Trigonelline hydrochloride attenuates silica-induced pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation.

BACKGROUND: Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it's unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear. METHODS: To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions. RESULTS: In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO2-induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-ß/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts. CONCLUSION: In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.

Calcineurin suppresses rat H9c2 cardiomyocyteprotective autophagy under chronic intermittent hypoxia by downregulating the AMPK pathway.

Calcineurin plays a key role in cardiovascular pathogenesis by exerting pro-apoptotic effects in cardiomyocytes. However, whether calcineurin can regulate cardiomyocyte autophagy under conditions of chronic intermittent hypoxia (CIH) remains unclear. Here, we showed that CIH induced calcineurin activity in H9c2 cells, which attenuated adenosine monophosphate-activated protein kinase (AMPK) signaling and inhibited autophagy. In H9c2 cells, autophagy levels, LC3 expression, and AMPK phosphorylation were significantly elevated under conditions of CIH within 3 days. However, after 5 days of CIH, these effects were reversed and calcineurin activity and apoptosis were significantly increased. The calcineurin inhibitor 17-Allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1.04,9]octacos-18- ene-2,3,10,16-tetrone (FK506) restored AMPK activation and LC3 expression and attenuated CIH-induced H9c2 cell apoptosis. In contrast, calcineurin overexpression significantly attenuated the increase in LC3 expression and enhanced H9c2 cell apoptosis under conditions of CIH. Calcineurin inhibition failed to induce autophagy or alleviate apoptosis in H9c2 cells expressing a kinase-dead K45R AMPK mutant. Autophagy inhibition abrogated the protective effects of FK506-mediated calcineurin inhibition. These results indicate that calcineurin suppresses adaptive autophagy during CIH by downregulating AMPK activation. Our findings reveal the underlying mechanism of calcineurin and autophagy regulation during H9c2 cell survival under conditions of CIH and may provide a new strategy for preventing CIH-induced cardiomyocyte damage.

Comprehensive bioinformatics analysis of the solute carrier family and preliminary exploration of SLC25A29 in lung adenocarcinoma.

According to the latest epidemiological investigation, lung adenocarcinoma (LUAD) is one of the most fatal cancer among both men and women. Despite continuous advancements in treatment approaches in recent years, the prognosis for LUAD remains relatively poor. Given the crucial role of the solute carrier (SLC) family in maintaining cellular energy metabolism stability, we conducted a comprehensive analysis of the association between SLC genes and LUAD prognosis. In the present study, we identified 71 genes among the SLC family members, of which 32 were downregulated and 39 were upregulated in LUAD samples. Based on these differentially expressed genes, a prognostic risk scoring model was established that was composed of five genes (SLC16A7, SLC16A4, SLC16A3, SLC12A8, and SLC25A15) and clinical characteristics; this model could effectively predict the survival and prognosis of patients in the cohort. Notably, SLC2A1, SLC25A29, and SLC27A4 were identified as key genes associated with survival and tumor stage. Further analysis revealed that SLC25A29 was underexpressed in LUAD tissue and regulated the phenotype of endothelial cells. Endothelial cell proliferation and migration increased and apoptosis decreased with a decrease in SLC25A29 expression. Investigation of the upstream regulatory mechanisms of SLC25A29 revealed that SLC25A29 expression gradually decreased as the lactate concentration increased. This phenomenon suggested that the expression of SLC25A29 may be related to lactylation modification. ChIP-qPCR experiments confirmed the critical regulatory role played by H3K14la and H3K18la modifications in the promoter region of SLC25A29. In conclusion, this study confirmed the role of SLC family genes in LUAD prognosis and revealed the role of SLC25A29 in regulating endothelial cell phenotypes. These study results provided important clues to further understand LUAD pathogenesis and develop appropriate therapeutic strategies.

MUC1 attenuates neutrophilic airway inflammation in asthma by reducing NLRP3 inflammasome-mediated pyroptosis through the inhibition of the TLR4/MyD88/NF-κB pathway.

BACKGROUND: Neutrophilic airway inflammation is a challenge in asthma management and is associated with poor patient prognosis. Mucin 1 (MUC1), which contains a cytoplasmic tail (MUC1-CT), has been found to mediate glucocorticoid sensitivity in asthma; however, its role in modulating neutrophilic airway inflammation in asthma remains unknown. METHODS: Human-induced sputum cells were collected from healthy participants (n = 12), patients with mild-to-moderate asthma (n = 34), and those with severe asthma (n = 18). In vitro human lung bronchial 1 epithelial cell line (BEAS-2B) was transfected with small interfering RNA against MUC1 (MUC1-siRNA) and then stimulated by lipopolysaccharide (LPS), where some cells were pretreated with a TLR4 inhibitor (TAK-242). In vivo mouse model of asthmatic neutrophil airway inflammation was induced by ovalbumin (OVA)/LPS. Some groups were intraperitoneally injected with MUC1-CT inhibitor (GO-203) and/or TAK-242 . RESULTS: The mRNA expression of MUC1 was downregulated in the induced sputum of patients with asthma and correlated with asthmatic neutrophilic airway inflammation. The mRNA expressions of TLR4, MyD88, nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3), caspase-1, interleukin (IL)-18, and IL-1ß in induced sputum cells of patients with asthma were upregulated and related to the mRNA expression of MUC1. LPS activated the TLR4 pathway and NLRP3-mediated pyroptosis in BEAS-2B cells in vitro, which were significantly aggravated after MUC1-siRNA transfection. Furthermore, MUCl-CT interacted with TLR4, and the interaction between TLR4 and MyD88 was significantly increased after MUCl-siRNA transfection. Moreover, TAK-242 ameliorated TLR4/MyD88/nuclear factor kappa B (NF-κB) pathway activation, NLRP3 inflammasome-mediated pyroptosis, and neutrophilic inflammation exacerbated by MUC1 downregulation. GO-203 exacerbated TLR4/MyD88/NF-κB pathway activation in vivo, and NLRP3 inflammasome-mediated pyroptosis reduced in a mouse model of asthmatic neutrophil airway inflammation induced by OVA/LPS; these pathological changes were partially alleviated after TAK-242 application. CONCLUSION: This study revealed that MUC1 downregulation plays an important role in asthmatic neutrophilic airway inflammation. MUC1-CT reduces NLRP3 inflammasome-mediated pyroptosis by inhibiting the activation of the TLR4/MyD88/NF-κB pathway, thereby attenuating neutrophil airway inflammation in patients with asthma.

Design and synthesis of indol-2-one derivatives as potential RET inhibitors.

We synthesized and assessed five series of indol-2-one derivatives for their potential as RET kinase inhibitors. Notably, compounds B3, B6, D1, D2, D3, and D5 demonstrated significant inhibitory activity. Among these, D5 exhibited the best activity of inhibiting RET kinase, which provided reference for the subsequent development of RET kinase inhibitors as anti-thyroid cancer chemical.

Digital economy, resource distortion and low-carbon inclusive development-Evidence from the perspectives of a threshold effect and knowledge spillover effect.

The low-carbon economy represents a global transformation that encompasses production methods, lifestyles, values, national interests, and the destiny of humanity. As a significant contributor to carbon emissions, China has made a momentous strategic decision on carbon peaking and neutralization, infusing momentum into the global effort to address climate change. The rapid growth of the digital economy offers a fresh approach to achieving the "double carbon" objective and advancing the development of low-carbon transformation. Based on the panel data of 30 provinces in China, this paper uses the least square method to investigate the impact of digital economy development on regional low-carbon inclusive development. It is found that there is a significant inverted U shape in the impact of the digital economy on low-carbon inclusive development and the mechanism is resource allocation and ecological inequality. The threshold test found that the role of the digital economy in promoting low-carbon inclusive development shows a marginal decreasing trend. The inverted U-shaped impact of the digital economy on low-carbon inclusive development in the eastern and coastal areas and areas with a low level of factor productivity is more significant. Based on the knowledge factor spillover perspective, we found that the impact of the digital economy on low-carbon inclusive development has a spatial spillover effect, and this effect is more obvious under the role of R&D personnel mobility.

A three-modal fluorescent sensor harnessing diverse luminescent mechanisms for the purpose of segmented Baijiu identification.

The classification and verification of segmented Baijiu hold significant importance as they profoundly influence the blending and overall quality of the Baijiu. Our scholarly investigation yielded a fluorescent sensor with three luminescent modes by integrating Tb3+ and RHB into UiO-66. The interplay between carboxyl-containing compounds and RHB/Tb@TLU-2 orchestrates a harmonious molecular association, where the convergence of carboxyl groups with Tb3+ yields a resonating impact on the antenna effect of BDC-SO3-. Furthermore, the acidity and alkalinity of reactants induced a charge transfer interaction between BDC-NH2 and Zr4+ and led to structural changes in RHB/Tb@TLU-2, resulting in observable fluorescence signal variations across the three emission centers. The sensor array successfully identified eight organic acids, achieving an impressive 97.5 % accuracy in discerning segmented Baijiu samples from four Baijiu pits. This meticulous methodology prioritizes simplicity, swiftness, and effectiveness, paving the path for comprehensive segmented Baijiu analysis in the esteemed realm of Brewing production.

Effect of the lack of access to handwashing facilities on the global burden of lower respiratory infections, 1990-2019: A systematic analysis from the global burden of disease study 2019.

A lack of access to handwashing facilities is a significant risk factor for lower respiratory infections(LRIs). However, no studies have reported epidemiologic changes in the burden of LRIs attributed to the lack of access to handwashing facilities. We conducted an integrated assessment of the burden of LRIs attributable to the lack of handwashing facilities from 1990 to 2019 using data from the Global Burden of Disease Study 2019. In 2019, 270,000 deaths were attributed to LRIs due to a lack of access to handwashing facilities, with DALYs reaching 14.02 million. The age-standardized mortality rate (ASMR) of LRIs caused by a lack of access to handwashing facilities was approximately 3.74, while the age-standardized DALY rate (ASDR) was reported to be 203.55 in 2019. Over the past 30 years, the burden of LRIs attributed to the lack of access to handwashing facilities has shown a global decline. In 2019, this burden was most pronounced in infants under 1 year of age and in those older than 95 years, reflecting the highest DALY (5591.83) and mortality rates (79.43), respectively. The burden of LRIs caused by the lack of access to handwashing facilities was found to be more severe in males and significantly more pronounced in regions with a low sociodemographic index (SDI), such as the Sahara African region. The development of targeted strategies to address the inadequate and unequal distribution of handwashing facilities holds important value in improving the disease burden of LRIs.

Adverse events associated with tezepelumab: a safety analysis of clinical trials and a pharmacovigilance system.

BACKGROUND: Tezepelumab is the first asthma biologic approved by the FDA that is not restricted by biomarker phenotypes. To date, there have been no studies reporting adverse events (AEs) associated with the real-world use of tezepelumab. RESEARCH DESIGN AND METHODS: This study included a comprehensive evaluation of AE reports related to tezepelumab since its approval (4th quarter of 2021 to 1st quarter of 2024) using the FAERS database, and compared with the currently reported clinical trial results (ClinicalTrials.gov). RESULTS: A total of 2153 reports of tezepelumab-related AEs were extracted. 256 preferred terms (PTs) of adverse reactions involving 27 system organ classes were identified. Significant AEs that were not reported on the drug label, such as 'dyspnea,' 'body temperature,' and 'tongue pruritus,' were reported. The median time to onset (TTO) of tezepelumab-related AEs was 35 days.The most frequent AEs in different sexes were 'arthralgia' and 'dyspnea,' with differences in signal strength ranking between the sexes. CONCLUSIONS: This study represents the largest report to date on tezepelumab-related AEs, providing valuable insights into the potential side effects of tezepelumab. This work is crucial for the broader clinical application of this novel biologic and improving outcomes for patients with severe asthma.

Obstructive sleep apnea hypopnea syndrome and vascular lesions: An update on what we currently know.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is the most prevalent sleep and respiratory disorder. This syndrome can induce severe cardiovascular and cerebrovascular complications, and intermittent hypoxia is a pivotal contributor to this damage. Vascular pathology is closely associated with the impairment of target organs, marking a focal point in current research. Vascular lesions are the fundamental pathophysiological basis of multiorgan ailments and indicate a shared pathogenic mechanism among common cardiovascular and cerebrovascular conditions, suggesting their importance as a public health concern. Increasing evidence shows a strong correlation between OSAHS and vascular lesions. Previous studies predominantly focused on the pathophysiological alterations in OSAHS itself, such as intermittent hypoxia and fragmented sleep, leading to vascular disruptions. This review aims to delve deeper into the vascular lesions affected by OSAHS by examining the microscopic pathophysiological mechanisms involved. Emphasis has been placed on examining how OSAHS induces vascular lesions through disruptions in the endothelial barrier, metabolic dysregulation, cellular phenotype alterations, neuroendocrine irregularities, programmed cell death, vascular inflammation, oxidative stress and epigenetic modifications. This review examines the epidemiology and associated risk factors for OSAHS and vascular diseases and subsequently describes the existing evidence on vascular lesions induced by OSAHS in the cardiovascular, cerebrovascular, retinal, renal and reproductive systems. A detailed account of the current research on the pathophysiological mechanisms mediating vascular lesions caused by OSAHS is provided, culminating in a discussion of research advancements in therapeutic modalities to mitigate OSAHS-related vascular lesions and the implications of these treatment strategies.

Recognition of apnea and hypopnea by non-contact optical fiber mattress and its application in the diagnosis of obstructive sleep apnea hypopnea syndrome: a retrospective study.

Objectives: This study sought to evaluate the diagnostic value of a non-contact optical fiber mattress for apnea and hypopnea and compare it with traditional polysomnography (PSG) in adult obstructive sleep apnea hypopnea syndrome (OSAHS). Methods: To determine the value of a non-contact optical fiber mattress for apnea and hypopnea, six healthy people and six OSAHS patients were selected from Tongji Hospital to design a program to identify apnea or hypopnea. A total of 108 patients who received polysomnography for drowsiness, snoring or other suspected OSAHS symptoms. All 108 patients were monitored with both the non-contact optical fiber mattress and PSG were collected. Results: Six healthy controls and six patients with OSAHS were included. The mean apnea of the six healthy controls was 1.22 times/h, and the mean hypopnea of the six healthy controls was 2 times/h. Of the six patients with OSAHS, the mean apnea was 12.63 times/h, and the mean hypopnea was 19.25 times/h. The non-contact optical fiber mattress results showed that the mean apnea of the control group was 3.17 times/h and the mean hypopnea of the control group was 3.83 times/h, while the mean apnea of the OSAHS group was 11.95 times/h and the mean hypopnea of the OSAHS group was 17.77 times/h. The apnea index of the non-contact optical fiber mattress was positively correlated with the apnea index of the PSG (P < 0.05, r = 0.835), and the hypopnea index of the non-contact optical fiber mattress was also positively correlated with the hypopnea index of the PSG (P < 0.05, r = 0.959). The non-contact optical fiber mattress had high accuracy (area under curve, AUC = 0.889), specificity (83.4%) and sensitivity (83.3%) for the diagnosis of apnea. The non-contact fiber-optic mattress also had high accuracy (AUC = 0.944), specificity (83.4%) and sensitivity (100%) for the diagnosis of hypopnea. Among the 108 patients enrolled, there was no significant difference between the non-contact optical fiber mattress and the polysomnography monitor in total recording time, apnea hypopnea index (AHI), average heart rate, tachycardia index, bradycardia index, longest time of apnea, average time of apnea, longest time of hypopnea, average time of hypopnea, percentage of total apnea time in total sleep time and percentage of total hypopnea time in total sleep time. The AHI value of the non-contact optical fiber mattress was positively correlated with the AHI value of the PSG (P < 0.05, r = 0.713). The specificity and sensitivity of the non-contact optical fiber mattress AHI in the diagnosis of OSAHS were 95% and 93%, with a high OSAHS diagnostic accuracy (AUC = 0.984). Conclusion: The efficacy of the non-contact optical fiber mattress for OSAHS monitoring was not significantly different than PSG monitoring. The specificity of the non-contact optical mattress for diagnosing OSAHS was 95% and its sensitivity was 93%, with a high OSAHS diagnostic accuracy.

Mild asthma is not mild: risk factors and predictive biomarkers for severe acute exacerbations and progression in mild asthma.

INTRODUCTION: Asthma is a common chronic respiratory disease characterized by chronic airway inflammation, airway hyperresponsiveness, reversible airflow limitation, and airway remodeling. Mild asthma is the most common type of asthma, but it is the most neglected. Sometimes mild asthma can lead to acute severe exacerbations or even death. AREAS COVERED: This article reviews the epidemiology, risk factors, and possible predictors of acute severe exacerbations and disease progression in mild asthma to improve the understanding of mild asthma and its severe acute exacerbations and progression. EXPERT OPINION: There is a necessity to improve asthma patient categorization and redefine mild asthma's concept to heighten patient and physician attention. Identifying mild asthma patients that are highly vulnerable to severe acute exacerbations and researching the mechanisms are future prioritizations.

Programmed Cell Death in Asthma: Apoptosis, Autophagy, Pyroptosis, Ferroptosis, and Necroptosis.

Bronchial asthma is a complex heterogeneous airway disease, which has emerged as a global health issue. A comprehensive understanding of the different molecular mechanisms of bronchial asthma may be an efficient means to improve its clinical efficacy in the future. Increasing research evidence indicates that some types of programmed cell death (PCD), including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, contributed to asthma pathogenesis, and may become new targets for future asthma treatment. This review briefly discusses the molecular mechanism and signaling pathway of these forms of PCD focuses on summarizing their roles in the pathogenesis and treatment strategies of asthma and offers some efficient means to improve clinical efficacy of therapeutics for asthma in the near future.

Efficacy of combination therapy in adolescent and adult patients with total-deafness sudden sensorineural hearing loss.

BACKGROUND: Combination therapy is the first-line option for total-deafness sudden sensorineural hearing loss (SSNHL). Age may act as a crucial prognostic factor. OBJECTIVE: The aim of this study was to compare efficacy of combination therapy between adolescent and adult patients with total-deafness SSNHL. MATERIALS AND METHODS: Twenty-five adolescent patients (adolescent group) and 106 adult patients (adult group) with total-deafness SSNHL were recruited. All the recruited patients underwent initial treatment with batroxobin, methylprednisolone, and gastrodin. After 10-day treatment, hearing outcomes were determined by pure-tone average measured by audiometry. Moreover, the total effective rates in the hearing recovery and improvement of tinnitus were calculated. RESULTS: There existed no significant difference between two groups in the total effective rate of the hearing recovery (p = .110). However, a significant difference was found in the total effective rate of improvement of tinnitus between two groups (p = .016). Both adolescent and adult patients could receive the optimal hearing gains at 500 Hz (20.2 ± 13.3 and 23.1 ± 13.9dB, respectively), followed by those at 1000 Hz (18.8 ± 12.5 and 22.7 ± 14.8dB, respectively). Yet, adult patients could get better hearing gains only at 500 Hz than adolescent patients (p = .02). CONCLUSION: Compared with adult patients, adolescent patients with total-deafness SSNHL undergoing combination therapy may be less likely to have hearing recovery and the improvement of tinnitus.

Nuclear PTEN-mediated growth suppression is independent of Akt down-regulation.

The tumor suppressor gene PTEN is a phosphoinositide phosphatase that is inactivated by deletion and/or mutation in diverse human tumors. Wild-type PTEN is expressed both in the cytoplasm and nucleus in normal cells, with a preferential nuclear localization in differentiated or resting cells. To elucidate the relationship between PTEN's subcellular localization and its biologic activities, we constructed different PTEN mutants that targeted PTEN protein into different subcellular compartments. Our data show that the subcellular localization patterns of a PTEN (deltaPDZB) mutant versus a G129R phosphatase mutant were indistinguishable from those of wild-type PTEN. In contrast, the Myr-PTEN mutant demonstrated an enhanced association with the cell membrane. We found that nuclear PTEN alone is capable of suppressing anchorage-independent growth and facilitating G1 arrest in U251MG cells without inhibiting Akt activity. Nuclear compartment-specific PTEN-induced growth suppression is dependent on possessing a functional lipid phosphatase domain. In addition, the down-regulation of p70S6K could be mediated, at least in part, through activation of AMP-activated protein kinase in an Akt-independent fashion. Introduction of a constitutively active mutant of Akt, Akt-DD, only partially rescues nuclear PTEN-mediated growth suppression. Our collective results provide the first direct evidence that PTEN can contribute to G1 growth arrest through an Akt-independent signaling pathway.

AMPK/TSC2/mTOR-signaling intermediates are not necessary for LKB1-mediated nuclear retention of PTEN tumor suppressor.

The regulation of the subcellular localization of phosphatase and tensin homologue (PTEN) is critical to its tumor-suppressing functions. Previously, we found that the activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR/S6 protein kinase (S6K) cascade triggers the nuclear export of PTEN during the G1/S transition. Because mTOR can be alternatively downregulated by tuberous sclerosis complex 2 (TSC2) activation mediated by 5' adenosine monophosphate-activated protein kinase (AMPK), we proposed that the activation of AMPK α1/2 by LKB1 and/or by calmodulin-dependent protein kinase kinase (CaMKK) would also block the nuclear export of PTEN in a manner similar to that of inhibitors of PI3K, mTOR, and S6K. We found that in LKB1-null A549 lung adenocarcinoma cells, an AMPK activator, metformin, failed to block the nuclear export of PTEN, and the reintroduction of functional LKB1 into these cells restored the metformin-mediated inhibition of the nuclear export of PTEN. In addition, the nuclear export of PTEN was blocked in cells treated with the CaMKK activator ATP, and this inhibition was reversed by the addition of inhibitors of either AMPK (compound C) or CaMKK (STO-609). Although the nuclear export of PTEN is blocked by metformin in MCF-7 breast cancer cells carrying wild-type LKB1, this inhibition could not be reversed by an AMPK inhibitor, suggesting that LKB1 could regulate the nuclear export of PTEN by bypassing AMPK α1/2. Moreover, ATP could not block the nuclear export of PTEN in AMPK α1/2(-/-) or TSC2(-/-) mouse embryonic fibroblasts. However, metformin was still able to induce the LKB1-mediated inhibition of the nuclear export of PTEN in these cells. Taken together, these findings strongly suggest that although CaMKK mediates the nuclear retention of PTEN mainly through the activation of AMPK, LKB1 can regulate the nuclear-cytoplasmic trafficking of PTEN, with or without the AMPK/TSC2/mTOR/S6K-signaling intermediates.

Cell cycle-dependent nuclear export of phosphatase and tensin homologue tumor suppressor is regulated by the phosphoinositide-3-kinase signaling cascade.

The tumor suppressor phosphatase and tensin homologue (PTEN) plays distinct growth-regulatory roles in the cytoplasm and nucleus. It has been shown to be preferentially localized to the nucleus in differentiated or resting cells, and to the cytoplasm in advanced tumor cells. Thus, the regulation of PTEN's subcellular localization seems to be critical to its tumor-suppressing functions. In this study, we showed that activation of the phosphoinositide-3-kinase (PI3K) pathway triggers PTEN's cell cycle-dependent chromosome region maintenance 1-mediated nuclear export, as PTEN was predominantly expressed in the cytoplasm of TSC2(-/-) mouse embryo fibroblasts or activated Akt mutant-transfected NIH3T3 cells. In contrast, dominant-negative mutants of Akt and pharmacologic inhibitors of PI3K, mTOR, and S6K1, but not of MEK, suppressed the nuclear export of PTEN during the G(1)-S transition. The nuclear-cytoplasmic trafficking of exogenous PTEN is likewise regulated by the PI3K cascade in PTEN-null U251MG cells. The nuclear export of PTEN could also be blocked by short interfering RNA to S6K1/2. In addition, PTEN interacts with both S6K1 and S6K2. Taken together, our findings strongly indicate that activation of the PI3K/Akt/mTOR/S6K cascade, specifically S6K1/2, is pivotal in regulating the subcellular localization of PTEN. This scenario exemplifies a reciprocal regulation between PI3K and PTEN that defines a novel negative-feedback loop in cell cycle progression.