Hypothalamic FTO promotes high-fat diet-induced leptin resistance in mice through increasing CX3CL1 expression.

Long-term consumption of a high-fat diet (HFD) disrupts energy homeostasis and leads to weight gain. The fat mass and obesity-associated (FTO) gene has been consistently identified to be associated with HFD-induced obesity. The hypothalamus is crucial for regulating energy balance, and HFD-induced hypothalamic leptin resistance contributes to obesity. FTO, an N6-methyladenosine (m6A) RNA methylation regulator, may be a key mediator of leptin resistance. However, the exact mechanisms remain unclear. Therefore, the present study aims to investigate the association between FTO and leptin resistance. After HFD or standard diet (SD) feeding in male mice for 22 weeks, m6A-sequencing and western blotting assays were used to identify target genes and assess protein level, and molecular interaction changes. CRISPR/Cas9 gene knockout system was employed to investigate the potential function of FTO in leptin resistance and obesity. Our data showed that chemokine (C-X3-C motif) ligand 1 (CX3CL1) was a direct downstream target of FTO-mediated m6A modification. Furthermore, upregulation of FTO/CX3CL1 and suppressor of cytokine signaling 3 (SOCS3) in the hypothalamus impaired leptin-signal transducer and activator of transcription 3 signaling, resulting in leptin resistance and obesity. Compared to wild-type (WT) mice, FTO deficiency in leptin receptor-expressing neurons of the hypothalamus significantly inhibited the upregulation of CX3CL1 and SOCS3, and partially ameliorating leptin resistance under HFD conditions. Our findings reveal that FTO involved in the hypothalamic leptin resistance and provides novel insight into the function of FTO in the contribution to hypothalamic leptin resistance and obesity.

Embedding oxophilic rare-earth single atom in platinum nanoclusters for efficient hydrogen electro-oxidation.

Designing Pt-based electrocatalysts with high catalytic activity and CO tolerance is challenging but extremely desirable for alkaline hydrogen oxidation reaction. Herein we report the design of a series of single-atom lanthanide (La, Ce, Pr, Nd, and Lu)-embedded ultrasmall Pt nanoclusters for efficient alkaline hydrogen electro-oxidation catalysis based on vapor filling and spatially confined reduction/growth of metal species. Mechanism studies reveal that oxophilic single-atom lanthanide species in Pt nanoclusters can serve as the Lewis acid site for selective OH- adsorption and regulate the binding strength of intermediates on Pt sites, which promotes the kinetics of hydrogen oxidation and CO oxidation by accelerating the combination of OH- and *H/*CO in kinetics and thermodynamics, endowing the electrocatalyst with up to 14.3-times higher mass activity than commercial Pt/C and enhanced CO tolerance. This work may shed light on the design of metal nanocluster-based electrocatalysts for energy conversion.

A Static Tin-Manganese Battery with 30000-Cycle Lifespan Based on Stabilized Mn3+/Mn2+ Redox Chemistry.

High-potential Mn3+/Mn2+ redox couple (>1.3 V vs SHE) in a static battery system is rarely reported due to the shuttle and disproportionation of Mn3+ in aqueous solutions. Herein, based on reversible stripping/plating of the Sn anode and stabilized Mn2+/Mn3+ redox couple in the cathode, an aqueous Sn-Mn full battery is established in acidic electrolytes. Sn anode exhibits high deposition efficiency, low polarization, and excellent stability in acidic electrolytes. With the help of H+ and a complexing agent, a reversible conversion between Mn2+ and Mn3+ ions takes place on the graphite surface. Pyrophosphate ligand is initially employed to form a protective layer through a complexation process with Sn4+ on the electrode surface, effectively preventing Mn3+ from disproportionation and hindering the uncontrollable diffusion of Mn3+ to electrolytes. Benefiting from the rational design, the full battery delivers satisfied electrochemical performance including a large capacity (0.45 mAh cm-2 at 5 mA cm-2), high discharge plateau voltage (>1.6 V), excellent rate capability (58% retention from 5 to 30 mA cm-2), and superior cycling stability (no decay after 30 000 cycles). The battery design strategy realizes a robustly stable Mn3+/Mn2+ redox reaction, which broadens research into ultrafast acidic battery systems.

Porous FeF3/MWCNTs composite cathode promoting high performance aluminum storage.

Rechargeable aluminum-ion batteries (RAIBs) attract great attention for stationary energy storage, but there remains a lack of suitable cathode materials for them. Here, a porous iron fluoride/multi wall carbon nanotube (FeF3/MWCNTs) composite as a cathode for RAIBs shows high discharge capacity (180 mA h g-1) and good rate performance, while MWCNTs play crucial roles in improving conductivity and cycle stability. Various characterizations elucidate its conversion-type mechanism, in particular, the Fe3+/Fe2+ conversion exhibits a high operating potential of 1.75 V and discharge capacity of 123 mA h g-1, which is very promising for practical applications.

Long-term exercise training down-regulates m6A RNA demethylase FTO expression in the hippocampus and hypothalamus: an effective intervention for epigenetic modification.

BACKGROUND: Exercise boosts the health of some brain parts, such as the hippocampus and hypothalamus. Several studies show that long-term exercise improves spatial learning and memory, enhances hypothalamic leptin sensitivity, and regulates energy balance. However, the effect of exercise on the hippocampus and hypothalamus is not fully understood. The study aimed to find epigenetic modifications or changes in gene expression of the hippocampus and hypothalamus due to exercise. METHODS: Male C57BL/6 mice were randomly divided into sedentary and exercise groups. All mice in the exercise group were subjected to treadmill exercise 5 days per week for 1 h each day. After the 12-week exercise intervention, the hippocampus and hypothalamus tissue were used for RNA-sequencing or molecular biology experiments. RESULTS: In both groups, numerous differentially expressed genes of the hippocampus (up-regulated: 53, down-regulated: 49) and hypothalamus (up-regulated: 24, down-regulated: 40) were observed. In the exercise group, increased level of N6-methyladenosine (m6A) was observed in the hippocampus and hypothalamus (p < 0.05). Furthermore, the fat mass and obesity-associated gene (FTO) of the hippocampus and hypothalamus were down-regulated in the exercise group (p < 0.001). In addition, the Fto co-expression genes of the mouse brain were studied and analyzed using database to determine the potential roles of exercise-downregulated FTO in the brain. CONCLUSION: The findings demonstrate that long-term exercise might elevates the levels of m6A-tagged transcripts in the hippocampus and hypothalamus via down-regulation of FTO. Hence, exercise might be an effective intervention for epigenetic modification.

Ultrafast and Long-Cycle Stable Aluminum Polyphenylene Batteries.

Rechargeable aluminum-ion batteries (RAIBs) are highly sought after due to the extremely high resource reserves and theoretical capacity (2980 mA h/g) of metal aluminum. However, the lack of ideal cathode materials restricts its practical advancement. Here, we report a conductive polymer, polyphenylene, which is produced by the polymerization of molecular benzene as a cathode material for RAIBs with an excellent electrochemical performance. In electrochemical redox, polyphenylene is oxidized and loses electrons to form radical cations [C6H4]3n+ and intercalates with [AlCl4]- anion to achieve electrical neutrality and realize electrochemical energy storage. The stable structure of polyphenylene makes its discharge specific capacity reach 92 mA h/g at 100 mA/g; the discharge plateau is about 1.4 V and exhibits an excellent rate performance and long cycle stability. Under the super high current density of 10 A/g (∼85 C), the charging can be completed in 25 s, and the capacities have almost no decay after 30,000 cycles. Aluminum polyphenylene batteries have the potential to be used as low-cost, easy-to-process, lightweight, and high-capacity superfast rechargeable batteries for large-scale stationary power storage.

A core-shelled Sb@C nanorod cathode with a graphene aerogel interlayer for high-capacity aluminum ion batteries.

Rechargeable aluminum-ion batteries, RAIBs, as a prime candidate for next-generation batteries, have attracted much attention due to their extremely high anode capacity and good safety. However, the lack of matching high-capacity cathode materials and reasonable design limit their practical development. Herein, core-shelled Sb@C nanorods are prepared by polymer coating and thermal reduction as a metal-based cathode for RAIBs. The carbon shell and graphene aerogel interlayer effectively block the diffusion and shuttling of charging products, thus exhibiting excellent electrochemical performance. This Al-Sb battery delivers an initial discharge capacity of 656 mA h g-1 at 100 mA g-1, a stable discharge voltage of 0.9 V, and excellent cycling stability maintained at 306 mA h g-1 after 500 cycles at 1 A g-1. Serial characterizations are used to monitor the structural changes of Sb in reversible reactions and to determine the configuration of the charged products, showing that the product exists in the form of [SbCl4]+ cations, that is, a five-electron transfer reaction occurs with a very high theoretical capacity (1100 mA h g-1). This study sheds light on the energy storage mechanism of a metallic Sb cathode in RAIBs, and provides new insights into the study of high-capacity cathodes and the rational design of battery structures.

Polycyclic Aromatic Hydrocarbons as a New Class of Promising Cathode Materials for Aluminum-Ion Batteries.

As an emerging post-lithium battery technology, aluminum ion batteries (AIBs) have the advantages of large Al reserves and high safety, and have great potential to be applied to power grid energy storage. But current graphite cathode materials are limited in charge storage capacity due to the formation of stage-4 graphite-intercalated compounds (GICs) in the fully charged state. Herein, we propose a new type of cathode materials for AIBs, namely polycyclic aromatic hydrocarbons (PAHs), which resemble graphite in terms of the large conjugated π bond, but do not form GICs in the charge process. Quantum chemistry calculations show that PAHs can bind AlCl4 - through the interaction between the conjugated π bond in the PAHs and AlCl4 - , forming on-plane interactions. The theoretical specific capacity of PAHs is negatively correlated with the number of benzene rings in the PAHs. Then, under the guidance of theoretical calculations, anthracene, a three-ring PAH, was evaluated as a cathode material for AIBs. Electrochemical measurements show that anthracene has a high specific capacity of 157 mAh g-1 (at 100 mA g-1 ) and still maintains a specific capacity of 130 mAh g-1 after 800 cycles. This work provides a feasible "theory guides practice" research model for the development of energy storage materials, and also provides a new class of promising cathode materials for AIBs.

Testicular injury during SARS-CoV-2 infection may be neglected: An assessment from scRNA-seq profiling and protein detection of angiotensin-converting enzyme II.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is outbreaking globally. SARS-CoV-2 invades host cells via angiotensin-converting enzyme II (ACE2) and causes multiple-organ injury. Autopsy studies indicated that the testis of patients with COVID-19 exhibited various degrees of spermatogenic cell reduction and injury, but the composition of ACE2-expressing cells and their proportion in the testes have remained to be determined. Recent clinical evidence suggested that the ratio of male sex hormones in males with COVID-19 was significantly changed. The present study aimed to explore whether SARS-CoV-2 is able to damage the male reproductive system. For this, the ACE2-expressing cell composition and proportion in male testes were analyzed using single-cell RNA sequencing (RNA-seq) datasets downloaded from the Gene Expression Omnibus (GEO) database and immunohistochemical (IHC) staining. The single-cell RNA-seq data indicated that ACE2 mRNA was highly expressed in myoid cells, Leydig cells and spermatogenic cells, accounting for 5.45, 1.24 and 0.423% of adult testicular cells. ACE2 mRNA-expressing Sertoli cells, spermatogenic cells and myoid cells accounted for 5.00, 0.56 and 0.73% of infant testicular cells. IHC demonstrated that ACE2 protein was also highly expressed in testicular tissues. In conclusion, the present results demonstrated that testicular injury may be missed by clinicians in patients with COVID-19 and male reproductive function should be closely followed up.

UPF1 impacts on mTOR signaling pathway and autophagy in endometrioid endometrial carcinoma.

Most EEC cases are associated with activities of the mTOR pathway, which regulates protein synthesis, cell growth and autophagy. While Up-Frameshift 1(UPF1) is a key protein factor in the nonsense-mediated mRNA degradation pathway (NMD), its role in carcinogenesis of EEC remains unclear. In this study, we first evaluated the expression level of UPF1 in EEC tissues and cell lines. Then, we investigated the effect of UPF1 on cellular function and mTOR signaling pathway; these effects were further validated in vivo. Finally, its effect on autophagy was evaluated by western blot and GFP-mRFP-LC3 staining. UPF1 expression in the EEC tissue samples was significantly higher than that of matched normal tissue samples. Overexpression of UPF1 promoted migration and invasion of EEC cells. Conversely, depletion of UPF1 suppressed migration and invasion of EEC cells. In addition, overexpression of UPF1 increased the in vivo growth of our EEC xenograft tumors. Finally, UPF1 increased the activity of the mTOR/P70S6K/4EBP1 signaling pathway and inhibited autophagy in EEC cells. These findings suggest that UPF1 functions as an oncogene to promote EEC carcinogenesis. Our findings propose UPF1 as a new potential therapeutic target for EEC.

ER-positive endocervical adenocarcinoma mimicking endometrioid adenocarcinoma in morphology and immunohistochemical profile: A case report of application of HPV RNAscope detection.

RATIONALE: Usual-type endocervical adenocarcinoma (ECA), high-risk HPV associated, is the most common type of glandular carcinoma in the endocervix. Mucin-depleted usual-type ECA is 1 end of morphological lineage of usual-type ECA and morphologically may show endometrioid features, which could cause diagnostic challenge with uterine endometrioid adenocarcinoma (EEC) and primary endometrioid ECA, especially in the setting of small biopsy and endocervical curettage (ECC). PATIENT CONCERNS: A 37-year-old women presented with dyspareunia for 1 year, showing atypical glandular cell on a liquid-based Pap TCT examination and positive for HPV16 detection. ECC showed EEC in another hospital based on its "endometrioid" morphology and immunohistochemical profiles (ER/PR/PAX8 strongly positive, though p16 also strongly positive). DIAGNOSES: The specimen of hysterectomy in our hospital displayed a lesion confined to the uterine cervix showing the same morphology and immunohistochemical profiles as ECC. Finally, we successfully performed HPV RNAscope and detected high-risk human papilloma virus (HPV) E6/E7 mRNA particles in tumor cells in situ, which warranted usual-type ECA with mucin-depleted feature, a rare deviation of usual-type of ECA. INTERVENTIONS: The patient underwent total hysterectomy with lymph node dissection. OUTCOMES: To date, 14 months after surgery, the patient is well without recurrence or distant metastasis, and undergoes regular reexamination. LESSONS SUBSECTIONS: We report a rare case of mucin-depleted usual-type ECA showing overlapping morphological and immunohistochemical profiles with EEC. The pathological diagnosis was confirmed by high-risk HPV RNAscope detection which is superior than immunohistochemistry to identify usual-type ECA, warranting an important role in assisting the diagnosis of morphological vague cases.

MiR-200a Regulates Nasopharyngeal Carcinoma Cell Migration and Invasion by Targeting MYH10.

Nasopharyngeal carcinoma (NPC), is one of the most common malignant tumor in southern China and southeast Asia. MYH10 is a coding gene of the NMMHC-IIB protein. Previous studies have shown that MYH10 expression was up-regulated in breast cancer, glioma and meningioma. Moreover, it was targeted by miR200 family. However, no relevant studies have been found in NPC. In present study, we found in 48 NPC specimens, MYH10 level was lower in most cancer areas than that in the adjacent normal tissue. Moreover, the depletion of MYH10 can promote the migration and invasion of NPC. In addition, we demonstrated that miR-200a has the strongest regulation to MYH10 among miR-200 family. miR-200a mimics could decrease MYH10 expression, while miR-200a inhibitor increase MYH10 expression. Next, we found that miR-200a bound directly to MYH10 using Dual-luciferase reporter. Finally, it was demonstrated that siMYH10 could reverse the effect of miR-200a inhibitor on NPC cell migration and invasion. Taken together, it can be concluded that MYH10 is lowly expressed in NPC compared with adjacent tissues, and the loss of MYH10 can promote the migration and invasion of NPC cells; Among the miR-200 family, miR-200a has the strongest regulatory effect on MYH10; MYH10 is a direct target gene of miR200a, and miR200a targets MYH10 to regulate the migration and invasion of NPC cells.

Small graphite nanoflakes as an advanced cathode material for aluminum ion batteries.

Here, we prepared small graphite nanoflakes (SGN) by a new strategy of pulverization as the cathode of aluminum ion batteries (AIBs). Electrochemical measurements show that SGN has a very high discharge capacity, excellent rate performance and good cycling stability mainly due to its enlarged edge plane, reduced thickness and high crystallinity. This work provides a new route for preparing high performance graphite-based materials for AIBs.

High-performance aqueous sodium-ion battery using a hybrid electrolyte with a wide electrochemical stability window.

The practical application of aqueous sodium-ion batteries (ASIBs) is limited by the electrolysis of water, which results in a low working voltage and energy density of ASIBs. Here, a NaClO4-based acetonitrile/water hybrid electrolyte (NaClO4(H2O)2AN2.4) is applied to ASIBs for the first time, which effectively extends the electrochemical stability window (ESW) to 3.0 V and reduces the internal resistance of the battery. Based on this hybrid electrolyte, an ASIB full cell using carbon coated Na2.85K0.15V2(PO4)3 and NaTi2(PO4)3 as the cathode and anode materials, respectively, can afford a discharge capacity and energy density of 52 mA h g-1 and 51 W h kg-1, respectively, at a current density of 1 A g-1. The energy density of this battery exceeds almost all reported traditional ASIBs.

Estrogen affects the negative feedback loop of PTENP1-miR200c to inhibit PTEN expression in the development of endometrioid endometrial carcinoma.

Endometrial carcinoma is one of the most common malignancies in the female reproductive system. It is well-known that estrogen plays an important role in the pathogenesis of endometrioid endometrial carcinoma (EEC), and induces the cancer suppressor gene PTEN deletion. However, how estrogen affects PTEN expression remains unknown. In the present study, we found in 40 EEC specimens, miR-200c level was higher in most cancer areas than that in the adjacent normal endometrium, while PTEN and PTENP1 were lower. Moreover, the expression of PTEN/PTENP1 and miR-200c also showed a converse relationship in EEC cell lines. In addition, we demonstrated that miR-200c bound directly to PTEN and PTENP1, and PTENP1 could reverse miR-200c inhibition function to PTEN using a dual-luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays. Next, 17ß-estradiol (E2) treatment could improve miR-200c and drop the PTEN level, which caused a consequential increase of the phospho-PI3K-AKT pathway genes. When we stably knocked down estrogen receptor α (ERα) expression in the EEC cell line, the effects of E2 on miR-200c and PTEN declined. In addition, it was demonstrated that E2 might modulate cell proliferation, migration and invasion relying on the expression of miR-200c. Taken together, it can be concluded that estrogen improves the miR-200c level by combining with ER, PTENP1 and PTEN could be inhibited by miR-200c, and then activate the PI3K-AKT pathway. This work provided a new mechanism of EEC development and a new potential therapeutic target.

MicroRNA-26a regulates ANXA1, rather than DAL-1, in the development of lung cancer.

The aim of the present study was to investigate the expression and role of microRNA-26a (miR-26a) in lung cancer, and to verify whether differentially expressed in adenocarcinoma of the lung (DAL-1) is the target protein of miR-26a. mRNA expression levels of miR-26a and DAL-1 were detected using reverse transcription-quantitative polymerase chain reaction. Protein expression levels of DAL-1 and annexin A1 (ANXA1) were evaluated by western blot analysis. Cell Counting Kit-8, Transwell and wound scratch healing assays were used to characterize the function of miR-26a in lung cancer cells. The association of DAL-1 with miR-26a or ANXA1 was determined by dual-luciferase reporter or two-dimensional gel electrophoresis assays. miR-26a revealed decreased expression levels in lung cancer tissues compared with normal lung tissues, and decreased expression levels in lung cancer cells compared with 16HBE cells. Inhibition of miR-26a promoted lung cancer cell growth, migration and invasion. The DAL-1 protein exhibited downregulated expression levels in lung cancer tissues. DAL-1 was not the direct target gene of miR-26a. The two-dimensional gel electrophoresis assay confirmed that DAL-1 and ANXA1 were associated proteins. Expression levels of the ANXA1 protein were increased following DAL-1 gene silencing. The altered expression level of miR-26a affected the expression of ANXA1, and not of DAL-1. miR-26a demonstrated decreased expression levels in lung cancer cells, and it has an important effect on the biological function of lung cancer cells. However, DAL-1 was not a target gene of miR-26a. As a DAL-1 associated protein, ANXA1 was regulated by miR-26a.

Identification and characterization of miR-96, a potential biomarker of NSCLC, through bioinformatic analysis.

Lung cancer is the leading cause of cancer-related death worldwide. The poor prognosis is partly due to lack of efficient methods for early diagnosis. MicroRNAs play roles in almost all aspects of cancer biology, and can be secreted into the circulation and serve as molecular biomarkers for the early diagnosis of cancer. In the present study, we determined the expression of miR-96 and the function of its target genes in lung cancer through bioinformatic analysis. Four microRNA expression profiles of lung cancer were downloaded from Gene Expression Omnibus and the data were analyzed using SPSS 16.0 software. Compared to the control group, expression of miR-96 was significantly increased in non-small cell lung cancer (NSCLC) (GSE51855), lung adenocarcinoma (GSE48414), stage I adenocarcinoma tissues (GSE63805) and the plasma of lung cancer patients (GSE68951). miR-96 was also elevated in six different NSCLC cell lines. However, the expression level of miR-96 was not related to the age, gender, clinical stage and histological subtype of the NSCLC patients. GO analysis of 78 predicted target genes of miR-96 showed that 42 of the obtained GO terms are highly associated with specific cellular processes including response to stimulus, signaling pathway, cell division, cell communication, cell migration and calcium signaling. KEGG results indicated that the miR-96 targets are mainly involved in the GnRH signaling pathway, long-term potentiation and insulin signaling pathway. In conclusion, miR-96, functioning as an oncogene, may play an important role in the development and progression of lung cancer. miR-96 may have the potential to serve as a molecular biomarker for the early diagnosis of NSCLC.

Knockdown of ANXA1 suppresses the biological behavior of human NSCLC cells in vitro.

Annexin A1 (ANXA1) is a member of the annexin superfamily. Previous studies have reported that ANXA1 is highly expressed in various types of malignant tumor; however, its role in the progression of non­small cell lung cancer (NSCLC) remains to be fully clarified. The present study aimed to investigate the oncogenic role of ANXA1 in NSCLC cells in vitro. RNA interference was used to downregulate ANXA1 expression in A549 and H1299 cells using a small interfering RNA lentiviral vector. Subsequently, cell proliferation and migration were detected using Cell Counting kit­8, clone formation, wound healing and Transwell chamber assays. Successful transfection was confirmed using fluorescence microscopy, which demonstrated that ANXA1 had been efficiently inhibited. ANXA1 knockdown suppressed the proliferation, migration and invasion of NSCLC cells. In conclusion, the present study provided evidence suggesting that ANXA1 may contribute to the growth and invasion of NSCLC cell lines, and ANXA1 may be exploited as an in vitro therapeutic target for the treatment of NSCLC.

DAL-1 attenuates epithelial-to mesenchymal transition in lung cancer.

BACKGROUND: Epithelial-to mesenchymal transition (EMT) involves in metastasis, causing loss of epithelial polarity. Metastasis is the major cause of carcinoma-induced death, but mechanisms are poorly understood. Here we identify differentially expressed in adenocarcinoma of the lung-1 (DAL-1), a protein belongs to the membrane-associated cytoskeleton protein 4.1 family, as an efficient suppressor of EMT in lung cancer. METHODS: The relationship between DAL-1 and EMT markers were analyzed by using immunohistochemistry in the clinical lung cancer tissues. Quantitative real-time PCR and western blot were used to characterize the expression of the EMT indicator mRNAs and proteins in DAL-1 overexpressed or knockdown cells. DAL-1 combined proteins were assessed by co-immunoprecipitation. RESULTS: DAL-1 levels were strongly reduced even lost in lymph node metastasis and advanced pathological stage of human lung carcinomas. Overexpression of DAL-1 altered the expression of numerous EMT markers, such as E-cadherin, ß-catenin Vimentin and N-cadherin expression, meanwhile changed the morphological shape of lung cancer cells, and whereas silencing DAL-1 had an opposite effect. DAL-1 directly combined with E-cadherin promoter and regulated its expression that could be the reason for impairing EMT and decreasing cell migration and invasion. Strikingly, HSPA5 was found as DAL-1 direct binding protein. CONCLUSIONS: These results suggest that tumor suppressor DAL-1 could also attenuate EMT and be important for tumor metastasis in the early transformation process in lung cancer.