Unlocking the potential of fondaparinux: guideline for optimal usage and clinical suggestions (2023).

Background: Thromboembolic disease is associated with a high rate of disability or death and gravely jeopardizes people's health and places considerable financial pressure on society. The primary treatment for thromboembolic illness is anticoagulant medication. Fondaparinux, a parenteral anticoagulant medicine, is still used but is confusing due to its disparate domestic and international indications and lack of knowledge about its usage. Its off-label drug usage in therapeutic settings and irrational drug use are also common. Objective: The aim of this guideline is to enhance the judicious clinical application of fondaparinux by consolidating the findings of evidence-based research on the drug and offering superior clinical suggestions. Methods: Seventeen clinical questions were developed by 37 clinical pharmacy experts, and recommendations were formulated under the supervision of three methodologists. Through methodical literature searches and the use of recommendation, assessment, development and evaluation grading techniques, we gathered evidence. Results: This guideline culminated in 17 recommendations, including the use of fondaparinux for venous thromboembolism (VTE) prevention and treatment, perioperative surgical prophylaxis, specific diseases, special populations, bleeding and overdose management. For different types of VTE, we recommend first assessing thrombotic risk in hospitalized patients and then administering the drug according to the patient's body mass. In surgical patients in the perioperative period, fondaparinux may be used for VTE prophylaxis, but postoperative use usually requires confirmation that adequate hemostasis has been achieved. Fondaparinux may be used for anticoagulation prophylaxis in patients hospitalized for oncological purposes, in patients with atrial fibrillation (AF) after resuscitation, in patients with cirrhosis combined with portal vein thrombosis (PVT), in patients with antiphospholipid syndrome (APS), and in patients with inflammatory bowel disease (IBD). Fondaparinux should be used with caution in special populations, such as pregnant female patients with a history of heparin-induced thrombocytopenia (HIT) or platelet counts less than 50 × 109/L, pregnant patients with a prethrombotic state (PTS) combined with recurrent spontaneous abortion (RSA), and children. For bleeding caused by fondaparinux, dialysis may partially remove the drug. Conclusion: The purpose of this guideline is to provide all healthcare providers with high-quality recommendations for the clinical use of fondaparinux and to improve the rational use of the drug in clinical practice. Currently, there is a lack of a dedicated antidote for the management of fondaparinux. The clinical investigation of activated prothrombin complex concentrate (APCC) or recombinant activated factor VII (rFⅦa) as potential reversal agents is still pending. This critical gap necessitates heightened scrutiny and research emphasis, potentially constituting a novel avenue for future inquiries into fondaparinux sodium. A meticulous examination of adverse events and safety profiles associated with the utilization of fondaparinux sodium will contribute significantly to a more comprehensive understanding of its inherent risks and benefits within the clinical milieu.

Zinc finger Asp-His-His-Cys palmitoyl -acyltransferase 19 accelerates tumor progression through wnt/ß-catenin pathway and is upregulated by miR-940 in osteosarcoma.

Osteosarcoma (OS) is the most frequent malignant primary bone tumor in children and young adults. Zinc finger Asp-His-His-Cys palmitoyl-acyltransferase 19 (ZDHHC19) is a key enzyme in protein palmitoylation and plays crucial roles in tumor progression. However, its expression profile and biological function in OS have been unclear. In the present study, the expression level of ZDHHC19 in OS cell lines was determined by qRT-PCR and Western blot. The effect of ZDHHC19 in cell growth, invasion and migration was analyzed by CCK8, EDU, transwell, wound healing assay in vitro, and xenograft tumor model in vivo. In addition, bioinformatics analysis was used to explore the potential mechanism of ZDHHC19 in OS. Furthermore, the luciferase reporter assay was conducted to determine the direct binding between miR-940 and ZDHHC19. We discovered that ZDHHC19 was overexpressed in OS cells compared with the normal cells. The functional investigation demonstrated that ZDHHC19 silencing could inhibit proliferation, invasion and migration of OS in vitro and suppress tumorigenicity and lung metastasis in a xenograft model in vivo. Mechanistically, we identified that ZDHHC19 was a direct target of miR-940 and forced ZDHHC19 expressions partially rescue the suppression of proliferation, migration and invasion induced by miR-940. Moreover, bioinformatics analysis combined with validation experiments revealed that activating wnt/ß-catenin pathway contributed to the pro-oncogenic effect induced by ZDHHC19. Furthermore, rescue experiments further verified that miR-940/ZDHHC19 axis regulated wnt/ß-catenin pathway. Overall, these findings indicated that miR-940/ZDHHC19 axis played a significant role in OS progression and might be considered as a novel target for OS treatment.Abbreviations: OS, osteosarcoma; miRNAs, microRNAs; 3'-UTR, 3'- untranslated region; TARGET, Therapeutically Applicable Research To Generate Effective Treatments; qRT-PCR, quantitative real-time PCR; IHC, Immunohistochemistry; GSVA, Gene Set Variation Analysis; GSEA, Gene Set Enrichment Analysis; KEGG, Kyoto Encyclopedia of Genes and Genomes.

Neuroprotective Effects of Danshen Chuanxiongqin Injection Against Ischemic Stroke: Metabolomic Insights by UHPLC-Q-Orbitrap HRMS Analysis.

The incidence of cerebral ischemic stroke characterized by high mortality is increasing every year. Danshen Chuanxiongqin Injection (DSCXQ), a traditional Chinese medicine (TCM) preparation, is often applied to treat cerebral apoplexy and its related sequelae. However, there is a lack of systematic research on how DSCXQ mediates its protective effects against cerebral ischemia stroke. Metabolomic analysis based on UHPLC-Q-Orbitrap HRMS was employed to explore the potential mechanisms of DSCXQ on ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). Pattern analysis and metabolomic profiling, combined by multivariate analysis disclosed that 55 differential metabolites were identified between Sham group and Model group, involving sphingolipid metabolism, glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, primary bile acid biosynthesis, pantothenate and CoA synthesis and valine, leucine and isoleucine biosynthesis pathways. DSCXQ could reverse brain metabolic deviations in stroke by significantly upregulating the levels of L-tryptophan, Lyso (18:0/0:0), LPC (18:2), Indole-3-methyl acetate, and downregulating the levels of sphinganine 1-phosphate, L-threonic acid, glutaconic acid and N6,N6,N6-Trimethyl-L-lysine. In our study, we focused on the neuroprotective effects of DSCXQ against neuroinflammatory responses and neuronal apoptosis on a stroke model based on sphingolipid metabolism. The expressions of Sphk1, S1PR1, CD62P, Bcl-2, Bax, and cleaved Caspase-3 in brain tissue were evaluated. The neurological deficit, cerebral infarct size and behavioral abnormality were estimated. Results showed that DSCXQ intervention significantly reduced cerebral infarct size, ameliorated behavioral abnormality, inhibited the expression of Sphk1, S1PR1, CD62P, Bax, Cleaved Caspase-3, while increased the level of Bcl-2, and prevented neuronal apoptosis. The limitations are that our study mainly focused on the verification of sphingolipid metabolism pathway in stroke, and while other metabolic pathways left unverified. Our study indicates that SphK1-SIP axis may potentiate neuroinflammatory responses and mediate brain damage through neuronal apoptosis, and DSCXQ could suppress the activity of SphK1-SIP axis to protect brain tissue in cerebral ischemia. In conclusion, this study facilitates our understanding of metabolic changes in ischemia stroke and the underlying mechanisms related to the clinical application of DSCXQ.

[Quality control of Dandeng Tongnao Ruanjiaonang based on UPLC fingerprint combined with chemical pattern recognition].

To establish the ultra performance liquid chromatography (UPLC) fingerprint of Dandeng Tongnao Ruanjiaonang and conduct a systemic, comprehensive quality evaluation of the drug by combining with a chemical pattern recognition method. In this study, Waters UPLC ultra-high performance liquid chromatography instrument and ACQUITY UPLCHSS T3 chromatographic colum n were employed to perform the separation with acetonitrile-0.1% formic acid aqueous solution as the mobile phase for gradient elution; and the detection wavelength was set at 256 nm to establish the UPLC fingerprint of 10 batches of Dandeng Tongnao Ruanjiaonang. Then, the further quality assessment of the drug was carried out by similarity evaluation, Cluster Analysis(CA), Principal Component Analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Finally, 77 peaks were recognised as common peaks in the fingerprint, and 15 peaks of them were identified using standard references. The similarity value of these 10 batches of drugs was all above 0.960, indicating a relatively stable quality. But minor differences were still discovered between the batches of the drug by CA and PCA. Finally, 6 common peaks were recognised as the quality makers using OPLS-DA method. The analysis method established in this study was scientific, accurate, reliable and simple; fingerprint combined with chemical pattern recognition technique can be used to systematically and comprehensively evaluate the drug quality of Dandeng Tongnao Ruanjiaonang; what's more, it could also provide a reference for the quality control of traditional Chinese medicine and its preparations at the same time.

Propofol inhibits cell proliferation and invasion in rheumatoid arthritis fibroblast-like synoviocytes via the nuclear factor-κB pathway.

Propofol is an anesthetic drug commonly used in the clinical practice. The aim of this study is to explore the effect of propofol on the aggressive behaviors of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). Propofol treatment for 48 or 72 h significantly inhibited the viability of RA-FLSs, but a 24-h treatment did not produce cytotoxic effects. Propofol exposure for 48 h led to reduction of proliferation and induction of apoptosis in RA-FLSs, which was coupled with increased Bax and decreased Bcl-2 and survivin levels. Additionally, treatment with propofol for 24 h significantly suppressed the migration and invasion of RA-FLSs. Mechanistically, propofol inhibited nuclear factor-κB (NF-κB) activity. Overexpression of constitutively active NF-κB p65 reversed the inhibitory effects of propofol on RA-FLSs. Taken together, propofol exerts anti-proliferative and anti-invasive effects on RA-FLSs via the NF-κB pathway and may have therapeutic potential in treatment of RA.

Acute caffeine ingestion reduces insulin sensitivity in healthy subjects: a systematic review and meta-analysis.

BACKGROUND: According to previous meta-analyses, coffee consumption reduces the risk of type 2 diabetes mellitus. However, the underlying mechanism remains unknown. Whether caffeine, the key ingredient in coffee, has a beneficial effect on the glycemic homeostasis and the anti-diabetic effect is particularly controversial. The aim of this study was to summarize the effect of acute caffeine ingestion on insulin sensitivity in healthy men. METHODS: A comprehensive literature search for papers published before April 2016 was conducted in EMBASE, PubMed, and Cochrane Library databases. Randomized controlled trials (RCTs) that investigated the effect of caffeine on insulin sensitivity in healthy humans without diabetes were included. A random effects meta-analysis was conducted using Review Manager 5.3. RESULTS: The search yielded 7 RCTs in which caffeine intake was the single variant. Compared with placebo, caffeine intake significantly decreased the insulin sensitivity index, with a standardized mean difference of -2.06 (95% confidence interval -2.67 to -1.44, I2 = 49%, P for heterogeneity = 0.06). CONCLUSION: Acute caffeine ingestion reduces insulin sensitivity in healthy subjects. Thus, in the short term, caffeine might shift glycemic homeostasis toward hyperglycemia. Long-term trials investigating the role of caffeine in the anti-diabetic effect of coffee are needed.

Emodin Attenuates Cigarette Smoke Induced Lung Injury in a Mouse Model via Suppression of Reactive Oxygen Species Production.

Emodin has antioxidative activities. Here, we investigated the effects of emodin on cigarette smoke (CS)-induced acute lung inflammation. Mice (C57BL/6) were exposed to CS. Emodin was administrated with intraperitoneal bolus injection of emodin (20 or 40 mg/kg) daily 1 h before CS exposure. Emodin inhibited CS-induced inflammatory cells infiltration in mouse lungs, especially at 40 mg/kg. Moreover, emodin resulted in significant reductions in total bronchoalveolar lavage fluid (BALF) cells, as compared with air exposure control, coupled with decreases in BALF cytokines. The activities of superoxide dismutase, catalase, and glutathione peroxidase were remarkably enhanced by emodin in CS-exposed mice. Emodin enhanced CS-induced expression of heme oxygenase-1 and nuclear factor-erythroid 2-related factor-2 (both are antioxidative genes) at both mRNA and protein levels, and profoundly promoted their activities in CS-treated mice. Collectively, our results suggested that emodin protects mouse lung from CS-induced lung inflammation and oxidative damage, most likely through its antioxidant activity.

Crisis-like behavior in China's stock market and its interpretation.

In order for China to play a bigger, more positive role in the world, it is important for China to have a healthy capital market. This perception motivates us to examine the health of China's capital market, especially the severity of the overall loss of the listed companies in China and the effects of accounting irregularities on the losses. We show the overall loss of the listed companies was very severe, in particular, crisis-like behavior emerged in the fourth quarter of 2002, 2004, 2005, and 2008. We further observe that loss in the fourth quarter was much greater than the average loss of the first three quarters in the same year. The most straightforward interpretation of this loss pattern is that companies underreported losses in the first three quarters, to boost their stock values in most time of the year. However, in the fourth quarter, accounting balance of the whole year dictated that the reported loss in the fourth quarter had to be much greater than the actual loss. Fortunately, such irregularity has been greatly reduced, thanks to the accounting reforms in China in 2007.