Realm of hepatitis E: Challenges and opportunities.

Hepatitis E virus (HEV), responsible for widespread viral hepatitis, infects approximately 2.3 billion individuals globally, with a significant mortality burden in Asia. The virus, primarily transmitted through contaminated water and undercooked meat, is often underdiagnosed, particularly in immunocompromised patients. Current HEV treatments, while effective, are limited by adverse effects, necessitating research into safer alternatives. Moreover, HEV's extrahepatic manifestations, impacting the nervous and renal systems, remain poorly understood. This study underscores the imperative for enhanced HEV research, improved diagnostic methods, and more effective treatments, coupled with increased public health awareness and preventive strategies.

Chondromyxoid fibroma of the temporomandibular joint - a rare case.

BACKGROUND: Chondromyxoid fibroma (CMF) is a rare cartilaginous tumor, accounting for < 1% of benign bone tumors. We report a case of temporomandibular joint (TMJ)-CMF, involving the pterygopalatine space and skull base and discuss its epidemiology, clinical characteristics, and management. CASE PRESENTATION: A 56-year-old woman presented with facial asymmetry and progressive mouth opening restriction due to a mass expanding upwardly to the auriculotemporal region. Using digital techniques to determine the lesion's boundary and reconstruct the normal glenoid fossa, the temporalis myofascial flap was transplanted between the titanium mesh and condyle to reconstruct the disc after tumor resection. CONCLUSION: This case highlights the importance of identifying patients with TMJ-CMF.

[Response of Relationship Between Microplastic Abundance and Nitrogen Metabolism Function Microorganisms and Genes in Water].

The impact of microplastics (MPs) as a new type of pollutant on water pollution has become a research hotspot. To explore the response relationship between the abundance of MPs and nitrogen metabolism function in a freshwater environment, Lake Ulansuhai was used as the research object; the abundance of MPs in the water was detected using a Zeiss microscope, and the distribution characteristics of nitrogen metabolism functional bacteria and functional genes in the water were analyzed using metagenomics sequencing. The correlation analysis method was used to explore the relationship between the abundance of MPs and nitrogen metabolism functional microorganisms and nitrogen metabolism functional genes. The results showed that the presence of MPs in freshwater environments had a higher impact on Cyanobacteria and Firmicutes as the dominant phyla, and the presence of MPs promoted their enrichment and growth. Among the dominant bacterial genera, MPs promoted the growth of Mycobacterium and inhibited Candidatus_Planktopila more significantly, further indicating that in freshwater environments, MPs affected normal nitrogen metabolism by affecting microbial communities, and pathways such as carbon and nitrogen fixation and denitrification were important pathways for MPs to affect nitrogen metabolism. From the perspective of nitrogen metabolism functional genes, it was found that the abundance of MPs significantly affected some functional genes during nitrification (pmoA-amoA, pmoB-amoB, and pmoC-amoC), denitrification (nirK and napA), and dissimilatory nitrate reduction (nrfA) processes (P < 0.05). Moreover, the influence of MPs abundance on different functional genes in the same pathway of nitrogen metabolism varied, making the impact of MPs on aquatic environments very complex; thus, its harm to the water environment cannot be underestimated.

Biomechanism of abnormal stress on promoting osteoarthritis of temporomandibular joint through Piezo1 ion channel.

OBJECTIVE: This study aimed to investigate whether flow fluid shear stress (FFSS)-mediated signal transduction affects the function of Piezo1 ion channel in chondrocyte and to further explore the role of mechanical overloading in development of temporomandibular joint osteoarthritis (TMJ OA). METHODS: Immunohistochemical staining was used to determine the expression of Piezo1 in TMJ OA tissue collected from rat unilateral anterior crossbite (UAC) models. Chondrocytes harvested from normal adult SD rats were treated with FFSS (0, 4, 8, 12 dyn/cm2) in vitro. Immunofluorescent staining, real-time polymerase chain reaction, western blotting, flow cytometry and phalloidin assay were performed to detect the changes of cellular morphology as well as the expression of Piezo1 and certain pro-inflammatory and degradative factors in chondrocyte. RESULTS: Immunohistochemical analysis revealed that significantly increased Piezo1 expression was associated with UAC stimulation (p < .05). As applied FFSS escalated (4, 8 and 12 dyn/cm2), the expression levels of Piezo1, ADAMTS-5, MMP-13 and Col-X gradually increased, compared with the non-FFSS group (p < .05). Administering Piezo1 ion channel inhibitor to chondrocytes beforehand, it was observed that expression of ADAMTS-5, MMP-13 and Col-X was substantially decreased following FFSS treatment (p < .05) and the effect of cytoskeletal thinning was counteracted. The activated Piezo1 ion channel enhanced intracellular Ca2+ excess in chondrocytes during abnormal mechanical stimulation and the increased intracellular Ca2+ thinned the cytoskeleton of F-actin. CONCLUSIONS: Mechanical overloading activates Piezo1 ion channel to promote pro-inflammation and degradation and to increase Ca2+ concentration in chondrocyte, which may eventually result in TMJ OA.

Nano­selenium alleviates cadmium-induced blood-brain barrier destruction by restoring the Wnt7A/ß-catenin pathway.

Selenium (Se), a highly beneficial animal feed additive, exhibits remarkable antioxidant and anti-inflammatory properties. Nano­selenium (Nano-Se) is an advanced formulation of Se featuring a specialized drug delivery vehicle, with good bioavailability, higher efficacy, and lower toxicity compared to the traditional form of Se. With the advancement of industry, cadmium (Cd) contamination occurs in different countries and regions and thereby contaminating different food crops, and the degree of pollution is degree increasing year by year. The present investigation entailed the oral administration of CdCl2 and/or Nano-Se to male chickens of the Hy-Line Variety White breed, which are one day old, subsequent to a 7-day adaptive feeding period, for a duration of 90 days. The study aimed to elucidate the potential protective impact of Nano-Se on Cd exposure. The study found that Nano-Se demonstrates potential in mitigating the blood-brain barrier (BBB) dysfunction characterized by impairment of adherens junctions (AJS) and tight junctions (TJS) by inhibiting reactive oxygen species (ROS) overproduction. In addition, the data uncovered that Nano-Se demonstrates a proficient ability in alleviating BBB impairment and inflammatory reactions caused by Cd through the modulation of the Wnt7A/ß-catenin pathway, highlights its potential to maintain brain homeostasis. Hence, this research anticipates that the utilization of Nano-Se effectively mitigate the detrimental impacts associated with Cd exposure on the BBB.

The FAK/occludin/ZO-1 complex is critical for cadmium-induced testicular damage by disruption of the integrity of the blood-testis barrier in chickens.

Cadmium (Cd) is a well-known testis toxicant. The blood-testis barrier (BTB) is a crucial component of the testis. Cd can disrupt the integrity of the BTB and reproductive function. However, the mechanism of Cd-induced disruption of BTB and testicular damage has not been fully elucidated. Here, our study investigates the effects of Cd on BTB integrity and testicular dysfunction. 80 (aged 1 day) Hy-Line white variety chickens were randomly designed into 4 groups and treated for 90 days, as follows: control group (essential diet), 35 Cd, 70 Cd and 140 Cd groups (35, 70 and 140 mg/kg Cd). The results found that Cd exposure diminished volume of the testes and induced histopathological lesions in the testes. Exposure to Cd induced an inflammatory response, disrupted the structure and function of the FAK/occludin/ZO-1 protein complex and disrupted the tight junction and adherens junction in the BTB. In addition, Cd exposure reduced the expression of steroid-related proteins and inhibited testosterone synthesis. Taken together, these data elucidate that Cd disrupts the integrity of the BTB and further inhibits spermatogenesis by dissociating the FAK/occludin/ZO-1 complex, which provides a basis for further investigation into the mechanisms of Cd-induced impairment of male reproductive function and pharmacological protection.

Nerve block reduces the incidence of 3-year postoperative mortality: a retrospective cohort study.

Purpose: A retrospective cohort study was performed to determine the effect of nerve block on the incidence of postoperative mortality in patients with hip replacement. Methods: According to the inclusion and exclusion criteria, patients who were undergoing hip replacement for the first time under general or intraspinal anesthesia, classified as ASA class I-IV, and aged ≥65 years were selected. We collected the general data, past medical history, preoperative laboratory test results, perioperative fluid intake and outflow data, perioperative anesthesia and related drug data, postoperative laboratory results, and correlation time index. Patients with preoperative combined nerve block were included in the N group, and those without combined nerve block were included in the NN group. The patients were followed up via telephone call to assess survival outcomes at 3 years after surgery. Propensity score matching and uni- and multivariate analyses were performed to determine the influence of nerve block and other related factors on postoperative mortality. Results: A total of 743 patients were included in this study, including 262 in the N group and 481 in the NN group. Two hundred five patients in both groups remained after propensity score matching. Main result: Preoperative nerve block was associated with reduced mortality three years after surgery. Conclusion: Nerve block reduces the incidence of 3-year postoperative mortality, and composite nerve block with general anesthesia and neuraxial anesthesia is worthy of promotion.

Effect of Prophylactic Placement of Percutaneous Endoscopic Gastrostomy on the Surgical Prognosis in Patients With Oral Cancer: A Pilot Study.

This study assessed the application of prophylactic percutaneous endoscopic gastrostomy (pPEG) in patients with newly diagnosed oral cancer (OC) who underwent surgery and were ready for subsequential chemoradiation. In total, 113 patients who underwent OC surgical treatment were divided into pPEG (n = 26), nasogastric tube (n = 54), and oral feeding (n = 33) groups. Their baseline characteristics, surgery-related outcomes, and nutritional data were analyzed using the Wilcoxon rank-sum test and χ2 test. No statistical significance was shown among the 3 groups using different flaps for reconstructing OC-related defects (P > 0.05). Patients of the pPEG group had the lowest incidence of surgical site infection (SSI; 23.1%, P = 0.006), but the longest hospital stay (24.1 ± 7.9 d, P < 0.001). Prophylactic percutaneous endoscopic gastrostomy may decrease the frequency of SSI but increase the length of hospitalization in SSI OC. However, multicentric prospective clinical controlled trials with large sample sizes are needed to further validate our findings.

Di (2-ethylhexyl) phthalate induced lipophagy-related renal ferroptosis in quail (Coturnix japonica).

Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical applied as a plasticizer. As an environmental toxicant, DEHP poses a serious health threat. Many studies have revealed that DEHP can cause lead to various degrees of damage to the kidney. However, the evidence of DEHP-induced renal ferroptosis has not been reported. The purpose of this work was to probe the specific role of lipophagy in DEHP-induced renal injury and to investigate the relationship between lipophagy and ferroptosis. Quail were treated with DEHP (250 mg/kg BW/day, 500 mg/kg BW/day and 750 mg/kg BW/day) for 45 days. Microstructural and ultrastructural observations showed that DEHP caused damage to glomerular and tubular cells, and autophagy with multilayer structures were observed, suggesting that DEHP can induce lipophagy. The results indicated that the iron homeostasis was abnormal and the lipid peroxidation was increased. SLC7A11 and SLC3A2 were down-regulated. PTGS2, ACSL4 and LPCAT3 were elevated. In conclusion, DEHP could induce lipid peroxidation, lead to ferroptosis, and damage renal cells. Therefore, the relationship between lipophagy and ferroptosis was elucidated, which provided a new basis for intervention and prevention of DEHP increased diseases.

Nano-selenium alleviates cadmium-induced neurotoxicity in cerebrum via inhibiting gap junction protein connexin 43 phosphorylation.

Cadmium (Cd) as a ubiquitous toxic heavy metal is reported to affect the nervous system. Selenium (Se) has been shown to have antagonistic effects against heavy metal toxicity. In addition, it shows potential antioxidant and anti-inflammatory properties. Thus, the purpose of this study was to determine the possible mechanism of brain injury after high Cd exposure and the mitigation of Nano-selenium (Nano-Se) against Cd-induced brain injury. In this study, the Cd-treated group showed a decrease in the number of neurons in brain tissue, swelling of the endoplasmic reticulum and mitochondria, and the formation of autophagosomes. Nano-Se intervention restored Cd-caused alterations in neuronal morphology, endoplasmic reticulum, and mitochondrial structure, thereby reducing neuronal damage. Furthermore, we found that some differentially expressed genes were involved in cell junction and molecular functions. Subsequently, we selected eleven (11) related differentially expressed genes for verification. The qRT-PCR results revealed the same trend of results as determined by RNA-Seq. Our findings also showed that Nano-Se supplementation alleviated Cx43 phosphorylation induced by Cd exposure. Based on immunofluorescence colocalization it was demonstrated that higher expression of GFAP and lower expressions of Cx43 were restored by Nano-Se supplementation. In conclusion, the data presented in this study establish a direct association between the phosphorylation of Cx43 and the occurrence of autophagy and neuroinflammation. However, it is noteworthy that the introduction of Nano-Se supplementation has been observed to mitigate these alterations. These results elucidate the relieving effect of Nano-Se on Cd exposure-induced brain injury.

A PRISMA meta-analysis for diagnostic value of microRNA-21 in head and neck squamous cell carcinoma along with bioinformatics research.

OBJECTIVES: The use of miR-21 expression remains vague in diagnosis of head and neck squamous cell carcinoma (HNSCC). This study aimed to systematically evaluate the diagnostic potential of the miR-21 expression in patients with HNSCCs through investigating and summarizing the results reported in the literature. METHODS: Extant medical databases were examined for articles of clinical study assessing the miR-21 expression in HNSCC cases, published in the past 20 years. Bioinformatics research was also performed for finding miR-21 targets differentially expressed in HNSCC so as to present their biological behaviors. RESULTS: Our meta-analysis comprised 11 studies including 622/450 cases in HNSCC/control group. Forest plots displayed miR-21 which possessed significantly good specificity (0.76, p < 0.001) and sensitivity (0.80, p < 0.001). Diagnostic odds ratio was 2.46 (95% CI 1.87-3.24). Positive and negative likelihood ratio was 3.40 (95% CI 1.94-5.97) and 0.26 (95% CI 0.18-0.38), respectively. Area under the receiver operating characteristic curve was 0.85. CONCLUSION: This study is the highest level of evidence presently available in diagnosing HNSCC. This PRISMA meta-analysis indicated that the pooled results were robust, confirming the oncogenic potential of miR-21 that could be used successfully as a screening biomarker in HNSCC patients. Specifically, the overexpression of miR-21 in these patients presents a worse survival outcome.

Radioresistance or/and radiosensitivity of head and neck squamous cell carcinoma: biological angle.

OBJECTIVE: This narrative review aimed to compile and summarize clinically relevant literature in radiation therapy and to discuss the potential in radioresistant and radiosensitive head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Google Scholar, PubMed, and the Cochrane Library were retrieved using combined key words such as "radiotherapy" and "head and neck cancer." Search strings additionally queried were "radioresistant," "radiosensitive," "head and neck region," "squamous cell carcinoma," in combination with Boolean operators 'AND' and 'OR.' Subsequently, the resulting publications were included for review of the full text. RESULTS: Radiotherapeutic responses currently in clinical observation referred to HNSCC scoping were selected into this review. The compiled mechanisms were then detailed concerning on the clinical significance, biological characteristics, and molecular function. CONCLUSIONS: Brachytherapy or/and external-beam radiotherapy are crucial for treating HNSCC especially the early stage patients, but in some patients with locally advanced tumors, their outcome with radiation therapy is poor due to obvious radioresistance. The curative effects mainly depend on the response to radiation therapy so an updated review is needed to optimize further applications in HNSCC radiotherapy.

Effect of Prognostic Factors of Postoperative Radiotherapy in Oral Squamous Cell Carcinoma: A SEER-Based Study.

Objective: The treatment of oral squamous cell carcinoma (OSCC) is dominated by surgery and radiochemotherapy, but its prognosis is still unsatisfactory, with around five tenths of 5-year survival. This study aimed to assess the prognosis of OSCC patients treated with surgery with and without postoperative radiotherapy. Study Design: Retrospective study. Methods: The clinicopathological information and follow-up datasets on patients with OSCC (T1-4 and/or N+) registered from 2010 to 2015 were downloaded from the Surveillance, Epidemiology, and End Results database. Totally 7231 enrolled subjects were divided into a case group (surgery alone, n = 4167) and a control group (surgery combined with postoperative radiotherapy, n = 3064). One-to-one matching was performed by propensity score matching to make the baseline data comparable between the 2 subgroups. Multivariate Cox regression analysis was used to calculate hazard ratios (HR) of various clinicopathological features. The Kaplan-Meier method and log-rank test were used to plot the survival curves. Results: The majority of patients in case group were tumor stage I (n = 2569, 61.7%), whereas most patients in control group were stages III to IV (n = 2360, 77.1%). In the case group, the 1-, 3-, and 5-year overall survival (OS; 76%, 59.5%, 53.7%) were significantly lower than those of the control group (85.1%, 64.1%, 55.8%; P < .0001). Similarly, the 1-, 3-, and 5-year cancer-specific survival (CSS) of the case group (80.2%, 66.6%, 63.3%) were significantly lower than those of the control group (87.2%, 69.3%, 63.9%, respectively; P < .0001). Cox multivariate analysis indicated that age, differentiation, clinical stage, and tumor-node-metastasis stage affected the prognosis of OSCC patients, while postoperative radiotherapy was a protective factor (OS: HR = 0.649, P < .001; CSS: HR = 0.702, P < .001). Conclusions: Postoperative radiation was an independent protective factor, hence, the combination of surgery plus radiotherapy is more beneficial for the survival of patients with OSCC, particularly for advanced cases.

A network meta-analysis of risk factors of infection among close contacts of COVID-19.

Objective: We aimed to use network meta-analysis to compare the impact of infection risk factors of close contacts with COVID-19, identify the most influential factors and rank their subgroups. It can provide a theoretical basis for the rapid and accurate tracking and management of close contacts. Methods: We searched nine databases from December 1, 2019 to August 2, 2023, which only took Chinese and English studies into consideration. Odd ratios (ORs) were calculated from traditional meta-estimated secondary attack rates (SARs) for different risk factors, and risk ranking of these risk factors was calculated by the surface under the cumulative ranking curve (SUCRA). Results: 25 studies with 152647 participants identified. Among all risk factors, the SUCRA of type of contact was 69.6 % and ranked first. Among six types of contact, compared with transportation contact, medical contact, social contact and other, daily contact increased risk of infection by 12.11 (OR: 12.11, 95 % confidence interval (CI): 6.51-22.55), 7.76 (OR: 7.76, 95 % CI: 4.09-14.73), 4.65 (OR: 4.65, 95 % CI: 2.66-8.51) and 8.23 OR: 8.23, 95 % CI: 4.23-16.01) times, respectively. Overall, SUCRA ranks from highest to lowest as daily contact (94.7 %), contact with pollution subjects (78.4 %), social contact (60.8 %), medical contact (31.8 %), other (27.9 %), transportation contact (6.4 %). Conclusion: The type of contact had the greatest impact on COVID-19 close contacts infection among the risk factors we included. Daily contact carried the greatest risk of infection among six types of contact, followed by contact with pollution subjects, social contact, other, medical contact and transportation contact. The results can provide scientific basis for rapid assess the risk of infection among close contacts based on fewer risk factors and pay attention to high-risk close contacts during management, thereby reducing tracking and management costs.

Risk assessment of venous thromboembolism in head and neck cancer patients and its establishment of a prediction model.

IMPORTANCE: Venous thromboembolism (VTE) is closely relevant to head and neck cancer (HNC) prognosis, but little data exist on the risk prediction of VTE in patients with HNC. OBJECTIVE: To study the risk factors regarding VTE in HNC patients and construct a nomogram model for its prediction. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional retrospective study was implemented to comparatively analyze 220 HNC patients from January 2018 to December 2021. The Lasso algorithm was used to optimize the selection of variables. A nomogram model for predicting HNC-associated VTE was established using multivariate logistic regression analysis. Internal validation of the model was performed by bootstrap resampling (1000 times). Calibration plot and decision curve analysis (DCA) were applied to evaluate the calibration capability of the prediction model. MAIN OUTCOME AND MEASURE: The demographics, medical history, blood biochemical indicators, and modalities of treatment were included for analysis. RESULTS: The incidence of HNC-associated VTE was 2.8% (55/1967) in authors' affiliation. Five variables of risk factors, including surgery, radiochemotherapy, D-dimer, aspartate transaminase, and globulin, were screened and selected as predictors by Lasso algorithm. A prediction model that incorporated these independent predictors was developed and presented as the nomogram. The model showed good discrimination with a C-index of 0.972 (95% CI: 0.934-0.997), and had an area under the receiver operating characteristic curve value of 0.981 (p < 0.001, 95% CI: 0.964-0.998). The calibration curve displayed good agreement of the predicted probability with the actual observed probability for HNC-associated VTE. The DCA plot showed that the application of this nomogram was associated with net benefit gains in clinical practice. CONCLUSIONS AND RELEVANCE: The high-performance nomogram model developed in this study may help early diagnose the risk of VTE in HNC patients and to guide individualized decision-making on thromboprophylaxis.

Nanoselenium Alleviates Cadmium-Induced Cerebral Injury via Regulating Cerebral Metal Transporters and Metal-Regulatory Transcription Factor 1.

Cadmium (Cd) is a hazardous environmental metal that poses a global public health concern due to its high toxic potential. Nanoselenium (Nano-Se) is a nanoform of elemental Se that is widely used to antagonize heavy metal toxicity owing to its high safety margin with low doses. However, the role of Nano-Se in relieving Cd-induced brain damage is unclear. For this study, Cd-exposure-induced cerebral damage was established by using a chicken model. Administration of Nano-Se with Cd significantly decreased the Cd-mediated elevation of cerebral ROS, MDA, and H2O2 levels as well as markedly increased the Cd-mediated reduced activities of antioxidant biomarkers (GPX, T-SOD, CAT, and T-AOC). Accordingly, co-treatment with Nano-Se significantly reduced Cd-mediated increased Cd accumulation and recovered the Cd-induced biometal imbalance, notably Se and Zn. Nano-Se downregulated the Cd-induced upregulation of ZIP8, ZIP10, ZNT3, ZNT5, and ZNT6 and upregulated the Cd-mediated decreased expressions of ATOX1 and XIAP. Nano-Se also increased the Cd-mediated decreased mRNA levels of MTF1 and its target genes MT1 and MT2. Surprisingly, co-treatment with Nano-Se regulated the Cd-induced increased total protein level of MTF1 by reducing its expression. Moreover, altered selenoproteins regulation was recovered after co-treatment with Nano-Se as evidenced by increased expression levels of antioxidant selenoproteins (GPx1-4 and SelW) and Se transport-related selenoproteins (SepP1 and SepP2). The histopathological evaluation and Nissl staining of the cerebral tissues also supported that Nano-Se markedly reduced the Cd-induced microstructural alterations and well preserved the normal histological architectures of the cerebral tissue. Overall, the results of this research reveal that Nano-Se may be beneficial in mitigating Cd-induced cerebral injury in the brains of chickens. This present study provides a basis for preclinical research for its usefulness as a potential therapeutic for the treatment of neurodegeneration in the heavy-metal-induced neurotoxicity.

Self-Powered Bipolar Photodetector Based on a Ce-BaTiO3 PTCR Semiconductor for Logic Gates.

Ferroelectric materials bring new opportunities for self-powdered photodetectors, taking advantage of their anomalous bulk photovoltaic effect. However, ferroelectric-based photodetectors suffer from relatively poor responsivity and detectivity due to obstacles of low electrical conductivity and low photoelectric conversion ability. The present work proposes a strategy based on heterovalent ion Ce-doping into BaTiO3 (Ce-BTO) that gives rise to a good room temperature conductivity combined with a significant PTCR (positive temperature coefficient of resistivity) effect. By utilizing a Ce-BTO PTCR semiconductor, a high-performance self-powered photodetector ITO/Ce-BTO/Ag is fabricated, demonstrating a polarity-switchable photoresponse with the change of wavelength due to the competition between hot electrons induced by the Ag plasmonic effect and electron-hole pairs separated by a Schottky barrier. Moreover, benefiting from the reduced bandgap and the introduced impurity states, good responsivity (9.85 × 10-5 A/W) and detectivity (1.25 × 1010 Jones) as well as fast response/recovery time (83/47 ms) is achieved under 450 nm illumination. Finally, four representative logic gates ("OR", "AND", "NOR", and "NAND") are demonstrated with one photodetector via the bipolar photoresponse. This work opens an avenue to promote the application of PTCR semiconductors in optoelectronics, offering a conceivable means toward high-performance self-powered photodetectors.

Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.