Adipocytes-derived exosomal miR-122 promotes non-alcoholic fat liver disease progression via targeting Sirt1.

AIMS: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects adipose function. This study aimed to explore the function of adipocytes-derived exosomal (ADEs) miR-122 in NAFLD. METHODS: A high-fat and high-fructose diet-induced rat model and a palmitic acid (PA)-induced in vitro model were established. The RNA level of miR-122 and Sirt1 was measured using qRT-PCR. The protein levels of exosome biomarkers, and lipogenesis, inflammation and fibrosis biomarkers were determined by western blotting. Cell viability and apoptosis were assessed using cell counting kit-8 and flow cytometry, respectively. Serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride levels were measured. Liver tissue damage was assessed using haematoxylin and eosin staining. The interaction between miR-122 and Sirt1 3'UTR was assessed using a luciferase reporter gene assay. RESULTS: ADEs exhibited abundant level of miR-122 and promoted lipogenesis, impaired hepatocyte survival, enhanced liver damage and increased serum lipid levels in vivo and in vitro. Inhibition of miR-122 in ADEs alleviated NAFLD progression, lipid and glucose metabolism, liver inflammation and fibrosis both in vivo and in vitro. miR-122 binds directly to the 3'UTR of Sirt1 to suppress its expression. Moreover, Sirt1 overexpression reversed the increase in cell apoptosis, glucose and lipid metabolism, liver inflammation and fibrosis induced by ADEs in vivo and in vitro. CONCLUSIONS: The ADEs miR-122 promotes the progression of NAFLD via modulating Sirt1 signalling in vivo and in vitro. The ADEs miR-122 may be a promising diagnostic biomarker and therapeutic target for NAFLD.

6-O-desulfated heparin attenuates myocardial ischemia/reperfusion injury in mice through the regulation of miR-199a-5p/klotho axis.

Heparin has been documented to reduce myocardial injury caused by ischemia/reperfusion (I/R), but its clinical application is limited due to its strong intrinsic anticoagulant property. Some desulfated derivatives of heparin display low anticoagulant activity and may have potential value as therapeutic agents for myocardial I/R injury. In this study, we observed that 6-O-desulfated heparin, a desulfated derivative of heparin, shortened the activated partial thromboplastin time and exhibited lower anticoagulant activity compared with heparin or 2-O-desulfated heparin (another desulfated derivative of heparin). Then, we explored whether 6-O-desulfated heparin could protect against myocardial I/R injury, and elucidated its possible mechanisms. Administration of 6-O-desulfated heparin significantly reduced creatine kinase activity, myocardial infarct size and cell apoptosis in mice subjected to 30 min of myocardial ischemia following 2 h of reperfusion, accompanied by a reverse in miR-199a-5p elevation, klotho downregulation and reactive oxygen species (ROS) accumulation. In cultured H9c2 cells, the mechanism of 6-O-desulfated heparin against myocardial I/R injury was further explored. Consistent with the results in vivo, 6-O-desulfated heparin significantly ameliorated hypoxia/reoxygenation-induced injury, upregulated klotho and decreased miR-199a-5p levels and ROS accumulation, and these effects were reversed by miR-199a-5p mimics. In conclusion, these results suggested that 6-O-desulfated heparin with lower anticoagulant activity attenuated myocardial I/R injury through miR-199a-5p/klotho and ROS signaling. Our study may also indicate that 6-O-desulfated heparin, as an excellent heparin derivative, is a potential therapeutic agent for myocardial I/R injury.

A Novel and Fast Encryption System Based on Improved Josephus Scrambling and Chaotic Mapping.

To address the shortcomings of weak confusion and high time complexity of the existing permutation algorithms, including the traditional Josephus ring permutation (TJRP), an improved Josephus ring-based permutation (IJRBP) algorithm is developed. The proposed IJRBP replaces the remove operation used in TJRP with the position exchange operation and employs random permutation steps instead of fixed steps, which can offer a better scrambling effect and a higher permutation efficiency, compared with various scrambling methods. Then, a new encryption algorithm based on the IJRBP and chaotic system is developed. In our scheme, the plaintext feature parameter, which is related to the plaintext and a random sequence generated by a chaotic system, is used as the shift step of the circular shift operation to generate the diffusion matrix, which means that a minor change in the source image will generate a totally different encrypted image. Such a strategy strikes a balance between plaintext sensitivity and ciphertext sensitivity to obtain the ability to resist chosen-plaintext attacks (CPAs) and the high robustness of resisting noise attacks and data loss. Simulation results demonstrate that the proposed image cryptosystem has the advantages of great encryption efficiency and the ability to resist various common attacks.

Prevalence and risk factors of thrombotic events on patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Coagulation abnormalities in COVID-19 patients accompanied with poor prognosis. This study aimed to determine the prevalence and risk factors of thrombotic events on COVID-19 patients. METHODS: We systematically reviewed all the studies about thrombotic events on COVID-19 patients in PubMed, Embase, Web of Science, MedRxiv, bioRxiv, from Dec 1, 2019 to July 5, 2020. The weighted mean difference (MD) or odds ratio (OR) or relative risk (RR) with 95 % confidence intervals (CI) for clinical data in COVID-19 patients with or without thrombotic events was calculated. RESULTS: 12 articles contained 1083 patients were included for meta-analysis. The prevalence of thrombosis was 22 % (95 % CI 0.08-0.40) in COVID-19 patients and increased to 43 % (95 % CI 0.29-0.65) after admission to the intensive care unit (ICU). Compared with non-thrombotic patients, thrombotic patients had higher levels of D-dimer (MD = 2.79 µg/ml, 95 % CI 2.27-3.31 µg/ml), lactate dehydrogenase (LDH) (MD = 112.71 U/L, 95 % CI 62.40-163.02 U/L), and white blood cells (WBC) (MD = 1.14 *109/L, 95 % CI 0.47-1.81*109/L) while decreased lymphocytes (MD= -0.20*109/L, 95 % CI -0.38 - -0.02*109/L). Age, platelet counts, and male sex tended to be risks while diabetes tended to be a protection for thrombosis for COVID-19 patients, although no statistical difference was achieved. Finally, patients with thrombosis were at a higher risk of death (OR = 2.39, 95 % CI 1.36-4.20). CONCLUSIONS: Prevalence of thrombosis in COVID-19 patients was high, especially in ICU, though pharmacologic thromboembolism prophylaxis was applied. Therefore, higher levels of D-dimer, LDH, WBC, and decreased lymphocytes needed to be paid close attention to in patients with COVID-19.

Design and ARM-Based Implementation of Bitstream-Oriented Chaotic Encryption Scheme for H.264/AVC Video.

In actual application scenarios of the real-time video confidential communication, encrypted videos must meet three performance indicators: security, real-time, and format compatibility. To satisfy these requirements, an improved bitstream-oriented encryption (BOE) method based chaotic encryption for H.264/AVC video is proposed. Meanwhile, an ARM-embedded remote real-time video confidential communication system is built for experimental verification in this paper. Firstly, a 4-D self-synchronous chaotic stream cipher algorithm with cosine anti-controllers (4-D SCSCA-CAC) is designed to enhance the security. The algorithm solves the security loopholes of existing self-synchronous chaotic stream cipher algorithms applied to the actual video confidential communication, which can effectively resist the combinational effect of the chosen-ciphertext attack and the divide-and-conquer attack. Secondly, syntax elements of the H.264 bitstream are analyzed in real-time. Motion vector difference (MVD) coefficients and direct-current (DC) components in Residual syntax element are extracted through the Exponential-Golomb decoding operation and entropy decoding operation based on the context-based adaptive variable length coding (CAVLC) mode, respectively. Thirdly, the DC components and MVD coefficients are encrypted by the 4-D SCSCA-CAC, and the encrypted syntax elements are re-encoded to replace the syntax elements of the original H.264 bitstream, keeping the format compatibility. Besides, hardware codecs and multi-core multi-threading technology are employed to improve the real-time performance of the hardware system. Finally, experimental results show that the proposed scheme, with the advantage of high efficiency and flexibility, can fulfill the requirement of security, real-time, and format compatibility simultaneously.

Modified percutaneous Kyphoplasty technique in the treatment of osteoporotic thoracolumbar burst fractures: could it reduce the odds of cement leakage?

BACKGROUND: Osteoporotic thoracolumbar burst fracture (OTLBF) is common in seniors. Due to the fracture of the posterior vertebra and spinal canal occupancy, the risk of cement leakage and spine injury is high in OTLBF patients, thus the application of vertebroplasty and kyphoplasty is limited in these patients. This study aims to investigate the efficacy and safety of the modified percutaneous kyphoplasty (MPKP) in the treatment of OTLBF. METHODS: Clinical data of the OTLBF patients treated with MPKP and the osteoporotic thoracolumbar compression fracture (OTLCF) patients undergone PKP from January 2014 to June 2016 were collected. The key procedure of the MPKP was to fill the bone cavity with gel-foam by the first balloon inflation and to press the gel-foam by a second balloon inflation. Pain intensity, Oswestry disability index (ODI), and bone cement leakage of the patients in the two groups were analyzed. RESULTS: In the burst fracture group, the overall spinal canal occupancy was relatively low, and the maximum occupancy was 1/3 of the sagittal diameter of the spinal canal. The surgical duration was longer in the burst fracture group (39.0 ± 5.0 min with 95% CI: 37.7, 40.3) than in the compression fracture group (31.7 ± 4.3 min with 95% CI: 31.1, 32.3), and the difference between the two groups was statistically significant (Z = -8.668 and P = 0.000). Both the Oswestry disability index (ODI) and the visual analog scales (VAS) were apparently improved, but there was no significant difference between the two groups. Cement leakage occurred in 13 out of the 53 cases (24.5%) in the burst fracture group and 35 out of the 193 cases (18.1%) in the compression fracture group, and there was no significant difference between the two groups (Z = - 1.038 and P = 0.299). Neither group had consequential symptoms, such as spinal cord lesion, pain, and numbness of the peripheral nerve. CONCLUSION: Similar to the efficacy of PKP in the treatment of OTLCF, MPKP efficiently reduced the cement leakage rate and improved the safety of the surgery, although it prolonged the surgical duration and introduced more surgical steps.

Asymmetric dimethylarginine aggravates blood-retinal barrier breakdown of diabetic retinopathy via inhibition of intercellular communication in retinal pericytes.

Blood-retinal barrier breakdown is the main pathological characteristics of diabetic retinopathy (DR). Asymmetric dimethylarginine (ADMA) was reported to be elevated in DR patients. In this study, we observed the dynamic profile of ADMA, retinal morphology and permeability of BRB at 2, 4 or 8 week of diabetic rats induced by a single intraperitoneal injection of streptozocin (60 mg/kg) and in cultured rat retinal pericytes pretreated with D-glucose (30 mM) for 1, 3, 5 and 7 days or ADMA (3, 10, 30 µM) for 24, 48 and 72 h, trying to explore the effects of ADMA on blood-retinal barrier in DR. Gap junction intercellular communication (GJIC) and the expression of blood-retinal barrier-specific component connexin 43 (Cx43) were examined in diabetic rats or cultured retinal pericytes to elucidate whether ADMA impacted blood-retinal barrier function via damaging Cx43-GJIC. The results showed that with increasing duration of diabetes, the ultrastructure of blood-retinal barrier of diabetic rats appeared cell junction damage, apoptosis of retinal pericytes and breakdown of barrier successively. The increases in retinal permeability, ADMA levels and Cx43 expression, and abnormal GJIC were observed in diabetic rats and retinal pericytes exposed to D-glucose (30 mM). A glucose-like effect was seen using ADMA or another L-arginine analogue NG-monomethyl-L-arginine or dimethylarginine dimethylaminohydrolases (DDAHs) siRNA, implicating that ADMA aggravated the breakdown of blood-retinal barrier via damaging Cx43-GJIC.

A Symmetric Plaintext-Related Color Image Encryption System Based on Bit Permutation.

Recently, a variety of chaos-based image encryption algorithms adopting the traditional permutation-diffusion structure have been suggested. Most of these algorithms cannot resist the powerful chosen-plaintext attack and chosen-ciphertext attack efficiently for less sensitivity to plain-image. This paper presents a symmetric color image encryption system based on plaintext-related random access bit-permutation mechanism (PRRABPM). In the proposed scheme, a new random access bit-permutation mechanism is used to shuffle 3D bit matrix transformed from an original color image, making the RGB components of the color image interact with each other. Furthermore, the key streams used in random access bit-permutation mechanism operation are extremely dependent on plain image in an ingenious way. Therefore, the encryption system is sensitive to tiny differences in key and original images, which means that it can efficiently resist chosen-plaintext attack and chosen-ciphertext attack. In the diffusion stage, the previous encrypted pixel is used to encrypt the current pixel. The simulation results show that even though the permutation-diffusion operation in our encryption scheme is performed only one time, the proposed algorithm has favorable security performance. Considering real-time applications, the encryption speed can be further improved.

A Simple Chaotic Map-Based Image Encryption System Using Both Plaintext Related Permutation and Diffusion.

Recently, to conquer most non-plain related chaos-based image cryptosystems' security flaws that cannot resist the powerful chosen/knownn plain-text attacks or differential attacks efficiently for less plaintext sensitivity, many plain related chaos-based image cryptosystems have been developed. Most cryptosystems that have adopted the traditional permutation-diffusion structure still have some drawbacks and security flaws: (1) most plaintext related image encryption schemes using only plaintext related confusion operation or only plaintext related diffusion operation relate to plaintext inadequately that cannot achieve high plaintext sensitivity; (2) in some algorithms, the generation of security key that needs to be sent to the receiver is determined by the original image, so these algorithms may not applicable to real-time image encryption; (3) most plaintext related image encryption schemes have less efficiency because more than one round permutation-diffusion operation is required to achieve high security. To obtain high security and efficiency, a simple chaotic based color image encryption system by using both plaintext related permutation and diffusion is presented in this paper. In our cryptosystem, the values of the parameters of cat map used in permutation stage are related to plain image and the parameters of cat map are also influenced by the diffusion operation. Thus, both the permutation stage and diffusion stage are related to plain images, which can obtain high key sensitivity and plaintext sensitivity to resist chosen/known plaintext attacks or differential attacks efficiently. Furthermore, only one round of plaintext related permutation and diffusion operation is performed to process the original image to obtain cipher image. Thus, the proposed scheme has high efficiency. Complete simulations are given and the simulation results prove the excellent security and efficiency of the proposed scheme.

Resveratrol derivative BTM-0512 mitigates obesity by promoting beige remodeling of subcutaneous preadipocytes.

Recent studies revealed that sirtuin 1 (SIRT1) is involved in the regulation of energy metabolism and its agonist resveratrol showed anti-obesity effect. This study aims to determine whether BTM-0512, a novel derivative of resveratrol, acts as an antagonist of obesity and to explore its possible mechanisms. High-fat diet (HFD)-induced obese mice were intragastrically administered with BTM-0512 (5, 10, and 20 mg/kg/day) or resveratrol (10 mg/kg/day). It was found that the body weight, Lee's index, ratio of visceral adipose tissue (VAT) to body weight, and blood glucose were significantly reduced in BTM-0512-treated mice when compared with those in mice treated with resveratrol. BTM-0512 up-regulated the expressions of SIRT1, full length PRDM16 (fPRDM16), total PRDM16 (tPRDM16, including fPPRDM16 and other PRDM16 isoforms), and uncoupling protein 1 (UCP1) in both brown and subcutaneous adipose tissues. Although BTM-0512 and resveratrol also up-regulated SIRT1 and tPRDM16 levels in VAT of HFD-induced obese mice, the expressions of fPRDM16, UCP1, and TMEM26 were down-regulated. In mouse primary subcutaneous preadipocytes cultured with or without adipogenic medium, BTM-0512 up-regulated fPRDM16, tPRDM16, and UCP1 expressions, which was reversed by SIRT1 antagonists. But in cultured brown and visceral adipocytes, the UCP1 protein level showed no significant change after treatment with 1 µM of BTM-0512. Moreover, transfection with human SIRT1 plasmid reduced lipid deposit, as well as the mRNA levels of fPRDM16, UCP1, and TMEM26, in cultured human visceral adipose-derived stem cells. In conclusion, BTM-0512 has stronger anti-obesity effect than resveratrol, which might be associated with activation of beige remodeling in subcutaneous adipose tissue.

LC-UV Determination of Baicalin in Rabbit Plasma and Tissues for Application in Pharmacokinetics and Tissue Distribution Studies of Baicalin after Intravenous Administration of Liposomal and Injectable Formulations.

A simple and sensitive LC-UV method to investigate the pharmacokinetics and biodistribution pattern of baicalin in rabbits was established and validated. Baicalin and the internal standard, rutin, were extracted from biosamples using acetonitrile as protein precipitation after pretreated with ammonium acetate buffer (pH 3.5; 1 M) to obtain a pure chromatographic peak and high extraction recovery. Chromatographic separation was achieved on a reverse-phase C18 column with a gradient elution at flow rate of 1.0 mL/min. UV absorption was set at 278 nm. Chromatographic response was linear over the ranges of 0.05-10.00 µg/mL in plasma and 0.05-300.00 µg/g in tissues with the limits of quantification of 50.0 ng/mL in plasma and tissues, and the limit of detection of baicalin in bio-samples of 15 ng/mL. The RSD of intra-and inter-day for the biosamples were from 4.19% to 10.84% and from 4.37% to 10.93%, respectively. The accuracy of plasma and tissue samples ranged from 81.6% to 95.2% and 80.8% to 98.4%, respectively. The extraction recoveries ranged from 81.5% to 88.3% for plasma, from 73.1% to 93.2% for tissues, respectively. Baicalin was stable in rabbit biosamples. The validated method was successfully applied to the study of the pharmacokinetics and tissue distribution of baicalin after intravenous administration of liposomal and injectable formulations to rabbits. Compared to baicalin injection, the pharmacokinetics and biodistribution behavior of baicalin was altered significantly in rabbits treated with its liposomes and drug concentration in the lungs was greatly increased.

Myeloperoxidase-derived hypochlorous acid promotes ox-LDL-induced senescence of endothelial cells through a mechanism involving ß-catenin signaling in hyperlipidemia.

Myeloperoxidase (MPO)-derived product hypochlorous acid (HOCl) is able to induce cellular senescence and MPO is also expressed in endothelial cells besides the well-recognized immune cells. This study aims to clarify the association of endothelium-derived MPO with endothelial senescence in hyperlipidemia. The rats were fed with high-fat diet for 8 weeks to establish a hyperlipidemic model, which showed an increase in plasma lipids, endothelium-derived MPO expression, endothelial senescence and endothelial dysfunction concomitant with a reduction in glycogen synthase kinase 3 beta (GSK-3ß) activity and phosphorylated ß-catenin (p-ß-catenin) level as well as an increase in ß-catenin and p53 levels within the endothelium. Next, human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low density lipoprotein (ox-LDL, 100 µg/ml) for 24 h to establish a senescent cell model in vitro. Consistent with the finding in vivo, ox-LDL-induced MPO expression and HUVECs senescence, accompanied by a decrease in GSK-3ß activity and p-ß-catenin level as well as an increase in HOCl content, ß-catenin and p53 levels; these phenomena were attenuated by MPO inhibitor. Replacement of ox-LDL with HOCl could also induce HUVECs senescence and activate the ß-catenin/p53 pathway. Based on these observations, we conclude that endothelium-derived MPO is upregulated in hyperlipidemic rats, which may contribute to the accelerated vascular endothelial senescence through a mechanism involving the ß-catenin/p53 pathway.

Association of coffee intake with bone mineral density: a Mendelian randomization study.

Background: In observational studies, the relationship between coffee intake and bone mineral density (BMD) is contradictory. However, residual confounding tends to bias the results of these studies. Therefore, we used a two-sample Mendelian randomization (MR) approach to further investigate the potential causal relationship between the two. Methods: Genetic instrumental variables (IVs) associated with coffee intake were derived from genome-wide association studies (GWAS) of the Food Frequency Questionnaire (FFQ) in 428,860 British individuals and matched using phenotypes in PhenoScanner. Summarized data on BMD were obtained from 537,750 participants, including total body BMD (TB-BMD), TB-BMD in five age brackets ≥60, 45-60, 30-45, 15-30, and 0-15 years, and BMD in four body sites: the lumbar spine, the femoral neck, the heel, and the ultradistal forearm. We used inverse variance weighting (IVW) methods as the primary analytical method for causal inference. In addition, several sensitivity analyses (MR-Egger, Weighted median, MR-PRESSO, Cochran's Q test, and Leave-one-out test) were used to test the robustness of the results. Results: After Bonferroni correction, Coffee intake has a potential positive correlation with total body BMD (effect estimate [Beta]: 0.198, 95% confidence interval [Cl]: 0.05-0.35, P=0.008). In subgroup analyses, coffee intake was potentially positively associated with TB-BMD (45-60, 30-45 years) (Beta: 0.408, 95% Cl: 0.12-0.69, P=0.005; Beta: 0.486, 95% Cl: 0.12-0.85, P=0.010). In addition, a significant positive correlation with heel BMD was also observed (Beta: 0.173, 95% Cl: 0.08-0.27, P=0.002). The results of the sensitivity analysis were generally consistent. Conclusion: The results of the present study provide genetic evidence for the idea that coffee intake is beneficial for bone density. Further studies are needed to reveal the biological mechanisms and offer solid support for clinical guidelines on osteoporosis prevention.

Piezoresistivity modeling of soft tissue electrical-mechanical properties: A validation study.

In general, the electrical property of soft tissues is sensitive to the force applied to their surface. To further study the relationship between the force and the electrical property of soft tissues, this paper attempts to investigate the effect of static and higher-order stresses on electrical properties. Overall, a practical experimental platform is designed to acquire the force information and the electrical property of soft tissues during a contact procedure, which is featured different compression stimuli, such as constant pressing force, constant pressing speed, and step-force compression, etc. Furthermore, the piezoresistive characteristic is innovatively introduced to model the mechanical-electrical properties of soft tissue. Finite Element Modeling (FEM) is adopted to fit the static piezoresistivity of the soft tissue. Finally, experimental studies were performed to demonstrate the effect of stress on the electrical properties and the feasibility of the proposed piezoresistive model to describe soft tissues' mechanical and electrical properties.

Research on evaluation index method of cloud-network convergence capability.

There is no measurable and evaluable index system for cloud-network convergence that provides guidance and reference for the subsequent construction and development of cloud-network convergence. It is a big project to select and evaluate the indexes of cloud-network convergence, which requires suitable index selection and index evaluation schemes. Based on analytic hierarchy process (AHP) and entropy weight method, this paper proposes an improved AHP (i-AHP) index selection scheme and index evaluation scheme leveraging the years of experts' experience, the geometric mean and the least square method. The improved weighted least square method (WLSM) is finally proved to be more stable for index evaluation scheme by adding abnormal data. In addition, the index weight obtained by the index evaluation scheme with WLSM are provided as a reference for the future development of cloud-network convergence. The simulation results show that the proposed scheme is superior to the existing index evaluation scheme and can avoid the weight deviation caused by the disturbance and fluctuation of abnormal data.

Associations of the circulating levels of cytokines with risk of ankylosing spondylitis: a Mendelian randomization study.

Background: Observational studies have shown that changes in circulating cytokine/growth factor levels occur throughout the initiation and progression of ankylosing spondylitis (AS), yet whether they are etiologic or downstream effects remains unclear. In this study, we performed a summarized-level bidirectional Mendelian randomization (MR) analysis to shed light on the causal relationship between the two. Methods: Genetic instrumental-variables (IVs) associated with circulating cytokine/growth factor levels were derived from a genome-wide association study (GWAS) of 8,293 European individuals, whereas summary data for the AS were obtained from a FinnGen GWAS of 166,144 participants. We used the inverse-variance-weighted (IVW) method as the main analysis for causal inference. Furthermore, several sensitivity analyses (MR-Egger, weighted median, MR-PRESSO and Cochran's Q test) were utilized to examine the robustness of the results. Finally, reverse MR analysis was performed to assess reverse causality between AS and circulating cytokine/growth factor levels. Results: After Bonferroni correction, circulating levels of Cutaneous T-cell attracting (CTACK) and Monocyte specific chemokine 3 (MCP-3) were positively associated with a higher risk of AS (odds ratio [OR]: 1.224, 95% confidence interval [95% Cl]: 1.022 ~ 1.468, P = 0.028; OR: 1.250, 95% Cl: 1.016 ~ 1.539, P = 0.035). In addition, elevated circulating levels of Basic fibroblast growth factor (FGF-basic), Granulocyte colony-stimulating factor (G-CSF) and MCP-3 was considered a consequence of AS disease (ß = 0.023, P = 0.017; ß = 0.017, P = 0.025; ß = 0.053, P = 0.025). The results of the sensitivity analysis were generally consistent. Conclusion: The present study supplies genetic evidence for the relationship between circulating cytokine levels and AS. Targeted interventions of specific cytokines may help to reduce the risk of AS initiation and progression.

Inhibit ALDH3A2 reduce ovarian cancer cells survival via elevating ferroptosis sensitivity.

Ovarian cancer (OC) is a malignant gynecologic tumor with high morbidity and mortality. As a newly discovered mode of programmed cell death, ferroptosis has been involved in various pathological processes of kinds of tumors in recent years. Aldehyde dehydrogenase 3 family member A2 (ALDH3A2) catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acid. ALDH3A2 has been shown to be associated with ferroptosis in acute myeloid leukemia (AML), but the mechanism remains unclear. In this study, we analyzed the TCGA and GTEx databases and showed that high ALDH3A2 expression predicted poor prognosis in ovarian cancer. Further studies found that knockout or overexpression of ALDH3A2 correspondingly increased or attenuated the ferroptosis sensitivity of ovarian cancer cells. And sequencing revealed that ALDH3A2 knockout led to the activation of lipid metabolic, GSH metabolic, phospholipid metabolic, and aldehyde metabolic pathways, suggesting that ALDH3A2 induced changes in the sensitivity of ovarian cancer cells to ferroptosis by affecting these metabolic processes. Our results provide a new promising therapeutic strategy for the treatment of OC.

UQCRFS1 serves as a prognostic biomarker and promotes the progression of ovarian cancer.

UQCRFS1 has been reported to be highly expressed in gastric and breast cancer, but the mechanism remains unclear. The prognosis and biological functions of UQCRFS1 in ovarian cancer (OC) have not been evaluated. The expression of UQCRFS1 in EOC was detected by GEPIA and HPA websites, and the prognosis value was investigated by Kaplan-Meier analysis. Then the correlation between the UQCRFS1 gene and tumor-related signature were analyzed by Spearman correlation analysis and rank sum test. Subsequently, the expression of the UQCRFS1 gene in four ovarian cancer cell lines was detected. A2780 and OVCAR8 with the highest expression of UQCRFS1 were selected in the following biological experiments. Cell proliferation was detected by CCK8 assay, cell cycle and apoptosis were determined by flow cytometry, reactive oxygen species (ROS) production was detected by DCFH-DA, DNA damage gene mRNA expression was analyzed by RT-PCR, and AKT/mTOR pathway protein expression were also examined by western blot after siRNA transfection. We found that UQCRFS1 was high-expression in EOC and associated with poor prognosis. Spearman correlation analysis revealed that the high expression of UQCRFS1 is associated with the cell cycle, apoptosis, oxidative phosphorylation, and DNA damage. Further studies found that knockdown of UQCRFS1 cells reduced cell proliferation, cell cycle arrest at the G1 phase, increased proportion of apoptosis, ROS production, and expression of DNA damage genes, inhibited ATK/mTOR pathway. The study suggested that UQCRFS1 may be a candidated target for diagnosis and treatments in OC.

Bepotastine Sensitizes Ovarian Cancer to PARP Inhibitors through Suppressing NF-κB-Triggered SASP in Cancer-Associated Fibroblasts.

Therapy-induced senescence (TIS) is common in tumor cells treated with PARP inhibitors (PARPis) and can serve as a promising target for improving PARPi efficacy. However, whether stromal components within the tumor microenvironment undergo TIS caused by PARPis and contribute to consequential treatment failure remain unclear. We previously revealed that PARPis triggered a senescence-like secretory phenotype in stromal fibroblasts. Here, we further explored PARPi-induced senescence in the stroma, its contribution to PARPi resistance, and opportunities to leverage stromal TIS for improved PARPi sensitivity. In this study, we demonstrated that tumor tissues from patients treated with neoadjuvant PARPis showed a significant senescence-like phenotype in the stroma. Moreover, PARPi-induced senescent cancer-associated fibroblasts (CAFs) displayed a senescence-associated secretory phenotype (SASP) profile that was sufficient to induce tumor resistance to PARPis in both homologous recombination-deficient (HRD) and -proficient ovarian cancer cells. Using the GLAD4U database, we found that bepotastine, an approved H1-antihistamine, inhibited the SASP of PARPi-primed CAFs at clinical serum concentrations. We further demonstrated that bepotastine attenuated fibroblast-facilitated tumor resistance to PARPis in three-dimensional organotypic cultures and HRD-positive patient-derived xenograft models. Mechanistically, bepotastine suppressed PARPi-triggered SASP by inhibiting NF-κB signaling independent of the histamine H1 receptor. Taken together, our results highlight the importance of stromal TIS and SASP in PARPi resistance, and targeting SASP with bepotastine may be a promising therapeutic option for improving PARPi sensitivity in ovarian cancer.

Macrophages facilitate tumor cell PD-L1 expression via an IL-1ß-centered loop to attenuate immune checkpoint blockade.

Tumor-associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)-1ß was among the most abundant cytokines within the in vitro tumor-macrophage coculture system, and enhanced IL-1ß expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL-1ß mediated immunosuppression during tumor-TAMs crosstalk. Mechanistically, we demonstrated that IL-1ß significantly boosted programmed death-ligand 1 (PD-L1) expression in tumor cells via the activation of the nuclear factor-κb signaling cascade. Specifically, IL-1ß released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation-dependent manner. IL-1ß sustained and intensified immunosuppression by promoting C-C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL-1ß neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti-PD-L1 antibody in tumor-bearing mouse models. Together, this study presents an IL-1ß-centered immunosuppressive loop between TAMs and tumor cells, highlighting IL-1ß as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.