoke discharge, convenient fixation, sensitive regulation of temperature, saving moxibustion material, lasting action, safety, besides the advantages of traditional moxibustion. CONCLUSION: The new type minor smoke warming moxibustion cup can use for treatment and prevention of diseases, suitable to clinical treatment and family health care.