m6A-methylated Lonp1 drives mitochondrial proteostasis stress to induce testicular pyroptosis upon environmental cadmium exposure.

Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as cell apoptosis and necrosis. However, as a new type of cell death, the role and mechanism of pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury.

A long-term prognosis study of human USP8-mutated ACTH-secreting pituitary neuroendocrine tumours.

OBJECTIVE: Somatic variants in the ubiquitin-specific protease 8 (USP8) gene are the most common genetic cause of Cushing disease. We aimed to explore the relationship between clinical outcomes and USP8 status in a single centre. DESIGN, PATIENTS AND MEASUREMENTS: We investigated the USP8 status in 48 patients with pituitary corticotroph tumours. A median of 62 months of follow-up was conducted after surgery from November 2013 to January 2015. The clinical, biochemical and imaging features were collected and analysed. RESULTS: Seven USP8 variants (p.Ser718Pro, p.Ser719del, p.Pro720Arg, p.Pro720Gln, p.Ser718del, p.Ser718Phe, p.Lys713Arg) were identified in 24 patients (50%). USP8 variants showed a female predominance (100% vs. 75% in wild type [WT], p = .022). Patients with p.Ser719del showed an older age at surgery compared to patients with the p.Pro720Arg variant (47- vs. 24-year-olds, p = .033). Patients with p.Pro720Arg showed a higher rate of macroadenoma compared to patients harbouring the p.Ser718Pro variant (60% vs. 0%, p = .037). No significant differences were observed in serum and urinary cortisol and adrenocorticotropin hormone (ACTH) levels. Immediate surgical remission (79% vs. 75%) and long-term hormone remission (79% vs. 67%) were not significantly different between the two groups. The recurrence rate was 21% (4/19) in patients harbouring USP8 variants and 13% (2/16) in WT patients. Recurrence-free survival presented a tendency to be shorter in USP8-mutated individuals (76.7 vs. 109.2 months, p = .068). CONCLUSIONS: Somatic USP8 variants accounted for 50% of the genetic causes in this cohort with a significant female frequency. A long-term follow-up revealed a tendency toward shorter recurrence-free survival in USP8-mutant patients.

Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

BACKGROUND: The relationship between socio-economic status and bone-related diseases is attracting increasing attention. Therefore, a bidirectional Mendelian randomization (MR) analysis was performed in this study. METHODS: Genetic data on factors associated with socio-economic status (average total household income before tax, years of schooling completed and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fracture (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses, and multivariable MR was performed to enhance the robustness of our findings. RESULTS: A higher educational attainment was associated with an increased level of eBMD (beta:0.06, 95% CI:0.01-0.10, P = 7.24 × 10-3), and decreased risk of osteoporosis (OR:0.78, 95% CI:0.65-0.94, P = 8.49 × 10-3), spine fracture (OR:0.76, 95% CI:0.66-0.88, P = 2.94 × 10-4), femur fracture (OR:0.78, 95% CI:0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR:0.79, 95% CI:0.70-0.88, P = 2.05 × 10-5), foot fracture (OR:0.78, 95% CI:0.66-0.93, P = 5.92 × 10-3) and wrist-hand fracture (OR:0.83, 95% CI:0.73-0.95, P = 7.15 × 10-3). Further, material deprivation seemed to harm the spine fracture (OR:2.63, 95% CI:1.43-4.85, P = 1.91 × 10-3). A higher level of FN-BMD positively affected increased household income (beta:0.03, 95% CI:0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index (BMI), type 2 diabetes, smoking initiation, and frequency of alcohol intake. CONCLUSIONS: The Mendelian randomization analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings offer valuable insights into the formulation of health guidelines and policy development.

We conducted stratified analyses to explore the causal links between socio-economic status and osteoporosis and various fractures and observed that education significantly reduced risk of osteoporosis and lower eBMD. It also lowered the risks of fractures of spine, femur, lower leg-ankle, foot, and wrist-hand, while material deprivation exhibited positive associations with spine fracture risk. Bidirectional MR analysis showed that an elevated score of FN-BMD was associated with a higher income level. Our study shows the importance of conducting routine BMD estimations and osteoporosis screening, to enhance knowledge and awareness among individuals to promote bone health and prevent fractures.

Young osteocyte-derived extracellular vesicles facilitate osteogenesis by transferring tropomyosin-1.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging. RESULTS: Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo. CONCLUSIONS: Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis.

NBR1-dependent autophagy activation protects against environmental cadmium-evoked placental trophoblast senescence.

Cadmium (Cd), a well-established developmental toxicant, accumulates in the placentae and disrupts its structure and function. Population study found adverse pregnancy outcomes caused by environmental Cd exposure associated with cell senescence. However, the role of autophagy activation in Cd-induced placental cell senescence and its reciprocal mechanisms are unknown. In this study, we employed animal experiments, cell culture, and case-control study to investigate the above mentioned. We have demonstrated that exposure to Cd during gestation induces placental senescence and activates autophagy. Pharmacological and genetic interventions further exacerbated placental senescence induced by Cd through the suppression of autophagy. Conversely, activation of autophagy ameliorated Cd-induced placental senescence. Knockdown of NBR1 exacerbated senescence in human placental trophoblast cells. Further investigations revealed that NBR1 facilitated the degradation of p21 via LC3B. Our case-control study has demonstrated a positive correlation between placental senescence and autophagy activation in all-cause fetal growth restriction (FGR). These findings offer a novel perspective for mitigating placental aging and placental-origin developmental diseases induced by environmental toxicants.

Transurethral surgical treatment for benign prostatic hyperplasia with detrusor underactivity: a systematic review and meta-analysis.

BACKGROUND: The efficacy of surgical treatment for benign prostatic hyperplasia (BPH) patients with detrusor underactivity (DU) remains controversial. METHODS: To summarize relevant evidence, three databases (PubMed, Embase, and Web of Science) were searched from database inception to May 1, 2023. Transurethral surgical treatment modalities include transurethral prostatectomy (TURP), photoselective vaporization of the prostate (PVP), and transurethral incision of the prostate (TUIP). The efficacy of the transurethral surgical treatment was assessed according to maximal flow rate on uroflowmetry (Qmax), International Prostate Symptom Score (IPSS), postvoid residual (PVR), quality of life (QoL), voided volume, bladder contractility index (BCI) and maximal detrusor pressure at maximal flow rate (PdetQmax). Pooled mean differences (MDs) were used as summary statistics for comparison. The quality of enrolled studies was evaluated by using the Newcastle-Ottawa Scale. Sensitivity analysis and funnel plots were applied to assess possible biases. RESULTS: In this study, 10 studies with a total of 1142 patients enrolled. In BPH patients with DU, within half a year, significant improvements in Qmax (pooled MD, 4.79; 95% CI, 2.43-7.16; P < 0.05), IPSS(pooled MD, - 14.29; 95%CI, - 16.67-11.90; P < 0.05), QoL (pooled MD, - 1.57; 95% CI, - 2.37-0.78; P < 0.05), voided volume (pooled MD, 62.19; 95% CI, 17.91-106.48; P < 0.05), BCI (pooled MD, 23.59; 95% CI, 8.15-39.04; P < 0.05), and PdetQmax (pooled MD, 28.62; 95% CI, 6.72-50.52; P < 0.05) were observed after surgery. In addition, after more than 1 year, significant improvements were observed in Qmax (pooled MD, 6.75; 95%CI, 4.35-9.15; P < 0.05), IPSS(pooled MD, - 13.76; 95%CI, - 15.17-12.35; P < 0.05), PVR (pooled MD, - 179.78; 95%CI, - 185.12-174.44; P < 0.05), QoL (pooled MD, - 2.61; 95%CI, - 3.12-2.09; P < 0.05), and PdetQmax (pooled MD, 27.94; 95%CI, 11.70-44.19; P < 0.05). Compared with DU patients who did not receive surgery, DU patients who received surgery showed better improvement in PVR (pooled MD, 137.00; 95%CI, 6.90-267.10; P < 0.05) and PdetQmax (pooled MD, - 8.00; 95%CI, - 14.68-1.32; P < 0.05). CONCLUSIONS: Our meta-analysis results showed that transurethral surgery can improve the symptoms of BPH patients with DU. Surgery also showed advantages over pharmacological treatment for BPH patients with DU. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023415188.

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.

Naphthalene Diimide-Based Metallacage as an Artificial Ion Channel for Chloride Ion Transport.

Developing synthetic molecular devices for controlling ion transmembrane transport is a promising research field in supramolecular chemistry. These artificial ion channels provide models to study ion channel diseases and have huge potential for therapeutic applications. Compared with self-assembled ion channels constructed by intermolecular weak interactions between smaller molecules or cyclic compounds, metallacage-based ion channels have well-defined structures and can exist as single components in the phospholipid bilayer. A naphthalene diimide-based artificial chloride ion channel is constructed through efficient subcomponent self-assembly and its selective ion transport activity in large unilamellar vesicles and the planar lipid bilayer membrane by fluorescence and ion-current measurements is investigated. Molecular dynamics simulations and density functional theory calculations show that the metallacage spans the entire phospholipid bilayer as an unimolecular ion transport channel. This channel transports chloride ions across the cell membrane, which disturbs the ion balance of cancer cells and inhibits the growth of cancer cells at low concentrations.

Maternal prednisone exposure during pregnancy elevates susceptibility to osteoporosis in female offspring: The role of mitophagy/FNDC5 alteration in skeletal muscle.

Maternal exposure to glucocorticoids has been associated with adverse outcomes in offspring. However, the consequences and mechanisms of gestational exposure to prednisone on susceptibility to osteoporosis in the offspring remain unclear. Here, we found that gestational prednisone exposure enhanced susceptibility to osteoporosis in adult mouse offspring. In a further exploration of myogenic mechanisms, results showed that gestational prednisone exposure down-regulated FNDC5/irisin protein expression and activation of OPTN-dependent mitophagy in skeletal muscle of adult offspring. Additional experiments elucidated that activated mitophagy significantly inhibited the expression of FNDC5/irisin in skeletal muscle cells. Likewise, we observed delayed fetal bone development, downregulated FNDC5/irisin expression, and activated mitophagy in fetal skeletal muscle upon gestational prednisone exposure. In addition, an elevated total m6A level was observed in fetal skeletal muscle after gestational prednisone exposure. Finally, gestational supplementation with S-adenosylhomocysteine (SAH), an inhibitor of m6A activity, attenuated mitophagy and restored FNDC5/irisin expression in fetal skeletal muscle, which in turn reversed fetal bone development. Overall, these data indicate that gestational prednisone exposure increases m6A modification, activates mitophagy, and decreases FNDC5/irisin expression in skeletal muscle, thus elevating osteoporosis susceptibility in adult offspring. Our results provide a new perspective on the earlier prevention and treatment of fetal-derived osteoporosis.

Environmental cadmium inhibits testicular testosterone synthesis via Parkin-dependent MFN1 degradation.

Low testosterone (T) levels are associated with many common diseases, such as obesity, male infertility, depression, and cardiovascular disease. It is well known that environmental cadmium (Cd) exposure can induce T decline, but the exact mechanism remains unclear. We established a murine model in which Cd exposure induced testicular T decline. Based on the model, we found Cd caused mitochondrial fusion disorder and Parkin mitochondrial translocation in mouse testes. MFN1 overexpression confirmed that MFN1-dependent mitochondrial fusion disorder mediated the Cd-induced T synthesis suppression in Leydig cells. Further data confirmed Cd induced the decrease of MFN1 protein by increasing ubiquitin degradation. Testicular specific Parkin knockdown confirmed Cd induced the ubiquitin-dependent degradation of MFN1 protein through promoting Parkin mitochondrial translocation in mouse testes. Expectedly, testicular specific Parkin knockdown also mitigated testicular T decline. Mito-TEMPO, a targeted inhibitor for mitochondrial reactive oxygen species (mtROS), alleviated Cd-caused Parkin mitochondrial translocation and mitochondrial fusion disorder. As above, Parkin mitochondrial translocation induced mitochondrial fusion disorder and the following T synthesis repression in Cd-exposed Leydig cells. Collectively, our study elucidates a novel mechanism through which Cd induces T decline and provides a new treatment strategy for patients with androgen disorders.

High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.

Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.

A Laparoscopically Compatible Rapid-Adhesion Bioadhesive for Asymmetric Adhesion, Non-Pressing Hemostasis, and Seamless Seal.

Bioadhesive hydrogels offer unprecedented opportunities in hemostatic agents and tissue sealing; however, the application of existing bioadhesive hydrogels through narrow spaces to achieve strong adhesion in fluid-rich physiological environments is challenged either by undesired indiscriminate adhesion or weak wet tissue adhesion. Here, a laparoscopically compatible asymmetric adhesive hydrogel (aAH) composed of sprayable adhesive hydrogel powders and injectable anti-adhesive glue is proposed for hemostasis and to seal the bloody tissues in a non-pressing way, allowing for preventing postoperative adhesion. The powders can seed on the irregular bloody wound to rapidly absorb interfacial fluid, crosslink, and form an adhesive hydrogel to hemostatic seal (blood clotting time and tissue sealing in 10 s, ≈200 mm Hg of burst pressure in sealed porcine tissues). The aAH can be simply formed by crosslinking the upper powder with injectable glue to prevent postoperative adhesion (adhesive strength as low as 1 kPa). The aAH outperforms commercial hemostatic agents and sealants in the sealing of bleeding organs in live rats, demonstrating superior anti-adhesive efficiency. Further, the hemostatic seamless sealing by aAH succeeds in shortening the time of warm ischemia, decreasing the blood loss, and reducing the possibility of rebleeding in the porcine laparoscopic partial nephrectomy model.

Repressing HIF-1α-induced HDAC9 contributes to the synergistic effect of venetoclax and MENIN inhibitor in KMT2Ar AML.

KMT2A-rearranged acute myeloid leukemia (KMT2Ar-AML) is an aggressive subtype of AML with poor response and prognosis. KMT2Ar-AML has been demonstrated to be sensitive to BCL2 inhibitor venetoclax (VEN), but these patients are unable to benefit from current VEN-based regimen (VEN plus azacitidine or low dose-cytarabine), so a novel and KMT2A rearrangement-specific targeting partner is required, and MENIN inhibitor (MEN1i) is a promising one. Herein, we investigated the effect and mechanism of VEN plus MEN1i in KMT2Ar-AML. Our results showed that VEN and MEN1i exhibited a striking synergistic effect in KMT2Ar-AML cell lines (in vitro), primary KMT2Ar-AML cells (ex vivo), and MOLM13 xenotransplantation model (in vivo). Furthermore, we found that VEN plus MEN1i significantly enhanced apoptotic induction in KMT2Ar-AML cell lines. VEN or MEN1i monotherapy disrupted balance of BCL-2/BCL-XL or down-regulated HOXA9/MEIS1, respectively, but these mechanisms were not further strengthened by their combination. RNA-Sequencing identified that HDAC9 was specifically repressed by VEN plus MEN1i rather than monotherapy. We demonstrated that HDAC9 was indispensable for KMT2Ar-AML proliferation and its repression contributed to proliferation inhibition of VEN plus MEN1i. Moreover, we found that hypoxia induced HDAC9 expression in KMT2Ar-AML, and VEN plus MEN1i inhibited hypoxia pathway, especially HIF-1A, and its target HDAC9. As our results indicated, VEN plus MEN1i-mediated HDAC9 down-regulation was partially dependent on HIF-1A repression in KMT2Ar-AML. Hypoxia induction sensitized KMT2Ar-AML to VEN plus MI-503-mediated proliferation inhibition and apoptosis induction. Therefore, repressing HIF-1A-induced HDAC9 contributed to the synergistic effect of VEN and MEN1i in KMT2Ar-AML.

Detection of Human Papillomavirus in Squamous Papilloma of the Esophagus.

Introduction: The etiology of esophageal squamous papilloma (ESP) is largely unknown. Previous studies have shown a variable association with human papillomavirus (HPV) with conflicting data. The aim of this study was to further investigate the possible association of HPV in our ESP series using RNA in-situ hybridization (ISH) and compare study groups from the United States of America and China. Methods: Demographic and clinical data of patients with ESP were retrieved from the University of California Los Angeles (UCLA) (1/2016-3/2019) and Peking Union Medical College Hospital (PUMCH) (9/2014-3/2019) pathology databases. Hematoxylin and eosin slides were reexamined. Confirmed cases were examined by high- and low-risk HPV RNA ISH. Results: For the UCLA cohort, 13 429 upper endoscopies were performed and 78 biopsies from 72 patients were identified as ESP (F:M = 45:27, 66.7% > 45 years). Seventy-four (94.9%) biopsies were designated as polyps or nodules and 46.6% were located in the mid-esophagus. Other abnormal findings included gastroesophageal reflux disease (48.6%), hiatal hernia (38.9%), and esophagitis (36.1%). For the PUMCH cohort, 63 754 upper endoscopies were performed and 73 biopsies from 71 patients were identified as ESP (F:M = 48:23, 71.8% > 45 years). Sixty-four (87.7%) biopsies were designated as polyps or nodules and 57.5% were located in the mid-esophagus. Other abnormal findings included esophagitis (19.7%), and hiatal hernia (8.5%). No features of conventional cytologic dysplasia or viral cytopathic change were found. None of the cases was associated with squamous cell carcinoma, and none showed positive HPV RNA ISH results. Conclusions: No association was found between ESP and active HPV infection in our 2 cohorts. Other etiopathogenetic mechanisms, such as aging, might contribute to the development of these innocent lesions.

Vascular wall microenvironment: exosomes secreted by adventitial fibroblasts induced vascular calcification.

Vascular calcification often occurs in patients with chronic renal failure (CRF), which significantly increases the incidence of cardiovascular events in CRF patients. Our previous studies identified the crosstalk between the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and the paracrine effect of VSMCs, which regulate the calcification of VSMCs. Herein, we aim to investigate the effects of exosomes secreted by high phosphorus (HPi) -induced adventitial fibroblasts (AFs) on the calcification of VSMCs and the underlying mechanism, which will further elucidate the important role of AFs in high phosphorus vascular wall microenvironment. The conditioned medium of HPi-induced AFs promotes the calcification of VSMCs, which is partially abrogated by GW4869, a blocker of exosomes biogenesis or release. Exosomes secreted by high phosphorus-induced AFs (AFsHPi-Exos) show similar effects on VSMCs. miR-21-5p is enriched in AFsHPi-Exos, and miR-21-5p enhances osteoblast-like differentiation of VSMCs by downregulating cysteine-rich motor neuron 1 (Crim1) expression. AFsHPi-Exos and exosomes secreted by AFs with overexpression of miR-21-5p (AFsmiR21M-Exos) significantly accelerate vascular calcification in CRF mice. In general, AFsHPi-Exos promote the calcification of VSMCs and vascular calcification by delivering miR-21-5p to VSMCs and subsequently inhibiting the expression of Crim1. Combined with our previous studies, the present experiment supports the theory of vascular wall microenvironment.

The regulation of circRNA and lncRNAprotein binding in cardiovascular diseases: Emerging therapeutic targets.

Noncoding ribonucleic acids (ncRNAs) are a class of ribonucleic acids (RNAs) that carry cellular information and perform essential functions. This class encompasses various RNAs, such as small nuclear ribonucleic acids (snRNA), small interfering ribonucleic acids (siRNA) and many other kinds of RNA. Of these, circular ribonucleic acids (circRNAs) and long noncoding ribonucleic acids (lncRNAs) are two types of ncRNAs that regulate crucial physiological and pathological processes, including binding, in several organs through interactions with other RNAs or proteins. Recent studies indicate that these RNAs interact with various proteins, including protein 53, nuclear factor-kappa B, vascular endothelial growth factor, and fused in sarcoma/translocated in liposarcoma, to regulate both the histological and electrophysiological aspects of cardiac development as well as cardiovascular pathogenesis, ultimately leading to a variety of genetic heart diseases, coronary heart disease, myocardial infarction, rheumatic heart disease and cardiomyopathies. This paper presents a thorough review of recent studies on circRNA and lncRNAprotein binding within cardiac and vascular cells. It offers insight into the molecular mechanisms involved and emphasizes potential implications for treating cardiovascular diseases.

circSLC25A13 acts as a ceRNA to regulate AML progression via miR-616-3p/ADCY2 axis.

Circular RNAs (circRNAs), a type of endogenous noncoding RNA (ncRNA), exert vital roles in leukemia progression and are promising prognostic factors. Here, we report a novel circRNA, circSLC25A13 (hsa_circ_0081188), which was increased in acute myeloid leukemia (AML) patients with poor overall survival (OS) comparing to patients with good prognosis. Knockdown of circSLC25A13 in AML cells inhibited proliferation and increased cell apoptosis in vitro and in vivo. Enhanced circSLC25A13 expression promoted the survival of AML cells. Mechanistically, circSLC25A13 played as a microRNA sponge of miR-616-3p, which inhibited the expression of adenylate cyclase 2 (ADCY2). Downregulation of miR-616-3p and overexpression of ADCY2 partially rescued circSLC25A13 deficient induced cell growth arrest. In summary, through competitive absorption of miR-616-3p and thereby upregulating ADCY2 expression, circSLC25A13 promoted AML progression. Moreover, circSLC25A13 may represent a potential novel biomarker for the prognosis of AML and offer a potential therapeutic target for AML treatment.

Sperm Rhoa m6A modification mediates intergenerational transmission of paternally acquired hippocampal neuronal senescence and cognitive deficits after combined exposure to environmental cadmium and high-fat diet in mice.

Little is currently known about the effect and mechanism of combined paternal environmental cadmium (Cd) and high-fat diet (HFD) on offspring cognitive ability. Here, using in vivo model, we found that combined paternal environmental Cd and HFD caused hippocampal neuronal senescence and cognitive deficits in offspring. MeRIP-seq revealed m6A level of Rhoa, a regulatory gene of cellular senescence, was significantly increased in combined environmental Cd and HFD-treated paternal sperm. Interestingly, combined paternal environmental Cd and HFD markedly enhanced Rhoa mRNA, its m6A and reader protein IGF2BP1 in offspring hippocampus. STM2457, the inhibitor of m6A modification, markedly mitigated paternal exposure-caused the elevation of hippocampal Rhoa m6A, neuronal senescence and cognitive deficits in offspring. In vitro experiments, Rhoa siR significantly reversed mouse hippocampal neuronal senescence. Igf2bp1 siR obviously reduced the level and stability of Rhoa in aging mouse hippocampal neuronal cells. In conclusion, combined paternal environmental Cd and HFD induce offspring hippocampal neuronal senescence and cognitive deficits by promoting IGF2BP1-mediated Rhoa stabilization in offspring hippocampus via elevating Rhoa m6A in paternal sperm.

Global publication trends and research trends of necroptosis application in tumor: A bibliometric analysis.

Introduction: Necroptosis is an alternative, caspase-independent programmed cell death that appears when apoptosis is inhibited. A gowing number of studies have reflected the link between necroptosis and tumors. However, only some systematical bibliometric analyses were focused on this field. In this study, we aimed to identify and visualize the cooperation between countries, institutions, authors, and journals through a bibliometric analysis to help understand the hotspot trends and emerging topics regarding necroptosis and cancer research. Methods: The articles and reviews on necroptosis and cancer were obtained from the Web of Science Core Collection on 16 September 2022. Countries, institutions, authors, references, and keywords in this field were visually analyzed by CtieSpace 5.8.R3, VOSviewer 1.6.18, and R package "bibliometrix." Results: From 2006 to 2022, 2,216 qualified original articles and reviews on necroptosis in tumors were published in 685 academic journals by 13,009 authors in 789 institutions from 75 countries/regions. Publications focusing on necroptosis and cancer have increased violently in the past 16 years, while the citation number peaked around 2008-2011. Most publications were from China, while the United States maintained the dominant position as a "knowledge bridge" in necroptosis and cancer research; meanwhile, Ghent University and the Chinese Academy of Sciences were the most productive institutions. Moreover, only a tiny portion of the articles were multiple-country publications. Peter Vandenabeele had the most significant publications, while Alexei Degterev was most often co-cited. Peter Vandenabeele also gets the highest h-index and g-index in this research field. Cell Death and Disease was the journal with the most publications on necroptosis and cancer, which was confirmed to be the top core source by Bradford's Law. At the same time, Cell was the leading co-cited journal, and the focus area of these papers was molecular, biology, and immunology. High-frequency keywords mainly contained those that are molecularly related (MLKL, NF-kB, TNF, RIPK3, RIPK1), pathological process related (necroptosis, apoptosis, cell-death, necrosis, autophagy), and mechanism related (activation, expression, mechanisms, and inhibition). Conclusion: This study comprehensively overviews necroptosis and cancer research using bibliometric and visual methods. Research related to necroptosis and cancer is flourishing. Cooperation and communication between countries and institutions must be further strengthened. The information in our paper would provide valuable references for scholars focusing on necroptosis and cancer.