Heterologous expression of sulfur: quinone oxidoreductase (Sqr) to improve Thioalkalivibrio versutus D301 desulfurization performance.

AIMS: Heterologous expression of sulfur: quinone oxidoreductase (Sqr) from Halomonas mongoliensis JS01, which is responsible for oxidizing sulfide to elemental sulfur, in Thioalkalivibrio versutus (T. versutus) D301 improves desulfurization. METHODS AND RESULTS: We expressed sqr in T. versutus D301 by conjugative transfer and then assayed its desulfurization capacity in an airlift reactor and analyzed its transcriptome at -380 mV ORP. Our findings demonstrate that the D301-sqr+ strain, utilizing sodium sulfide as a sulfur source under optimal ORP conditions (-380 mV), achieved an elemental sulfur yield of 95%. This represents an 8% increase over the T. versutus D301. Moreover, the sodium sulfide utilization rate for D301-sqr+ showed a marked improvement [0.741 vs. 0.651 mmol∙(l·h)-1], with a concurrent increase in the rate of elemental sulfur production when compared to the T. versutus D301 (0.716 vs. 0.518 mmol ∙(l·h)-1). Transcriptome analysis revealed that the flavocytochrome c (fcc) and the sox system were differentially transcriptionally down-regulated in D301-sqr+ compared with the T. versutus D301. CONCLUSIONS: Heterologous expression of the gene sqr altered the transcription of related genes in T. versutus D301 sulfur oxidation pathway, increasing the yield of elemental sulfur and the rate of sulfur oxidation, and making D301-sqr+ more potential for industrial applications.

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.

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.

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.

Laparoscopic Nerve-Sparing Radical Hysterectomy vs Laparoscopic Radical Hysterectomy in Cervical Cancer: A Systematic Review and Meta-Analysis of Clinical Efficacy and Bladder Dysfunction.

It is widely accepted that nerve-sparing radical hysterectomy is associated with less postoperative morbidity compared with radical hysterectomy, whereas clinical safety is similar in the 2 procedures. However, there is insufficient evidence to compare these procedures performed via a laparoscopic approach. We performed a systematic review and meta-analysis of studies to compare the clinical efficacy and the rate of bladder dysfunction, including urodynamic assessment, in laparoscopic nerve-sparing radical hysterectomy (LNSRH) and laparoscopic radical hysterectomy (LRH). Thirty articles including a total of 2743 participants were analyzed. Operating times were shorter (MD, 29.88 minutes; 95% confidence interval [CI], 11.92-47.83 minutes) and hospital stays were longer (MD, -1.56 days; 95% CI, -2.27 to -0.84 days) in the LRH group compared with the LNSRH group. In addition, blood loss and the number of resected lymph nodes were not significantly different between the 2 groups. However, resected parametrium length (MD, -0.02 cm; 95% CI, -0.05 to -0.00 cm) and vaginal cuff width (MD, -0.06 cm; 95% CI, -0.09 to -0.04) were smaller in the LNSRH group. Furthermore, LNSRH tended to result in more satisfactory micturition (odds ratio, 2.90; 95% CI, 2.01-4.19), shorter catheterization time (MD, -7.20 days; 95% CI, -8.10 to -6.29 days), and shorter recovery to normal postvoid residual urine time (MD, -7.71 days; 95% CI, -8.92 to -6.50 days). Other bladder dysfunction symptoms, including urinary retention, nocturia, dysuria, urinary incontinence, and frequency/urgency were more frequent in the LRH group. Furthermore, LNSRH achieved better results in urodynamic assessments (all p < .05). In conclusion, LNSRH was associated with lower rates of impaired bladder function and a shorter extent of resection compared with LRH. Clinical applications involving LNSRH should be explored with caution.

Results of Sacral Neuromodulation Therapy for Urinary Voiding Dysfunction: Five-Year Experience of a Retrospective, Multicenter Study in China.

PURPOSE: This five-year, retrospective, multicenter study evaluated the long-term safety and efficiency of sacral neuromodulation (SNM) in Chinese patients with urinary voiding dysfunction. PATIENTS AND METHODS: This is a Chinese national, multicenter, retrospective study that included 247 patients (51.2% female) who received an implantable pulse generator (IPG) (InterStim, Medtronic, Minneapolis, MN, USA) between 2012 and 2016. Success was considered if the initial ≥50% improvement in any of primary voiding diary variables persisted compared with baseline. The results were further stratified by identifying patients who showed >50% improvement and those although showed <50% improvement but still wanted to receive IPG; these data were collected and analyzed for general improvement. RESULTS: Following test stimulation, 187 patients (43%) declined implantation and 247 (57%) underwent implantation using InterStim®. Among 247 patients, 34 (13.7%) had overactive bladder (OAB), 59 (23.8%) had interstitial cystitis/bladder pain syndrome (IC/BPS), 47 (19%) had idiopathic urinary retention (IUR), and 107 (44.1%) had neurogenic bladder (NB). IPG efficiency rate for OAB, interstitial cystitis/bladder pain syndrome, idiopathic urinary retention, and neurogenic bladder were 42.5, 72.4, 51.6, and 58.8%, respectively. The mean duration of follow-up was 20.1 ± 12.8 months. CONCLUSIONS: SNM appears effective in the long term, with a total IPG implantation rate of approximately 57% (ranging between 42.5 and 72.4% depending on indication). Interstitial cystitis/bladder pain syndrome appear to be the best indication for stage I testing. Chinese neurogenic bladder patients are most inclined to choose SNM. SNM is relatively safe, with low postoperation adverse events of 16.1% and reoperation rate of 3.2% during the follow-up period.

Microrna-139-5p inhibits epithelial-mesenchymal transition and fibrosis in post-menopausal women with interstitial cystitis by targeting LPAR4 via the PI3K/Akt signaling pathway.

The study explores whether miR-139-5p targeting LPAR4 affects epithelial-mesenchymal transition (EMT) and fibrosis in post-menopausal women with interstitial cystitis (IC) via the PI3K/Akt signaling pathway. Bladder tissues of IC and normal bladder tissues were collected. The pathology of bladder tissues was observed by HE, Masson and Picrosirius red staining. LPAR4 positive expression rate were determined by IHC. ELISA was performed to detect the levels of IL-6, IL-8, IL-10, and TNF-α. Rat IC models were randomized into seven different groups. miR-139-5p, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, P13K, Akt, E-cadherin, N-cadherin, Vimentin, TGF-ß1, and CTGF expression were determined by RT-qPCR and Western blotting. Dual luciferase reporter gene assay verified that LPAR4 is a target gene of miR-139-5p. Fibrosis was a pathological manifestation of IC. The IC group showed higher LPAR4, PI3K, Akt, p-PI3K, p-Akt, N-cadherin, Vimentin, TGF-ß1, and CTGF expression but lower miR-139-5p and E-cadherin expression than the normal group. The levels of IL-6, IL-8, IL-10, and TNF-α expression decreased while HB-EGF increased in the IC group in comparison of the normal group. Compared with the blank and NC groups, E-cadherin expression was increased in the miR-139-5p mimic and siRNA-LPAR4 groups, while LPAR4, PI3K, Akt, p-P13K, p-Akt, N-cadherin, Vimentin, TGF-ß1, and CTGF expression were decreased. An opposite trend was found in the miR-139-5p inhibitor group. The miR-139-5p decreased in the miR-139-5p inhibitor + siRNA-LPAR4 and miR-139-5p inhibitor + wortmannin groups. Conclusively, miR-139-5p targeting LPAR4 inhibits EMT and fibrosis in post-menopausal IC women through the PI3K/Akt signaling pathway.

Efficacy of Electrical Pudendal Nerve Stimulation versus Transvaginal Electrical Stimulation in Treating Female Idiopathic Urgency Urinary Incontinence.

PURPOSE: We compared the efficacy of electrical pudendal nerve stimulation vs transvaginal electrical stimulation to treat female idiopathic urgency urinary incontinence. MATERIALS AND METHODS: A total of 120 female patients with idiopathic urgency urinary incontinence refractory to medication were randomized at a ratio of 2:1 to group 1 of 80 patients and group 2 of 40. Groups 1 and 2 were treated with electrical pudendal nerve stimulation and transvaginal electrical stimulation, respectively. To perform electrical pudendal nerve stimulation long acupuncture needles were deeply inserted into 4 sacrococcygeal points and electrified to stimulate pudendal nerves. Outcome measures were the 24-hour pad test and a questionnaire to measure the severity of symptoms and quality of life in women with urgency urinary incontinence. RESULTS: The median severity of symptoms and quality of life score on the urgency urinary incontinence questionnaire (urgency urinary incontinence total score) was 13 (range 7 to 18.75) in group 1 and 11 (range 8 to 16) in group 2 before treatment, which decreased to 2 (range 0 to 6.75) in group 1 and 6.5 (range 3.25 to 10.75) in group 2 (both p <0.01) after the completion of treatment. At the end of treatment in group 1 complete symptom resolution was noted in 34 patients (42.5%), with a 50% or greater symptom improvement rate in 70.1%. In group 2 complete symptom resolution was noted in 1 patient (2.5%) with a 50% or greater symptom improvement rate in 45.0%. The posttreatment urgency urinary incontinence total score was lower and the therapeutic effect was better in group 1 than in group 2 (both p <0.01). CONCLUSIONS: Electrical pudendal nerve stimulation is more effective than transvaginal electrical stimulation in treating drug refractory, female idiopathic urgency urinary incontinence.

Development of SSR markers and identification of major quantitative trait loci controlling shelling percentage in cultivated peanut (Arachis hypogaea L.).

KEY MESSAGE: A total of 204,439 SSR markers were developed in diploid genomes, and 25 QTLs for shelling percentage were identified in a RIL population across 4 years including five consistent QTLs. Cultivated peanut (Arachis hypogaea L.) is an important grain legume providing edible oil and protein for human nutrition. Genome sequences of its diploid ancestors, Arachis duranensis and A. ipaensis, were reported, but their SSRs have not been well exploited and utilized hitherto. Shelling percentage is an important economic trait and its improvement has been one of the major objectives in peanut breeding programs. In this study, the genome sequences of A. duranensis and A. ipaensis were used to develop SSR markers, and a mapping population (Yuanza 9102 × Xuzhou 68-4) with 195 recombinant inbred lines was used to map QTLs controlling shelling percentage. The numbers of newly developed SSR markers were 84,383 and 120,056 in the A. duranensis and A. ipaensis genomes, respectively. Genotyping of the mapping population was conducted with both newly developed and previously reported markers. QTL analysis using the phenotyping data generated in Wuhan across four consecutive years and genotyping data of 830 mapped loci identified 25 QTLs with 4.46-17.01% of phenotypic variance explained in the four environments. Meta-analysis revealed five consistent QTLs that could be detected in at least two environments. Notably, the consistent QTL cqSPA09 was detected in all four environments and explained 10.47-17.01% of the phenotypic variance. The segregation in the progeny of a residual heterozygous line confirmed that the cpSPA09 locus had additive effect in increasing shelling percentage. These consistent and major QTL regions provide opportunity not only for further gene discovery, but also for the development of functional markers for breeding.

Comparative transcript profiling of resistant and susceptible peanut post-harvest seeds in response to aflatoxin production by Aspergillus flavus.

BACKGROUND: Aflatoxin contamination caused by Aspergillus flavus in peanut (Arachis hypogaea) including in pre- and post-harvest stages seriously affects industry development and human health. Even though resistance to aflatoxin production in post-harvest peanut has been identified, its molecular mechanism has been poorly understood. To understand the mechanism of peanut response to aflatoxin production by A. flavus, RNA-seq was used for global transcriptome profiling of post-harvest seed of resistant (Zhonghua 6) and susceptible (Zhonghua 12) peanut genotypes under the fungus infection and aflatoxin production stress. RESULT: A total of 128.72 Gb of high-quality bases were generated and assembled into 128, 725 unigenes (average length 765 bp). About 62, 352 unigenes (48.43%) were annotated in the NCBI non-redundant protein sequences, NCBI non-redundant nucleotide sequences, Swiss-Prot, KEGG Ortholog, Protein family, Gene Ontology, or eukaryotic Ortholog Groups database and more than 93% of the unigenes were expressed in the samples. Among obtained 30, 143 differentially expressed unigenes (DEGs), 842 potential defense-related genes, including nucleotide binding site-leucine-rich repeat proteins, polygalacturonase inhibitor proteins, leucine-rich repeat receptor-like kinases, mitogen-activated protein kinase, transcription factors, ADP-ribosylation factors, pathogenesis-related proteins and crucial factors of other defense-related pathways, might contribute to peanut response to aflatoxin production. Notably, DEGs involved in phenylpropanoid-derived compounds biosynthetic pathway were induced to higher levels in the resistant genotype than in the susceptible one. Flavonoid, stilbenoid and phenylpropanoid biosynthesis pathways were enriched only in the resistant genotype. CONCLUSIONS: This study provided the first comprehensive analysis of transcriptome of post-harvest peanut seeds in response to aflatoxin production, and would contribute to better understanding of molecular interaction between peanut and A. flavus. The data generated in this study would be a valuable resource for genetic and genomic studies on crops resistance to aflatoxin contamination.

The combination of herbal medicine Weng-li-tong with Tolterodine may be better than Tolterodine alone in the treatment of overactive bladder in women: a randomized placebo-controlled prospective trial.

BACKGROUND: To assess the efficacy and safety of the herbal medicine, Weng-li-tong (WLT) as monotherapy or combined with tolterodine in women with overactive bladder (OAB). METHODS: A prospective, randomized, single-blind multi-center trial was performed which included 182 OAB patients treated with either placebo (n = 26), WLT (n = 52), tolterodine (n = 52) or WLT plus tolterodine (n = 52). The overactive bladder symptom score (OABSS) and micturition behavior were measured to evaluate treatment efficacy. RESULTS: In total, 146 patients [placebo (n = 23), WLT (n = 39), tolterodine (n = 41) and WLT plus tolterodine (n = 43)] completed 8 weeks of treatment. Compared to those treated with placebo, patients in three intervention groups showed significant improvements in the OABSS, voiding frequency, average voided volume and urgency incontinence. WLT had a slower onset than tolterodine or combination therapy in reducing urgency incontinence. Compared with tolterodine, WLT had a weaker effect in improving OABSS (P = 0.022) and daily voiding frequency (P = 0.034). The combination therapy had better efficacy than WLT or tolterodine alone in improving the OABSS, voiding frequency and voided volume. No significant differences in the changes in quality of life scores were observed among the three intervention groups. Residual urine increased significantly in tolterodine group (P = 0.004), but not in combination group. WLT resulted in fewer adverse effects than tolterodine such as dry mouth (P = 0.002), weak stream (P = 0.002) and less residual urine (P < 0.001). CONCLUSIONS: WLT could improve OAB symptoms in women, while it had slower onset and weaker efficacy but fewer adverse effects than tolterodine. The combination of WLT and tolterodine was more efficacious than tolterodine alone in improving OAB symptoms. TRIAL REGISTRATION: Chinese Clinical Trial Registry [ ChiCTR-IPR-14005626 ]. Date of registration: 7 December 2014.

Netrin-1 induces the migration of Schwann cells via p38 MAPK and PI3K-Akt signaling pathway mediated by the UNC5B receptor.

Schwann cells (SCs) play an essentially supportive role in the regeneration of injured peripheral nerve system (PNS). As Netrin-1 is crucial for the normal development of nervous system (NS) and can direct the process of damaged PNS regeneration, our study was designed to determine the role of Netrin-1 in RSC96 Schwann cells (an immortalized rat Schwann cell line) proliferation and migration. Our studies demonstrated that Netrin-1 had no effect on RSC96 cells proliferation, while significantly promoted RSC96 cells migration. The Netrin-1-induced RSC96 cells migration was significantly attenuated by inhibition of p38 and PI3K through pretreatment with SB203580 and LY294002 respectively, but not inhibition of MEK1/2 and JNK by U0126-EtOH and SP600125 individually. Treatment with Netrin-1 enhanced the phosphorylation of p38 and Akt. QRT-PCR indicated that Netrin-1 and only its receptors Unc5a, Unc5b and Neogenin were expressed in RSC96 cells, among which Unc5b expressed the most. And UNC5B protein was significantly increased after stimulated by Netrin-1. In conclusion, we show here that Netrin-1-enhanced SCs migration is mediated by activating p38 MAPK and PI3K-Akt signal cascades via receptor UNC5B, which suggests that Netrin-1 could serve as a new therapeutic strategy and has potential application value for PNS regeneration.

Involvement of periostin-sclerostin-Wnt/ß-catenin signaling pathway in the prevention of neurectomy-induced bone loss by naringin.

Periostin has an essential role in mechanotransduction in bone. Naringin, a natural flavonoid, has been evidenced for its osteoprotective role in osteoporosis, while its mechanism is far from clear. Here we show that down-regulation of periostin, and up-regulation of its downstream sclerostin and inactivation of Wnt/ß-catenin signaling were implicated in neurectomy-induced bone loss. Naringin could up-regulate periostin and prevent neurectomy-induced deterioration of BMD, trabecular microstructure and bone mechanical characteristics. In conclusion, naringin could prevent progress of disuse osteoporosis in rats, which may be mediated by increased periostin expression and subsequently inhibition of sclerostin and activation of Wnt/ß-catenin signaling pathways.

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.

Ethical concerns in aging research: perspectives of global frontline researchers.

This study investigated the ethical landscape of aging research amid the increasing global focus on extending the human lifespan and health span. Our global survey of 180 researchers across 38 jurisdictions revealed divergent perceptions of aging, a consensus regarding the feasibility of delaying aging, and multiple perspectives regarding lifespan extension. The present findings underscore a paradigm shift toward inclusive and ethically sound research, emphasizing the need for an approach that strikes a balance between basic and clinical research. In addition, this study highlighted key ethical concerns in aging research, including the effects of misleading advertising, potential inequality in access to aging interventions, and risks pertaining to the extrapolation of research findings from lower-model organisms to humans. The insights presented in this paper call for an integrated approach for overcoming the complex ethical and societal challenges in aging research to ensure responsible and equitable advancements in this burgeoning field.

Construction of a 5-Gene super-enhancer-related signature for osteosarcoma prognosis and the regulatory role of TNFRSF11B in osteosarcoma.

Osteosarcoma, one of the most common primary malignancies in children and adolescents, has the primary characteristics of a poor prognosis and high rate of metastasis. This study used super-enhancer-related genes derived from two different cell lines to construct five novel super-enhancer-related gene prognostic models for patients with osteosarcoma. The training and testing datasets were used to confirm the prognostic models of the five super-enhancer-related genes, which resulted in an impartial predictive element for osteosarcoma. The immunotherapy and prediction of the response to anticancer drugs have shown that the risk signature of the five super-enhancer-related genes positively correlate with chemosensitivity. Furthermore, functional analysis of the risk signature genes revealed a significant relationship between gene groups and the malignant characteristics of tumours. TNF Receptor Superfamily Member 11b (TNFRSF11B) was selected for functional verification. Silencing of TNFRSF11B suppressed the proliferation, migration, and invasion of osteosarcoma cells in vitro and suppressed osteosarcoma growth in vivo. Moreover, transcriptome sequencing was performed on MG-63 cells to study the regulatory mechanism of TNFRSF11B in osteosarcoma cells, and it was discovered that TNFRSF11B is involved in the development of osteosarcoma via the phosphoinositide 3-kinase signalling pathway. Following the identification of TNFRSF11B as a key gene, we selected an inhibitor that specifically targeted this gene and performed molecular docking simulations. In addition, risedronic acid inhibited osteosarcoma growth at both cellular and molecular levels. In conclusion, the super-enhancer-related gene signature is a viable therapeutic tool for osteosarcoma prognosis and treatment.

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.

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 level of oxidative stress and ferroptosis in IC/BPS patients and LRM rats was 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 tissues. Expression of NRF2 was up-regulated, and GPX4 was decreased in IC/BPS patients compared with normal tissues. IC model cells underwent 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, the 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, the Wnt/ß-catenin signaling suppressed oxidative stress-induced ferroptosis by down-regulating NF-κB to improve bladder injury in IC/BPS.

Preliminary analysis of stimulation parameters for sacral neuromodulation in different indications: a multicenter 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, the authors 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 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 internal pulse generator 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 nonobstructive 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.

Galectin-3 inhibition reduces fibrotic scarring and promotes functional recovery after spinal cord injury in mice.

BACKGROUND: In the context of spinal cord injury (SCI), infiltrating macrophages assume prominence as the primary inflammatory cells within the lesion core, where the fibrotic scar is predominantly orchestrated by platelet-derived growth factor receptor beta (PDGFRß+) fibroblasts. Galectin-3, a carbohydrate-binding protein of the lectin family, is notably expressed by infiltrating hematogenous macrophages and mediates cell-cell interactions. Although Galectin-3 has been shown to contribute to the endocytic internalization of PDGFRß in vitro, its specific role in driving fibrotic scar formation after SCI has not been determined. METHODS: We employed a crush mid-thoracic (T10) SCI mouse model. Galectin-3 inhibition after SCI was achieved through intrathecal injection of the Galectin-3 inhibitor TD139 or in situ injection of lentivirus carrying Galectin-3-shRNA (Lv-shLgals3). A fibrosis-induced mice model was established by in situ injection of platelet-derived growth factor D (PDGFD) or recombinant Galectin-3 (rGalectin-3) into the uninjured spinal cord. Galectin-3 internalization experiments were conducted in PDGFRß+ fibroblasts cocultured in conditioned medium in vitro. RESULTS: We identified the spatial and temporal correlation between macrophage-derived Galectin-3 and PDGFRß in fibroblasts from 3 to 56 days post-injury (dpi). Administration of TD139 via intrathecal injection or in situ injection of Lv-shLgals3 effectively mitigated fibrotic scar formation and extracellular matrix deposition within the injured spinal cord, leading to better neurological outcomes and function recovery after SCI. Furthermore, the fibrosis-inducing effects of exogenous PDGFD in the uninjured spinal cord could be blocked by TD139. In vitro experiments further demonstrated the ability of PDGFRß+ fibroblasts to internalize Galectin-3, with Galectin-3 inhibition resulting in reduced PDGFRß expression. CONCLUSIONS: Our finding underscores the pivotal role of macrophage-derived Galectin-3 in modulating the sustained internalized activation of PDGFRß within fibroblasts, providing a novel mechanistic insight into fibrotic scarring post-SCI.