Wnt/ß-catenin signaling inhibits oxidative stress-induced ferroptosis to improve interstitial cystitis/bladder pain syndrome by reducing NF-κB.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a bladder syndrome of unknown etiology. Reactive oxygen species (ROS) plays a major role in ferroptosis and bladder dysfunction of IC/BPS, while the role of ferroptosis in IC/BPS progression is still unclear. This study aims to investigate the role and mechanism of ROS-induced ferroptosis in IC/BPS using cell and rat model. METHODS: We collected IC/BPS patient bladder tissue samples and established a LPS-induced IC/BPS rat model (LRM). The expression of oxidative stress and ferroptosis in IC/BPS patients and LRM rats were analyzed. Function and regulatory mechanism of ferroptosis in IC/BPS were explored by in vitro and in vivo experiments. RESULTS: The patients with IC/BPS showed mast cells and inflammatory cells infiltration in bladder epithelial tissue. Expression of NRF2 was up-regulated, and GPX4 was decreased in IC/BPS patients compared with normal tissues. IC model cells undergo oxidative stress, which induced ferroptosis. These above results were validated in LRM rat models, and inhibition of ferroptosis ameliorated bladder dysfunction in LRM rats. Wnt/ß-catenin signaling was deactivated in IC/BPS patients and animals, and activation of Wnt/ß-catenin signaling reduced cellular free radical production thereby inhibited ferroptosis in IC model cells. Mechanistically, Wnt/ß-catenin signaling pathway inhibited oxidative stress-induced ferroptosis by down-regulating NF-κB, thus contributing to recover IC/BPS both in vitro and in vivo. CONCLUSIONS: We demonstrate for the first time that oxidative stress-induced ferroptosis plays an important role in the pathology of IC/BPS. Mechanistically, Wnt/ß-catenin signaling suppressed oxidative stress-induced ferroptosis by down-regulating NF-κB to improve bladder injury in IC/BPS.

Effect of Myelin Debris on the Phenotypic Transformation of Astrocytes after Spinal Cord Injury in Rats.

After spinal cord injury (SCI), the accumulation of myelin debris can serve as proinflammatory agents, hindering axon regrowth and exacerbating damage. While astrocytes have been implicated in the phagocytosis of myelin debris, the impact of this process on the phenotypic transformation of astrocytes and their characteristics following SCI in rats is not well understood. Here, we demonstrated that the conditioned medium of myelin debris can trigger apoptosis in rat primary astrocytes in vitro. Using a compressional SCI model in rats, we observed that astrocytes can engulf myelin debris through ATP-binding cassette transporter sub-family A member 1 (ABCA1), and these engulfed cells tend to transform into A1 astrocytes, as indicated by C3 expression. At 4 days post-injury (dpi), astrocytes rapidly transitioned into A1 astrocytes and maintained this phenotype from 4 to 28 dpi, while A2 astrocytes, characterized by S100, were only detected at 14 and 28 dpi. Reactive astrocytes, identified by Nestin, emerged at 4 and 7 dpi, whereas scar-forming astrocytes, marked by N-cadherin, were evident at 14 and 28 dpi. This study illustrates the distribution patterns of astrocyte subtypes and the potential interplay between astrocytes and myelin debris after SCI in rats. We emphasize that myelin debris can induce astrocyte apoptosis in vitro and promote the transformation of astrocytes into A1 astrocytes in vivo. These two classification methods are not mutually exclusive, but rather complementary.

Preliminary analysis of stimulation parameters for sacral neuromodulation in different indications: A multi-center retrospective cohort study from China.

BACKGROUND: Sacral neuromodulation (SNM) is an effective approach for treating lower urinary tract dysfunction (LUTD), and stimulation programming is essential for successful treatment. However, research on SNM programming for various indications is limited. Thus, we aimed to determine whether there were differences in the stimulation parameters for different SNM indications and the appropriate programming recommendations. MATERIALS AND METHODS: Clinical data were retrospectively collected from patients with LUTD who underwent SNM and completed internal pulse generator (IPG) implantation. The parameters with the highest patient satisfaction or the most symptom improvement during the test period were considered optimal and used to set the programming after IPG implantation. RESULTS: After screening, 282 patients were enrolled and categorized into four groups based on the following indications: refractory overactive bladder (OAB) (n=61), neurogenic lower urinary tract dysfunction (nLUTD) (n=162), interstitial cystitis/painful bladder syndrome (IC/BPS) (n=24), and idiopathic non-obstructive urinary retention (NOUR) (n=35). When analyzing the optimal stimulus parameters, disparities in the stimulation amplitude and pulse frequency were noted among the four groups. The stimulation amplitude in the nLUTD group was higher than that in the idiopathic NOUR group (P=0.013). Differences in pulse frequency were observed between the refractory OAB and nLUTD groups (P<0.001) and between the refractory OAB and idiopathic NOUR groups (P=0.001). No differences in the electrode configuration or pulse width settings existed among the four groups. CONCLUSIONS: The stimulation parameters for SNM varied among the different indications. For the initial programming of stage I, most patients are recommended to start with stimulation amplitudes below 2 V, although patients with nLUTD may benefit from higher amplitudes. A standard pulse width of 210 µs is recommended for all patients. However, for individuals experiencing nLUTD or idiopathic NOUR, the pulse frequency can begin above the standard 14 Hz but not exceed 50 Hz.

Unintended dural tears during unilateral biportal endoscopic lumbar surgery: incidence and risk factors.

BACKGROUND: An unintended dural tear (DT) is the most common intraoperative complication of lumbar spine surgery. The unilateral biportal endoscopic technique (UBE) has become increasingly popular for treating various degenerative diseases of the lumbar spine; however, the DT incidence and risk factors specific to UBE remain undetermined. Therefore, this study aimed to evaluate the incidence and risk factors of DTs in UBE. METHOD: Data from all patients who underwent UBE for degenerative lumbar spinal diseases from November 2018 to December 2021 at our institution were used to assess the effects of demographics, diagnosis, and type of surgery on unintended DT risk. RESULTS: Overall, 24/608 patients (3.95%) experienced DTs and were treated with primary suture repair or bed rest. Although several patients experienced mild symptoms of cerebrospinal fluid (CSF) leaks, no serious postoperative sequelae such as nerve root entrapment, meningitis, or intracranial hemorrhage occurred. Additionally, no significant correlations were identified between DT and sex (P = 0.882), body mass index (BMI) (P = 0.758), smoking status (P = 0.506), diabetes (P = 0.672), hypertension (P = 0.187), or surgeon experience (P = 0.442). However, older patients were more likely to experience DT than younger patients (P = 0.034), and patients with lumbar spinal stenosis (LSS) were more likely to experience DT than patients with lumbar disc herniation (LDH) (P = 0.035). Additionally, DT was more common in revision versus primary surgery (P < 0.0001) and in unilateral laminotomy with bilateral decompression (ULBD) versus unilateral decompression (P = 0.031). Univariate logistic regression analysis revealed that age, LSS, ULBD, and revision surgery were significant risk factors for DT. CONCLUSIONS: In this UBE cohort, we found that the incidence of DT was 3.95%. Additionally, older age, LSS, ULBD, and revision surgery significantly increased the risk of DT in UBE surgery.

hBcl2 overexpression in BMSCs enhances resistance to myelin debris-induced apoptosis and facilitates neuroprotection after spinal cord injury in rats.

After spinal cord injury (SCI), the accumulation of myelin debris at the lesion exacerbates cell death and hinders axonal regeneration. Transplanted bone marrow mesenchymal stem cells (BMSCs) have been proven to be beneficial for SCI repair, but they are susceptible to apoptosis. It remains unclear whether this apoptotic process is influenced by myelin debris. Here, we constructed rat BMSCs overexpressing human B-cell lymphoma 2 (hBcl2) alone (hBcl2 group), BMSCs overexpressing hBcl2 with an endoplasmic reticulum-anchored segment (hBcl2-cb) (cb group), and a negative control group (NC group) for transplantation in this study. Immunocytochemistry staining validated the successful expression of hBcl2 in BMSCs within the hBcl2 group and cb group. All BMSCs from each group exhibited the ability to phagocytize myelin debris. Nevertheless, only BMSCs derived from the hBcl2 group exhibited heightened resistance to apoptosis and maintained prolonged viability for up to 5 days when exposed to myelin debris. Notably, overexpression of hBcl2 protein, rather than its endoplasmic reticulum-anchored counterpart, significantly enhanced the resistance of BMSCs against myelin debris-induced apoptosis. This process appeared to be associated with the efficient degradation of myelin debris through the Lamp1+ lysosomal pathway in the hBcl2 group. In vivo, the hBcl2 group exhibited significantly higher numbers of surviving cells and fewer apoptotic BMSCs compared to the cb and NC groups following transplantation. Furthermore, the hBcl2 group displayed reduced GFAP+ glial scarring and greater preservation of NF200+ axons in the lesions of SCI rats. Our results suggest that myelin debris triggers apoptosis in transplanted BMSCs, potentially elucidating the low survival rate of these cells after SCI. Consequently, the survival rate of transplanted BMSCs is improved by hBcl2 overexpression, leading to enhanced preservation of axons within the injured spinal cord.

Technical specifications for ethics review of human stem cell research.

The rapid advancement of human stem cell research and its expansion into emerging areas has resulted in an escalation of ethical challenges associated with these studies. As a result, there has been a corresponding increase in both the volume and complexity of institutional ethics reviews, coupled with higher expectations for the quality of the review process. In response to these challenges, this standard provides a comprehensive outline of the fundamental principles, content, types, and procedures of ethics review, specifically focusing on non-clinical human stem cell research. Its purpose is to provide clear operational and procedural guidelines, as well as recommendations, for the ethics review of such studies. The document was originally published by the Chinese Society for Cell Biology on August 30, 2022. It is our hope that the publication of these guidelines will facilitate the integration of ethical considerations and evaluations in a structured manner throughout the entire process of stem cell research, ultimately fostering a healthy and orderly development of the field.

Correlation of serum circulating testosterone levels with stress urinary incontinence in postmenopausal women.

OBJECTIVES: Our study aimed to elucidate the possible relationship between endogenous circulating testosterone and the beginning and development of stress urinary incontinence (SUI) in postmenopausal women. PATIENTS AND METHODS: The clinical data of female patients with SUI who underwent surgery at our hospital from January 2014 to February 2023 and healthy female volunteers recruited during the same period were retrospectively analyzed according to age and body mass index (BMI). Venous blood samples were taken from all subjects, and levels of estradiol, luteinizing hormone, prolactin, follicle-stimulating hormone, progesterone, and testosterone were measured by radioimmunoassay. After adjusting for age, BMI, hypertension, mode of delivery, hysterectomy, and profession, multiple logistic regression analysis was used to determine the relationship between SUI and serum testosterone levels in postmenopausal women. RESULTS: Serum testosterone levels were significantly lower in women with SUI than in healthy control women (0.92 ± 0.67 vs. 1.28 ± 1.10; P < 0.05). Further comparison of testosterone levels between postmenopausal SUI women and healthy postmenopausal women in postmenopausal subjects revealed that testosterone levels were significantly lower in postmenopausal SUI women than in healthy postmenopausal women (0.84 ± 0.64 vs. 1.23 ± 1.10; P < 0.05). This difference in testosterone levels remained significant after controlling for age, BMI, hypertension, mode of delivery, hysterectomy, and profession in postmenopausal women. CONCLUSION: The results of the present study indicate that low levels of serum testosterone are associated with an increased likelihood of stress urinary incontinence in women. Low serum testosterone levels may be a risk factor for SUI in postmenopausal women.

Serpina3n/serpina3 alleviates cyclophosphamide-induced interstitial cystitis by activating the Wnt/ß-catenin signal.

BACKGROUND/OBJECTIVE: Serpina3n/Serpina3 has been identified to be implicated in inflammatory diseases, but its role in interstitial cystitis/bladder pain syndrome (IC/BPS) remains unknown. Here, we aimed to reveal serpina3n/serpina3 role in IC/BPS in vivo and in vitro. METHODS: The IC/BPS model in mice was induced by intraperitoneal injection of 150 mg/kg of cyclophosphamide (CYP). HE and toluidine blue staining were used for histology assessment. Serpina3n/serpina3 expression in the bladder tissues from IC/BPS patients and mouse models were determined by qPCR, immunohistochemistry and western blotting. XAV-939 treatment was applied to inhibit ß-catenin activation. Serpina3 role in modulating the growth and apoptosis of HBlEpCs, a human primary bladder epithelial cell line, was assessed by CCK-8 and flow cytometry assays. RESULTS: Serpina3n/serpina3 expression was decreased in both human and mice bladder tissues with IC/BPS. Upregulation of serpina3n significantly alleviated CYP-induced bladder injury, with decreased mast cells and pro-inflammatory factor levels, including IL-1ß, IL-6, and TNF-α, while increased IL-10 level. In addition, serpina3 overexpression inhibited the apoptosis of HBlEpCs, and increased cell growth. In mechanism, we found that serpina3 overexpression promoted the activation of wnt/ß-catenin signaling. And, the inhibition of wnt/ß-catenin signaling with XAV-939 abolished serpina3n/serpina3 role in protecting bladder tissues from CYP-induced cystitis, as well as inhibiting HBlEpC apoptosis. CONCLUSION: Serpina3n/serpina3 expression was decreased in IC/BPS. Overexpression of serpina3n could alleviate CYP-induced IC/BPS by activating the Wnt/ß-catenin signal. This study may provide a new therapeutic strategy for IC/BPS.

[Clinical observation on electroacupuncture at "four points of sacral region" on moderate to severe stress urinary incontinence after radical prostatectomy].

OBJECTIVE: To compare the clinical therapeutic effect between electroacupuncture at "four points of sacral region" and transurethral Erbium laser in treatment of moderate to severe stress urinary incontinence after radical prostatectomy. METHODS: A total of 68 patients of moderate to severe stress urinary incontinence after radical prostatectomy were divided into an electroacupuncture group (34 cases) and an Erbium laser group (34 cases, 3 cases dropped off) according to the settings. In the electroacupuncture group, electroacupuncture was applied at "four points of sacral region", i.e. points of 0.5 cun beside bilateral sacrococcygeal joints and bilateral Huiyang (BL 35), with continuous wave, 2 Hz in frequency, 60 min each time, once every other day, 3 times a week, 12 times as one course of treatment. In the Erbium laser group, transurethral Erbium laser technology was given, once every 4 weeks as one course of treatment. Both groups were treated for 5 courses. The scores of the International Consultation on Incontinence questionnaire-short form (ICI-Q-SF) and the incontinence quality of life questionnaire (I-QOL) were observed before treatment, after each course of treatment and in follow-up after 1 and 2 months of treatment completion, respectively, and the clinical efficacy was evaluated after treatment in the two groups. RESULTS: Compared with those before treatment, the ICI-Q-SF scores were decreased while the I-QOL scores were increased after 5 courses of treatment and in follow-up after 1, 2 months of treatment completion in the two groups (P<0.01). The ICI-Q-SF score in follow-up after 2 months of treatment completion were higher than that after 5 courses of treatment in the Erbium laser group (P<0.05). After 3, 4, 5 courses of treatment and in follow-up after 1 and 2 months of treatment completion, the ICI-Q-SF scores in the electroacupuncture group were lower than those in the Erbium laser group (P<0.05, P<0.01); after 2, 3, 4, 5 courses of treatment and in follow-up after 1 and 2 months of treatment completion, the I-QOL scores in the electroacupuncture group were higher than those in the Erbium laser group (P<0.01). The change ranges of ICI-Q-SF score and I-QOL score between before treatment and after each course of treatment in the electroacupuncture group were lager than those in the Erbium laser group (P<0.01, P<0.05). The total effective rate was 61.8% (21/34) in the electroacupuncture group, which was superior to 19.4 (6/31) in the Erbium laser group (P<0.01). CONCLUSION: Both electroacupuncture at "four points of sacral region" and transurethral Erbium laser can improve the clinical symptoms and the quality of life in patients of moderate to severe stress urinary incontinence after radical prostatectomy. The short-term efficacy and long-term efficacy of electroacupuncture are superior to the Erbium laser technology.

Identification of a novel MYC target gene set signature for predicting the prognosis of osteosarcoma patients.

Osteosarcoma is a primary malignant tumor found mainly in teenagers and young adults. Patients have very little long-term survival. MYC controls tumor initiation and progression by regulating the expression of its target genes; thus, constructing a risk signature of osteosarcoma MYC target gene set will benefit the evaluation of both treatment and prognosis. In this paper, we used GEO data to download the ChIP-seq data of MYC to obtain the MYC target gene. Then, a risk signature consisting of 10 MYC target genes was developed using Cox regression analysis. The signature indicates that patients in the high-risk group performed poorly. After that, we verified it in the GSE21257 dataset. In addition, the difference in tumor immune function among the low- and high-risk populations was compared by single sample gene enrichment analysis. Immunotherapy and prediction of response to the anticancer drug have shown that the risk signature of the MYC target gene set was positively correlated with immune checkpoint response and drug sensitivity. Functional analysis has demonstrated that these genes are enriched in malignant tumors. Finally, STX10 was selected for functional experimentation. STX10 silence has limited osteosarcoma cell migration, invasion, and proliferation. Therefore, these findings indicated that the MYC target gene set risk signature could be used as a potential therapeutic target and prognostic indicator in patients with osteosarcoma.

Acting on ethics and governance of aging research.

Rapid advances in aging research and clinical translation come with numerous ethical and societal issues that the current regulatory framework may not be sufficient to address. To fill this gap, we propose a responsible and comprehensive governance framework to cope with these issues while maximizing the benefits of aging research.

Sacral neuromodulation remote programming in patients with refractory lower urinary tract dysfunction: China's experience during the COVID-19 pandemic.

Objectives: Sacral neuromodulation is an effective, minimally invasive treatment for refractory lower urinary tract dysfunction. However, regular postoperative programming is crucial for the maintenance of the curative effects of electronic sacral stimulator devices. The outbreak of coronavirus disease 2019 (COVID-19) limited the ability of practitioners to perform traditional face-to-face programming of these stimulators. Therefore, this study aimed to evaluate the application of remote programming technology for sacral neuromodulation during the COVID-19 pandemic in China. Materials and methods: We retrospectively collected data including baseline and programming information of all patients with lower urinary tract dysfunction who underwent sacral neuromodulation remote programming in China after the outbreak of COVID-19 (i.e., December 2019). The patients also completed a self-designed telephone questionnaire on the subject. Results: A total of 51 patients from 16 centers were included. They underwent 180 total remote programming visits, and 118, 2, 25, and 54 voltage, current, pulse width, and frequency adjustments, respectively, were performed. Additionally, remote switching on and off was performed 8 times; impedance test, 54 times; and stimulation contact replacement, 25 times. The demand for remote programming was the highest during the first 6 months of sacral neuromodulation (average, 2.39 times per person). In total, 36 out of the 51 patients completed the questionnaire survey. Of these, all indicated that they chose remote programming to minimize unnecessary travel because they had been affected by COVID-19. The questionnaire also showed that remote programming could reduce the number of patient visits to the hospital, save time, reduce financial costs, and would be easy for patients to master. All surveyed patients indicated that they were satisfied with remote programming and were willing to recommend it to other patients. Conclusion: Remote programming for sacral neuromodulation is feasible, effective, safe, and highly recommended by patients with refractory lower urinary tract dysfunction. Remote programming technology has great development and application potential in the post-pandemic era.

Biomarkers of aging.

Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.

Responsible governance of human germline genome editing in China†.

Considerable improvements have been made to gene editing technology, which has been increasingly applied to research involving humans. Nevertheless, human heritable germline genome editing is associated with a series of potential ethical, legal, and social risks, which have generated major controversies and discussions worldwide, especially after the "gene-edited babies" incident. Influenced by this incident, China has realized the importance of ethical governance in the field of life science and technology, has accelerated legislative and policy efforts in this field, and has gradually moved toward the direction of "precautionary" ethical governance. Black letter analysis, big data public opinion analysis, and other research methods are used in this paper. This paper explores the scientific background, ethical debates, and latest developments regarding China's regulatory framework for human germline gene editing after the "gene-edited babies" controversy and provides several recommendations on the future governance system of human germline gene editing in China. This paper argues that in recent years, the ethics governance of germline genome editing in China has been accelerated and great changes have been made. However, the regulatory system for germline genome editing requires further improvement in three aspects: coordination of legislation and agencies, establishment of an ethics review system at high levels, and public participation and education.

Short-term Efficacy and Mechanism of Electrical Pudendal Nerve Stimulation Versus Pelvic Floor Muscle Training Plus Transanal Electrical Stimulation in Treating Post-radical Prostatectomy Urinary Incontinence.

OBJECTIVE: To assess the short-term efficacy of electrical pudendal nerve stimulation (EPNS) versus pelvic floor muscle training (PFMT) plus transanal electrical stimulation (TES) for the early treatment of post-radical prostatectomy urinary incontinence (PRPUI) and explore its mechanism of action. SUBJECTS AND METHODS: A parallel designed randomized controlled trial was conducted at a research institute and a university hospital. Ninety-six PRPUI patients were allocated to EPNS group (64 cases) and PFMT+TES group (32 cases) and treated by EPNS and biofeedback-assisted PFMT plus TES, 3 times a week for 8 weeks, respectively. Outcome measurements were improvement rate, scores of the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) and the number of used diapers. RESULTS: After 24 treatments, the efficacy rate of 68.7% in EPNS group was significantly higher than that of 34.4% in PFMT+TES group (P=0.005). The ICIQ-UI SF score, and urine leakage amount score, diaper score, symptom and quality of life improved significantly in both groups and showed Therapy x Treatment interaction, and the above scores in EPNS group were significantly lower than these in PFMT+TES group. Perineal ultrasonographic recordings showed that PFM movement amplitude during EPNS (≥1- <3 mm) was similar to that during PFMT, however, PFM movement EMG amplitude was significantly higher during EPNS than during PFMT (P <0.001). CONCLUSION: EPNS is more effective than PFMT+TES in short-term (8 weeks) treatments of early urinary incontinence after radical prostatectomy. Its mechanism of action is that EPNS can excite the pudendal nerve and simulate PFMT.

The protective effect of manganese superoxide dismutase from thermophilic bacterium HB27 on hydrochloric acid-induced chemical cystitis in rats.

PURPOSE: To evaluate the effects of manganese superoxide dismutase (Mn-SOD) from thermophilic bacterium HB27 (name as Tt-SOD) on chemical cystitis. METHODS: Control and experimental rats were infused by intravesical saline or hydrochloric acid (HCl) on the first day of the experiments. Saline, sodium hyaluronate (SH) or Tt-SOD were infused intravesically once a day for three consequent days. On the fifth day, the rats were weighted and sacrificed following a pain threshold test. The bladder was harvested for histological and biochemical analyses. RESULTS: Tt-SOD could reduce the bladder index, infiltration of inflammatory cells in tissues, serum inflammatory factors and SOD levels, mRNA expression of inflammatory factors in tissues, and increase perineal mechanical pain threshold and serum MDA and ROS levels in HCl-induced chemical cystitis. Furthermore, Tt-SOD alleviated inflammation and oxidative stress by the negative regulation of the NF-κB p65 and p38 MAPK signaling pathway. CONCLUSIONS: Intravesical instillation of Tt-SOD provides protective effects against HCl-induced cystitis.