Intermittent Hypobaric Hypoxia Ameliorates Autistic-Like Phenotypes in Mice.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B -/- and Fmr1 -/y mice, we found that IHH training at an altitude of 5,000 m for 4 h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B -/- mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.

P62 promotes FSH-induced antral follicle formation by directing degradation of ubiquitinated WT1.

In females, the pathophysiological mechanism of poor ovarian response (POR) is not fully understood. Considering the expression level of p62 was significantly reduced in the granulosa cells (GCs) of POR patients, this study focused on identifying the role of the selective autophagy receptor p62 in conducting the effect of follicle-stimulating hormone (FSH) on antral follicles (AFs) formation in female mice. The results showed that p62 in GCs was FSH responsive and that its level increased to a peak and then decreased time-dependently either in ovaries or in GCs after gonadotropin induction in vivo. GC-specific deletion of p62 resulted in subfertility, a significantly reduced number of AFs and irregular estrous cycles, which were same as pathophysiological symptom of POR. By conducting mass spectrum analysis, we found the ubiquitination of proteins was decreased, and autophagic flux was blocked in GCs. Specifically, the level of nonubiquitinated Wilms tumor 1 homolog (WT1), a transcription factor and negative controller of GC differentiation, increased steadily. Co-IP results showed that p62 deletion increased the level of ubiquitin-specific peptidase 5 (USP5), which blocked the ubiquitination of WT1. Furthermore, a joint analysis of RNA-seq and the spatial transcriptome sequencing data showed the expression of steroid metabolic genes and FSH receptors pivotal for GCs differentiation decreased unanimously. Accordingly, the accumulation of WT1 in GCs deficient of p62 decreased steroid hormone levels and reduced FSH responsiveness, while the availability of p62 in GCs simultaneously ensured the degradation of WT1 through the ubiquitin‒proteasome system and autophagolysosomal system. Therefore, p62 in GCs participates in GC differentiation and AF formation in FSH induction by dynamically controlling the degradation of WT1. The findings of the study contributes to further study the pathology of POR.

ROCK1 is a multifunctional factor maintaining the primordial follicle reserve and follicular development in mice.

The follicle is the basic structural and functional unit of the ovary in female mammals. The excessive depletion of follicles will lead to diminished ovarian reserve or even premature ovarian failure, resulting in diminished ovarian oogenesis and endocrine function. Excessive follicular depletion is mainly due to loss of primordial follicles. Our analysis of published human ovarian single-cell sequencing results by others revealed a significant increase in rho-associated protein kinase 1 (ROCK1) expression during primordial follicle development. However, the role of ROCK1 in primordial follicle development and maintenance is not clear. This study revealed a gradual increase in ROCK1 expression during primordial follicle activation. Inhibition of ROCK1 resulted in reduced primordial follicle activation, decreased follicular reserve, and delayed development of growing follicles. This effect may be achieved through the HIPPO pathway. The present study indicates that ROCK1 is a key molecule for primordial follicular reserve and follicular development.NEW & NOTEWORTHY ROCK1, one of the Rho GTPases, plays an important role in primordial follicle reserve and follicular development. ROCK1 was primarily expressed in the cytoplasm of oocytes and granulosa cell in mice. Inhibition of ROCK1 significantly reduced the primordial follicle reserve and delayed growing follicle development. ROCK1 regulates primordial follicular reserve and follicle development through the HIPPO signaling pathway. These findings shed new lights on the physiology of sustaining female reproduction.

Pregranulosa cell-derived FGF23 protects oocytes from premature apoptosis during primordial follicle formation by inhibiting p38 MAPK in mice.

A large number of oocytes in the perinatal ovary in rodents get lost for unknown reasons. The granulosa cell-oocyte mutual communication is pivotal for directing formation of the primordial follicle; however, little is known if paracrine factors participate in modulating programmed oocyte death perinatally. We report here that pregranulosa cell-derived fibroblast growth factor 23 (FGF23) functioned in preventing oocyte apoptosis in the perinatal mouse ovary. Our results showed that FGF23 was exclusively expressed in pregranulosa cells, while fibroblast growth factor receptors (FGFRs) were specifically expressed in the oocytes in perinatal ovaries. FGFR1 was one of the representative receptors in mediating FGF23 signaling during the formation of the primordial follicle. In cultured ovaries, the number of live oocytes declines significantly, accompanied by the activation of the p38 mitogen-activated protein kinase signaling pathway, under the condition of FGFR1 disruption by specific inhibitors of FGFR1 or silencing of Fgf23. As a result, oocyte apoptosis increased and eventually led to a decrease in the number of germ cells in perinatal ovaries following the treatments. In the perinatal mouse ovary, pregranulosa cell-derived FGF23 binds to FGFR1 and activates at least the p38 mitogen-activated protein kinase signaling pathway, thereby regulating the level of apoptosis during primordial follicle formation. This study reemphasizes the importance of granulosa cell-oocyte mutual communication in modulating primordial follicle formation and supporting oocyte survival under physiological conditions.

OsSGT1 promotes melatonin-ameliorated seed tolerance to chromium stress by affecting the OsABI5-OsAPX1 transcriptional module in rice.

Chromium (Cr) pollution threatens plant development and growth. Application of melatonin (Mel) is emerging as an effective ally to resist stress, but how Mel ameliorates seed germination upon exposure to heavy metals is poorly understood. Here, we found (i) that seed priming with Mel considerably alleviated Cr stress during rice (Oryza sativa) seed germination and (ii) that germination performance was significantly improved in suppressor of the G2 allele of skp1 (OsSGT1) overexpression lines, while mutations of OsSGT1 and/or abscisic acid-insensitive 5 (OsABI5) noticeably abrogated such Mel-induced tolerance to Cr. Complementation assays suggested that the restored expression of OsSGT1 could not rescue the weak germination of sgt1-1abi5 under Cr stress, even upon Mel priming, but the expression of OsABI5 driven by the promoter of OsSGT1 significantly restored the Mel-ameliorated germination and the expression of ascorbate peroxidase 1 (OsAPX1) in sgt1-1abi5. Further analysis indicated that OsABI5 directly regulated the transcriptional expression of OsAPX1, whose encoding products promoted H2 O2 scavenging to maintain redox homeostasis, which is essential for germination. Collectively, this work demonstrates that OsSGT1 regulates OsABI5 to target OsAPX1, mediating the stimulatory effects of Mel on germination of Cr-stressed seeds, which provides a guide for the application of Mel in rice production.

Effect of Eleutheroside E on an MPTP-Induced Parkinson's Disease Cell Model and Its Mechanism.

This research investigated the effects of eleutheroside E (EE) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease cell model and its mechanism. Methods: To create a cell model of Parkinson's disease, MPTP (2500 µmol/L) was administered to rat adrenal pheochromocytoma cells (PC-12) to produce an MPTP group. Selegiline (50 µmol/L) and MPTP had been administered to the positive group beforehand. The eleutheroside E group was divided into low-, medium-, and high-concentration groups, in which the cells were pretreated with eleutheroside E at concentrations of 100 µmol/L, 300 µmol/L, and 500 µmol/L. Next, MPTP was added to the cells separately. The CCK-8 method was used to measure the cell survival rate. Apart from the CCK-8 method, mitochondrial membrane potential detection, cell reactive oxygen species (ROS) detection, and other methods were also adopted to verify the effect of low, medium, and high concentrations of eleutheroside E on the MPTP-induced cell model. Western blot analysis was used to detect changes in the expression of intracellular proteins CytC, Nrf2, and NQO1 to clarify the mechanism. The results are as follows. Compared with the MPTP group, the survival rates of cells at low, medium, and high concentrations of eleutheroside E all increased. The mitochondrial membrane potential at medium and high concentrations of eleutheroside E increased. The ROS levels at medium and high concentrations of eleutheroside E decreased. Moreover, the apoptosis rate decreased and the expression levels of the intracellular proteins CytC, Nrf2, and NQO1 were upregulated. Conclusion: Eleutheroside E can improve the MPTP-induced apoptosis of PC-12 cells by increasing the mitochondrial membrane potential and reducing the level of intracellular reactive oxygen species (ROS). Moreover, the apoptosis of cells is regulated by the expression of CytC, Nrf2, and NQO1 proteins.

A Review of the Research Applications of Centipeda minima.

Centipeda minima is a traditional Chinese medicine with wide applications and diverse pharmacological effects. Scholars have conducted extensive studies on its relevant clinical applications, especially its remarkable efficacy in cancer treatment. This paper thoroughly investigates the chemical composition and identification, pharmacological effects, and toxicity, along with the safety of Centipeda minima, so as to lay the foundation for corresponding clinical applications and product development. Furthermore, as global scholars have conducted extensive research on such clinical applications and made significant progress, the future development and utilization of Centipeda minima's active ingredients to create novel drugs are of great clinical significance.

Hypoxia downregulated miR-4521 suppresses gastric carcinoma progression through regulation of IGF2 and FOXM1.

BACKGROUND: MicroRNAs (miRNAs) show considerable promise as therapeutic agents to improve tumor treatment, as they have been revealed as crucial modulators in tumor progression. However, our understanding of their roles in gastric carcinoma (GC) metastasis is limited. Here, we aimed to identify novel miRNAs involved in GC metastasis and explored their regulatory mechanisms and therapeutic significance in GC. METHODS: The microRNA expression profiles of GC tumors at different stages and at different metastasis statuses were compared respectively using the stomach adenocarcinoma (STAD) miRNASeq dataset in TCGA. Using the above method, miR-4521 was picked out for further study. miR-4521 expression in GC tissues was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). Highly and lowly invasive cell sublines were established using a repetitive transwell assay. Gain-of-function and loss-of-function analyses were performed to investigate the functions of miR-4521 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Moreover, we investigated the therapeutic role of miR-4521 in a mouse xenograft model. RESULTS: In this study, we found that miR-4521 expression was downregulated in GC tissues compared with adjacent normal tissues and that its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. Functional experiments revealed that miR-4521 inhibited GC cell invasion and metastasis in vitro and in vivo. Further studies showed that hypoxia repressed miR-4521 expression via inducing ETS1 and miR-4521 mitigated hypoxia-mediated metastasis, while miR-4521 inactivated the AKT/GSK3ß/Snai1 pathway by targeting IGF2 and FOXM1, thereby inhibiting the epithelial-mesenchymal transition (EMT) process and metastasis. In addition, we demonstrated that therapeutic delivery of synthetic miR-4521 suppressed gastric carcinoma progression in vivo. CONCLUSIONS: Our results suggest an important role for miR-4521 in regulating GC metastasis and hypoxic response of tumor cells as well as the therapeutic significance of this miRNA in GC.

[Research progress of cyclic adenosine monophosphate in mammalian follicular development].

Cyclic adenosine monophosphate (cAMP) is one of the significant and conserved second messengers in mammals, and it participates in regulating the developmental and physiological functions of various organs and tissues through transducting extracellular signals. Studies have shown that the process of meiosis in female mammalian oocytes is closely related to the level of cAMP and strictly regulated. In oocytes, cAMP is mainly synthesized by adenylate cyclase 3 (AC3) and degraded by phosphodiesterase 3A (PDE3A), both of which jointly regulate the level of cAMP in oocytes and play important roles in the follicular development and oogenesis of female ovaries. It has been well illuminated that high level of cAMP in the cytoplasm of oocytes in growing follicles could maintain the arrest of the first meiotic of oocytes for a long time. The oocytes will resume meiosis and mature either when the synthesis of cAMP is down-regulated, or when cAMP is degraded by PDE3A. In recent years, the novo physiological functions of cAMP in oogenesis have been reported. To better understand the regulatory role and mechanism of cAMP in mammalian gametogenesis, this paper reviews the relevant research regarding the relationship between cAMP and germ cell development.

Genome-wide association study of familial lung cancer.

To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.

CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.

Pathological cardiac hypertrophy is an independent risk factor for heart failure. Disruption of mitochondrial protein homeostasis plays a key role in pathological cardiac hypertrophy; however, the mechanism of maintaining mitochondrial homeostasis in pathological cardiac hypertrophy remains unclear. In this study, we investigated the regulatory mechanisms of mitochondrial protein homeostasis in pathological cardiac hypertrophy. Wildtype (WT) mice, knockout mice, and mice transfected with lentivirus overexpressing mouse C1q-tumor necrosis factor-related protein-3 (CTRP3) underwent transverse aortic constriction or sham surgery. After 4 weeks, cardiac function, mitochondrial function, and oxidative stress injury were examined. For mechanistic studies, neonatal rat cardiomyocytes were treated with small interfering RNA or overexpression plasmids for the relevant genes. CTRP3 overexpression attenuated transverse aortic constriction (TAC) induced pathological cardiac hypertrophy, mitochondrial dysfunction, and oxidative stress injury compared to that in WT mice. TAC or Ang II resulted in compensatory activation of UPRmt, but this was not sufficient to counteract pathologic cardiac hypertrophy. CTRP3 overexpression further induced activation of UPRmt during pathologic cardiac hypertrophy and thereby alleviated pathologic cardiac hypertrophy, whereas CTRP3 knockout or knockdown inhibited UPRmt. ATF5 was a key regulatory molecule of UPRmt, as ATF5 knockout prevented the cardioprotective effect of CTRP3 in TAC mice. In vitro, SIRT1 was identified as a possible downstream CTRP3 effector molecule, and SIRT1 knockout blocked the cardioprotective effects of CTRP3. Our results also suggest that ATF5 may be regulated by SIRT1. Our study demonstrates that CTRP3 activates UPRmt via the SIRT1/ATF5 axis under pathological myocardial hypertrophy, thus attenuating mitochondrial dysfunction and oxidative stress injury.

Oocytes maintain low ROS levels to support the dormancy of primordial follicles.

Primordial follicles (PFs) function as the long-term reserve for female reproduction, remaining dormant in the ovaries and becoming progressively depleted with age. Oxidative stress plays an important role in promoting female reproductive senescence during aging, but the underlying mechanisms remain unclear. Here, we find that low levels of reactive oxygen species (ROS) are essential for sustaining PF dormancy. Compared to growing follicles, oocytes within PFs were shown to be more susceptible to ROS, which accumulates and damages PFs to promote reproductive senescence. Mechanistically, oocytes within PFs were shown to express high levels of the intracellular antioxidant enzyme superoxide dismutase 1 (SOD1), counteracting ROS accumulation. Decreased SOD1 expression, as a result of aging or through the experimental deletion of the Sod1 gene in oocytes, resulted in increased oxidative stress and triggered ferroptosis within PFs. In conclusion, this study identified antioxidant defense mechanisms protecting PFs in mouse ovaries and characterized cell death mechanisms of oxidative stress-induced PF death.

Enhancing HIF-1α-P2X2 signaling in dorsal raphe serotonergic neurons promotes psychological resilience.

Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5-HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.

LSD1 promotes the FSH responsive follicle formation by regulating autophagy and repressing Wt1 in the granulosa cells.

In a growing follicle, the survival and maturation of the oocyte largely depend on support from somatic cells to facilitate FSH-induced mutual signaling and chemical communication. Although apoptosis and autophagy in somatic cells are involved in the process of FSH-induced follicular development, the underlying mechanisms require substantial study. According to our study, along with FSH-induced antral follicles (AFs) formation, both lysine-specific demethylase 1 (LSD1) protein levels and autophagy increased simultaneously in granulosa cells (GCs) in a time-dependent manner, we therefore evaluated the importance of LSD1 upon facilitating the formation of AFs correlated to autophagy in GCs. Conditional knockout of Lsd1 in GCs resulted in significantly decreased AF number and subfertility in females, accompanied by marked suppression of the autophagy in GCs. On the one hand, depletion of Lsd1 resulted in accumulation of Wilms tumor 1 homolog (WT1), at both the protein and mRNA levels. WT1 prevented the expression of FSH receptor (Fshr) in GCs and thus reduced the responsiveness of the secondary follicles to FSH induction. On the other hand, depletion of LSD1 resulted in suppressed level of autophagy by upregulation of ATG16L2 in GCs. We finally approved that LSD1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity. Therefore, the importance of LSD1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.

Benralizumab efficacy and safety in severe asthma: A randomized trial in Asia.

BACKGROUND: Benralizumab is indicated as add-on therapy in patients with uncontrolled, severe eosinophilic asthma; it has not yet been evaluated in a large Asian population with asthma in a clinical trial. OBJECTIVE: To evaluate the efficacy and safety of benralizumab in patients with severe asthma in Asia. METHODS: MIRACLE (NCT03186209) was a randomized, Phase 3 study in China, South Korea, and the Philippines. Patients aged 12-75 years with severe asthma receiving medium-to-high-dose inhaled corticosteroid/long-acting ß2-agonists, stratified (2:1) by baseline blood eosinophil count (bEOS) (≥300/µL; <300/µL), were randomized (1:1) to benralizumab 30 mg or placebo. Endpoints included annual asthma exacerbation rate (AAER; primary endpoint), change from baseline at Week 48 in pre-bronchodilator (BD) forced expiratory volume in 1 second (pre-BD FEV1) and total asthma symptom score (TASS). Safety was evaluated ≤ Week 56. RESULTS: Of 695 patients randomized, 473 had baseline bEOS ≥300/µL (benralizumab n = 236; placebo n = 237). In this population, benralizumab significantly reduced AAER by 74% (rate ratio 0.26 [95% CI 0.19, 0.36], p < 0.0001) and significantly improved pre-BD FEV1 (least squares difference [LSD] 0.25 L [95% CI 0.17, 0.34], p < 0.0001) and TASS (LSD -0.25 [-0.45, -0.05], p = 0.0126) versus placebo. In patients with baseline bEOS <300/µL, there were numerical improvements in AAER, pre-BD FEV1, and TASS with benralizumab versus placebo. The frequency of adverse events was similar for benralizumab (76%) and placebo (80%) in the overall population. CONCLUSIONS: MIRACLE data reinforces the efficacy and safety of benralizumab for severe eosinophilic asthma in an Asian population, consistent with the global Phase 3 results.

Secure and efficient authenticated group key agreement protocol for AI-based automation systems.

Automation systems are soaring due to the innovation of artificial intelligence (AI) technologies. In this paper, we mainly concentrate on the security and efficiency of data transmission in AI-based automation systems, especially, for data sharing in a group manner in distributed networks. To this end, an authenticated group key agreement protocol is proposed for secure data transmission in AI-based automation systems. In order to release the computational overhead of distributed nodes, a semi-trusted authority (STA) is introduced to enable precomputation operations. Moreover, to overcome the predominantly distributed denial of service (DDoS) attack, a dynamic batch verification mechanism is devised. The presented dynamic batch verification mechanism guarantees that the proposed protocol can be run properly among legitimate nodes regardless of the existence of nodes who suffered from the DDoS attack. Finally, the session key security of the proposed protocol is proved and the performance is evaluated.

Predictive value of tumor mutational burden for PD-1/PD-L1 inhibitors in NSCLC: A meta-analysis.

BACKGROUND: To investigate the association between tumor mutational burden (TMB) and the therapeutic effect of Programmed Death 1/Programmed Death Ligand 1 inhibitors in non-small cell lung cancer. METHODS: Four electronic databases, PubMed, Embase, Web of Science, and Cochrane Library, were searched on May 10, 2023, and no time limitation was applied. Analyses were performed using STATA17.0. We assessed the methodological quality of each randomized controlled trial using the Newcastle-Ottawa scale. RESULTS: After exhaustive database search and rigorous screening, 10 studies were included in the meta-analysis. Our findings indicate that high TMB significantly improves progression-free survival but reduces overall response rate. The overall survival was not significantly different between the high and low TMB groups. No significant publication bias was observed. CONCLUSION: High TMB serves as a potential predictive biomarker for improved progression-free survival and reduced overall response rate in patients with non-small cell lung cancer treated with programmed death 1/programmed death ligand 1 inhibitors. However, its predictive value in overall survival requires further investigation.

Helicobacter pylori-induced NAT10 stabilizes MDM2 mRNA via RNA acetylation to facilitate gastric cancer progression.

BACKGROUND: N4-acetylcytidine (ac4C), a widespread modification in human mRNAs that is catalyzed by the N-acetyltransferase 10 (NAT10) enzyme, plays an important role in promoting mRNA stability and translation. However, the biological functions and regulatory mechanisms of NAT10-mediated ac4C were poorly defined. METHODS: ac4C mRNA modification status and NAT10 expression levels were analyzed in gastric cancer (GC) samples and compared with the corresponding normal tissues. The biological role of NAT10-mediated ac4C and its upstream and downstream regulatory mechanisms were determined in vitro and in vivo. The therapeutic potential of targeting NAT10 in GC was further explored. RESULTS: Here, we demonstrated that both ac4C mRNA modification and its acetyltransferase NAT10 were increased in GC, and increased NAT10 expression was associated with disease progression and poor patient prognosis. Functionally, we found that NAT10 promoted cellular G2/M phase progression, proliferation and tumorigenicity of GC in an ac4C-depedent manner. Mechanistic analyses demonstrated that NAT10 mediated ac4C acetylation of MDM2 transcript and subsequently stabilized MDM2 mRNA, leading to its upregulation and p53 downregulation and thereby facilitating gastric carcinogenesis. In addition, Helicobacter pylori (Hp) infection contributed to NAT10 induction, causing MDM2 overexpression and subsequent p53 degradation. Further investigations revealed that targeting NAT10 with Remodelin showed anti-cancer activity in GC and augmented the anti-tumor activity of MDM2 inhibitors in p53 wild-type GC. CONCLUSIONS: These results suggest the critical role of NAT10-mediated ac4C modification in GC oncogenesis and reveal a previously unrecognized signaling cascade involving the Hp-NAT10-MDM2-p53 axis during GC development.

cAMP controls the balance between dormancy and activation of primordial follicles in mouse ovaries.

In mammalian ovaries, the balance between dormancy and activation of primordial follicles determines the female fecundity and endocrine homeostasis. Recently, several functional molecules and pathways have been reported to be involved in the activation of primordial follicles. However, the homeostasis regulatory mechanisms of primordial follicle activation are still scant. Our previous study has proved that a relatively higher concentration of cyclic AMP (cAMP) is required for primordial follicle formation. Here, we identified that cAMP also plays a vital role in the balance between dormancy and activation of primordial follicles. Our results showed that the concentration of cAMP remained stable in neonatal mouse ovaries, which is due to ADCY3, the synthetase of cAMP, and PDE3A, the hydrolytic enzyme of cAMP, were synchronously increased during the activation of primordial follicles in mouse ovaries. Once the concentration of cAMP in neonatal ovaries was either elevated or reduced in vitro, the activation of primordial follicles was either accelerated or decelerated accordingly. In addition, a higher concentration of cAMP in the ovaries of puberty mice improved primordial follicle activation in vivo. Finally, cAMP promoted primordial follicle activation via canonical mTORC1-PI3K signaling cascades and PKA signaling. In conclusion, our findings reveal that the concentration of cAMP acts as a key regulator in balancing the dormancy and activation of primordial follicles in the mouse ovary.

Safety, Tolerability, and Pharmacokinetics of Benralizumab: A Phase 1, Randomized, Single-Blind Study of Healthy Chinese Participants.

Purpose: Biological therapies targeting eosinophils have been shown to be effective in treating patients with severe eosinophilic asthma. Benralizumab (Fasenra®, AstraZeneca) is a humanized monoclonal antibody binding to the alpha subunit of the interleukin-5 receptor, which rapidly depletes eosinophils via antibody-dependent cellular cytotoxicity. The aim of this Phase 1 study was to assess the safety, tolerability, and pharmacokinetics of benralizumab in healthy Chinese individuals. Materials and Methods: In this randomized, single-blind study (NCT03928262), healthy Chinese adult participants aged 18 to 45 years, weighing 50 to 100 kg, were randomized 1:1:1 to receive a single subcutaneous (SC) injection of benralizumab 10 mg, 30 mg, or 100 mg in the upper arms on Day 1. Safety was monitored throughout the study (up to Day 85), and blood samples were taken to determine serum benralizumab concentrations and for detection of anti-drug antibody. A non-compartmental analysis was conducted to estimate the pharmacokinetic parameters. Results: Thirty-six healthy participants were enrolled, 12 in each dose group (mean [SD] age 26 [6] years). Following a single SC injection of benralizumab, 13 adverse events were reported by 10 participants (28%), with one mild injection-site reaction assessed as related. The mean serum benralizumab concentrations increased in a dose proportional manner, followed by exponential decreases. The mean terminal half-lives were 15.1 days for the 10 mg dose, 14.4 days for the 30 mg dose, and 15.4 days for the 100 mg dose. All doses resulted in near-complete depletion of eosinophils on Day 2, which was maintained throughout the study to Day 85. Conclusion: A single SC injection of benralizumab was well tolerated by healthy Chinese participants, with no new or unexpected safety findings. The pharmacokinetics of benralizumab in Chinese participants was dose-proportional and consistent with those of non-Chinese participants observed in previous studies. Clinical Trial Registration: NCT03928262 (https://clinicaltrials.gov/ct2/show/NCT03928262).