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Abstract Purpose To analyze the role of and mechanism underlying obstructive sleep apnea (OSA)-derived exosomes in inducing non-alcoholic fatty liver (NAFLD). Methods The role of OSA-derived exosomes was analyzed in inducing hepatocyte fat accumulation in mice models both in vivo and in vitro. Results OSA-derived exosomes caused fat accumulation and macrophage activation in the liver tissue. These exosomes promoted fat accumulation; steatosis was more noticeable in the presence of macrophages. Macrophages could internalize OSA-derived exosomes, which promoted macrophage polarization to the M1 type. Moreover, it inhibited sirtuin-3 (SIRT3)/AMP-activated protein kinase (AMPK) and autophagy and promoted the activation of nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasomes. The use of 3-methyladenine (3-MA) to inhibit autophagy blocked NLRP3 inflammasome activation and inhibited the M1 polarization of macrophages. miR-421 targeting inhibited SIRT3 protein expression in the macrophages. miR-421 was significantly increased in OSA-derived exosomes. Additionally, miR-421 levels were increased in OSA + NAFLD mice- and patient-derived exosomes. In the liver tissues of OSA and OSA + NAFLD mice, miR-421 displayed similar co-localization with the macrophages. Intermittent hypoxia-induced hepatocytes deliver miR-421 to the macrophages via exosomes to inhibit SIRT3, thereby participating in macrophage M1 polarization. After OSA and NAFLD modeling in miR-421−/− mice, liver steatosis and M1 polarization were significantly reduced. Additionally, in the case of miR-421 knockout, the inhibitory effects of OSA-derived exosomes on SIRT3 and autophagy were significantly alleviated. Furthermore, their effects on liver steatosis and macrophage M1 polarization were significantly reduced. Conclusions OSA promotes the delivery of miR-421 from the hepatocytes to macrophages. Additionally, it promotes M1 polarization by regulating the SIRT3/AMPK-autophagy pathway, thereby causing NAFLD.

Abstract A correlation exists between obstructive sleep apnoea (OSA) and the severity of metabolic dysfunction-associated steatotic liver disease (MASLD), OSA can induce more severe MASLD. However, the underlying regulatory mechanism between the two is unclear. To this end, this study explored the role and possible molecular mechanisms of adipocyte-derived exosomes under OSA in aggravating MASLD. Through sequencing technology, miR-455-3p was identified as a co-differentially expressed miRNA between the MASLD + OSA and Control groups and between the MASLD + OSA and MASLD groups. Upregulation of TCONS-00039830 and Smad2 and downregulation of miR-455-3p in the MASLD and MASLD + OSA groups were validated in vivo and in vitro. TCONS-00039830, as a differentially expressed LncRNA in exosomes found in the sequencing results, transfection notably downregulated miR-455-3p and upregulated Smad2 in hepatocytes. TCONS_00039830 overexpression increased fat, triglyceride and cholesterol levels, while miR-455-3p overexpression decreased these levels. Furthermore, exosome administration promoted the accumulation of fat, triglyceride and cholesterol, upregulated TCONS_00039830 and Smad2, and downregulated miR-455-3p. Overexpression of miR-455-3p reversed the increased fat accumulation and upregulated TCONS_00039830 and Smad2. In conclusion, OSA-derived exosomes promoted hepatocyte steatosis by regulating TCONS_00039830/miR-455-3p/Smad2 axis, thereby aggravating liver damage in MASLD.

BackgroundThe escalation of global population aging has accentuated the prominence of senile diabetes mellitus (SDM) as a consequential public health concern. Oxidative stress and chronic inflammatory cascades prevalent in individuals with senile diabetes significantly amplify disease progression and complication rates. Traditional Chinese Medicine (TCM) emerges as a pivotal player in enhancing blood sugar homeostasis and retarding complication onset in the clinical management of senile diabetes. Nonetheless, an evident research gap persists regarding the integration of TCM’s renal tonification pharmacological mechanisms with experimental validation within the realm of senile diabetes therapeutics.AimsThe objective of this study was to investigate the mechanisms of action of New Shenqi Pills (SQP) in the treatment of SDM and make an experimental assessment.MethodsNetwork analysis is used to evaluate target pathways related to SQP and SDM. Mitochondrial-related genes were obtained from the MitoCarta3.0 database and intersected with the common target genes of the disease and drugs, then constructing a protein-protein interaction (PPI) network making use of the GeneMANIA database. Representative compounds in the SQP were quantitatively measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to ensure quality control and quantitative analysis of the compounds. A type 2 diabetes mice (C57BL/6) model was used to investigate the pharmacodynamics of SQP. The glucose lowering efficacy of SQP was assessed through various metrics including body weight and fasting blood glucose (FBG). To elucidate the modulatory effects of SQP on pancreatic beta cell function, we measured oral glucose tolerance test (OGTT), insulin histochemical staining and tunel apoptosis detection, then assessed the insulin-mediated phosphoinositide 3-kinase (PI3K)/protein kinase A (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway in diabetic mice via Western blotting. Additionally, we observe the structural changes of the nucleus, cytoplasmic granules and mitochondria of pancreatic islet β cells.ResultsIn this investigation, we identified a total of 1876 genes associated with senile diabetes, 278 targets of SQP, and 166 overlapping target genes, primarily enriched in pathways pertinent to oxidative stress response, peptide response, and oxygen level modulation. Moreover, an intersection analysis involving 1,136 human mitochondrial genes and comorbidity targets yielded 15 mitochondria-related therapeutic targets. Quality control assessments and quantitative analyses of SQP revealed the predominant presence of five compounds with elevated concentrations: Catalpol, Cinnamon Aldehyde, Rehmanthin D, Trigonelline, and Paeonol Phenol. Vivo experiments demonstrated notable findings. Relative to the control group, mice in the model group exhibited significant increases in body weight and fasting blood glucose levels, alongside decreased insulin secretion and heightened islet cell apoptosis. Moreover, β-cells nuclear condensation and mitochondrial cristae disappearance were observed, accompanied by reduced expression levels of p-GSK-3β protein in islet cells (p < 0.05 or p < 0.01). Conversely, treatment groups administered SQP and Rg displayed augmented expressions of the aforementioned protein markers (p < 0.05 or p < 0.01), alongside preserved mitochondrial cristae structure in islet β cells.ConclusionOur findings suggest that SQP can ameliorate diabetes by reducing islet cell apoptosis and resist oxidative stress. These insulin-mediated PI3K/AKT/GSK-3β pathway plays an important regulatory role in this process.

This review provides a comprehensive analysis of the critical role played by macrophages and their underlying mechanisms in the progression of diabetic cardiomyopathy (DCM). It begins by discussing the origins and diverse subtypes of macrophages, elucidating their spatial distribution and modes of intercellular communication, thereby emphasizing their significance in the pathogenesis of DCM. The review then delves into the intricate relationship between macrophages and the onset of DCM, particularly focusing on the epigenetic regulatory mechanisms employed by macrophages in the context of DCM condition. Additionally, the review discusses various therapeutic strategies aimed at targeting macrophages to manage DCM. It specifically highlights the potential of natural food components in alleviating diabetic microvascular complications and examines the modulatory effects of existing hypoglycemic drugs on macrophage activity. These findings, summarized in this review, not only provide fresh insights into the role of macrophages in diabetic microvascular complications but also offer valuable guidance for future therapeutic research and interventions in this field.

BackgroundDespite advancements, breast cancer outcomes remain stagnant, highlighting the need for precise biomarkers in precision medicine. Traditional TNM staging is insufficient for identifying patients who will respond well to treatment.MethodsOur study involved over 6,900 breast cancer patients from 14 datasets, including in-house clinical data and single-cell data from 8 patients (37,451 cells). We integrated 10 machine learning algorithms in 55 combinations and analyzed 100 existing breast cancer signatures. IHC assays were conducted for validation, and potential immunotherapies and chemotherapies were explored.ResultsWe pinpointed six stable Panoptosis-related genes from multi-center cohorts, leading to a robust Panoptosis-model. This model outperformed existing clinical and molecular features in predicting recurrence and mortality risks, with high-risk patients showing worse outcomes. IHC validation from 30 patients confirmed our findings, indicating the model’s broader applicability. Additionally, the model suggested that low-risk patients benefit more from immunotherapy, while high-risk patients are sensitive to specific chemotherapies like BI-2536 and ispinesib.ConclusionThe Panoptosis-model represents a major advancement in breast cancer prognosis and treatment personalization, offering significant insights for effectively managing a wide range of breast cancer patients.

DNA repair is a vital mechanism in cells that protects against DNA damage caused by internal and external factors. It involves a network of signaling pathways that monitor and transmit damage signals, activating various cellular activities to repair DNA damage and maintain genomic integrity. Dysfunctions in this repair pathway are strongly associated with the development and progression of cancer. However, they also present an opportunity for targeted therapy in breast cancer. Extensive research has focused on developing inhibitors that play a crucial role in the signaling pathway of DNA repair, particularly due to the remarkable success of PARP1 inhibitors (PARPis) in treating breast cancer patients with BRCA1/2 mutations. In this review, we summarize the current research progress and clinical implementation of BRCA and BRCAness in targeted treatments for the DNA repair pathway. Additionally, we present advancements in diverse inhibitors of DNA repair, both as individual and combined approaches, for treating breast cancer. We also discuss the clinical application of DNA repair-targeted therapy for breast cancer, including the rationale, indications, and summarized clinical data for patients with different breast cancer subtypes. We assess their influence on cancer progression, survival rates, and major adverse reactions. Last, we anticipate forthcoming advancements in targeted therapy for cancer treatment and emphasize prospective areas of development.

Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.

Abstract Achieving satisfactory performance for a solid‐state Na‐metal battery (SSNMB) with an inorganic solid electrolyte (SE), especially under freezing temperatures, poses a challenge for stabilizing a Na‐metal anode. Herein, this challenge is addressed by utilizing a Natrium super ionic conductor (NASICON) NASICON‐type solid electrolyte, enabling the operation of a rechargeable SSNMB over a wide temperature range from −20 to 45 °C. The interfacial resistance at the Na metal/SE interface is only 0.4 Ω cm2 at 45 °C and remains below 110 Ω cm2 even at −20 °C. Remarkably, long‐term Na‐metal plating/stripping cycles lasting over 2000 h at −20 °C are achieved with minimal polarization voltages at 0.1 mA cm−2. Further analysis reveals the formation of a uniform Na3−xCaxPO4 interphase layer at the interface, which significantly contributes to the exceptional interfacial performance observed. By employing a Na3V1.5Al0.5(PO4)3 cathode, the full battery system demonstrates excellent adaptability to low temperatures, exhibiting a capacity of 80 mA h g−1 at −20 °C over 50 cycles and retaining a capacity of 108 mAh g−1 (88.5% of the capacity at 45 °C) at 0 °C over 275 cycles. This research significantly reduces the temperature threshold for SSNMB operation and paves the way toward solid‐state batteries suitable for all‐season applications.

Defects on fabric surfaces are difficult to identify owing to unsuitable computing devices, highly complex algorithms, small size, and high degree of integration with the fabric. To this end, this study proposes a lightweight fabric defect-detection network, YOLO-SCD, based on attention mechanism. The introduction of depth-wise separable convolution and the attention mechanism enhanced the capacity of the neck network to extract the defective features and increased the detection speed of the overall network. The extensive experimental results revealed that YOLO-SCD achieved an average accuracy of 82.92%, effective improvement of 8.49% in mAP, and an improvement of 37 fps compared to the original YOLOv4 on a standard fabric defect dataset. By leveraging its swift detection speed and high efficiency, YOLO-SCD excels in both the general fabric defect category and the difficult-to-detect fabric. Overall, it exhibited strong performance in detecting both minor flaws and flaws with high fabric integration. Furthermore, the proposed model was extended to steel datasets with similar characteristics.

Abstract The structural parameters of multibell underreamed anchors play a crucial role in anchoring performance. The parameters of multibell underreamed anchor investigations are helpful when exploring optimized anchor structures. Based on the results of small-scale physical modelling tests, two types of multibell underreamed anchors were adopted under vertical uplifting loads. Numerical investigations were employed to study the effect of bell spacing, underream structure and bell dimension on the ultimate uplift bearing capacity. After an analysis of the anchorage mechanism, the anchoring efficiency was evaluated by the anchoring force provided by the unit concrete usage of the anchor, and the structural parameter λ equal to the surface area ratios of the expanded bell cone to the straight shaft between bells was defined. Then, the anchoring efficiency optimized structural parameters were presented. An analysis of model tests and simulation results showed that compared to concave bell surfaces, the convex shape could enhance the ultimate bearing capacity of a multibell underreamed anchor. There is an optimal value for the spacing of neighbouring bells, and there are three models of mechanisms for multibell anchors pulling out. When λ ∈ [1, 1.8], the multibell anchors can perform most efficiently to achieve their structural advantages.

Cognitive dysfunction is increasingly recognized as a complication and comorbidity of diabetes, supported by evidence of abnormal brain structure and function. Although few mechanistic metabolic studies have shown clear pathophysiological links between diabetes and cognitive dysfunction, there are several plausible ways in which this connection may occur. Since, brain functions require a constant supply of glucose as an energy source, the brain may be more susceptible to abnormalities in glucose metabolism. Glucose metabolic abnormalities under diabetic conditions may play an important role in cognitive dysfunction by affecting glucose transport and reducing glucose metabolism. These changes, along with oxidative stress, inflammation, mitochondrial dysfunction, and other factors, can affect synaptic transmission, neural plasticity, and ultimately lead to impaired neuronal and cognitive function. Insulin signal triggers intracellular signal transduction that regulates glucose transport and metabolism. Insulin resistance, one hallmark of diabetes, has also been linked with impaired cerebral glucose metabolism in the brain. In this review, we conclude that glucose metabolic abnormalities play a critical role in the pathophysiological alterations underlying diabetic cognitive dysfunction (DCD), which is associated with multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, inflammation, and others. Brain insulin resistance is highly emphasized and characterized as an important pathogenic mechanism in the DCD.

Colorectal cancer (CRC) is a major health burden, accounting for approximately 10% of all new cancer cases worldwide. Accumulating evidence suggests that the crosstalk between the host mucins and gut microbiota is associated with the occurrence and development of CRC. Mucins secreted by goblet cells not only protect the intestinal epithelium from microorganisms and invading pathogens but also provide a habitat for commensal bacteria. Conversely, gut dysbiosis results in the dysfunction of mucins, allowing other commensals and their metabolites to pass through the intestinal epithelium, potentially triggering host responses and the subsequent progression of CRC. In this review, we summarize how gut microbiota and bacterial metabolites regulate the function and expression of mucin in CRC and novel treatment strategies for CRC.

The pathophysiological mechanisms of diabetic cardiomyopathy have been extensively studied, but there is still a lack of effective prevention and treatment methods. The ability of flavonoids to protect the heart from diabetic cardiomyopathy has been extensively described. In recent years, epigenetics has received increasing attention from scholars in exploring the etiology and treatment of diabetes and its complications. DNA methylation, histone modifications and non-coding RNAs play key functions in the development, maintenance and progression of diabetic cardiomyopathy. Hence, prevention or reversal of the epigenetic alterations that have occurred during the development of diabetic cardiomyopathy may alleviate the personal and social burden of the disease. Flavonoids can be used as natural epigenetic modulators in alternative therapies for diabetic cardiomyopathy. In this review, we discuss the epigenetic effects of different flavonoid subtypes in diabetic cardiomyopathy and summarize the evidence from preclinical and clinical studies that already exist. However, limited research is available on the potential beneficial effects of flavonoids on the epigenetics of diabetic cardiomyopathy. In the future, clinical trials in which different flavonoids exert their antidiabetic and cardioprotective effects through various epigenetic mechanisms should be further explored.

Abstract The Shanghai High repetition rate XFEL and Extreme Light Facility (SHINE), an advanced XFEL project, is now being built at Shanghai Advanced Research Institute (SARI), Chinese Academy of Sciences. It includes a hard X-ray free electron laser and a 100 pW intense laser facilities with overall length of 3.1 km. The XFEL part including an 8 GeV LINAC and 3 undulator lines is cooled with forced superfluid and supercritical helium at 2 K/4 K. The cryogenic system of SHINE consists of test facility cryogenic system (TFCS), accelerator cryogenic system (ACCS), and undulator cryogenic system (UNCS). A dedicated control system based on Experimental Physics and Industrial Control System (EPICS) will be built to automate the cryogenic system with process control, PID control loops, real-time data acquisition and storage, alarm handler and human machine interface. It is capable of automatic recovery as well. This paper describes details of control system structure, interfaces, controllers and the integration under EPICS framework.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection swept through Wuhan and spread across China and overseas beginning in December 2019. To identify predictors associated with disease progression, we evaluated clinical risk factors for exacerbation of SARS-CoV-2 infection. Methods A retrospective analysis was used for PCR-confirmed COVID-19 (coronavirus disease 2019)-diagnosed hospitalized cases between January 19, 2020, and February 19, 2020, in Zhejiang, China. We systematically analysed the clinical characteristics of the patients and predictors of clinical deterioration. Results One hundred patients with COVID-19, with a median age of 54 years, were included. Among them, 49 patients (49%) had severe and critical disease. Age ([36–58] vs [51–70], P = 0.0001); sex (49% vs 77.6%, P = 0.0031); Body Mass Index (BMI) ([21.53–25.51] vs [23.28–27.01], P = 0.0339); hypertension (17.6% vs 57.1%, P

At present, China’s energy distribution and economic development are extremely unbalanced. In order to make rational use of resources, China has promoted the “west to East power transmission” and “north to South Power Transmission” pattern. HVDC transmission has obvious advantages in this long-distance transmission, but there are some shortcomings in the traditional LCC-HVDC system. Therefore, a new system LCL-HVDC is proposed. Firstly, some advantages of the system are introduced; secondly, LCC-HVDC and LCL-HVDC models are built in Simulink, in which the current distortion rate of valve side winding of converter transformer is measured; finally, compared with LCC-HVDC, the loss of LCL-HVDC converter transformer is studied by using method 2 recommended by IEEE standard, and the kn value of the new system is calculated.

Abstract Background Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and remains the leading cause of blindness in adults. Retinal inflammation is playing a crucial role in the development of DR, and targeting inflammatory mediators is a promising strategy for controlling DR. Here, we investigated compound Chinese medicine Luo Tong formula (LTF) alleviated retinal inflammatory responses in a STZ-induced diabetic rat model. Methods Sprague–Dawley rats were divided into four groups: control, streptozotocin-induced diabetic, LTF-treated diabetic, and calcium dobesilate (CaD)-treated diabetic rats. Blood samples were collected for blood glucose examination. Hematoxylin–eosin and periodic acid-Schiff staining were conducted for light microscopy observations. Retinal cell apoptosis was detected using the TUNEL assay. Proteins expression was quantified by Western blotting and/or immunohistochemistry, and gene expression was assessed by real-time PCR. Results Diabetic rats showed significant increases in the expression of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), nuclear factor-κB (NF-κB), and the phospho-p38 mitogen-activated protein kinase (p-p38-MAPK)/p38 MAPK ratio compared to control rats. LTF treatment significantly improved both retinal and pancreatic pathological injury, LTF treatment also inhibited inducible the p-p38 MAPK/p38 MAPK ratio and NF-κB activation and decreased the subsequent induction of the retinal expression of proinflammatory mediators TNF-α, IL-1β, MCP-1 and ICAM-1 compared to diabetic rats. LTF also exhibited a protective effect on islet function. Conclusions LTF before the onset of DR can alleviate retinal pathological injury, LTF may play an anti-inflammatory role by inhibiting p38-MAPK and then inhibiting NF-κB pathway. But further studies are needed to confirm this conclusion. Trial registration This is an animal experiment, trial registration is not necessary.

Introduction. Serine hydroxymethyltransferase 2 (SHMT2) has a critical role in serine-glycine metabolism to drive cancer cell proliferation. Yet, the function of SHMT2 in tumorigenesis, especially in human colorectal cancer (CRC) progression, remains largely unclear. Materials and Methods. CRC and paired normal samples were collected in the Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, and assessed by real-time polymerase chain reaction (qPCR) analysis, western blot (WB), and immunohistochemistry (IHC). Moreover, SHMT2 expression in human CRC cells was identified by qPCR and WB. The CRC cell proliferation, migration, and invasion after SHMT2 knockdown were explored through in vitro and in vivo assays. mRNA-seq assays were used to investigate the underlying mechanisms behind the SHMT2 function. Results. It was found that SHMT2 mRNA and protein were overexpressed in CRC tissue compared to the levels in normal mucosa. Positive expression of SHMT2 was significantly correlated with TNM stage and lymph node metastasis, and elevated expression of SHMT2 resulted as an independent prognostic factor in patients with CRC. SHMT2 knockdown impaired the proliferation of CRC in vitro and in vivo and induced cell cycle arrest by regulating UHRF1 expression. Conclusion. Taken together, our findings reveal that UHRF1 is a novel target gene of SHMT2, which can be used as a potential therapeutic strategy for CRC therapy.

Abstract Background Diabetic kidney disease (DKD) is the main cause of end-stage kidney disease and has become a heavy economic and social burden due to its high prevalence and morbidity. The most effective strategy is that patients with DKD should be diagnosed and treated early. Preliminary studies showed that the Chinese herbal Tangshen Formula (TSF) may delay the progression of DKD, reducing microalbuminuria and macroalbuminuria and improving renal function. We designed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of TSF in patients with DKD. Methods/design This trial is a 13-center, randomized, double-blind, placebo-controlled study. A total of 632 participants will be randomized in a 1:1 ratio to an experiment group (TSF plus losartan) and a control group (placebo plus losartan). The trial cycle will last 24 weeks. The primary outcome will be the change in the urine microalbumin–creatinine ratio from baseline to week 24. The secondary outcome will be the change in the rate of progression to the clinical proteinuria period after intervention, the rate of urine microalbumin negative conversion, the rate of normal urinary microalbumin, the doubling rate of the baseline creatinine value and the glomerular filtration rate between the two groups. Safety in medication will also be evaluated. Discussion We hypothesize that patients with type 2 diabetes in the early stage of DKD will benefit from TSF. If successful, this study will provide evidence-based recommendations for clinicians. Trial registration ClinicalTrials.gov, NCT03009864. Registered January 2017.

Psychological disorders are associated with increased risk of severe inflammatory bowel disease (IBD) by causing gut microbiota dysbiosis and colonic mucosal barrier damage. However, the interaction between chronic restraint stress (CRS), gut microbiota composition, and colonic mucus remains unclear. We demonstrated that mice under CRS conditions exhibited alterations in microbiota composition, disruption of colonic mucus, and aggravation of colitis. In addition, the abundance of Akkermansia muciniphila was significantly decreased in mice under CRS and UC patients with depression, and positively associated with the expression of MUC2. After antibiotic treatment, the recipient mice colonized with CRS microbiota showed barrier defects and severe colitis. Administration of Akkermansia muciniphila was found to restore colonic mucus and modify the gut microbiota. We confirm that CRS-mediated gut microbiota dysbiosis results in colonic mucosal barrier damage and aggravation of colitis. Our results suggest that A. muciniphila is expected to be a potential probiotic to protect and treat colonic mucus that is involved in IBD with psychological disorders.

Stanniocalcin-1 (STC1) is a glycoprotein hormone whose abnormal expression has been reported to be associated with a variety of tumors, but its function in breast cancer is not well understood. Through modulation of STC1 expression in different breast cancer cell lines, our study found that STC1 could promote the proliferation and growth of breast cancer cells and promote metastasis. Furthermore, STC1 reduced apoptosis induction by irradiation. We also found that STC1 could promote a homologous recombination-mediated DNA damage repair by recruiting BRCA1 to sites of damage. Moreover, STC1 silencing sensitized breast cancer cells to treatment with irradiation (IR), olaparib, or cisplatin in vitro. In clinical settings, the serum concentration of STC1 was higher in breast cancer patients than in healthy women, as detected by enzyme-linked immunosorbent assay (ELISA). In addition, immunohistochemical staining of breast cancer specimens showed that a high expression of STC1 was negatively correlated with recurrence-free survival in breast cancer, indicating that STC1 expression could be used as a predictive marker for a poor prognosis in breast cancer. All these findings indicate that STC1 promotes breast cancer tumorigenesis and that breast cancers with a high level of STC1 are more resistant to treatment, probably through homologous recombination (HR) promotion. Furthermore, combining STC1 inhibition and DNA damage-inducing drugs may be a novel approach to improve the survival of patients with STC1-expressing breast cancer.

Abstract Background Sheng Mai San (SMS) has been proven to exhibit cardio-protective effects. This study aimed to explore the molecular mechanisms of SMS on hyperglycaemia (HG)-induced apoptosis in H9C2 cells. Methods HG-induced H9C2 cells were established as the experimental model, and then treated with SMS at 25, 50, and 100 μg/mL. H9C2 cell viability and apoptosis were quantified using MTT and Annexin V-FITC assays, respectively. Furthermore, Bcl-2/Bax signalling pathway protein expression and Fas and FasL gene expression levels were quantified using western blotting and RT-PCR, respectively. Results SMS treatments at 25, 50, 100 μg/mL significantly improved H9C2 cell viability and inhibited H9C2 cell apoptosis (p

Abstract Background Hirudin, an extract from Hirudo spp., is an anticoagulant used to treat a variety of renal diseases, including diabetic nephropathy (DN). Currently, hirudin has to be used at high dosages to treat DN because it poorly targets the kidneys, although at high dosages it can have severe side effects. Developing a targeted drug delivery system for hirudin, then, could boost its positive therapeutic effects while lowering the risk of side effects. Liposomes have been demonstrated to have significant renal targeting potential, but here we show that a hirudin-loaded liposome is an effective delivery method for patients with DN. Method In this study, we prepared a hirudin/liposome complex and tested its efficacy by injecting it into a rat model. We then compared the renal accumulation of hirudin between complex-injected rat models and rat models that received injections of hirudin alone. We also investigated the mechanisms behind the complex’s effects. Result The hirudin/liposome complex increased the accumulation of hirudin in kidney tissues and relieved the renal injury in DN rat models. Moreover, the hirudin/liposome complex down-regulated the expression of TGF-β1 and VEGF in the kidneys. Conclusion We demonstrated that a hirudin/liposome complex can have a significant positive effect on DN. The mechanism may be that the complex inhibits the expression of VEGF and TGF-β1.

The squared envelope spectrum (SES) is one of the most effective methods in rolling element bearing fault diagnosis. Being a technique based on demodulation, the success of SES depends highly on the extraction of information caused by the bearings fault. Therefore, a preprocessing step of choosing an optimal frequency band (OFB), before the implementation of the SES, is absolutely needed and should always be taken prior. Fast kurtogram (FK), as the most commonly used method targeting resonance frequency band which is excited by the bearing fault, is applied as the benchmark tool for the selection of the OFB. However, recent theoretical works show that the kurtosis used as the criterion for OFB selection was both sensitive to the impulsiveness and cyclostationarity, which means irrelevant impulsive and cyclostationary components are able to mislead the kurtosis based OFB selection techniques and subsequently bring great difficulties in bearing fault diagnosis. To tackle this problem, in this paper, a novel statistical model parameter-based method, called Distcsgram, is proposed as a substitution to the traditional FK technique so that an OFB can be selected with the least influences from the irrelevant cyclostationary and impulsive interferences. Together with the SES, the Distcsgram is explained and validated in both simulation and experimental studies. Furthermore, through the comparisons with the traditional methods, the superiority of the proposed method over those traditional methods for the diagnosis of rolling element bearing is proved.

Background: Diabetic retinopathy (DR) is one of the most common and severe microvascular complications of diabetes mellitus (DM), which results in blindness among adults worldwide. Presently, the efficacy of drug treatments for diabetic retinopathy (DR) is not satisfactory, thus urgently necessitating effective drug treatment measures. TangWang prescription (TWP) has been found to have retinal protection effects in previous clinical and basic research. However, there is a lack of rigorous, randomized, and controlled studies. This study aims to evaluate the efficacy and safety of TWP in delaying the development of DR.Methods: This study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial, consisting of 384 participants to be randomized in a 1:1 ratio in the treatment and control groups. Furthermore, the treatment and control groups will be administered the TangWang prescription and the placebo, respectively, each at a dose of one bag twice a day. The study period will last for 48 weeks. The primary outcome measure will be the changes in the degree of retinal microvascular lesions before and after treatment. The secondary outcome will be changes in the degree of hemangioma, microvascular bleeding, microvascular leakage, macular edema, and vision. All statistical tests will be two-sided, and a p < 0.05 will be considered statistically significant.Discussion: We hypothesize that the patients with DR will benefit from TangWang prescription, and in addition to the central random system and platform of dynamic information collection, the patients’ conditions will be monitored, and the data collected for analysis. If successful, this study will provide evidence that the TWP formulation delays in the progression of DR.Trial registration: The design of this trial has been registered with the ClinicalTrials.gov (NCT03025399).

Aim: Diabetic retinopathy (DR) is a serious complication of diabetes (DM). Luo Tong formula (LTF) exerts protective effects against DR in rats, but its underlying mechanism remains unknown. Methods: Sprague-Dawley rats injected with streptozotocin (STZ) were used as an experimental diabetes model. LTF or calcium dobesilate (CaD) was administered to diabetic rats via gastric gavage. After the 12 weeks of treatment, blood and tissue samples were collected to determine serum glucose and retinal structure. Blood samples were collected for blood glucose and hemorheology analysis. Gene or protein expression levels were evaluated by immunohistochemistry, western blotting and/or quantitative real-time polymerase chain reaction (PCR). Results: DM rats exhibits significantly increased blood retinal-barrier (BRB) breakdown and VEGF/VEGFR expression in the retina, and decreased miR-200b and tight junction ZO-1/Occludin/ Claudin-5 genes expression, as well as Ang-1/Tie-2 expressions in the retina compared to normal control group. LTF treatment significantly moderated histological abnormalities in diabetic rats, independent of blood glucose level; improved some hemorrheological parameters; decreased the expressions of VEGF/VEGFR and BRB breakdown, significantly increased PEDF and tight junction proteins ZO-1/Occludin, as well as increased retinal miR-200b expression compared to non-treatment diabetic rats. Moreover, LTF prevented the reduction in Ang-1/Tie-2 expression. Conclusions: LTF treatment ameliorated DR through its repair vascular and attenuate vascular leakage. A mechanism involving miR-200b may contribute to benefit effects.

Background. Banxia Xiexin Decoction (BXXD) reportedly regulates glycolipid metabolism and inhibits pancreatic β-cell apoptosis. This study is aimed at investigating the protective effect of BXXD on tert-butyl hydroperoxide- (t-BHP-) induced apoptosis in MIN6 cells and the underlying mechanisms. Methods. MIN6 cells were preincubated with BXXD or liraglutide (Li) with or without PI3K inhibitor LY294002 (LY) for 12 h, following which t-BHP was added to induce MIN6 cell apoptosis. The protective effects of BXXD on MIN6 cells were evaluated by detecting cell viability and proliferation and glucose-stimulated insulin secretion (GSIS). The antiapoptotic effects were evaluated by Hoechst 33342 staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay (TUNEL). Malondialdehyde and glutathione peroxidase content and superoxide dismutase activity were measured using commercial kits. The expression of PI3K/AKT/FOXO1 signaling pathway-related signal molecules, and that of apoptotic indicators Bax, P27, and Caspase-3, was quantified using western blotting. Results. Preincubation with BXXD significantly improved t-BHP-induced proliferation inhibition and apoptosis and enhanced GSIS. t-BHP induced the generation of reactive oxygen species and inhibited the activities of antioxidant enzymes, which could be neutralized by pretreatment with BXXD. BXXD promoted the phosphorylation of AKT and FOXO1 in t-BHP-induced MIN6 cells. Moreover, BXXD attenuated the expression of related apoptotic indicators Bax, P27, and Caspase-3. LY abolished these effects of BXXD. Conclusion. BXXD protected MIN6 cells against t-BHP-induced apoptosis and improved insulin secretory function through modulation of the PI3K/AKT pathway and the downstream FOXO1, thus suggesting a novel therapeutic approach for type 2 diabetes mellitus (T2DM).

BACKGROUND AND PURPOSE: Breast cancer is now recognized as a clinically heterogeneous disease with a wide spectrum of epidemiological and clinicopathologic features. We aimed to evaluate whether epidemiological and clinicopathologic features are associated with the histological tumor grade of breast carcinomas in Western China. METHODS: We retrospectively collected data from the Western China Clinical Cooperation Group and assessed associations between clinicopathologic factors and histological tumor grade in 8619 female breast cancer patients. Patients were divided into two groups: Group I (tumor grade I/II) and Group II (tumor grade III). Univariable analysis and multivariable logistic regression models were used to analyze the relationships between clinicopathologic factors and tumor grade. RESULTS: Patients presenting with positive axillary lymph nodes, large tumor size (>2 cm), lymphovascular invasion, hormone receptor negativity, human epidermal growth factor receptor 2 (HER-2) positivity, and triple negativity tended to have an increased risk of a high tumor grade. However, the number of pregnancies or births was inversely correlated with the risk of a high tumor grade. In addition, patients presenting with grade III tumors were more likely to receive aggressive treatment, such as adjuvant chemotherapy, anti–HER-2 therapy, and level III axillary lymph node dissection. CONCLUSIONS: Our results suggested that several clinicopathologic factors were associated with high tumor grade of breast cancer patients in Western China.

Osteosarcoma is among the most common malignant bone tumors in human skeletal system. The conventional treatment of osteosarcoma mainly consists of combining neoadjuvant chemotherapy with surgical approach. However, it is crucial to design an artificial implant that possesses excellent biomechanical properties and is capable of sustaining local release of chemotherapeutics. In this study, we envision that the highly efficient combination of gemcitabine (GEM) hydrochloride loaded liposomes with gelatin methacryloyl (GelMA) of in situ photocrosslinkable hydrogel will lead to a multifunctional implant with unique antitumor, mechanical, and biodegradable properties. A sustained controlled release was observed; more specifically, the release of GEM in vitro lasted for 4 days long. Furthermore, its capability in killing MG63 cells was further explored by using the lixivium of GEM-Lip@Gel and GEM-GelMA hydrogel in vitro (composite hydrogel by GEM loaded liposomes blending with GelMA, short for GEM-Lip@Gel), which agreed with the drug release outcome. In addition, these hydrogel showed excellent ability in inhibiting osteosarcoma in vivo by Balb/c mice bearing MG63 cells. Therefore, GEM-loaded lipo-hydrogel certainly has presented itself as a promising strategy for the development of implant in the field of osteosarcoma treatment.

Abstract Background Diabetic distal symmetric polyneuropathy (DSPN) is one of the most common microvascular complications of diabetes mellitus, and it has become a major public health problem worldwide because of its high and increasing prevalence, morbidity, and disability rate. The current medications for DSPN are not entirely satisfactory. Preliminary studies indicated that the Chinese herbal TangBi Formula may alleviate signs and symptoms and improve the velocity of nerve conduction in patients with DSPN. This study was designed to determine if Chinese herbal medicine used in combination with conventional treatment is more effective than conventional treatment alone. Methods/design We are conducting a multicenter, placebo-controlled, double-blind, randomized, controlled clinical trial as a means of assessing the therapeutic effects of traditional Chinese medicine (TCM) treatment. A total of 188 patients will be randomized in a 1:1 ratio to a treatment group (TangBi Formula plus mecobalamin) and a control group (placebo plus mecobalamin). The test period lasts 6 months, during which all of the patients will be given standard medical care as recommended by established guidelines. The primary outcome will be development of differences in changes in clinical symptoms and signs in patients and changes in Michigan Diabetic Neuropathy Score (MDNS) between the two groups before and after treatment. The secondary outcome will be changes in nerve conduction velocity and in single clinical signs and symptoms. Safety assessments and adverse events will also be evaluated. Discussion We postulate that patients with DSPN will benefit from therapy that includes TCM. If successful, this work will provide an evidence-based complementary therapeutic approach for treatment of DSPN. Trial registration ClinicalTrials.gov, NCT03010241 . Registered on 2 January 2017

Background: The gut microbiota plays important roles in the occurrence and development of obesity and diabetes through participating in nutrient absorption and metabolism. Microecological regulation is likely to be key to understanding the effects of Chinese medicine. The Linggui Zhugan (LGZG) formula is a well-known Chinese medicine for controlling obesity in the clinic. However, its pharmacological effects and mechanism of action in diabetes require further exploration.Objective: To evaluate the effects of LGZG on body weight, glycemic control, lipid levels, and gut microbiota in high-fat diet-induced diabetic mice.Methods: High-fat diet-induced diabetic mice were subjected to an 8-week protocol of LGZG administration. We then evaluated the pharmacological effects of LGZG and its influence on gut microbes in fecal samples using the 16S rRNA-based microbiome profiling technique.Results: LGZG administration significantly reduced body weight and body fat mass in diabetic mice. Compared with the high-fat diet control group, LGZG favorably influenced blood glucose control, decreased blood glucose levels, and increased glucose tolerance, accompanied by an improvement in lipid metabolism. Furthermore, the global community composition and relative abundance of many taxa differed between mice fed chow or a high-fat diet. As expected, LGZG supplementation altered the general community structure of gut microbiota, the Firmicutes/Bacteroidetes ratio, and the relative abundance of certain bacteria, such as Bacteroides, Lactobacillus, Oscillospira, and Helicobacter.Conclusion: LGZG effectively controlled obesity and relieved insulin resistance, which may be closely related to its impact on gut microbiota.

Background. Single nucleotide polymorphisms (SNPs) in genes encoding microRNAs may play important role in the development of gastric cancer. It has been reported that common SNPs rs2910164 in miR-146a and rs11614913 in miR-196a2 are associated with susceptibility to gastric cancer. The published results remain inconclusive or even controversial. A meta-analysis was conducted to quantitatively assess potential association between the two common SNPs and gastric cancer risk. Methods. A comprehensive literature search was performed in multiple internet-based electronic databases. Data from 12 eligible studies were extracted to estimate pooled odds ratios (ORs) and 95% confidence intervals (95% CI). Results. C allele of rs2910164 is associated with reduced gastric cancer risk in heterozygote model and dominant model whereas rs11614913 indicates no significant association. Subgroup analysis demonstrates that C allele of rs2910164 and rs11614913 may decrease susceptibility to diffuse type gastric cancer in dominant model and recessive model, respectively, while rs11614913 increased intestinal type gastric cancer in dominant model. Conclusion. SNPs rs2910164 and rs11614913 might have effect on gastric cancer risk in certain genetic models and specific types of cancer. Further well-designed studies should be considered to validate the potential effect.

High-speed railway tunnels in various countries have continuously reported accidents of vault falling concrete blocks. Once the concrete block falling occurs, serious consequences follow, and traffic safety may be endangered. The aerodynamic shockwave evolves from the initial compression wave may be an important inducement causing the tunnel lining cracks to grow and form falling concrete blocks. A joint calculation framework is established based on ANSYS Fluent, ABAQUS, and FRANC3D for calculating the crack tip field under the aerodynamic shockwave. The intensification effect of aerodynamic shockwaves in the crack is revealed, and the evolution characteristics of the crack tip field and the influence factors of stress intensity factor (SIF) are analyzed. Results show that (1) the aerodynamic shockwave intensifies after entering the crack, resulting in more significant pressure in the crack than the input pressure. The maximum pressure of the inclined and longitudinal cracks is higher than the corresponding values of the circumferential crack, respectively. (2) The maximum SIF of the circumferential, inclined, and longitudinal crack appears at 0.5, 0.68, and 0.78 times the crack front length. The maximum SIF of the circumferential crack is higher than that of the inclined and longitudinal crack. The possibility of crack growth of the circumferential crack is the highest under aerodynamic shockwaves. (3) The influence of train speed on the SIF of the circumferential crack is more than 40%. When the train speed, crack depth, and crack length change, the change of pressure in the crack is the direct cause of the change of SIF. [ABSTRACT FROM AUTHOR]