Spatial multi-omics at subcellular resolution via high-throughput in situ pairwise sequencing.

Technology for spatial multi-omics aids the discovery of new insights into cellular functions and disease mechanisms. Here we report the development and applicability of multi-omics in situ pairwise sequencing (MiP-seq), a method for the simultaneous detection of DNAs, RNAs, proteins and biomolecules at subcellular resolution. Compared with other in situ sequencing methods, MiP-seq enhances decoding capacity and reduces sequencing and imaging costs while maintaining the efficacy of detection of gene mutations, allele-specific expression and RNA modifications. MiP-seq can be integrated with in vivo calcium imaging and Raman imaging, which enabled us to generate a spatial multi-omics atlas of mouse brain tissues and to correlate gene expression with neuronal activity and cellular biochemical fingerprints. We also report a sequential dilution strategy for resolving optically crowded signals during in situ sequencing. High-throughput in situ pairwise sequencing may facilitate the multidimensional analysis of molecular and functional maps of tissues.

H2S-Powered Nanomotors for Active Therapy of Tumors by Inducing Ferroptosis and Lactate-Pyruvate Axis Disorders.

Disruption of the symbiosis of extra/intratumoral metabolism is a good strategy for treating tumors that shuttle resources from the tumor microenvironment. Here, we report a precision treatment strategy for enhancing pyruvic acid and intratumoral acidosis to destroy tumoral metabolic symbiosis to eliminate tumors; this approach is based on PEGylated gold and lactate oxidase-modified aminated dendritic mesoporous silica with lonidamine and ferrous sulfide loading (PEG-Au@DMSNs/FeS/LND@LOX). In the tumor microenvironment, LOX oxidizes lactic acid to produce pyruvate, which represses tumor cell proliferation by inhibiting histone gene expression and induces ferroptosis by partial histone monoubiquitination. In acidic tumor conditions, the nanoparticles release H2S gas and Fe2+ ions, which can inhibit catalase activity to promote the Fenton reaction of Fe2+, resulting in massive ·OH production and ferroptosis via Fe3+. More interestingly, the combination of H2S and LND (a monocarboxylic acid transporter inhibitor) can cause intracellular acidosis by lactate, and protons overaccumulate in cells. Multiple intracellular acidosis is caused by lactate-pyruvate axis disorders. Moreover, H2S provides motive power to intensify the shuttling of nanoparticles in the tumor region. The findings confirm that this nanomedicine system can enable precise antitumor effects by disrupting extra/intratumoral metabolic symbiosis and inducing ferroptosis and represents a promising active drug delivery system candidate for tumor treatment.

In vivo mitochondria-targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy.

Gestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nitric oxide-dependent mechanisms and stimulation of large conductance Ca2+ -activated K+ -channels. Maternal in vivo oral treatment with the mitochondria-targeted antioxidant MitoQ in hypoxic pregnancy normalises uterine artery reactivity and prevents vascular remodelling. From days 6-20 of gestation (term ∼22 days), female Wistar rats were randomly assigned to normoxic or hypoxic (13-14% O2 ) pregnancy ± daily maternal MitoQ treatment (500 µm in drinking water). At 20 days of gestation, maternal, placental and fetal tissue was frozen to determine MitoQ uptake. The uterine arteries were harvested and, in one segment, constrictor and dilator reactivity was determined by wire myography. Another segment was fixed for unbiased stereological analysis of vessel morphology. Maternal administration of MitoQ in both normoxic and hypoxic pregnancy crossed the placenta and was present in all tissues analysed. Hypoxia increased uterine artery constrictor responses to norepinephrine, angiotensin II and the protein kinase C activator, phorbol 12,13-dibutyrate. Hypoxia enhanced dilator reactivity to sodium nitroprusside, the large conductance Ca2+ -activated K+ -channel activator NS1619 and ACh via increased nitric oxide-dependent mechanisms. Uterine arteries from hypoxic pregnancy showed increased wall thickness and MitoQ treatment in hypoxic pregnancy prevented all effects on uterine artery reactivity and remodelling. The data support mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy. KEY POINTS: Dysfunction and remodelling of the uterine artery are strongly implicated in many pregnancy complications, including advanced maternal age, maternal hypertension of pregnancy, maternal obesity, gestational diabetes and pregnancy at high altitude. Such complications not only have immediate adverse effects on the growth of the fetus, but also they can also increase the risk of cardiovascular disease in the mother and offspring. Despite this, there is a significant unmet clinical need for therapeutics that treat uterine artery vascular dysfunction in adverse pregnancy. Here, we show in a rodent model of gestational hypoxia that in vivo oral treatment of the mitochondria-targeted antioxidant MitoQ protects against uterine artery vascular dysfunction and remodelling, supporting the use of mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy.

Association of echocardiography-related parameters with the prognosis of decompensated cirrhosis: a retrospective cohort study.

BACKGROUND: Cardiac morphology and function, which are conventionally evaluated by echocardiography, are often abnormal in decompensated cirrhosis. We aimed to evaluate the association of echocardiography-related parameters with prognosis in cirrhosis. METHODS: This retrospective study included 104 decompensated cirrhotic patients, in whom cardiac structure and function were measured by echocardiography, including mitral inflow early diastolic velocity/mitral inflow late diastolic velocity (E/A), left atrium diameter, left ventricular end-diastolic dimension, interventricular septal thickness, left ventricular posterior wall thickness, right atrial transverse diameter, right atrial longitudinal diameter, right ventricular dimension (RVD), stroke volume, cardiac output, left ventricular ejection fraction, and fractional shortening. Cox regression and competing risk analyses and Kaplan-Meier and Nelson-Aalen cumulative risk curves were used to evaluate their associations with further decompensation and death in cirrhotic patients, if appropriate. RESULTS: Lower RVD was a predictor of further decompensation in Cox regression (adjusted by Child-Pugh score: p = 0.138; adjusted by MELD score: p = 0.034) and competing risk analyses (p = 0.003), and RVD ≤17 mm was significantly associated with higher cumulative incidence of further decompensation in Kaplan-Meier (p = 0.002) and Nelson-Aalen cumulative risk curves (p = 0.002). E/A ≤ 0.8 was a significant predictor of death in Cox regression (adjusted by Child-Pugh score: p = 0.041; adjusted by MELD score: p = 0.045) and competing risk analyses (p = 0.024), and E/A ≤ 0.8 was significantly associated with higher cumulative incidence of death in Kaplan-Meier (p = 0.023) and Nelson-Aalen cumulative risk curves (p = 0.024). Other echocardiography-related parameters were not significantly associated with further decompensation or death. CONCLUSION: RVD and E/A may be considered for the prognostic assessment of decompensated cirrhosis.

ACAT2 may be a novel predictive biomarker and therapeutic target in lung adenocarcinoma.

BACKGROUND: Acyl-coenzyme A cholesterol acyltransferase (ACAT) is a membrane-binding enzyme localized in the endoplasmic reticulum. ACAT2 can promote the development of colon cancer, but its efficacy in lung adenocarcinoma (LUAD) remains uncertain. METHOD: ACAT2 expression was performed by using the TIMER2.0 database. The GEPIA database was utilized to analyze the correlation between ACAT2 expression and pathological stage of the tumor. Clinical prognosis was assessed through the Kaplan-Meier analysis. The CancerSEA database was employed to scrutinize the correlations between the ACAT2 expression and the functional status of various tumors, which were subsequently visualized as a heatmap. Furthermore, molecular interaction network analysis was performed by the STRING tool. RESULTS: High ACAT2 expression was associated with a poor DFS and OS in LUAD patients. Cox regression analysis indicated that the poor outcomes may be related to tumor stage, nodal stage, distant metastatic stage. ACAT2 was found to play a crucial role in various biological processes, including the cell cycle, DNA repair, DNA damage response, and proliferation. Enrichment pathway analysis revealed four ACAT2 related genes, ACOX1, EHHADH, OXCT1, and DLAT. CONCLUSION: Our study showed that ACAT2 was upregulated in LUAD, and had a worse survival. ACAT2 could be a novel predictive biomarker and therapeutic target in LUAD.

Abnormal Behavior Monitoring Method of Larimichthys crocea in Recirculating Aquaculture System Based on Computer Vision.

It is crucial to monitor the status of aquaculture objects in recirculating aquaculture systems (RASs). Due to their high density and a high degree of intensification, aquaculture objects in such systems need to be monitored for a long time period to prevent losses caused by various factors. Object detection algorithms are gradually being used in the aquaculture industry, but it is difficult to achieve good results for scenes with high density and complex environments. This paper proposes a monitoring method for Larimichthys crocea in a RAS, which includes the detection and tracking of abnormal behavior. The improved YOLOX-S is used to detect Larimichthys crocea with abnormal behavior in real time. Aiming to solve the problems of stacking, deformation, occlusion, and too-small objects in a fishpond, the object detection algorithm used is improved by modifying the CSP module, adding coordinate attention, and modifying the part of the structure of the neck. After improvement, the AP50 reaches 98.4% and AP50:95 is also 16.2% higher than the original algorithm. In terms of tracking, due to the similarity in the fish's appearance, Bytetrack is used to track the detected objects, avoiding the ID switching caused by re-identification using appearance features. In the actual RAS environment, both MOTA and IDF1 can reach more than 95% under the premise of fully meeting real-time tracking, and the ID of the tracked Larimichthys crocea with abnormal behavior can be maintained stably. Our work can identify and track the abnormal behavior of fish efficiently, and this will provide data support for subsequent automatic treatment, thus avoiding loss expansion and improving the production efficiency of RASs.

Iatrogenic or predetermined aortic dysplasia?

Coarctation of aorta post-transcatheter occlusion of patent ductus arteriosus is rare. We report a special case of infant with patent ductus arteriosus complicated by bicuspid aortic valve, who presented severe coarctation of aorta and aortic valve dysfunction post-patent ductus arteriosus occlusion during follow-up, eventually receiving surgical operations. A genetic rather than iatrogenic predisposition towards post-procedural complications has been discussed.

Preparation of phosphoric-modified aloe vera/chitosan aerogels and their efficient adsorption of U(VI).

The efficient adsorption of radioactive elements from nuclear wastewater is an important research topic in the environmental field. The unique three-dimensional porous structure of aerogels has great potential in the field of adsorption. Phosphoric-modified aloe vera/chitosan aerogel (CS/AL-AP) was prepared from chitosan, phosphoric acid, and aloe powder by vacuum freeze-drying self-assembly. The maximum adsorption of uranyl ions by CS/AL-AP was found to be 322.34 mg/g at pH 6, adsorption time of 120 min, solid-to-liquid ratio of 0.125 g/L, reaction temperature of 303 K, and initial uranyl ion concentration of 50 mg/L. The adsorption process is consistent with the Langmuir isotherm model and the quasi-secondary kinetic model, indicating that the adsorption process is monolayer adsorption. The type of adsorption is mainly chemisorption. FTIR and XPS analyses indicate that the adsorption of U(VI) by CS/AL-AP results from the combined action of coordination or chelation of amino, hydroxyl, and carboxyl groups. In addition, CS/AL-AP shows excellent adsorption capacity in the presence of complex co-existing ions. After five adsorption-desorption experiments, the adsorption capacity of CS/AL-AP for uranyl ions remained at a high level. It indicates that CS/AL-AP has good stability and recoverability. The results indicate that CS/AL-AP has excellent potential in the field of uranium removal.

Association between serum free fatty acid levels and tophus in patients with gout: a cross-sectional study.

OBJECTIVES: To explore the relationship between serum free fatty acid (FFA) and tophus in gout patients, and to investigate whether FFA increases the risk of tophus deposition by lowering urine pH. METHODS: A total of 595 patients with gout aged 18 to 80 were enrolled between June 2018 and August 2021. The subjects were divided into four groups according to FFA. Logistic regression was used to analyse the association between serum FFA and tophus. Receiver operating curves (ROC) were plotted to explore the predictive value of FFA on the occurrence of tophus. RESULTS: Accompanying the increase of FFA levels, the prevalence of tophus in groups Q3 and Q4 was significantly higher than in groups Q1 and Q2 (33.6%, 36.5% vs. 6.3%, 19.6%, p<0.001). According to the Spearman correlation, serum FFA levels were positively correlated with tophus while negatively with urine pH (p<0.001). FFA had a significant interaction with urine pH on tophus risk. Multivariate logistic regression showed that participants in Q2-Q4 had a higher OR of tophus than those in Q1 (OR were 2.770, 5.878 and 7.958 in Q2-Q4, respectively). ROC showed the best cut-off value of serum FFA level in predicting the onset of tophus was 0.46 mmol/L. Serum FFA had a great discriminant ability to predict tophus. CONCLUSIONS: High FFA levels are independently associated with tophus risk and FFA may promote tophi deposition by lowering urine pH. Serum FFA levels have a great screening value to identify tophus.

A detection method of the rescue targets in the marine casualty based on improved YOLOv5s.

In recent years, with the deep exploitation of marine resources and the development of maritime transportation, ship collision accidents occur frequently, which leads to the increasingly heavy task of maritime Search and Rescue (SAR). Unmanned Aerial Vehicles (UAVs) have the advantages of flexible maneuvering, robust adaptability and extensive monitoring, which have become an essential means and tool for emergency rescue of maritime accidents. However, the current UAVs-based drowning people detection technology has insufficient detection ability and low precision for small targets in high-altitude images. Moreover, limited by the load capacity, UAVs do not have enough computing power and storage space, resulting in the existing object detection algorithms based on deep learning cannot be directly deployed on UAVs. To solve the two issues mentioned above, this paper proposes a lightweight deep learning detection model based on YOLOv5s, which is used in the SAR task of drowning people of UAVs at sea. First, an extended small object detection layer is added to improve the detection effect of small objects, including the extraction of shallow features, a new feature fusion layer and one more prediction head. Then, the Ghost module and the C3Ghost module are used to replace the Conv module and the C3 module in YOLOv5s, which enable lightweight network improvements that make the model more suitable for deployment on UAVs. The experimental results indicate that the improved model can effectively identify the rescue targets in the marine casualty. Specifically, compared with the original YOLOv5s, the improved model mAP@0.5 value increased by 2.3% and the mAP@0.5:0.95 value increased by 1.1%. Meanwhile, the improved model meets the needs of the lightweight model. Specifically, compared with the original YOLOv5s, the parameters decreased by 44.9%, the model weight size compressed by 39.4%, and Floating Point Operations (FLOPs) reduced by 22.8%.

A universal coating strategy for inhibiting the growth of bacteria on materials surfaces.

The development of a versatile antibacterial coating, irrespective of material characteristics, is greatly attractive but still a challenge. In this work, mussel-inspired dopamine-modified sodium alginate (SA-DA) was successfully synthesized as the adhesion layer, and antibacterial coatings on three types of substrates, namely cotton fabric, aluminum sheet, and polyurethane membrane, were constructed through the layer-by-layer (LbL) deposition of polyhexamethylene guanidine and sodium alginate. Among the coated materials, the coated cotton fabric was systematically characterized, and the results showed that it still exhibited ideal hydrophilicity, and its liquid absorption capacity increased with an increase in the coating layers. The growth of Escherichia coli and Staphylococcus aureus was notably inhibited on the coated cotton fabric, and 10 coating bilayers achieved 100% inhibition of bacterial growth within 10 min. Furthermore, an ideal antibacterial ability maintained after 10 cycles of antibacterial trials or 50 washing or soaping cycles. In vitro evaluation of the hemostatic effect indicated that the coated cotton fabric could promote blood clotting by concentrating the components of blood and activating the platelets, and no significant hemolysis and cytotoxicity were observed in the coated cotton fabric. Moreover, the coated aluminum and polyurethane film also displayed an obvious antibacterial effect, which proved that the constructed coating could successfully adhere to the metal and polymer surfaces. Therefore, this work provided a proper way for the progress of a current antibacterial coating tactics for different substrate surfaces.

Intentional replantation combined root resection therapy for the treatment of type III radicular groove with two roots: A case report.

BACKGROUND: A radicular groove is an anatomic malformation that usually initiates at the central fossa, extending along the root at varying lengths and depths and predisposes the involved tooth to a severe periodontal defect. Severe grooves that extend to the root apex often lead to complex combined periodontal-endodontic lesions. They are a serious challenge for doctors to diagnose and treat. CASE SUMMARY: In this report, we described a patient with a maxillary lateral incisor with a deep palatogingival groove with two roots, which led to complex combined periodontal-endodontic lesions. Suggested treatment modalities included curettage of the affected tissues, elimination of the groove by grinding and/or sealing with a variety of filling materials, and surgical procedures. In this case, a combination of endodontic therapy, intentional replantation, and root resection were used, which resulted in periodontal/periradicular healing after 12 mo. CONCLUSION: Intentional replantation and root resection offer a predictable procedure and should be considered a viable treatment modality for the management of palatogingival grooves, especially for two-rooted teeth.

The Extraglycemic Effect of SGLT-2is on Mineral and Bone Metabolism and Bone Fracture.

Type 2 diabetes mellitus (T2DM) is a risk factor for osteoporosis. The effects of T2DM and anti-diabetic agents on bone and mineral metabolism have been observed. Sodium-glucose co-transporter 2 inhibitors (SGLT-2is) promote urinary glucose excretion, reduce blood glucose level, and improve the cardiovascular and diabetic nephropathy outcomes. In this review, we focused on the extraglycemic effect and physiological regulation of SGLT-2is on bone and mineral metabolism. SGLT-2is affect the bone turnover, microarchitecture, and bone strength indirectly. Clinical evidence of a meta-analysis showed that SGLT-2is might not increase the risk of bone fracture. The effect of SGLT-2is on bone fracture is controversial, and further investigation from a real-world study is needed. Based on its significant benefit on cardiovascular and chronic kidney disease (CKD) outcomes, SGLT-2is are an outstanding choice. Bone mineral density (BMD) and fracture risk evaluation should be considered for patients with a high risk of bone fracture.

Identification of Two Novel Mutations of ABCD1 Gene in Pedigrees with X-Linked Adrenoleukodystrophy and Review of the Literature.

Background: X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal metabolism disorder, resulting from the loss-of-function mutation of ATP-binding cassette protein subfamily D1 (ABCD1) gene. The dysfunction of ALD protein, a peroxisomal ATP-binding cassette transporter, results in the excessive saturated very long-chain fatty acids (VLCFAs) accumulation in organs including the brain, spine, and adrenal cortex. X-ALD is characterized as the childhood, adolescent, adult cerebral ALD, adrenomyeloneuropathy (AMN), adrenal insufficiency, and asymptomatic phenotypes, exhibiting a high variety of clinical neurological manifestations with or without adrenocortical insufficiency. Results: In this study, we reported two cases of X-ALD, which were first diagnosed as adrenal insufficiency (Addison's disease) and treated with adrenocortical supplement. However, both of the cases progressed as neurological symptoms and signs after decades. Elevated VLCFAs level, brain MRI scan, and genetic analysis confirmed final diagnosis. In addition, we identified two novel mutations of ABCD1 gene, NM_000033.3 (ABCD1): c.874_876delGAG (p.Glu292del) and NM_000033.3 (ABCD1): c.96_97delCT (p.Tyr33Profs∗161), in exon 1 of ABCD1 gene. Sanger sequencing confirmed that the proband's mother of the first case was heterozygous carrying the same variant. Adrenal insufficiency-only type is very rare; however, it may be the starting performance of X-ALD. In addition, we summarized reported mutation sites and clinical manifestations to investigate the correlationship of phenotype-genotype of X-ALD. Conclusions: The early warning manifestations should be noticed, and the probability of X-ALD should be considered. This report could be beneficial for the early diagnosis and genetic counseling for patients with X-ALD.

Treatment Strategies for Ventricular Septal Rupture After Myocardial Infarction: A Single-Center Experience.

Objective: To analyze treatment strategies, prognosis, and related risk factors of patients with postinfarction ventricular septal rupture, as well as the impact of timing of surgical intervention. Methods: A total of 23 patients diagnosed with postinfarction ventricular septal rupture who were non-selectively admitted to Shanxi Provincial Cardiovascular Hospital between October 2017 and August 2021 were included in this study. The relevant clinical data, operation-related conditions, and follow-up data were summarized for all patients. The Kaplan-Meier method and log-rank test were used for the cumulative incidence of unadjusted mortality in patients with different treatment methods. Multivariate logistic regression was used to evaluate the independent risk factors for in-hospital patient mortality. Results: The mean age of the study patients was 64.43 ± 7.54 years, 12(52.2%) were females. There was a significant difference in terms of postoperative residual shunt between the surgical and interventional closure groups (5.9 vs. 100%, respectively; P < 0.001). The overall in-hospital mortality rate was 21.7%; however, even though the surgical group had a lower mortality rate than the interventional closure group (17.6 vs. 33%, respectively), this difference was not statistically significant (P = 0.576). Univariate analysis showed that in-hospital survival group patients were significantly younger than in-hospital death group patients (62.50 ± 6.53 vs. 71.40 ± 7.37 years, respectively; P = 0.016), and that women had a significantly higher in-hospital mortality rate than men (P = 0.037). The average postoperative follow-up time was 18.11 ± 13.92 months; as of the end of the study all 14 patients in the surgical group were alive, Two out of four patients survived and two patients died after interventional closure. Univariate analysis showed that interventional closure was a risk factor for long-term death (P < 0.05). Conclusion: Surgical operation is the most effective treatment for patients with postinfarction ventricular septal rupture; however, the best timing of the operation should be based on the patient's condition and comprehensively determined through real-time evaluation and monitoring. We believe that delaying the operation time as much as possible when the patient's condition permits can reduce postoperative mortality. Interventional closure can be used as a supplementary or bridge treatment for surgical procedures.

LncRNA ZFAS1 regulates the proliferation, oxidative stress, fibrosis, and inflammation of high glucose-induced human mesangial cells via the miR-588/ROCK1 axis.

BACKGROUND: Diabetic nephropathy (DN) is a critical and the most common microvascular complication and its pathogenesis is still faintly understood. Thus, this study was performed to examine the long non-coding RNA ZNFX1 Antisense Gene Protein 1 (lncRNA ZFAS1) biological function and mechanism of regulation in DN. METHOD: Human glomerular mesangial cells (HGMC) were induced with high glucose (HG, 25 mM) to establish HG-induced cell viability, pro-inflammation observed in DN. After, target miRNA and mRNA were predicted through Lncbase and Targetscan. Subsequently, the expression of ZFAS1, miR-588, and ROCK1 in DN clinical samples and cell-model was examined through qRT-PCR and western blot analysis. We upheld the targeted interaction between miR-588 and ZFAS1 or ROCK1 through a dual-luciferase reporter assay. The proliferation of the cell was also examined through CCK-8 assay, while the level of HG-induced oxidative stress was established by measuring reactive oxygen species (ROS) level, and also the activities of antioxidant enzymes in the cell. Lastly, the level of accumulated extracellular matrix (ECM) protein-fibronectin and collagen type IV, and inflammatory cytokines produced by the cell was analyzed through western blot analysis and ELISA. RESULTS: ZFAS1 was significantly upregulated in the DN blood samples and HG-induced HGMC. Prediction result revealed that the ZFAS1 endogenously targets the miR-588 seed sequence while miR-588 plays a role in post-transcriptional regulation of ROCK1 mRNA. Moreover, we found that miR-588 expression was significantly downregulated in DN blood samples and negatively correlates with ZFAS1 expression. Further results show that silencing ZFAS1 had a protective effect on HG-induced proliferation, oxidative stress, fibrosis, and inflammation in HGMC while miR-588 inhibition and ROCK1 overexpression reversed this effect. CONCLUSIONS: Altogether, our data suggest that ZFAS1 regulates the proliferation, oxidative stress, fibrosis, and inflammation of high glucose-induced diabetic nephropathy through the miR-588/ROCK1 axis.

Hyperuricemia and the Risk of Heart Failure: Pathophysiology and Therapeutic Implications.

The association between hyperuricemia and cardiovascular disease (CVD) has been reported and studied in the past two decades. Xanthine oxidase (XO) induced uric acid (UA) serves as a risk factor and has the independent prognostic and functional impact of heart failure (HF), but whether it plays a positive role in the pathogenesis of HF has remained unclear. Growing evidence suggest the up-regulated XO avtivity and increased production of free oxygen radical (ROS) correspondingly are the core pathogenesis of HF with hyperuricemia, which results in a whole cluster of pathophysiologic cardiovascular effects such as oxidative stress, endothelial dysfunction, vascular inflammation, left ventricular (LV) dysfunction as well as insulin resistance (IR). The use of XO inhibition represents a promising therapeutic choice in patients with HF due to its dual effect of lowering serum UA levels as well as reducing ROS production. This review will discuss the pathophysiologic mechanisms of hyperuricemia with HF, the targeted therapeutic interventions of UA lowering therapies (ULT) with XO inhibition and mechanism underlying beneficial effects of ULT. In addition, the review also summarizes current evidence on the role of ULT in HF and compares CV risk between allopurinol and febuxostat for practical and clinical purposes. Guidelines and implementation of CV risk management in daily practice will be discussed as well.

Bupivacaine inhibits the malignant biological behavior of oral squamous cell carcinoma cells by inhibiting the activation of ERK1/2 and STAT3.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is an aggressive malignant tumor. Bupivacaine (Bupi), a local anesthetic drug, has been shown to display anti-tumor activity against a variety of tumors. METHODS: We selected OSCC CAL-27 cells as the in vitro model. Cell toxicity, proliferation, apoptosis, and stemness were conducted, respectively. The protein levels of Ki67, PCNA, caspase-3, caspase-9, survivin, SOX2, NANOG, OCT4, STAT3, p-STAT3, ERK1/2, and p-ERK1/2 were evaluated by western blotting. Male BALB/c nude mice xenograft model was used to evaluate the effect of Bupi on tumor growth in vivo. RESULTS: Compared with the control group, Bupi (0.2, 0.5, or 1 µm) significantly decreased the cell viability and the proliferation of CAL-27 cells. Meanwhile, Bupi significantly promoted apoptosis of CAL-27 cells compared with the control group. Additionally, Bupi inhibited the stemness of CAL-27 cells which was evidenced by a sphere formation assay. Bupi decreased the phosphorylation level of STAT3 and ERK1/2 in a dose-dependent manner. The addition of interferon-γ (IFN-γ, 20 ng/mL) in the experiment verified the role of Bupi on STAT3 and ERK1/2 signaling. In vivo, Bupi (40 µmol/kg) obviously suppressed the weight and size of the xenograft tumor, the number of apoptotic cells and Ki67+ decreased. Also, Bupi treatment inhibited the expression of stem-like marker proteins. CONCLUSIONS: Bupi could be used as an anticancer drug against the growth and stemness ability of OSCC. The underlying mechanism may be due to down-regulation of STAT3 and ERK1/2 signaling. This study provides a new insight for the application of Bupi.

A comparative study of acarbose, vildagliptin and saxagliptin intended for better efficacy and safety on type 2 diabetes mellitus treatment.

As a complicated metabolic disorder, type 2 diabetes mellitus (T2DM) is becoming a major health concern worldwide. Drugs including acarbose, saxagliptin and vildagliptin are applied, but their efficacy is still required to be compared. Therefore, the study aimed to evaluate the efficacy and safety of acarbose, saxagliptin and vildagliptin in the treatment of T2DM. Ninety patients diagnosed with T2DM were treated with acarbose, saxagliptin and vildagliptin, respectively (30 patients for each drug). All patients were examined at 0, 4 and 12 weeks after treatment with vital signs recorded. Fasting blood glucose and blood biochemical indices were analyzed. In addition, fecal samples were taken for microbial macrogenome sequencing and safety evaluation within 12 weeks after treatment. Blood glucose level decreased at 4 and 12 weeks after treatment, and the total cholesterol (TC) and high-density lipoprotein (HDL) levels at 12 weeks were different. Genus abundance of intestinal flora was altered at different time points. Acarbose increased Butyricimonas level first and then decreased it during drug treatment. Saxagliptin increased Megamonas and decreased Turicibacter genus level gradually. Pseudomonas, Klebsiella, Blautia, Faecalibacterium and Roseburia levels fluctuated after Vildagliptin treatment, which increased fasting C-peptide level greater than the other two drugs. Saxagliptin showed higher adverse reactions than acarbose and vildagliptin. Collectively, acarbose, vildagliptin, and saxagliptin can effectively reduce the HbA1c level and affect the intestinal flora distribution in T2DM patients, and the adverse reactions of acarbose and vildagliptin are less than saxagliptin, providing alternative strategies for the treatment of T2DM.