Vascular smooth muscle-specific LRRC8A knockout ameliorates angiotensin II-induced cerebrovascular remodeling by inhibiting the WNK1/FOXO3a/MMP signaling pathway.

Hypertensive cerebrovascular remodeling involves the enlargement of vascular smooth muscle cells (VSMCs), which activates volume-regulated Cl- channels (VRCCs). The leucine-rich repeat-containing family 8 A (LRRC8A) has been shown to be the molecular identity of VRCCs. However, its role in vascular remodeling during hypertension is unclear. In this study, we used vascular smooth muscle-specific LRRC8A knockout (CKO) mice and an angiotensin II (Ang II)-induced hypertension model. The results showed that cerebrovascular remodeling during hypertension was ameliorated in CKO mice, and extracellular matrix (ECM) deposition was reduced. Based on the RNA-sequencing analysis of aortic tissues, the level of matrix metalloproteinases (MMPs), such as MMP-9 and MMP-14, were reduced in CKO mice with hypertension, which was further verified in vivo by qPCR and immunofluorescence analysis. Knockdown of LRRC8A in VSMCs inhibited the Ang II-induced upregulation of collagen I, fibronectin, and matrix metalloproteinases (MMPs), and overexpression of LRRC8A had the opposite effect. Further experiments revealed an interaction between with-no-lysine (K)-1 (WNK1), which is a "Cl--sensitive kinase", and Forkhead transcription factor O3a (FOXO3a), which is a transcription factor that regulates MMP expression. Ang II induced the phosphorylation of WNK1 and downstream FOXO3a, which then increased the expression of MMP-2 and MMP-9. This process was inhibited or potentiated when LRRC8A was knocked down or overexpressed, respectively. Overall, these results demonstrate that LRRC8A knockout in vascular smooth muscle protects against cerebrovascular remodeling during hypertension by reducing ECM deposition and inhibiting the WNK1/FOXO3a/MMP signaling pathway, demonstrating that LRRC8A is a potential therapeutic target for vascular remodeling-associated diseases such as stroke.

Application of three-dimensional technology in video-assisted thoracoscopic surgery sublobectomy.

Background: Due to the widespread use of imaging techniques, the detection rate of early-stage lung cancer has increased. Video-assisted thoracoscopic surgery (VATS) sublobectomy has emerged as a prominent alternative to lobectomy, offering advantages like reduced resection range, better preservation of lung function, and enhanced postoperative quality of life. However, sublobectomy is more intricate than lobectomy, necessitating a higher level of surgical proficiency and anatomical understanding. Methods: Three electronic databases were searched to capture relevant studies from January 2016 to March 2023, which related to the application of three-dimensional(3D) technology in VATS sublobectomy. Results: Currently, clinical departments such as orthopedics, hepatobiliary surgery, and urology have started using 3D technology. This technology is expected to be widely used in thoracic surgery in future. Now 3D technology assists in preoperative planning, intraoperative navigation and doctor-patient communication. Conclusion: 3D technologies, instrumental in locating pulmonary nodules and identifying variations in target lung segmental vessels and bronchi, play pivotal roles in VATS sublobectomy, especially in preoperative planning, intraoperative navigation, and doctor-patient communication. The limitations of 3D technology in clinical application are analyzed, and the future direction of existing 3D technology development is prospected.

Antihyperlipidemic drug rosuvastatin suppressed tumor progression and potentiated chemosensitivity by downregulating CCNA2 in lung adenocarcinoma.

Rosuvastatin (RSV) is widely used to treat hyperlipidemia and hypercholesterolemia and is recommended for the primary and secondary prevention of cardiovascular diseases (CVD). In this study, we aimed to explore its action and mechanism in lung adenocarcinoma (LUAD) therapy. Lewis and CMT64 cell-based murine subcutaneous LUAD models were employed to explore the effects of RSV monotherapy combined with cisplatin and gemcitabine. Human lung fibroblasts and human LUAD cell lines were used to assess the effects of RSV on normal and LUAD cells. Bioinformatics and RNA interference were used to observe the contribution of cyclin A2 (CCNA2) knockdown to RSV inhibition and to improve chemosensitivity in LUAD. RSV significantly suppressed grafted tumor growth in a murine subcutaneous LUAD model and exhibited synergistic anti-tumor activity with cisplatin and gemcitabine. In vitro and in vivo experiments demonstrated that RSV impaired the proliferation and migration of cancer cells while showing little inhibition of normal lung cells. RNA interference and CCK8 detection preliminarily indicated that RSV inhibited tumor growth and enhanced the chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2. RSV suppressed LUAD progression and enhanced chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2, which should be prior consideration for the treatment of LUAD, especially for patients co-diagnosed with hyperlipidemia and hypercholesterolemia.

The transplant rejection response involves neutrophil and macrophage adhesion-mediated trogocytosis and is regulated by NFATc3.

The anti-foreign tissue (transplant rejection) response, mediated by the immune system, has been the biggest obstacle to successful organ transplantation. There are still many enigmas regarding this process and some aspects of the underlying mechanisms driving the immune response against foreign tissues remain poorly understood. Here, we found that a large number of neutrophils and macrophages were attached to the graft during skin transplantation. Furthermore, both types of cells could autonomously adhere to and damage neonatal rat cardiomyocyte mass (NRCM) in vitro. We have demonstrated that Complement C3 and the receptor CR3 participated in neutrophils/macrophages-mediated adhesion and damage this foreign tissue (NRCM or skin grafts). We have provided direct evidence that the damage to these tissues occurs by a process referred to as trogocytosis, a damage mode that has never previously been reported to directly destroy grafts. We further demonstrated that this process can be regulated by NFAT, in particular, NFATc3. This study not only enriches an understanding of host-donor interaction in transplant rejection, but also provides new avenues for exploring the development of novel immunosuppressive drugs which prevent rejection during transplant therapy.

Dual action of macrophage miR-204 confines cyclosporine A-induced atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA-204 (miR-204) transcription. We therefore hypothesised that miR-204 is involved in the development of CsA-induced atherosclerosis. EXPERIMENTAL APPROACH: ApoE-/- mice with macrophage-miR-204 overexpression were generated to determine the effects of miR-204 on CsA-induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR-204 effects. KEY RESULTS: CsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high-fat diet-induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE-/- mice, respectively. miR-204 levels decreased in circulating monocytes and plaque lesions during CsA-induced atherosclerosis. The upregulation of miR-204 in macrophages inhibited CsA-induced atherosclerotic plaque formation but did not affect serum lipid levels. miR-204 limited the CsA-induced foam cell formation by reducing the expression of the scavenger receptors SR-BII and CD36. SR-BII was post-transcriptionally regulated by mature miR-204-5p via 3'-UTR targeting. Additionally, nuclear-localised miR-204-3p prevented the CsA-induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR-BII or CD36 expression restoration dampened the beneficial effects of miR-204 on CsA-induced atherosclerosis. CONCLUSION AND IMPLICATIONS: Macrophage miR-204 ameliorates CsA-induced atherosclerosis, suggesting that miR-204 may be a potential target for the prevention and treatment of CsA-related atherosclerotic side effects.

Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1.

BACKGROUND: Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. METHODS: We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE-/-- mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. RESULTS: We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. CONCLUSION: Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

Intestinal flora study reveals the mechanism of Danggui Shaoyao San and its decomposed recipes to improve cognitive dysfunction in the rat model of Alzheimer's disease.

Background: Alzheimer's disease (AD), characterized by a severe decline in cognitive function, significantly impacts patients' quality of life. Traditional Chinese Medicine (TCM) presents notable advantages in AD treatment, closely linked to its regulation of intestinal flora. Nevertheless, a comprehensive exploration of the precise role of intestinal flora in AD remains lacking. Methods: We induced an AD model through bilateral intracerebroventricular injection of streptozotocin in rats. We divided 36 rats randomly into 6 groups: sham-operated, model, Danggui Shaoyao San (DSS), and 3 DSS decomposed recipes groups. Cognitive abilities were assessed using water maze and open field experiments. Nissl staining examined hippocampal neuron integrity. Western blot analysis determined synaptoprotein expression. Additionally, 16S rDNA high-throughput sequencing analyzed intestinal flora composition. Results: DSS and its decomposed recipe groups demonstrated improved learning and memory in rats (P<0.01). The open field test indicated increased central zone residence time and locomotor activity distance in these groups (P<0.05). Furthermore, the DSS and decomposed recipe groups exhibited reduced hippocampal neuronal damage and increased expression levels of synapsin I (P<0.05) and PSD95 (P<0.01) proteins. Alpha and Beta diversity analyses showed that the intestinal flora species richness and diversity in the DSS and decomposed recipe groups were similar to those in the sham-operated group, signifying a significant restorative effect (P<0.05). Conclusion: The combination of DSS and its decomposed recipes can reduce the abundance of harmful gut microbiota, leading to improvements in cognitive and learning abilities.

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Stable isotope technique is important for understanding the structure and function of soil food web, which is considered as a belowground black box. We reviewed typical application cases of stable isotope techniques in the research of soil food webs, including to determine food sources and feeding preferences of soil fauna by using isotopes, and to analyze the trophic structure of soil food webs through isotope fractionation effects during the process of feeding and nutrient sequestration by soil fauna. Additionally, stable isotope techniques could reveal the role of soil biota at different trophic levels within soil food web in ecosystem matter and energy flow, which favored to carry out accurate and efficient research on the contribution of soil food webs to soil carbon and nitrogen cycling process and the corresponding influence mechanism. We further put forward the limitations of current stable isotope techniques and the future development directions.

The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC.

This study aimed to explore the role and mechanism of felodipine in lung cancer therapy. Murine subcutaneous lung squamous cancer (LUSC) models constructed by KLN-205 cells were utilized to assess the effect of felodipine monotherapy and in combination with the programmed cell death protein 1 antibody (PD1ab) and cytotoxic T lymphocyte-associated antigen-4 (CTLA4ab). Immunohistochemistry analysis was subsequently applied to detect the number of CD8+ T cells and Ki67+ cells. Lastly, a series of in vitro and in vivo experiments were performed to evaluate the effects of felodipine on human LUSC cells and explore the preliminary mechanism underlying felodipine inhibition. The results revealed that felodipine monotherapy exerted a significant inhibitory effect on LUSC growth and synergistic antitumoral activity with PD1ab and CTLA4ab. Meanwhile, immunohistochemistry analysis displayed that felodipine promoted CD8+ T-cell infiltration and downregulated Ki67 expression in tumor cells. Moreover, in vitro and in vivo experiments utilizing human LUSC cells determined that felodipine impaired the proliferative and migratory abilities of cancer cells. In addition, TCGA data analysis uncovered that nuclear factor of activated T cell (NFAT1) expression was positively correlated with overall survival and disease-free survival. Finally, the cell counting kit-8 assay signaled that felodipine might suppress tumor growth by modulating NFAT1.

[Association between maternal gestational diabetes mellitus and the risk of autism spectrum disorder in offspring]. / æ¯äº²å¦Šå¨ ç³–å°¿ç— ä¸Žå­ä»£å­¤ç‹¬ç—‡è°±ç³»éšœç¢å‘ç”Ÿé£Žé™©çš„å ³è”åˆ†æž.

OBJECTIVES: To explore the association between maternal gestational diabetes mellitus (GDM) exposure and the development of autism spectrum disorder (ASD) in offspring. METHODS: A case-control study was conducted, recruiting 221 children with ASD and 400 healthy children as controls. Questionnaires and interviews were used to collect information on general characteristics of the children, socio-economic characteristics of the family, maternal pregnancy history, and maternal disease exposure during pregnancy. Multivariate logistic regression analysis was used to investigate the association between maternal GDM exposure and the development of ASD in offspring. The potential interaction between offspring gender and maternal GDM exposure on the development of ASD in offspring was explored. RESULTS: The proportion of maternal GDM was significantly higher in the ASD group compared to the control group (16.3% vs 9.4%, P=0.014). After adjusting for variables such as gender, gestational age, mode of delivery, parity, and maternal education level, maternal GDM exposure was a risk factor for ASD in offspring (OR=2.18, 95%CI: 1.04-4.54, P=0.038). On the basis of adjusting the above variables, after further adjusting the variables including prenatal intake of multivitamins, folic acid intake in the first three months of pregnancy, and assisted reproduction the result trend did not change, but no statistical significance was observed (OR=1.94, 95%CI: 0.74-5.11, P=0.183). There was an interaction between maternal GDM exposure and offspring gender on the development of ASD in offspring (P<0.001). Gender stratified analysis showed that only in male offspring of mothers with GDM, the risk of ASD was significantly increased (OR=3.67, 95%CI: 1.16-11.65, P=0.027). CONCLUSIONS: Maternal GDM exposure might increase the risk of ASD in offspring. There is an interaction between GDM exposure and offspring gender in the development of ASD in offspring.

Inflammasome activation by viral infection: mechanisms of activation and regulation.

Viral diseases are the most common problems threatening human health, livestock, and poultry industries worldwide. Viral infection is a complex and competitive dynamic biological process between a virus and a host/target cell. During viral infection, inflammasomes play important roles in the host and confer defense mechanisms against the virus. Inflammasomes are polymeric protein complexes and are considered important components of the innate immune system. These immune factors recognize the signals of cell damage or pathogenic microbial infection after activation by the canonical pathway or non-canonical pathway and transmit signals to the immune system to initiate the inflammatory responses. However, some viruses inhibit the activation of the inflammasomes in order to replicate and proliferate in the host. In recent years, the role of inflammasome activation and/or inhibition during viral infection has been increasingly recognized. Therefore, in this review, we describe the biological properties of the inflammasome associated with viral infection, discuss the potential mechanisms that activate and/or inhibit NLRP1, NLRP3, and AIM2 inflammasomes by different viruses, and summarize the reciprocal regulatory effects of viral infection on the NLRP3 inflammasome in order to explore the relationship between viral infection and inflammasomes. This review will pave the way for future studies on the activation mechanisms of inflammasomes and provide novel insights for the development of antiviral therapies.

Aberrant spontaneous brain activity in patients with thyroid-associated ophthalmopathy with and without optic neuropathy: a resting-state functional MRI study.

OBJECTIVES: To investigate the brain functional alterations in dysthyroid optic neuropathy (DON) by evaluating spontaneous neural activity, using functional magnetic resonance imaging (fMRI) with regional homogeneity (ReHo), and its relationship with ophthalmologic performance. METHODS: Forty-seven patients with thyroid-associated ophthalmopathy (TAO; 20 with DON, 27 with non-DON) and 33 age-, sex-, and education-matched healthy controls (HCs) underwent fMRI. ReHo values were compared using one-way analysis of variance (ANOVA) with post hoc pairwise comparisons (voxel-level p < 0.01, Gaussian random field correction, cluster-level p < 0.05). Correlations between ReHo values and ophthalmological metrics were assessed for DONs, with Bonferroni correction for multiple comparisons (p < 0.004). ROC curves were applied to evaluate the diagnostic performance of ReHo metrics. RESULTS: ReHo values were significantly lower in the left insula and right superior temporal gyrus, and higher in the left posterior cingulate cortex (LPCC), of DON than of non-DON patients. ReHo values were also significantly lower in the right middle temporal, left insula, and left precentral gyrus in DON than in HCs. Meanwhile, ReHo values were higher in LPCC in non-DON than in HCs. ReHo values correlated with ophthalmic examinations to varying degrees in DON. For distinguishing DON, the ReHo values in LPCC showed optimal individually (AUC = 0.843), the combination of the ReHo in both the left insula and LPCC performed better (AUC = 0.915). CONCLUSION: Spontaneous brain activity differed between TAO with and without DON, which may reflect the underlying pathological mechanism of DON. The ReHo index can be considered a diagnostic biomarker. CLINICAL RELEVANCE STATEMENT: Spontaneous brain activity in DON differed from that in TAO without DON, which may reflect the underlying pathological mechanism of DON. The ReHo index can be considered a diagnostic biomarker for early detection of DON. KEY POINTS: • Dysthyroid optic neuropathy (DON) affects brain activity, which contributes in the understanding of its visual dysfunction. • Regional homogeneity values differ between thyroid-associated ophthalmopathy with and without DON in various brain regions. • Regional homogeneity values can be used as a biomarker in the differential diagnosis of DON.

Importance of GWAS risk loci and clinical data in predicting asthma using machine-learning approaches.

INTRODUCTION: To understand the risk factors of asthma, we combined genome-wide association study (GWAS) risk loci and clinical data in predicting asthma using machine-learning approaches. METHODS: A case-control study with 123 asthmatics and 100 controls was conducted in the Zhuang population in Guangxi. GWAS risk loci were detected using polymerase chain reaction, and clinical data were collected. Machine-learning approaches were used to identify the major factors that contribute to asthma. RESULTS: A total of 14 GWAS risk loci with clinical data were analyzed on the basis of 10 times the 10-fold cross-validation for all machine-learning models. Using GWAS risk loci or clinical data, the best performances exhibited area under the curve (AUC) values of 64.3% and 71.4%, respectively. Combining GWAS risk loci and clinical data, the XGBoost established the best model with an AUC of 79.7%, indicating that the combination of genetics and clinical data can enable improved performance. We then sorted the importance of features and found the top six risk factors for predicting asthma to be rs3117098, rs7775228, family history, rs2305480, rs4833095, and body mass index. CONCLUSION: Asthma-prediction models based on GWAS risk loci and clinical data can accurately predict asthma, and thus provide insights into the disease pathogenesis.

Phylogenomic analysis, cryptic species discovery, and DNA barcoding of the genus Cibotium in China based on plastome data.

Germplasm resources are the source of herbal medicine production. The cultivation of superior germplasm resources helps to resolve the conflict between long-term population persistence and growing market demand by consistently producing materials with high quality. The fern species Cibotium barometz is the original plant of cibotii rhizoma ("Gouji"), a traditional Chinese medicine used in the therapy of pain, weakness, and numbness in the lower extremities. Long-history medicinal use has caused serious wild population decline in China. Without sufficient understanding of the species and lineage diversity of Cibotium, it is difficult to propose a targeted conservation scheme at present, let alone select high-quality germplasm resources. In order to fill such a knowledge gap, this study sampled C. barometz and relative species throughout their distribution in China, performed genome skimming to obtain plastome data, and conducted phylogenomic analyses. We constructed a well-supported plastome phylogeny of Chinese Cibotium, which showed that three species with significant genetic differences are distributed in China, namely C. barometz, C. cumingii, and C. sino-burmaense sp. nov., a cryptic species endemic to NW Yunnan and adjacent regions of NE Myanmar. Moreover, our results revealed two differentiated lineages of C. barometz distributed on the east and west sides of a classic phylogeographic boundary that was probably shaped by monsoons and landforms. We also evaluated the resolution of nine traditional barcode loci and designed five new DNA barcodes based on the plastome sequence that can distinguish all these species and lineages of Chinese Cibotium accurately. These novel findings on a genetic basis will guide conservation planners and medicinal plant breeders to build systematic conservation plans and exploit the germplasm resources of Cibotium in China.

A patient with refractory proliferative lupus nephritis treated with telitacicept: A case report.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Lupus nephritis (LN) is a common type of organ damage which occurs in SLE patients and is characterized by recurrent proteinuria. Activation of B lymphocytes can lead to refractory LN, which is an important pathogenic factor in SLE. B lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL) are predominantly produced by myeloid cells (monocytes, dendritic cells, neutrophils, etc) to regulate B lymphocyte function. Telitacicept was the first dual-targeting biological drug which targeted both BLyS and APRIL. Telitacicept has passed a phase II clinical trial and has since been approved for the treatment of SLE. CASE PRESENTATION: We report a case of SLE confirmed by renal biopsy as proliferative lupus nephritis (PLN) with massive proteinuria, which was treated with telitacicept (European League Against Rheumatism / American College of Rheumatology 2019 standard). During the 19 months of follow-up, the patient's renal function was stable, massive proteinuria was relieved, and creatinine and blood pressure did not increase. CONCLUSIONS: During the 19 months of telitacicept treatment (160 mg once weekly), PLN reduced blood system damage and proteinuria without increasing the risk of infection.

Field ponding water exacerbates the dissemination of manure-derived antibiotic resistance genes from paddy soil to surrounding waterbodies.

Farmlands fertilized with livestock manure-derived amendments have become a hot topic in the dissemination of antibiotic resistance genes (ARGs). Field ponding water connects rice paddies with surrounding water bodies, such as reservoirs, rivers, and lakes. However, there is a knowledge gap in understanding whether and how manure-borne ARGs can be transferred from paddy soil into field ponding water. Our studies suggest that the manure-derived ARGs aadA1, bla1, catA1, cmlA1-01, cmx(A), ermB, mepA and tetPB-01 can easily be transferred into field ponding water from paddy soil. The bacterial phyla Crenarchaeota, Verrucomicrobia, Cyanobacteria, Choloroflexi, Acidobacteria, Firmicutes, Bacteroidetes, and Actinobacteria are potential hosts of ARGs. Opportunistic pathogens detected in both paddy soil and field ponding water showed robust correlations with ARGs. Network co-occurrence analysis showed that mobile genetic elements (MGEs) were strongly correlated with ARGs. Our findings highlight that manure-borne ARGs and antibiotic-resistant bacteria in paddy fields can conveniently disseminate to the surrounding waterbodies through field ponding water, posing a threat to public health. This study provides a new perspective for comprehensively assessing the risk posed by ARGs in paddy ecosystems.

Stellate ganglion block alleviates postoperative cognitive dysfunction via inhibiting TLR4/NF-κB signaling pathway.

Postoperative cognitive dysfunction (POCD) is common in aged patients after major surgery and is associated with increased risk of long-term morbidity and mortality. However, the underlying mechanism remains largely unknown and the clinical management of POCD is still controversial. Stellate ganglion block (SGB) is a clinical treatment for nerve injuries and circulatory issues. Recent evidence has identified the benefits of SGB in promoting learning and memory. We thus hypothesize that SGB could be effective in improving cognitive function after surgery. In present study, we established POCD model in aged rats via partial liver resection surgery. We found that the development of POCD was associated with the activation of toll-like receptor 4/nuclear factor kapa-B (TLR4/NF-κB) signaling pathway in the microglia in dorsal hippocampus, which induced the production of pro-inflammatory mediators (TNF-α, IL-1ß, IL-6) and promoted neuroinflammation. More importantly, we showed evidence that preoperative treatment with SGB could inhibit microglial activation, suppress TLR4/NF-κB-mediated neuroinflammation and effectively attenuate cognitive decline after the surgery. Our study suggested that SGB may serve as a novel treatment to prevent POCD in elderly patients. As SGB is safe procedure widely used in clinic, our findings can be easily translated into clinical practice and benefit more patients.

CircFAM114A2 inhibits the progression of hepatocellular carcinoma via miR-630/HHIP axis.

BACKGROUND: Many studies have shown that circular RNAs (circRNAs) are abnormally expressed in various tumor tissues and served as a key regulator in the occurrence and development of cancer. However, in hepatocellular carcinoma (HCC), the molecular mechanism of circRNAs in body fluids remains to be further explored. METHODS: The expression levels of genes and proteins were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Cell counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), wound healing assay, Transwell assays, flow cytometry, and tumor formation models in nude mice were conducted to investigate the effects of circFAM114A2 on HCC cells both in vitro and in vivo. RNA antisense purification (RAP), dual luciferase reporter assays and rescue assays were carried out to verify the interaction between circFAM114A2, miR-630 and HHIP. RESULTS: CircFAM114A2 was significantly downregulated in HCC tissues and was associated with microvascular invasion and lymph node metastasis of HCC patients. We also observed that circFAM114A2 was lowly expressed in HCC plasma, which may serve as an effective biomarker to screen HCC patients from healthy controls (area under curve (AUC)=0.922). In vitro, circFAM114A2 overexpression significantly blunted HCC cell proliferation, migration, invasion, and promoted apoptosis, whereas circFAM114A2 silencing posed opposite effects. In vivo, circFAM114A2 overexpression inhibited the growth of HCC cells. Mechanistically, circFAM114A2 could increase the expression of the tumor suppressor HHIP via acting as a sponge for miR-630. CONCLUSIONS: CircFAM114A2 exerts a tumor suppressor role in HCC through miR-630/HHIP axis, and may be served as a potential diagnostic and therapeutic biomarker for HCC patients.

Downregulation of lncRNA SLC7A11-AS1 decreased the NRF2/SLC7A11 expression and inhibited the progression of colorectal cancer cells.

Colorectal cancer (CRC) is ranked as the second leading cause of cancer-related death worldwide. Many abnormally expressed long non-coding RNAs (lncRNAs) in CRC were identified with the development of next-generation sequencing, most functions of which are largely unclear. In this study, we report that the lncRNA SLC7A11-AS1 was significantly overexpressed in CRC by analyzing TCGA database and 6 pairs of clinical samples. High SLC7A11-AS1 level was related to poor CRC overall survival and SLC7A11-AS1 knockdown could inhibit the proliferation, migration and invasion of CRC cell lines. Furthermore, we found there was a positive correlation between the expression of SLC7A11-AS1 and its' sense transcript SLC7A11. In HCT-8 cells, SLC7A11-AS1 knockdown decreased expression of both SLC7A11 and the nuclear level of NRF2, which happens to be the activator of SLC7A11 transcription. Interestingly, in SLC7A11-AS1 overexpressed CRC tissues, SLC7A11 and NRF2 were also upregulated. Moreover, the ROS levels increased with SLC7A11-AS1 knockdown in HCT-8 cells. And the down regulated expression of SLC7A11 and lower ROS level causing by SLC7A11-AS1 knocked down could be relieved by overexpressed NRF2. These results suggested that upregulated SLC7A11-AS1 might promote the formation and progression of CRC by increasing the expression of NRF2 and SLC7A11, which decreases the ROS level in cancer cells. Therefore, SLC7A11-AS1 could be a potential therapeutic target and diagnostic marker of CRC.

Design, synthesis, and antitumor evaluation of morpholine substituted bisnaphthalimides as DNA targeting agents.

A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro anticancer activities against four cancer cell lines. Some compounds exhibited relatively good antiproliferative activity on the cell lines tested, in comparison with mitonafide and amonafide. It is noteworthy that bisnaphthalimide A6 was identified as the most potent compound in anti-proliferation against MGC-803 cells, with an IC50 lowered to 0.09 µM, a far greater potency than that of mono-naphthalimide A7, mitonafide, and amonafide. A gel electrophoresis assay revealed that DNA and Topo I were the potential targets of compounds A6 and A7. The treatment of CNE-2 cells with compounds A6 and A7 resulted in an S phase cell cycle arrest, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of CDK2 and cyclin E. In addition, compounds A6 and A7-induced apoptosis was further confirmed by flow cytometry, ROS generation assay, and Hoechst 33,258 staining. In particular, in vivo antitumor assay results revealed that bisnaphthalimide A6 exhibited potent anticancer efficiency in an MGC-803 xenograft tumor model, in comparison with mitonafide, and had lower toxicity than mono-naphthalimide A7. In brief, the results suggested that bisnaphthalimide derivatives containing 3-nitro and 4-morpholine moieties might serve as DNA binding agents for the development of new antitumor agents.