Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis.

Photoreceptor connecting cilium (CC) is structurally analogous to the transition zone (TZ) of primary cilia and gates the molecular trafficking between the inner and the outer segment (OS). Retinal dystrophies with underlying CC defects are manifested in a broad array of syndromic conditions known as ciliopathies as well as nonsyndromic retinal degenerations. Despite extensive studies, many questions remain in the mechanism of protein trafficking across the photoreceptor CC. Here, we genetically inactivated mouse Tmem138, a gene encoding a putative transmembrane protein localized to the ciliary TZ and linked to ciliopathies. Germline deletion of Tmem138 abolished OS morphogenesis, followed by rapid photoreceptor degeneration. Tmem138 was found localized to the photoreceptor CC and was required for localization of Ahi1 to the distal subdomain of the CC. Among the examined set of OS proteins, rhodopsin was mislocalized throughout the mutant cell body prior to OS morphogenesis. Ablation of Tmem138 in mature rods recapitulated the molecular changes in the germline mutants, causing failure of disc renewal and disintegration of the OS. Furthermore, Tmem138 interacts reciprocally with rhodopsin and a related protein Tmem231, and the ciliary localization of the latter was also altered in the mutant photoreceptors. Taken together, these results suggest a crucial role of Tmem138 in the functional organization of the CC, which is essential for rhodopsin localization and OS biogenesis.

Recent Advances in Enterovirus A71 Infection and Antiviral Agents.

Enterovirus A71 (EV-A71) is one of the major causative agents of hand, foot, and mouth disease (HFMD) that majorly affects children. Most of the time, HFMD is a mild disease but can progress to severe complications, such as meningitis, brain stem encephalitis, acute flaccid paralysis, and even death. HFMD caused by EV-A71 has emerged as an acutely infectious disease of highly pathogenic potential in the Asia-Pacific region. In this review, we introduced the properties and life cycle of EV-A71, and the pathogenesis and the pathophysiology of EV-A71 infection, including tissue tropism and host range of virus infection, the diseases caused by the virus, as well as the genes and host cell immune mechanisms of major diseases caused by enterovirus 71 (EV-A71) infection, such as encephalitis and neurologic pulmonary edema. At the same time, clinicopathologic characteristics of EV-A71 infection were introduced. There is currently no specific medication for EV-A71 infection, highlighting the urgency and significance of developing suitable anti-EV-A71 agents. This overview also summarizes the targets of existing anti-EV-A71 agents, including virus entry, translation, polyprotein processing, replication, assembly and release; interferons; interleukins; the mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase B signaling pathways; the oxidative stress pathway; the ubiquitin-proteasome system; and so on. Furthermore, it overviews the effects of natural products, monoclonal antibodies, and RNA interference against EV-A71. It also discusses issues limiting the research of antiviral drugs. This review is a systematic and comprehensive summary of the mechanism and pathological characteristics of EV-A71 infection, the latest progress of existing anti-EV-A71 agents. It would provide better understanding and guidance for the research and application of EV-A71 infection and antiviral inhibitors.

Age and light damage influence Fzd5 regulation of ocular growth-related genes.

Genetic and environmental factors can independently or coordinatively drive ocular axis growth. Mutations in FRIZZLED5 (FZD5) have been associated with microphthalmia, coloboma, and, more recently, high myopia. The molecular mechanism of how Fzd5 participates in ocular growth remains unknown. In this study, we compiled a list of human genes associated with ocular growth abnormalities based on public databases and a literature search. We identified a set of ocular growth-related genes from the list that was altered in the Fzd5 mutant mice by RNAseq analysis at different time points. The Fzd5 regulation of this set of genes appeared to be impacted by age and light damage. Further bioinformatical analysis indicated that these genes are extracellular matrix (ECM)-related; and meanwhile an altered Wnt signaling was detected. Altogether, the data suggest that Fzd5 may regulate ocular growth through regulating ECM remodeling, hinting at a genetic-environmental interaction in gene regulation of ocular axis control.

Environmentally Relevant Concentrations of Tetrabromobisphenol A Exposure Impends Neurovascular Formation through Perturbing Mitochondrial Metabolism in Zebrafish Embryos and Human Primary Endothelial Cells.

Tetrabromobisphenol A (TBBPA), the most extensively utilized brominated flame retardant, has raised growing concerns regarding its environmental and health risks. Neurovascular formation is essential for metabolically supporting neuronal networks. However, previous studies primarily concerned the neuronal injuries of TBBPA, its impact on the neurovascularture, and molecular mechanism, which are yet to be elucidated. In this study, 5, 30, 100, 300 µg/L of TBBPA were administered to Tg (fli1a: eGFP) zebrafish larvae at 2-72 h postfertilization (hpf). The findings revealed that TBBPA impaired cerebral and ocular angiogenesis in zebrafish. Metabolomics analysis showed that TBBPA-treated neuroendothelial cells exhibited disruption of the TCA cycle and the Warburg effect pathway. TBBPA induced a significant reduction in glycolysis and mitochondrial ATP production rates, accompanied by mitochondrial fragmentation and an increase in mitochondrial reactive oxygen species (mitoROS) production in neuroendothelial cells. The supplementation of alpha-ketoglutaric acid, a key metabolite of the TCA cycle, mitigated TBBPA-induced mitochondrial damage, reduced mitoROS production, and restored angiogenesis in zebrafish larvae. Our results suggested that TBBPA exposure impeded neurovascular injury via mitochondrial metabolic perturbation mediated by mitoROS signaling, providing novel insight into the neurovascular toxicity and mode of action of TBBPA.

Gestational and Postpartum Exposure to PM2.5 Components and Glucose Metabolism in Chinese Women: A Prospective Cohort Study.

Pregnant women are physiologically prone to glucose intolerance, while the puerperium represents a critical phase for recovery. However, how air pollution disrupts glucose homeostasis during the gestational and early postpartum periods remains unclear. This prospective cohort study conducted an oral glucose tolerance test and measured the insulin levels of 834 pregnant women in Guangzhou, with a follow-up for 443 puerperae at 6-8 weeks postpartum. Residential PM2.5 and five chemical components were estimated by an established spatiotemporal model. The adjusted linear model showed that an IQR increase in gestational PM2.5 exposure was associated with an increase of 0.17 mmol/L (95% CI: 0.06, 0.28) in fasting plasma glucose (FPG) and 0.24 (95% CI: 0.05, 0.42) in the insulin resistance index. Postpartum PM2.5 exposure was linked to a 0.17 mmol/L (95% CI: 0.05, 0.28) elevation in FPG per IQR, with a strengthened association found in women with gestational diabetes (Pinteraction = 0.003). In the quantile-based g-computation model, NO3- consistently contributed to the combined effect of PM2.5 components on gestational and postpartum FPG. This study was the first to suggest that PM2.5 components were associated with exacerbated gestational insulin resistance and elevated postpartum FPG. Targeted interventions reducing the emissions of toxic PM2.5 components are essential to improving maternal glucose metabolism.

Genome-Driven Discovery of Antiviral Atralabdans A-C from the Soil-Dwelling Streptomyces atratus.

Heterologous expression of an atr terpenoid gene cluster derived from Streptomyces atratus Gö66 in S. albus J1074 led to the discovery of three novel labdane diterpenoids featuring an unprecedented 6/6/5-fused tricyclic skeleton, designated as atralabdans A-C (1-3), along with a known compound, labdanmycin A. Compounds 1-3 were identified through extensive spectroscopic analysis, including NMR calculations with DP4+ probability analysis, and a comparative assessment of experimental and theoretical electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway for these compounds was proposed. Compounds 1-3 exhibited inhibitory activity against the human neurotropic coxsackievirus B3 (CVB3); 1 was the most potent, surpassing the positive control ribavirin with a higher therapeutic index.

Unveiling Distribution of Per- and Polyfluoroalkyl Substances in Matched Placenta-Serum Tetrads: Novel Implications for Birth Outcome Mediated by Placental Vascular Disruption.

The placenta is pivotal for fetal development and maternal-fetal transfer of many substances, including per- and polyfluoroalkyl substances (PFASs). However, the intraplacental distribution of PFASs and their effects on placental vascular function remain unclear. In this study, 302 tetrads of matched subchorionic placenta (fetal-side), parabasal placenta (maternal-side), cord serum, and maternal serum samples were collected from Guangzhou, China. Eighteen emerging and legacy PFASs and five placental vascular biomarkers were measured. Results showed that higher levels of perfluorooctanoic (PFOA), perfluorooctane sulfonic acid (PFOS), and chlorinated polyfluorinated ether sulfonic acids (Cl-PFESAs) were detected in subchorionic placenta compared to parabasal placenta. There were significant associations of PFASs in the subchorionic placenta, but not in the serum, with placental vascular biomarkers (up to 32.5%) and lower birth size. Birth weight was negatively associated with PFOA (ß: -103.8, 95% CI: -186.3 and -21.32) and 6:2 Cl-PFESA (ß: -80.04, 95% CI: -139.5 and -20.61), primarily in subchorionic placenta. Mediation effects of altered placental angiopoietin-2 and vascular endothelial growth factor receptor-2 were evidenced on associations of adverse birth outcomes with intraplacental PFOS and 8:2 Cl-PFESA, explaining 9.5%-32.5% of the total effect. To the best of our knowledge, this study is the first to report on differential intraplacental distribution of PFASs and placental vascular effects mediating adverse birth outcomes and provides novel insights into the placental plate-specific measurement in PFAS-associated health risk assessment.

Parental Exposure to Environmentally Relevant Concentrations of Bisphenol-A Bis(diphenyl phosphate) Impairs Vascular Development in Offspring through DNA/RNA Methylation-Dependent Transmission.

Bisphenol-A bis(diphenyl phosphate) (BDP) has been increasingly detected in indoor environmental and human samples. Little is known about its developmental toxicity, particularly the intergenerational effects of parental exposure. In this study, adult zebrafish were exposed to BDP at 30-30,000 ng/L for 28 days, with results showing that exposure did not cause a transfer of BDP or its metabolites to offspring. Vascular morphometric profiling revealed that parental exposure to BDP at 30 and 300 ng/L exerted significant effects on the vascular development of offspring, encompassing diverse alterations in multiple types of blood vessels. N6-Methyladenosine (m6A) methylated RNA immunoprecipitation sequencing of larvae in the 300 ng/L group revealed 378 hypomethylated and 350 hypermethylated m6A peaks that were identified in mRNA transcripts of genes crucial for vascular development, including the Notch/Vegf signaling pathway. Concomitant changes in 5 methylcytosine (m5C) DNA methylation and gene expression of m6A modulators (alkbh5, kiaa1429, and ythdf1) were observed in both parental gonads and offspring exposed to BDP. These results reveal that parental exposure to low concentrations of BDP caused offspring vascular disorders by interfering with DNA and RNA methylation, uncovering a unique DNA-RNA modification pattern in the intergenerational transmission of BDP's developmental toxicity.

The change of eosinophils in the perioperative period is significantly associated with the prognosis in patients with lung cancer.

Background: This research focuses on the relationship between the changes in peripheral blood eosinophils (PBEs) perioperatively and the prognosis of lung cancer. Methods: The study included 414 lung cancer patients. These patients were divided into the DOWN (186 patients) and UP (209 patients) groups according to perioperative changes in PBEs. Furthermore, overall survival was compared based on pathological stage, pathological type, tumor location, age and sex. Furthermore, the authors analyzed the prediction of PBEs on the prognosis of chemotherapy. Results: The results showed that lung cancer patients in the DOWN group had a better prognosis (p = 0.0121; 95% CI: 0.6915 [0.5184-0.9224]), and the DOWN group patients with normal postoperative PBEs had a better prognosis (p = 0.0115; 95% CI: 0.6721 [0.4938-0.9148]). Conclusion: Lung cancer patients whose postoperative PBEs were lower than preoperative PBEs had a better prognosis.

Maternal exposure to nano-titanium dioxide impedes fetal development via endothelial-to-mesenchymal transition in the placental labyrinth in mice.

BACKGROUND: Extensive production and usage of commercially available products containing TiO2 NPs have led to accumulation in the human body. The deposition of TiO2 NPs has even been detected in the human placenta, which raises concerns regarding fetal health. Previous studies regarding developmental toxicity have frequently focused on TiO2 NPs < 50 nm, whereas the potential adverse effects of large-sized TiO2 NPs received less attention. Placental vasculature is essential for maternal-fetal circulatory exchange and ensuring fetal growth. This study explores the impacts of TiO2 NPs (100 nm in size) on the placenta and fetal development and elucidates the underlying mechanism from the perspective of placental vasculature. Pregnant C57BL/6 mice were exposed to TiO2 NPs by gavage at daily dosages of 10, 50, and 250 mg/kg from gestational day 0.5-16.5. RESULTS: TiO2 NPs penetrated the placenta and accumulated in the fetal mice. The fetuses in the TiO2 NP-exposed groups exhibited a dose-dependent decrease in body weight and length, as well as in placental weight and diameter. In vivo imaging showed an impaired placental barrier, and pathological examinations revealed a disrupted vascular network of the labyrinth upon TiO2 NP exposure. We also found an increase in gene expression related to the transforming growth factor-ß (TGF-ß) -SNAIL pathway and the upregulation of mesenchymal markers, accompanied by a reduction in endothelial markers. In addition, TiO2 NPs enhanced the gene expression responsible for the endothelial-to-mesenchymal transition (EndMT) in cultured human umbilical vein endothelial cells, whereas SNAIL knockdown attenuated the induction of EndMT phenotypes. CONCLUSION: Our study revealed that maternal exposure to 100 nm TiO2 NPs disrupts placental vascular development and fetal mice growth through aberrant activation of EndMT in the placental labyrinth. These data provide novel insight into the mechanisms of developmental toxicity posed by NPs.

Bacterial diversity in primary infected root canals of a Chinese cohort: analysis of 16 S rDNA sequencing.

PURPOSE: To characterize the bacterial community in the primarily infected root canals. METHODS: A total of 13 samples were collected from the primarily infected root canals. 16 S rDNA sequencing was performed to define bacterial community. Taxonomic annotation, bacterial hierarchical structures, community richness and diversity, and inter-subject variability of the bacterial community in the root canal samples were analyzed. Gender, age, and duration of the toothache-specific bacterial community associated with the patient groups were analyzed. RESULTS: A total of 359 Species were annotated and identified in the whole study cohort. The Alpha diversity analysis showed that the species diversity and detection rate of the 13 samples were high, which reflected the authenticity of sequencing results. The Beta diversity analysis was used to compare the degree of difference between different root canal samples. The 13 samples were divided into two groups according to the results, group A was samples I1-I12, and group B was samples I13. The bacterial species of group A samples were analyzed with the clinical characteristics of patients, and it was found that gender, and duration specific differences in bacterial species, and there was no significant difference in species types among different ages of patients. CONCLUSION: There were a wide diversity and inter-subject variability in the bacterial community in the primary infected root canals. While Porphyromonas gingivalis was the most abundant species, Fusobacterium nucleatum was the most variable species in the bacterial community of the root canal. The bacterial community at different taxonomic levels varied from sample to sample, despite consistent disease diagnoses. There was gender, duration-specific differences in the bacterial species in the primary infected root canals.

Optimum immunotherapy method according to PD-L1 expression in advanced lung cancer: a network meta-analysis.

Aim: To compare the survival of advanced lung cancer patients treated with immune checkpoint inhibitors in different PD-L1 expression. Methods: We performed a network meta-analysis based on 25 trials involving 12,224 patients with different PD-L1 expression levels. Results: The results showed platinum-based chemotherapy plus pembrolizumab or nivolumab and ipilimumab was associated with the best survival rates for patients with <1% PD-L1 expression, while only platinum-based chemotherapy plus pembrolizumab produced better survival than chemotherapy in patients with 1-49% PD-L1 expression. As for patients with ≥50% PD-L1 expression, platinum-based chemotherapy plus pembrolizumab/atezolizumab and pembrolizumab/cemiplimab monotherapy were associated with better survival than chemotherapy. Conclusion: These results provide reference for selecting the optimum immunotherapy method based on the expression of PD-L1 in patients with advanced lung cancer.

Plain language summary Lung cancer has a high incidence and mortality rate, and there are many treatment strategies, including surgery, chemotherapy, targeted therapy and immunotherapy. The emergence of immunotherapy has effectively improved the treatment effect of lung cancer, but different immunotherapy strategies and drugs have inconsistent efficacy in different patients. In this study the expression of PD-L1 was used to differentiate patients, and the survival difference of patients receiving different immunotherapy strategies was explored through statistical methods. This study may help clinicians choose the best immunotherapy methods and drugs for different patients. Systematic review registration: PROSPERO CRD42020186947.

A single-cell survey unveils cellular heterogeneity and sensitive responses in mouse cortices induced by oral exposure to triphenyl phosphate.

Triphenyl phosphate (TPhP) is a non-halogenated organophosphorus flame retardant, and there is a higher exposure risk in children. TPhP has been found to be neurotoxic upon developmental exposure, yet the specific mechanism remains unclear. To characterize the cellular responses underlying TPhP-induced developmental neurotoxicity, we administered TPhP (0.5, 5 or 50 mg/kg/day) to neonatal mice from postnatal day 10 (P10)-P70. A total of 17,229 cells and 26,338 genes were identified in cortical samples from control and low-dose (the internal doses of metabolite DPhP comparable to human exposure level) groups using single-cell RNA sequencing (scRNA-seq). TPhP exposure led to heterogeneous transcriptional alterations and intercellular crosstalk among neurons, neural stem/progenitor cells (NSPCs), endothelial cells, and immunocytes. Deprivation of NSPCs, loss of mature neurons, and concomitant neuroinflammation mediated by extrinsic and intrinsic immunocytes were found in TPhP-exposed cortices. In addition, we observed blood-brain barrier destruction prior to the anxiety/depression-like neurobehavioral changes. These results reveal the distinctive cellular processes in TPhP's neurodevelopmental toxicity and uncover that the impeded neurogenesis, disrupted vascular barrier, and concomitant neuroinflammation are the sensitive responses to TPhP exposure. Our study paves the way for the application of scRNA-seq in toxicity assessments for emerging neurotoxic pollutants.

Differential protein metabolism and regeneration in hypertrophic diaphragm and atrophic gastrocnemius muscles in hibernating Daurian ground squirrels.

NEW FINDINGS: What is the central question of this study? The aim was to investigate whether diaphragm hypertrophy and gastrocnemius atrophy during hibernation of Daurian ground squirrels involve differential regulation of protein metabolism and regeneration. What is the main finding and its importance? We clarified the differences in protein metabolism and muscle regenerative potential in the diaphragm and gastrocnemius of hibernating ground squirrels, reflecting the different adaptability of muscles. ABSTRACT: Are differences in the regulation of protein metabolism and regeneration involved in the different phenotypic adaptation mechanisms of muscle hypertrophy and atrophy in hibernators? Two fast-type muscles (diaphragm and gastrocnemius) in summer active and hibernating Daurian ground squirrels were selected to detect changes in cross-sectional area (CSA) and protein expression indicative of protein synthesis metabolism (protein expression of P-Akt, P-mTORC1, P-S6K1 and P-4E-BP1), protein degradation metabolism (MuRF1, atrogin-1, calpain-1, calpain-2, calpastatin, desmin, troponin T, Beclin1 and LC3-II) and muscle regeneration (MyoD, myogenin and myostatin). In the hibernation group compared with the summer active group, the CSA of the diaphragm muscle increased significantly by 26.1%, whereas the CSA of the gastrocnemius muscle decreased significantly by 20.4%. Our study also indicated that increased protein synthesis, decreased protein degradation and increased muscle regenerative potential contributed to diaphragm muscle hypertrophy, whereas decreased protein synthesis, increased protein degradation and decreased muscle regenerative potential contributed to gastrocnemius muscle atrophy. In conclusion, the differences in muscle regeneration and regulatory pattern of protein metabolism might contribute to the different adaptive changes observed in the diaphragm and gastrocnemius muscles of ground squirrels.

Recent advances of enterovirus 71 [Formula: see text] targeting Inhibitors.

With CA16, enterovirus-71 is the causative agent of hand foot and mouth disease (HFMD) which occurs mostly in children under 5 years-old and responsible of several outbreaks since a decade. Most of the time, HFMD is a mild disease but can progress to severe complications such as meningitis, brain stem encephalitis, acute flaccid paralysis (AFP) and even death; EV71 has been identified in all severe cases. Therefore, it is actually one of the most public health issues that threatens children's life. [Formula: see text] is a protease which plays important functions in EV71 infection. To date, a lot of [Formula: see text] inhibitors have been tested but none of them has been approved yet. Therefore, a drug screening is still an utmost importance in order to treat and/or prevent EV71 infections. This work highlights the EV71 life cycle, [Formula: see text] functions and [Formula: see text] inhibitors recently screened. It permits to well understand all mechanisms about [Formula: see text] and consequently allow further development of drugs targeting [Formula: see text]. Thus, this review is helpful for screening of more new [Formula: see text] inhibitors or for designing analogues of well known [Formula: see text] inhibitors in order to improve its antiviral activity.

Neonatal exposure to organophosphorus flame retardant TDCPP elicits neurotoxicity in mouse hippocampus via microglia-mediated inflammation in vivo and in vitro.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a phosphorus-based flame retardant common in consumer goods and baby products. Concerns have been raised about TDCPP exposure and neurodevelopmental toxicity. However, the mechanism and early response for TDCPP-induced neurotoxicity are poorly understood. This study investigates the role of microglia-mediated neuroinflammation in TDCPP-induced neurotoxicity in mice and primary cells. TDCPP was administered to C57BL/6 pups (0, 5, or 50 mg/kg/day) via an oral gavage from postnatal days 10-38 (28 days). The results showed that TDCPP exposure for 28 days altered the gene expression of neuronal markers Tubb3, Nefh, and Nes, and led to apoptosis in the hippocampus. The mRNA levels of pro-inflammatory factors Il-1ß, Tnfα and Ccl2 dose dependently increased in the hippocampus at both 24 h and 28 days following exposure, accompanied by microglia activation characterized by an amoeboid-like phenotype. In in vitro studies using the primary microglia isolated from neonatal mice, exposure to TDCPP (0-100 µM) for 24 h resulted in cellular activation. It also increased the expression of genes responsible for inflammatory responses including surface markers and pro-inflammatory cytokines. These changes occurred in a dose-dependent fashion. Neurite outgrowth of primary mouse hippocampal neurons was inhibited by treatment with the conditioned medium harvested from microglia exposed to TDCPP. These results reveal that neonatal exposure to TDCPP induces neuronal damage through microglia-mediated inflammation. This provides insight into the mechanism of TDCPP's neurodevelopmental toxicity, and suggests that microglial cell is a sensitive responder for OPFRs exposure.

Antiviral Effects of Novel 2-Benzoxyl-Phenylpyridine Derivatives.

Coxsackievirus B3 (CVB3) is the most common cause of acute and chronic viral myocarditis, primarily in children, while human adenovirus infections represent a significant cause of morbidity and mortality worldwide, in people of all ages. A series of novel 2-benzoxyl-phenylpyridine derivatives were evaluated for their potential antiviral activities against CVB3 and adenovirus type 7 (ADV7). Preliminary assays indicated that some of these compounds exhibited excellent antiviral effects on both CVB3 and ADV7 viruses; they could effectively inhibit virus-induced cytopathic effects, reduce viral progeny yields, and had similar or superior antiviral activities compared with the control drug, ribavirin. Further, these compounds targeted the early stages of CVB3 replication in cells, including viral RNA replication and protein synthesis, rather than inactivating the virus directly, inhibiting virus adsorption/entry, or affecting viral release from cells. Our data demonstrate that the tested 2-benzoxyl-phenylpyridine derivatives are effective inhibitors of CVB3 and ADV7, raising the possibility that these compounds might be feasible candidates for anti-viral agents.

Prosurvival roles mediated by the PERK signaling pathway effectively prevent excessive endoplasmic reticulum stress-induced skeletal muscle loss during high-stress conditions of hibernation.

Stress conditions like hypoxia, ischemia, and ischemia/reperfusion can trigger excessive endoplasmic reticulum stress (ERS), which can lead to cell apoptosis-induced skeletal muscle atrophy in non-hibernators. However, although hibernators experience multiple stress conditions during hibernation, their skeletal muscles appear to be well protected. We hypothesize that hibernators effectively avoid cell apoptosis, at least partially, by controlling ERS level. Here, we focused on the potential occurrence of ERS and how hibernators cope with it during different hibernation states. Results indicated that the protein expression levels of glucose-regulated protein 78 (GRP78), phosphorylated PKR-like ER protein kinase, phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), and activating transcription factor 4 were significantly increased during hibernation, but primarily recovered in posthibernation. In the torpor-arousal cycle, the expression levels of the above indicators were lower during inter-bout arousal (IBA) than that during late torpor (LT). However, there was no change in C/EBP homologous protein expression and no apoptosis in skeletal muscles during the different hibernation states. In conclusion, the upregulation of p-eIF2α and GRP78 were identified as two crucial mechanisms mediated by the PERK signaling pathway to alleviate elevated ERS. The downregulation of ERS during IBA may be a unique countermeasure for hibernating squirrels to prevent excessive ERS. Thus, these special anti-excessive ERS abilities of ground squirrels contribute to the prevention of skeletal muscle cell apoptosis during hibernation.

Combined detection of estrogen and tumor markers is an important reference factor in the diagnosis and prognosis of lung cancer.

The correlation between lung cancer tumor markers and sex differences in lung cancer remains a clinical problem that is worthy of further study. This study investigated the significance of the combined detection of 17ß-estrogen (E2) and tumor markers in the diagnosis and prognosis of lung cancer. A total of 174 patients, including 117 patients with non-small-cell lung cancer (NSCLC) and 57 patients with benign pulmonary lesions (BPL), were enrolled. An enzyme-linked immunosorbent assay was used to detect the expression of E2, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) in patients with NSCLC and BPL to analyze the correlation between E2 and CEA, NSE or CYFRA21-1 expression, and its correlation with clinicopathological features and prognosis. The expression of tumor markers was then examined in different lung cancer cells (A549, H1795, H460, and SK-MES-1). The expression of tumor markers was detected by a real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. The expressions of p-p44/42 mitogen-activated protein kinase (MAPK) and phospho-AKT (p-AKT) were detected by Western blot analysis. The expression levels of E2, CEA, NSE, and CYFRA21-1 in patients with NSCLC were significantly higher than those in patients with BPL ( P < .05); E2 was positively correlated with tumor markers ( P < .01). Patients with a high expression of E2 and tumor markers showed a poor prognosis ( P < .05). RT-quantitative PCR and Western blot analysis showed that the expression levels of CEA, NSE, CYFRA21-1, p-p44/42 MAPK, and p-AKT in the E2 group were higher than those in the other groups ( P < .05). These studies indicate that the interaction of E2 and tumor markers can significantly improve the role of tumor markers in the diagnosis and prognosis of lung cancer.

Interaction of estrogen receptor ß5 and interleukin 6 receptor in the progression of non-small cell lung cancer.

Numerous studies have shown that the estrogen receptor beta (ERß) and interleukin 6 receptor (IL-6R) had interaction in many tumors, including lung cancer. Previous studies found that ERß5 exhibits a different biological function compared with the other subtypes of ERß. Therefore, this study mainly explores the interaction between ERß5 and IL-6R in the progression of lung cancer. We found that the expression of ERß5, IL-6 and glycoprotein 130 (GP130) were significantly increased (P < 0.001) and the 5-year survival rate with the co-expression of ERß5 and GP130 is significantly lower (P = 0.0315) in non-small cell lung cancer (NSCLC) patients. The cell proliferation, invasion, and cell cycle were markedly increased, and the cell apoptotic was markedly inhibited with the concurrent action of ERß5 and IL-6 in A549 cells (P < 0.05). In addition, the expression of ERß5, GP130, p-AKT, and p-44/42 MAPK was also significantly increased in A549 cells (P < 0.05). These results indicate that ERß5 and GP130 can synergistically promote the progression of NSCLC and maybe combined as an independent prognostic factor in patients. In addition, these results also provide a theoretical basis for the combined targeting therapy of ERß5 and GP130 in NSCLC.