Vitamin K: New insights related to senescence and cancer metastasis.

Several clinical trials and experimental studies have recently shown that vitamin K (VK) supplementation benefits the human body. Specifically, VK participates in coagulation and is associated with cellular senescence and cancer. VK has a potential anticancer effect in various cancers, such as pancreatic and prostate cancers. Through anti-inflammatory and antioxidant effects, VK can prevent senescence and inhibit cancer metastasis. Therefore, cancer prognosis can be improved by preventing cellular senescence. In addition, VK can inhibit the proliferation, growth, and differentiation of cancer cells through various mechanisms, including induction of c-myc and c-fos genes, regulation of B-cell lymphoma-2 (Bcl-2) and p21 genes, and angiogenesis inhibition. This review aims to discuss the relationship among VK, cellular senescence, and cancer metastasis and thus may improve comprehension of the specific functions of VK in human health. The potential application of VK as an adjuvant therapy for cancer (or in combination with traditional chemotherapy drugs or other vitamins) has also been highlighted.

Impact of operator expertise on transperineal free-hand mpMRI-fusion-targeted biopsies under local anaesthesia for prostate cancer diagnosis: a multicenter prospective learning curve.

PURPOSE: Transperineal mpMRI-targeted fusion prostate biopsies (TPFBx) are recommended for prostate cancer diagnosis, but little is known about their learning curve (LC), especially when performed under local anaesthesia (LA). We investigated how operators' and institutions' experience might affect biopsy results. METHODS: Baseline, procedure and pathology data of consecutive TPFBx under LA were prospectively collected at two academic Institutions, from Sep 2016 to May 2019. Main inclusion criterion was a positive MRI. Endpoints were biopsy duration, clinically significant prostate cancer detection rate on targeted cores (csCDR-T), complications, pain and urinary function. Data were analysed per-centre and per-operator (with ≥ 50 procedures), comparing groups of consecutive patient, and subsequently through regression and CUSUM analyses. Learning curves were plotted using an adjusted lowess smoothing function. RESULTS: We included 1014 patients, with 27.3% csCDR-T and a median duration was 15 min (IQR 12-18). A LC for biopsy duration was detected, with the steeper phase ending after around 50 procedures, in most operators. No reproducible evidence in favour of an impact of experience on csPCa detection was found at operator's level, whilst a possible gentle LC of limited clinical relevance emerged at Institutional level; complications, pain and IPSS variations were not related to operator experience. CONCLUSION: The implementation of TPFBx under LA was feasible, safe and efficient since early phases with a relatively short learning curve for procedure time.

Effect of clove on improving running ability in aging mice.

In this study, a D-galactose-induced aging mouse model was established, and Syringa oblata Lindl. extract (SOLE) was administered orally to observe the effect and mechanism of SOLE on the running ability of aging mice. The role of SOLE was evaluated by H&E histopathological observation, detection of serum biochemical indices, and detection of mRNA expression levels by qPCR experiments. The experimental results showed that SOLE could increase the exhaustive running time of aging mice and reduce the oxidative aging of the liver and kidney. At the same time, the levels of BUN, lactic acid, GOT, GPT, MDA, iNOS, and TNF-α in the serum of the mice were decreased, and the relative mRNA expression levels of nNOS, iNOS, TNF-α and syncytin-1 in the liver tissue and skeletal muscle tissue of the mice were downregulated. In addition, it increased the levels of CAT, GSH-Px, and T-SOD in mouse serum and upregulated the relative mRNA expression of Cu/Zn-SOD, Mn-SOD, and CAT in mouse liver tissue and muscle tissue. The analysis results showed that SOLE mainly contained rutin, isoquercitrin, ferulic acid, dihydroquercetin, and quercitrin. In summary, SOLE can enhance the running ability and exercise ability of aging mice and slow down aging. PRACTICAL APPLICATIONS: Clove is used as health tea or traditional Chinese medicine in China, but there is no relevant research and application on the improvement of human exercise ability. This study found this new function of clove, which accumulated a theoretical basis for further popularizing its application.

Lipidomic Profiling of Ipsilateral Brain and Plasma after Celastrol Post-Treatment in Transient Middle Cerebral Artery Occlusion Mice Model.

Celastrol, a pentacyclic triterpene isolated from the traditional Chinese medicine Tripterygium wilfordii Hook. F., exhibits effectiveness in protection against multiple central nervous system (CNS) diseases such as cerebral ischemia, but its influence on lipidomics still remains unclear. Therefore, in the present study, the efficacy and potential mechanism of celastrol against cerebral ischemia/reperfusion (I/R) injury were investigated based on lipidomics. Middle cerebral artery occlusion (MCAO) followed by reperfusion was operated in mice to set up a cerebral I/R model. TTC staining and TUNEL staining were used to evaluate the therapeutic effect of celastrol. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) was employed for lipidomics analysis in ipsilateral hemisphere and plasma. Celastrol remarkably reduced cerebral infarct volume and apoptosis positive cells in tMCAO mice. Furthermore, lipidomics analysis showed that 14 common differentially expressed lipids (DELs) were identified in brain and five common DELs were identified in plasma between the Sham, tMCAO and Celastrol-treated tMCAO groups. Through enrichment analysis, sphingolipid metabolism and glycerophospholipid metabolism were demonstrated to be significantly enriched in all the comparison groups. Among the DELs, celastrol could reverse cerebral I/R injury-induced alteration of phosphatidylcholine, phosphatidylethanolamine and sulfatide, which may be responsible for the neuroprotective effect of celastrol. Our findings suggested the neuroprotection of celastrol on cerebral I/R injury may be partially associated with its regulation of lipid metabolism.

Research progress of natural compounds in anti-liver fibrosis by affecting autophagy of hepatic stellate cells.

Chronic liver diseases caused by various pathogenesis are marked by inflammatory infiltration and wound healing reaction, while their normal regeneration ability is impaired. The unbalance between the generation and the degradation of extracellular matrix (ECM) leads to collagen accumulation and develops into liver fibrosis. Inflammation, oxidative stress, and autophagy interact closely in the pathogenesis of hepatic fibrosis. Reactive Oxygen Species (ROS) can not only stimulate Kupffer cells to release massive inflammatory factors, but induce autophagy. However, the latter may suppress inflammatory reaction by inhibiting proinflammatory complex formation directly, and removing damaged organelles or pathogenic microorganism indirectly. At present, effective anti-fibrosis drugs are still lacking. Previous studies have found various natural compounds enabled liver protection through anti-inflammatory, antioxidant, and other mechanisms. In recent years, autophagy, a vital life activity, has been found to be involved in the mechanism of liver fibrosis. As a new target, developing anti-liver fibrosis drugs that regulate the activity of autophagy is very promising. In this review, we summarize the latest studies about natural compounds in the treatment of liver fibrosis by regulating autophagy.

Transperineal freehand multiparametric MRI fusion targeted biopsies under local anaesthesia for prostate cancer diagnosis: a multicentre prospective study of 1014 cases.

OBJECTIVE: To assess the outcomes of multiparametric magnetic resonance imaging (mpMRI) transperineal targeted fusion biopsy (TPFBx) under local anaesthesia. PATIENTS AND METHODS: We prospectively screened 1327 patients with a positive mpMRI undergoing TPFBx (targeted cores and systematic cores) under local anaesthesia, at two tertiary referral institutions, between September 2016 and May 2019, for inclusion in the present study. Primary outcomes were detection of clinically significant prostate cancer (csPCa) defined as (1) International Society of Urological Pathologists (ISUP) grade >1 or ISUP grade 1 with >50% involvement of prostate cancer (PCa) in a single core or in >2 cores (D1) and (2) ISUP grade >1 PCa (D2). Secondary outcomes were: assessment of peri-procedural pain (numerical rating scale [NRS]) and procedure timings; erectile (International Index of Erectile Function) and urinary (International Prostate Symptom Score) function changes; and complications. We also investigated the value of systematic sampling and concordance with radical prostatectomy (RP). RESULTS: A total of 1014 patients were included, of whom csPCa was diagnosed in 39.4% (n = 400). The procedure was tolerable (NRS pain score 3.1 ± 2.3), with no impact on erectile (P = 0.45) or urinary (P = 0.58) function, and a low rate of complications (Clavien-Dindo grades 1 or 2, n = 8; grade >2, n = 0). No post-biopsy sepsis was recorded. Twenty-two men (95% confidence interval [CI] 17-29) needed to undergo additional systematic biopsy to diagnose one csPCa missed by targeted biopsies (D1). ISUP grade concordance of biopsies with RP was as follows: k = 0.40 (95% CI 0.31-0.49) for targeted cores alone and k = 0.65 (95% CI 0.57-0.72; P < 0.05) overall. CONCLUSIONS: The use of TPFBx under local anaesthesia yielded good csPCa detection and was feasible, quick, well tolerated and safe. Infectious risk was negligible. Addition of systematic to targeted cores may not be needed in all men, although it improves csPCa detection and concordance with RP.

Cognitive Computing-Based CDSS in Medical Practice.

Importance. The last decade has witnessed the advances of cognitive computing technologies that learn at scale and reason with purpose in medicine studies. From the diagnosis of diseases till the generation of treatment plans, cognitive computing encompasses both data-driven and knowledge-driven machine intelligence to assist health care roles in clinical decision-making. This review provides a comprehensive perspective from both research and industrial efforts on cognitive computing-based CDSS over the last decade.Highlights. (1) A holistic review of both research papers and industrial practice about cognitive computing-based CDSS is conducted to identify the necessity and the characteristics as well as the general framework of constructing the system. (2) Several of the typical applications of cognitive computing-based CDSS as well as the existing systems in real medical practice are introduced in detail under the general framework. (3) The limitations of the current cognitive computing-based CDSS is discussed that sheds light on the future work in this direction.Conclusion. Different from medical content providers, cognitive computing-based CDSS provides probabilistic clinical decision support by automatically learning and inferencing from medical big data. The characteristics of managing multimodal data and computerizing medical knowledge distinguish cognitive computing-based CDSS from other categories. Given the current status of primary health care like high diagnostic error rate and shortage of medical resources, it is time to introduce cognitive computing-based CDSS to the medical community which is supposed to be more open-minded and embrace the convenience and low cost but high efficiency brought by cognitive computing-based CDSS.

Pain in Men Undergoing Transperineal Free-Hand Multiparametric Magnetic Resonance Imaging Fusion Targeted Biopsies under Local Anesthesia: Outcomes and Predictors from a Multicenter Study of 1,008 Patients.

PURPOSE: Several transperineal biopsy series have proven feasibility under local anesthesia. However, there is a lack of large analyses detailing pain outcomes and factors influencing pain. MATERIALS AND METHODS: From 2016 to 2019 we performed a multicenter prospective study in men undergoing multiparametric magnetic resonance imaging-transperineal fusion biopsies (target+systematic cores) under local anesthesia. Primary outcomes were 1) pain scores (assessed through a 0 to 10-point numeric rating scale) and 2) identification of factors associated with severe pain. The secondary outcome was to evaluate pain influence on clinically significant prostate cancer target cores detection. RESULTS: We included 1,008 men undergoing transperineal fusion biopsies under local anesthesia. Mean±SD numeric rating scale pain scores were 3.9±2.1 at local anesthesia administration and 3.1±2.3 when performing biopsies. Pain was not associated with lower clinically significant prostate cancer detection on targeted cores (p=0.23 and p=0.47 depending on clinically significant prostate cancer definition). On multivariate analysis age (OR 0.96, 95% CI 0.94-0.99) and severe anxiety (OR 2.99, 95% CI 1.83-4.89) were a protective and risk factor, respectively, for severe biopsy pain. Procedural time was also associated with an increased risk of experiencing severe biopsy pain (OR 1.04, 95% CI 1.00-1.08). If aiming to test the possible effects of anxiety preventive measures on pain, an anxiety cutoff greater than 6 on a numeric rating scale would decrease to 13% the number of patients being treated while identifying 56% of those experiencing severe pain. CONCLUSIONS: Transperineal fusion biopsies under local anesthesia result in moderate pain. Pain does not influence clinically significant prostate cancer target detection. Patient anxiety predicts pain. A numeric rating scale based anxiety assessment may be used to identify those at higher risk for experiencing severe pain in men undergoing transperineal fusion biopsies.

Perovskite-Based Multifunctional Cathode with Simultaneous Supplementation of Substrates and Electrons for Enhanced Microbial Electrosynthesis of Organics.

Microbial electrosynthesis (MES) is an electricity-driven technology for the microbial reduction of CO2 to organic commodities. However, the limited solubility of CO2 in a solution and the inefficient electron transfer make it impossible for microorganisms to obtain an efficient surface for catalytic interaction, thus resulting in the low efficiency of MES. To address this, we introduce a multifunctional perovskite-based cathode material Pr0.5(Ba0.5Sr0.5)0.5Co0.8Fe0.2O3-δ-carbon felt (Pr0.5BSCF-CF), which provides a simultaneously significant increase in CO2 absorption and hydrogen production. As a result, the volumetric acetate production rate of MES obtained by Pr0.5BSCF-CF is 0.24 ± 0.01 g L-1 day-1, and it achieves a maximum acetate titer of 13.74 ± 0.20 g L-1 within 70 days. An adequate supply of CO2 and H2 also provides a sufficient amount of substrates and energy for the self-replication of the biocatalysts in the MES reactor. This effect not only increases the amount of biocatalysts but also optimizes the functions of the biocatalysts; the above benefits further improve the production efficiency of the MES system. This strategy demonstrates that the development of perovskite-based multifunctional cathodes with a simultaneous supplementation of substrates and electrons is a promising approach toward improving the MES efficiency.

Anti-inflammatory properties of uvaol on DSS-induced colitis and LPS-stimulated macrophages.

BACKGROUND: Apocynum venetum leaves are used as a kind of phytomedicine and the main ingredient in some traditional Chinese medicine products for the relief of colitis. To understand the bioactive constituents of A. venetum L., we did a phytochemistry study and investigated anti-Inflammatory effects of compounds and explored the underlying mechanisms. METHODS: We isolated compounds from ethanol extract of A. venetum L. leaf and detected the most effective compound by NO inhibition assay. We investigated anti-Inflammatory effects on dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The disease activity index was determined by scores of body weight loss, diarrhea and rectal bleeding; histological damage was analyzed by H&E staining; macrophages change in the colon were analyzed by immunohistochemistry (IHC); myeloperoxidase activity was measured by myeloperoxidase assay kits; levels of proinflammatory cytokines were determined by qPCR and ELISA; protein production such as COX-2, iNOS, STAT3 and ERK1/2 were determined by western blotting. RESULTS: We isolated uvaol from ethanol extract of A. venetum L. leaf and found uvaol has excellent potential of inhibiting NO production. We further found uvaol could attenuate disease activity index (DAI), colon shortening, colon injury, and colonic myeloperoxidase activity in DSS-induced colitis mice. Moreover, uvaol significantly reduces mRNA expression and production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß, and MCP-1) and infiltration of macrophages in colonic tissues of colitis mice. Studies on LPS challenged murine macrophage RAW246.7 cells also revealed that uvaol reduces mRNA expression and production of pro-inflammatory cytokines and mediators. Mechanically, uvaol inhibits the pro-inflammatory ERK/STAT3 axis in both inflamed colonic tissues and macrophages. CONCLUSIONS: A. venetum leaf contains uvaol and uvaol has potent anti-inflammatory effects on DSS-induced experimental colitis and LPS-stimulated RAW264.7 macrophage cells. These results suggest uvaol is a prospective anti-inflammatory agent for colonic inflammation.

Structure-Based Design and Discovery of a Long-Acting Cocaine Hydrolase Mutant with Improved Binding Affinity to Neonatal Fc Receptor for Treatment of Cocaine Abuse.

Despite decades of efforts to develop a pharmacotherapy for cocaine abuse treatment, there is still no FDA-approved treatment of diseases associated with this commonly abused drug. Our previously designed highly efficient cocaine hydrolases (CocHs) and the corresponding Fc-fusion proteins (e.g., CocH3-Fc) are recognized as potentially promising therapeutic enzyme candidates for cocaine abuse treatment, but all with limited biological half-lives. In order to prolong the biological half-life and, thus, decrease the required frequency of the enzyme administration for cocaine abuse treatment, we have modeled the Fc-fusion CocH binding with neonatal Fc receptor (FcRn) in the present study. This approach led to the design and testing of CocH3-Fc(M6), a CocH3-Fc mutant with nearly 100-fold increased binding affinity: from Kd = ~ 4 µM to Kd = 43 nM. As a result, CocH3-Fc(M6) indeed revealed a markedly prolonged biological half-life (t1/2 = 206 ± 7 h or ~ 9 days) in rats, longer than other known Fc-fusion protein drugs such as abatacept and alefacept (for other therapeutic purposes) in the same species (rats). It has been demonstrated that a single dose of 3 mg/kg CocH3-Fc(M6) effectively blocked 20 mg/kg cocaine-induced hyperactivity on day 18 after CocH3-Fc(M6) administration. This is the first attempt to rationally design long-acting Fc-fusion enzyme mutant based on combined computational modeling and experimental measurement of the Fc-fusion CocH binding with FcRn. The similar structure-based design strategy may be used to prolong the biological half-lives of other Fc-fusion protein drugs.

Rivaroxaban versus enoxaparin for the prevention of venous thromboembolism after total knee arthroplasty: A meta-analysis.

OBJECTIVE: This article analyzed the clinical efficacy and tolerability of rivaroxaban and enoxaparin in patients undergoing total knee arthroplasty (TKA) surgery. METHODS: Five randomized, controlled clinical trials on rivaroxaban versus enoxaparin in patients who underwent TKA were identified and included in this meta-analysis. RESULTS: The meta-analysis indicated that rivaroxaban prophylaxis was associated with lower rates of symptomatic venous thromboembolism (VTE) (relative risk[RR]:0.55; 95% confidence interval [CI]: 0.35-0.86; P = .009), symptomatic deep vein thrombosis (DVT) (RR 0.44, 95% CI 0.25-0.80, P = .007), asymptomatic DVT (RR: 0.57; 95% CI: 0.37-0.89; P = .01), distal DVT (RR: 0.62; 95% CI: 0.45-0.85; P = .003) and proximal DVT (RR: 0.42; 95% CI: 0.24-0.75; P = .004). Compared with the enoxaparin group, the incidence of symptomatic pulmonary embolism (PE) (RR: 0.48; 95% CI: 0.19-1.24; P = .13) in the rivaroxaban group was not significantly different. A nonsignificant trend towards all-cause death (RR: 0.38; 95% CI: 0.03-4.92; P = .46) or major bleeding (RR: 1.59; 95% CI: 0.77-3.27; P = .21) risk between rivaroxaban and enoxaparin prophylaxis was found. CONCLUSION: Compared with the enoxaparin group, the group using rivaroxaban after TKA had a significantly lower rate of symptomatic VTE, symptomatic DVT, asymptomatic DVT, distal DVT, and proximal DVT. Our study shows that rivaroxaban after TKA is more effective than enoxaparin and did not increase major bleeding or all-cause mortality.

Oxymatrine inhibits aldosterone-induced rat cardiac fibroblast proliferation and differentiation by attenuating smad-2,-3 and-4 expression: an in vitro study.

BACKGROUND: We previously demonstrated oxymatrine, an alkaloid from the Chinese medicine radix Sophorae flavescentis, ameliorates hemodynamic disturbances and cardiac fibrosis; however, the underlying mechanisms are unclear. Here, we investigated the effect and mechanism of action of oxymatrine on aldosterone-induced cardiac fibroblast to myofibroblast differentiation in vitro. METHODS: Cardiac fibroblasts were isolated purified from neonatal Sprague Dawley rats. The optimal concentration of aldosterone to stimulate cardiac fibroblast proliferation was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cardiac fibroblasts were pretreated with 7.57 × 10(-4) mol/L or 3.78 × 10(-4) mol/L oxymatrine or without oxymatrine for 2 h, and then coincubated with 1 × 10(-8) mol/L aldosterone for 48 h. The MTT assay and Masson staining were used to detect the cardiac fibroblast proliferation and myofibroblast differentiation. The secretion of type I and III collagen was measured by commercial ELISA kits, and the hydroxyproline content was determined by the colorimetric assay. Western blotting assayed the Smad-2, Smad-3, and Smad-4 protein expression in cardiac fibroblasts. RESULTS: The present results confirmed that aldosterone induced cardiac fibroblast to myofibroblast proliferation and differentiation. The MTT assay and Masson staining indicated oxymatrine significantly inhibited aldosterone-induced cardiac fibroblast proliferation and myofibroblast differentiation. Oxymatrine significantly inhibited aldosterone-induced secretion of type I and III collagen, as indicated by commercial ELISA kits, and aldosterone-induced increase in hydroxyproline content, as indicated by a colorimetric assay. Western blotting revealed oxymatrine attenuated aldosterone-induced Smad-2, Smad-3, and Smad-4 expression in cardiac fibroblasts. CONCLUSION: Oxymatrine can inhibit cardiac fibroblast proliferation and differentiation into myofibroblasts via a mechanism linked to attenuation of the Smad signaling pathway.

Lipid-lowering, hepatoprotective, and atheroprotective effects of the mixture Hong-Qu and gypenosides in hyperlipidemia with NAFLD rats.

BACKGROUND: Hyperlipidemia and its complications are among the most harmful of diseases with a worldwide impact, which creates an urgent imperative to find safe and effective drugs for treatment. HG is mainly composed of two kinds of traditional Chinese medicines (TCM), Hong-Qu and gypenosides. Previously, the ingredients of the mixture mainly composed by Hong-Qu and gypenosides (HG) were widely used for purposes of lipid-lowering, antiatherosclerosis effects, and maintaining cardiovascular health in China. The purpose of this study was to determine whether HG provides any benefit to patients with hyperlipidemia. METHODS: Forty-eight adult male Sprague-Dawley rats with fatty liver disease were randomly divided into six groups: normal, model, two positive controls, and two doses of HG-treated groups. The normal rats were fed a basal diet, and the other rats were fed a high-fat diet. Thereafter, the serum lipid profiles, hepatic steatosis, cytokines, enzymes, and relevant mRNA of rats were analyzed in serum, aorta tissue or hepatic tissues, respectively. RESULTS: After 65 days of feeding the high-fat diet to rats, there were significantly disordered serum lipid profiles, elevated oxidative stress biomarkers, and decreased antiinflammatory cytokines in the serum levels. Additionally, aortic foam cell formation was increased. The gene expression levels including hydroxymethylglutaryl-CoA reductase (HMGR), peroxisome proliferator-activated receptor alpha (PPAR-α), sterol response element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase-1 (ACC-1) and carnitine palmitoyl transferase-1(CPT-1) in hepatic tissue were also altered by a high-fat diet fed to Sprague-Dawley rats, and HG treatment significantly resolved and normalized these alterations. Moreover, HG not only caused a significant decrease in the lipid drops on the hepatic tissues, but also restored the antioxidant components. CONCLUSION: HG is beneficial for regulating the stability of blood lipids, has atheroprotective characteristics and may prevent nonalcoholic fatty liver disease (NAFLD), providing more than just a theoretical basis for drug research of cardiovascular disease (CVD) treatment.