Objective:To investigate the expression of the proinflammatory factor IL-18-mediated NOD-like receptor thermal protein domain associated protein 3/nuclear factor κB(NLRP3/NF-κB)signaling pathway in penile tissues of rats with high-fat diet-in-duced erectile dysfunction(ED),and to explore the intervention effect of sildenafil.Methods:Fifty-five sexually normal male SD rats were randomly divided into 10 cases as the normal control group,and the rest of the rats were fed with high-fat chow to establish the ED rat model,and the successfully screened ED rats were randomly divided into the ED group,the Sil group,the IL-18 group,and the IL-18+Sil group,with 8 rats in each group.Following 14 days of nonstop treatment,the morphological alterations in the penile tis-sue were observed by HE staining.Using immunohistochemistry,the amount and distribution of NF-κB p65 and Adropin in penile tis-sues were found.RT-qPCR was used to identify the expression of NLRP3 and NF-κB p65 mRNA in penile tissues.Western blot exami-nation showed the expression of the proteins NLRP3,pro-IL-18,p-NF-κB p65,NF-κB p65,and Adropin in penile tissues.Results:The ED group showed altered penis tissue morphology,destroyed muscle fibers,enlarged sinus cavity,increased mRNA and protein expressions of NLRP3,p-NF-κB p65/NF-κB p65,and pro-IL-18(all P<0.05),and decreased Adropin protein expression(P<0.05).While the protein expression of Adropin was increased(P<0.05),the mRNA and protein expressions of NLRP3,p-NF-κB p65/NF-κB p65,and pro-IL-18 in the penis tissues were decreased(all P<0.05)when compared to the ED group.The muscle fibers and sinus cav-ities of the penis were recovered to varying degrees in the Sil group.The IL-18 group experienced the destruction of muscle fibers,an enlargement of the sinus cavity,an increase in the mRNA and protein expressions of NLRP3,p-NF-κB p65/NF-κB p65,and pro-IL-18 in the penile tissues(all P<0.05),as well as a decrease in the protein expression of Adropin(P<0.05).The rat penile tissues in the IL-18+Sil group showed variable degrees of recovery in the muscle fibers and sinus cavities when compared to the IL-18 group.Ad-ditionally,there was a drop(all P<0.05)in the expressions of NLRP3,pro-IL-18 m RNA and protein,p-NF-κB p65/NF-κB p65,and p-NF-κB p65 in the penile tissues.The expression of the Adropin protein was elevated(P<0.05).Conclusion:Significant changes have been observed in the NLRP3/NF-κB signaling pathway,which is regulated by IL-18,in the hyperlipidemia ED rat model.In ED rats,sildenafil can increase erectile function by promoting the production of Adropin and blocking the activation of this pathway.

Objective To analyze the clinical significance of subjective visual vertical (SVV) tests at different head deflection angles in assessing utricle function in patients with benign paroxysmal positional vertigo (BPPV). Methods A total of 61 BPPV patients who were treated at the Hearing Impairment and Vertigo Diagnosis and Treatment Center of Otolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from August 2022 to May 2023 were retrospectively included, and 29 healthy adults were selected as controls. SVV tests were performed on all research subjects at different head deflection angles: upright head (0°), left head 45° (L45°), right head 45° (R45°). The test results between the two groups were compared. Results SVV absolute value at R45° in BPPV group was lower than that in the control group (P＝0.003); there was no significant difference in SVV values at 0° and L45° between the two groups. There was no statistical difference in SVV values at different head deflection angles between the control group and the left BPPV group. SVV absolute value at R45° in right BPPV group was lower than that in the control group (P＜0.001); there was no statistical difference in SVV values at 0° and L45° between the two groups. Conclusions SVV test can provide subjective information about the utricle, and SVV tests at different head deflection angles can fine-tune evaluate the function of the utricle in BPPV patients.

Sennoside A(SA),a typical prodrug,exerts its laxative effect only after its transformation into rhei-nanthrone catalyzed by gut microbial hydrolases and reductases.Hydrolases have been identified,but reductases remain unknown.By linking a photoreactive group to the SA scaffold,we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling(ABPP).From lysates of an active strain,Bifidobacterium pseudocatenulatum(B.pseu-docatenulatum),397 proteins were enriched and subsequently identified using mass spectrometry(MS).Among these proteins,chromate reductase/nicotinamide adenine dinucleotide(NADH)phosphate(NADPH)-dependent flavin mononucleotide(FMN)reductase/oxygen-insensitive NADPH nitroreductase(nfrA)was identified as a potent SA reductase through further bioinformatic analysis and The Universal Protein Resource(UniProt)database screening.We also determined that recombinant nfrA could reduce SA.Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.

Sennoside A (SA), a typical prodrug, exerts its laxative effect only after its transformation into rheinanthrone catalyzed by gut microbial hydrolases and reductases. Hydrolases have been identified, but reductases remain unknown. By linking a photoreactive group to the SA scaffold, we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling (ABPP). From lysates of an active strain, Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), 397 proteins were enriched and subsequently identified using mass spectrometry (MS). Among these proteins, chromate reductase/nicotinamide adenine dinucleotide (NADH) phosphate (NADPH)-dependent flavin mononucleotide (FMN) reductase/oxygen-insensitive NADPH nitroreductase (nfrA) was identified as a potent SA reductase through further bioinformatic analysis and The Universal Protein Resource (UniProt) database screening. We also determined that recombinant nfrA could reduce SA. Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.

Objective:To investigate the relationship between symptoms of vertigo and vestibular functions and short-term hearing outcomes in patients with flat descending sudden sensorineural hearing loss （SSNHL）. Methods:A retrospective review was conducted of the vestibular symptoms observed in 48 patients with unilateral flat-down sudden sensorineural hearing loss treated at the Department of Otolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. Symptoms of vertigo and the results of cervical vestibular-evoked myogenic potentials （cVEMP）, ocular VEMP （oVEMP）, caloric test and video head-impulse test （vHIT） were collected to determine whether these factors could predict therapeutic efficacy. Results:The symptoms of vertigo was not correlated with prognosis （P>0.05） or with abnormal vestibular functions （P>0.05）. Patients with abnormal cVEMP, oVEMP, caloric test or vHIT showed significantly lower effective rates （32.0%, 44.0%, 32.0%, and 24.0%, respectively）; the greater the number of abnormal tests, the poorer the outcome. Patients with all four tests abnormal gained only （3.13±15.97） dB HL in hearing recovery, whereas those with normal cVEMP, oVEMP, caloric test or vHIT showed better chances of hearing improvements by （29.22±20.31）, （31.18±21.59）, （26.17±21.31）, and （26.38±24.05） dB HL, respectively. Conclusion:Vestibular function effectively predicts prognosis in flat descending SSNHL. Patients with abnormal vestibular tests, regardless of symptoms of vertigo, responded poorly to treatment, whereas those with normal cVEMP, oVEMP, caloric test and vHIT results achieved better hearing recovery. Abnormal vestibular function implies more extensive and severe inner-ear lesions in patients with SSNHL.
Humans ; Male ; Female ; Retrospective Studies ; Prognosis ; Adult ; Middle Aged ; Vertigo/diagnosis* ; Hearing Loss, Sensorineural/diagnosis* ; Young Adult ; Hearing Loss, Sudden/diagnosis* ; Adolescent ; Aged ; Vestibular Evoked Myogenic Potentials

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver condition globally, lacks adequate and effective therapeutic remedies in clinical practice. Recent studies have increasingly highlighted the close connection between the ubiquitin-proteasome system (UPS) and the progression of MASLD. This relationship is crucial for understanding the disease's underlying mechanism. As a sophisticated process, the UPS govern protein stability and function, maintaining protein homeostasis, thus influencing a multitude of elements and biological events of eukaryotic cells. It comprises four enzyme families, namely, ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin-protein ligases (E3), and deubiquitinating enzymes (DUBs). This review aims to delve into the array of pathways and therapeutic targets implicated in the ubiquitination within the pathogenesis of MASLD. Therefore, this review unveils the role of ubiquitination in MASLD while spotlighting potential therapeutic targets within the context of this disease.

Acute liver injury (ALI) serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders. The prevention and treatment of ALI is still a serious global challenge. Given the limited therapeutic options for ALI, exploring novel targeted therapeutic agents becomes imperative. The potential therapeutic efficacy of inhibiting RIPK2 is highlighted, as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling. Herein, we propose a CMD-OPT model, a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties. Compound RP20, which targets the ATP binding site, demonstrated excellent kinase specificity, ideal oral pharmacokinetics, and superior therapeutic effects in a model of APAP-induced ALI, positioning RP20 as a promising preclinical candidate. This marks the first application of RIPK2 inhibitors in ALI treatment, opening a novel therapeutic pathway for clinical applications. These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules, showcasing its significant potential in drug discovery.

Objective:To investigate the clinical and pathological significance of the DICER1 mutation in follicular thyroid carcinoma (FTC).Methods:Sixty-eight cases of primary FTC resected between 2009 and 2023 were retrieved from The Affiliated Hospital of Qingdao University, Qingdao, China. Sanger sequencing was performed to identify DICER1 and TERT promoter mutations in all cases. Cases with DICER1 or TERT promoter mutations were subject to additional examination of potential mutations in KRAS, HRAS, and NRAS. The clinical and pathological features of DICER1-mutant FTCs were then analyzed. The relationship between DICER1 mutations and TERT-promoter/RAS mutations was also assessed.Results:DICER1 mutations were detected in 16 of the 68 FTC cases (23.5%), with 11 near E1813 at exon 25, 6 near D1709 at exon 24, and 1 in the splice region of exon 25. Two cases harbored two (distinct) mutations. All patients with DICER1-mutant FTC were female. Compared with patients with DICER1-wild-type FTC, those with DICER1-mutant were much younger, and had a higher proportion of minimally invasive subtype. Nine FTCs with DICER1 mutations were subject to further sequencing on adjacent non-cancerous tissues or lymph node tissues, but no mutations were detected. TERT-promoter or RAS hotspot mutations were not identified in any of the DICER1-mutant cases. However, TERT-promoter mutation was found in 6 DICER1-wild-type cases (8.8%, 6/68), with 3 cases also having RAS hotspot mutations and exhibiting highly aggressive biological behaviors.Conclusion:DICER1 mutations may occur in FTCs and appear mutually exclusive with RAS and TERT-promoter mutations, warranting further study as RAS-like mutations.

This study aims to prepare nanobodies for the epitopes of spike protein(S)of porcine ep-idemic diarrhea virus(PEDV),and verify its reactivity.The expression vector pCZN1-SN was con-structed by the prokaryotic expression system,and SN fragment was expressed in prokaryotic ex-pression and purified by Ni-NTA chromatography column.The SN nanobodies were displayed u-sing phage display technology and screened from the natural nanobody library.The results showed that SN fragments with a size of 26 kDa were obtained by prokaryotic induction,and the specific nanobodies were obtained through three rounds screening by phage display technology.One strain with the best reactivity was selected for prokaryotic expression and purified.The nanobodies were obtained with a size of 14 kDa by Western blot and demonstrated to have a good binding ability to PEDV SN protein.In summary,nanobodies with epitope fragments of PEDV S protein were suc-cessfully screened and prepared based on the phage display technology,which provided a new way for the in-depth application of nanobodies.

Objective:To explore the mediating effect of depression between self-efficacy and fear of progression in elderly patients with post-stroke epilepsy.Methods:From January 2023 to June 2024, 200 elderly patients with post-stroke epilepsy at Zhumadian Central Hospital were selected as study subjects using convenience sampling. The survey was conducted using the General Information Questionnaire, General Self-Efficacy Scale (SSEQ), Patient Health Questionnaire-9 (PHQ-9), and Fear of Progression Questionnaire-Short Form (FOP-Q-SF) .Results:A total of 200 questionnaires were distributed, and 198 valid questionnaires were collected, with a valid response rate of 99.00%. Among 198 elderly patients with post-stroke epilepsy, the SSEQ, PHQ-9, and FOP-Q-SF scores were (52.35±4.20), (13.46±1.57), and (35.70±2.10), respectively. Pearson correlation analysis revealed that SSEQ scores were negatively correlated with both PHQ-9 and FOP-Q-SF scores, while PHQ-9 scores were positively correlated with FOP-Q-SF scores ( P<0.01). Mediating analysis showed that depression partially mediated the relationship between self-efficacy and fear of progression in elderly patients with post-stroke epilepsy. The mediating effect was -0.046, with a total effect of -0.346, and the mediating effect accounted for 13.30% of the total effect. Conclusions:Depression partially mediates the relationship between self-efficacy and fear of progression in elderly patients with post-stroke epilepsy. Controlling depression not only helps enhance patients' self-efficacy but may also reduce their fear of progression.