Combination of stem cells and nerve guide conduit for the treatment of peripheral nerve injury: A meta-analysis.

INTRODUCTION/AIMS: Many small-sized, single-center preclinical studies have investigated the benefits of introducing stem cells into the interior of nerve conduit. The aims of this meta-analysis are to review and contrast the effects of various types of stem cells in in vivo models used to reconstruct peripheral nerve injuries (PNIs) and to assess the reliability and stability of the available evidence. METHODS: A systematic search was conducted using Cochrane Library, Embase, PubMed, and Web of Science to identify studies conducted from January 1, 2000, to September 21, 2022, and investigate stem cell therapy in peripheral nerve reconstruction animal models. Studies that met the relevant criteria were deemed eligible for this meta-analysis. RESULTS: Fifty-five preclinical studies with a total of 1234 animals were incorporated. Stem cells demonstrated a positive impact on peripheral nerve regeneration at different follow-up times in the forest plots of five outcome indicators: compound muscle action potential (CMAP) amplitude, latency, muscle mass ratio, nerve conduction velocity, and sciatic functional index (SFI). In most comparisons, stem cell groups showed substantial differences compared with the control groups. The superior performance of adipose-derived stem cells (ADSCs) in terms of SFI, CMAP amplitude, and latency (p < .001) was identified. DISCUSSION: The findings consistently demonstrated a favorable outcome in the reconstruction process when utilizing different groups of stem cells, as opposed to control groups where stem cells were not employed.

A quadratic isothermal amplification fluorescent biosensor without intermediate purification for ultrasensitive detection of circulating tumor DNA.

Circulating tumor DNA (ctDNA) is an auspicious tumor biomarker released into the bloodstream by tumor cells, offering abundant information concerning cancer genes. It plays a crucial role in the early diagnosis of cancer. However, due to extremely low levels in body fluids, achieving a simple, sensitive, and highly specific detection of ctDNA remains challenging. Here, we constructed a purification-free fluorescence biosensor based on quadratic amplification of ctDNA by combining nicking enzyme mediated amplification (NEMA) and catalytic hairpin assembly (CHA) reactions. After double isothermal amplification, this biosensor achieved an impressive signal amplification of nearly 107-fold, enabling it to detect ctDNA with ultra-sensitivity. And the detection limit of this biosensor is as low as 2 aM. In addition, we explored the influence of human serum on the performance of the biosensor and found that it showed favorable sensitivity in the presence of serum. This biosensor eliminates the need for an intermediate purification step, resulting in enhanced sensitivity and convenience. Thus, our purification-free fluorescent biosensor exhibits ultra-high sensitivity when compared to other biosensors and has the potential to serve as an effective diagnostic tool for early detection of cancer.

A Novel Curcumin-Loaded Nanoplatform Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the degradation of articular cartilage. Recent studies have demonstrated that chondrocyte ferroptosis plays a crucial role in the progression of OA. Consequently, developing nanomedicines that suppress chondrocyte ferroptosis is a promising strategy for OA treatment. However, there are few reports on nanomedicines specifically targeting chondrocyte ferroptosis for OA therapy. In this study, Curcumin-loaded nanoparticles (Cur-NPs) are fabricated to suppress chondrocyte ferroptosis by regulating reactive oxygen species (ROS), ferrous ion (Fe2⁺), and Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) levels of chondrocyte. This is achieved by combining the functions of curcumin and an amphiphilic block copolymer with ROS scavenging and iron-chelating properties. The in vitro anti-ferroptotic effects of Cur-NPs are thoroughly investigated. The findings indicate that Cur-NPs decrease the expression of ferroptosis markers such as ROS, Fe2⁺, and ACSL4, while protecting the mitochondrial membrane potential of chondrocytes. Additionally, Cur-NPs attenuated lipid peroxidation in chondrocytes. Furthermore, Cur-NPs significantly reduced the expression of the catabolic factor Matrix Metallopeptidase 13 (MMP13) and increased the expression of the anabolic factor Collagen type II (Col II) in vitro. This study demonstrates that Cur-NPs exhibit enhanced chondroprotective effects through anti-ferroptotic actions, presenting a promising approach for inhibiting chondrocyte ferroptosis using bioactive nanomaterials in OA treatment.

Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway.

Heart failure with preserved ejection fraction (HFpEF) is closely associated with metabolic derangement. Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) exert anti-HFpEF effects, but the underlying mechanisms remain unclear. In this study, we explored the anti-HFpEF effects of empagliflozin and liraglutide and the underlying molecular mechanisms in a mouse model of HFpEF. This model was established by high-fat diet (HFD) feeding plus Nω-nitro-L-arginine methyl ester (L-NAME) treatment. The mice were treated with empagliflozin (20 mg·kg-1·d-1, i.g.) or liraglutide (0.3 mg·kg-1·d-1, i.p.) or their combination for 4 weeks. At the end of the experimental protocol, cardiac function was measured using ultrasound, then mice were euthanized and heart, liver, and kidney tissues were collected. Nuclei were isolated from frozen mouse ventricular tissue for single-nucleus RNA-sequencing (snRNA-seq). We showed that administration of empagliflozin or liraglutide alone or in combination significantly improved diastolic function, ameliorated cardiomyocyte hypertrophy and cardiac fibrosis, as well as exercise tolerance but no synergism was observed in the combination group. Furthermore, empagliflozin and/or liraglutide lowered body weight, improved glucose metabolism, lowered blood pressure, and improved liver and kidney function. After the withdrawal of empagliflozin or liraglutide for 1 week, these beneficial effects tended to diminish. The snRNA-seq analysis revealed a subcluster of myocytes, in which Erbb4 expression was down-regulated under HFpEF conditions, and restored by empagliflozin or liraglutide. Pseudo-time trajectory analysis and cell-to-cell communication studies confirmed that the Erbb4 pathway was a prominent pathway essential for both drug actions. In the HFpEF mouse model, both empagliflozin and liraglutide reversed Erbb4 down-regulation. In rat h9c2 cells, we showed that palmitic acid- or high glucose-induced changes in PKCα and/or ERK1/2 phosphorylation at least in part through Erbb4. Collectively, the single-cell atlas reveals the anti-HFpEF mechanism of empagliflozin and liraglutide, suggesting that Erbb4 pathway represents a new therapeutic target for HFpEF. Effects and mechanisms of action of empagliflozin and liraglutide in HFpEF mice. HFpEF was induced with a high-fat diet and L-NAME for 15 weeks, and treatment with empagliflozin and liraglutide improved the HFpEF phenotype. Single nucleus RNA sequencing (snRNA-seq) was used to reveal the underlying mechanism of action of empagliflozin and liraglutide.

A novel mouse model of familial combined hyperlipidemia and atherosclerosis.

Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg-1·d-1) and fenofibrate (100 mg·kg-1·d-1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia.

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.

The Exploratory Study of the PTEN-AKT/mTOR Signaling Pathway in the Corresponding Dorsal Root Ganglion during Compensatory Repair via Small Gap Amplification in Sciatic Nerve Injury.

BACKGROUND: Peripheral nerve injury is a challenging orthopedic issue in clinical management that often leads to limb dysfunction or even disability in severe cases. A thorough exploration of the repair process of peripheral nerve injury and the underlying mechanism contributes to formulate more effective therapeutic strategies. METHODS: In the present study, we established a sciatic nerve transection injury model in Sprague-Dawley (SD) rats. A 12-week compensatory repair of sciatic nerve transection injury using a chitin cannula for small gap anastomosis was then performed via sleeve jointing the proximal common peroneal nerve to the distal tibial nerve and common peroneal nerve, with a 2 mm interval. Compensatory repair via small gap amplification was observed via gross observation of nerve specimen, osmic acid staining, and electrophysiological stimulation of sciatic nerve branches of the tibial and common peroneal nerve. Rat limbs were observed, and the functional recovery of effector muscles of the gastrocnemius and tibialis anterior muscles was assessed through weighing the muscle wet weight, Hematoxylin and Eosin (H&E) staining, and muscle strength detection. H&E staining, Masson staining, and toluidine blue staining were performed to observe the morphological changes of the dorsal root ganglion. Positive expressions of key proteins involved in the Phosphatase and tensin homologue deleted on chromosome ten (PTEN)-protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, including PTEN, AKT, mTOR, Toll-like receptor 4 (TLR4), and Caspase9 in the dorsal root ganglion during compensatory repair of sciatic nerve after injury via small gap amplification, were detected by immunohistochemical staining. RESULTS: It is found that the compensatory repair of sciatic nerve transection injury using a chitin cannula for small gap anastomosis via sleeve jointing effectively restored the continuity, number of myelinated nerve fibers, and nerve conduction velocity. It promoted toe abduction recovery, improved muscle fiber morphology and increased the wet weight and muscle strength of the gastrocnemius muscle and tibialis anterior muscle. Moreover, it increased the number of neurons and nerve fibers, and improved their morphology. Downregulated PTEN, TLR4, and Caspase9 in the dorsal root ganglia and upregulated AKT and mTOR were observed after small gap amplification than those of the transection injury group, which were closer to those of the control group. CONCLUSIONS: Compensatory repair of sciatic nerve transection injury using a chitin cannula for small gap anastomosis via sleeve jointing can restore the morphology and function of the sciatic nerve, effector muscles, and corresponding dorsal root ganglia by activating the PTEN-AKT/mTOR signaling pathway in the dorsal root ganglia. Our findings provide novel therapeutic targets for peripheral nerve injuries.

Unruptured brain arteriovenous malformations causing seizures localize to one common brain network.

Seizures are a frequent symptom of unruptured brain arteriovenous malformations (bAVMs). However, the brain regions responsible for these seizures remain unclear. To identify the brain regions causally involved in bAVM-related seizures, we retrospectively reviewed 220 patients with unruptured bAVMs. Using voxel-based lesion-symptom mapping (VLSM) analyses, we tested whether individual brain regions were associated with unruptured bAVM-related seizures. The result revealed that unruptured bAVMs causing seizures are anatomically heterogeneous at the voxel level. Subsequently, lesion network mapping (LNM) analyses was performed to determine whether bAVMs causing seizures belonged to a distributed brain network. LNM analyses indicated that these lesions were located in a functional network characterized by connectivity to the left caudate and precuneus. Moreover, the discrimination performance of the identified seizure network was evaluated in discovery set by calculating the individualized network damage score and was tested in validation set. Based on the calculated network damage scores, patients were divided into low-, medium-, and high-risk groups. The prevalence of seizures significantly differed among the three risk categories in both discovery (p = .003) and validation set (p = .004). Finally, we calculated the percentage of voxels in the canonical resting-state networks that overlapped with the seizure-susceptible brain regions to investigate the involvement of resting-state networks. With an involvement percentage over 50%, the frontoparietal control (82.9%), limbic function (76.7%), and default mode network (69.3%) were considered to be impacted in bAVM-related seizures. Our study identified the seizure-susceptible brain regions for unruptured bAVMs, which could be a plausible neuroimaging biomarker in predicting possible seizures.

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies.

The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury. Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.

Patient characteristics and procedural variables are associated with length of stay and hospital cost among unilateral primary total hip arthroplasty patients: a single-center retrospective cohort study.

BACKGROUND: Total hip arthroplasty (THA) is a successful treatment for many hip diseases. Length of stay (LOS) and hospital cost are crucial parameters to quantify the medical efficacy and quality of unilateral primary THA patients. Clinical variables associated with LOS and hospital costs haven't been investigated thoroughly. METHODS: The present study retrospectively explored the contributors of LOS and hospital costs among a total of 452 unilateral primary THA patients from January 2019 to January 2020. All patients received conventional in-house rehabilitation services within our institute prior to discharge. Outcome parameters included LOS and hospital cost while clinical variables included patient characteristics and procedural variables. Multivariable linear regression analysis was performed to assess the association between outcome parameters and clinical variables by controlling confounding factors. Moreover, we analyzed patients in two groups according to their diagnosis with femur neck fracture (FNF) (confine THA) or non-FNF (elective THA) separately. RESULTS: Among all 452 eligible participants (266 females and 186 males; age 57.05 ± 15.99 year-old), 145 (32.08%) patients diagnosed with FNF and 307 (67.92%) diagnosed with non-FNF were analyzed separately. Multivariable linear regression analysis revealed that clinical variables including surgery duration, transfusion, and comorbidity (stroke) among the elective THA patients while the approach and comorbidities (stoke, diabetes mellitus, coronary heart disease) among the confine THA patients were associated with a prolonged LOS (P < 0.05). Variables including the American Society of Anesthesiologists classification (ASA), duration, blood loss, and transfusion among the elective THA while the approach, duration, blood loss, transfusion, catheter, and comorbidities (stoke and coronary heart disease) among the confine THA were associated with higher hospital cost (P < 0.05). The results revealed that variables were associated with LOS and hospital cost at different degrees among both elective and confine THA. CONCLUSIONS: Specific clinical variables of the patient characteristics and procedural variables are associated the LOS and hospital cost, which may be different between the elective and confine THA patients. The findings may indicate that evaluation and identification of detailed perioperative factors are beneficial in managing perioperative preparation, adjusting patients' anticipation, decreasing LOS, and reducing hospital cost.

Osteoarthritis: Role of Peroxisome Proliferator-Activated Receptors.

Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates the prevalence of OA, thereby imposing an immense annual economic burden on societies worldwide. The current therapeutic landscape falls short in offering reliable pharmaceutical interventions and efficient treatment methodologies to tackle this growing problem. However, the scientific community continues to dedicate significant efforts towards advancing OA treatment research. Contemporary studies have discovered that the progression of OA may be slowed through the strategic influence on peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated receptors within the nuclear hormone receptor family. The three distinctive subtypes-PPARα, PPARß/δ, and PPARγ-find expression across a broad range of cellular terminals, thus managing a multitude of intracellular metabolic operations. The activation of PPARγ and PPARα has been shown to efficaciously modulate the NF-κB signaling pathway, AP-1, and other oxidative stress-responsive signaling conduits, leading to the inhibition of inflammatory responses. Furthermore, the activation of PPARγ and PPARα may confer protection to chondrocytes by exerting control over its autophagic behavior. In summation, both PPARγ and PPARα have emerged as promising potential targets for the development of effective OA treatments.

Synthesis of Low-Cost and High-Performance Dual-Atom Doped Carbon-Based Materials with a Simple Green Route as Anodes for Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) are promising alternatives to replace lithium-ion batteries as future energy storage batteries because of their abundant sodium resources, low cost, and high charging efficiency. In order to match the high energy capacity and density, designing an atomically doped carbonous material as the anode is presently one of the important strategies to commercialize SIBs. In this work, we report the preparation of high-performance dual-atom-doped carbon (C) materials using low-cost corn starch and thiourea (CH4N2S) as the precursors. The electronegativity and radii of the doped atoms and C are different, which can vary the embedding properties of sodium ions (Na+) into/on C. As sulfur (S) can effectively expand the layer spacing, it provides more channels for embedding and de-embedding Na+. The synergistic effect of N and S co-doping can remarkably boost the performance of SIBs. The capacity is preserved at 400 mAh g -1 after 200 cycles at 500 mA g-1; more notably, the initial Coulombic efficiency is 81%. Even at a high rate of high current of 10 A g-1, the cell capacity can still reach 170 mAh g-1. More importantly, after 3000 cycles at 1 A g-1, the capacity decay is less than 0.003% per cycle, which demonstrates its excellent electrochemical performance. These results indicate that high-performance carbon materials can be prepared using low-cost corn starch and thiourea.

Thymic epithelial tumors: examining the GTF2I mutation and developing a novel prognostic signature with LncRNA pairs to predict tumor recurrence.

BACKGROUND: General transcription factor IIi (GTF2I) mutations are very common in thymic epithelial tumors (TETs) and are related to a more favorable prognosis in TET patients. However, limited research has been conducted on the role of GTF2I in the tumor immune microenvironment (TIME). Further, long non-coding RNAs (lncRNAs) have been associated with the survival of patients with TETs. Therefore, this study aimed to explore the relationship between GTF2I mutations and TIME and build a new potential signature for predicting tumor recurrence in the TETs. Research data was downloaded from The Cancer Genome Atlas database and the CIBERSORT algorithm was used to evaluate TIME differences between GTF2I mutant and wild-type TETs. Relevant differentially expressed lncRNAs based on differentially expressed immune-related genes were identified to establish lncRNA pairs. We constructed a signature using univariate and multivariate Cox regression analyses. RESULTS: GTF2I is the most commonly mutated gene in TETs, and is associated with an increased number of early-stage pathological types, as well as no history of myasthenia gravis or radiotherapy treatment. In the GTF2I wild-type group, immune score and immune cell infiltrations with M2 macrophages, activated mast cells, neutrophils, plasma, T helper follicular cells, and activated memory CD4 T cells were higher than the GTF2I mutant group. A risk model was built using five lncRNA pairs, and the 1-, 3-, and 5-year area under the curves were 0.782, 0.873, and 0.895, respectively. A higher risk score was related to more advanced histologic type. CONCLUSION: We can define the GTF2I mutant-type TET as an immune stable type and the GTF2I wild-type as an immune stressed type. A signature based on lncRNA pairs was also constructed to effectively predict tumor recurrence.

Advances in the research of osteosarcoma stem cells and its related genes.

Osteosarcoma is a malignant tumor that often occurs in adolescents. There is an urgent need for new treatment options for osteosarcoma due to its poor prognosis after metastasis. Cancer stem cell (CSC) theory states that CSCs represent a small proportion of cancer cells. These CSC have self-renewal ability and are closely associated with cancer growth and metastasis as well as chemotherapy resistance. Similarly, osteosarcoma stem cells (OSCs) play an important role in the growth, metastasis, and chemotherapy resistance of osteosarcoma cells. Targeting OSCs may represent a future treatment of osteosarcoma. Furthermore, some genes have been shown to regulate the growth, metastasis, and chemotherapy resistance of osteosarcoma cells by altering the stemness of OSCs. Targeting these genes may help in the treatment of osteosarcoma. This review mainly discusses recent advances in the research of OSCs and their related genes.

Therapeutic potential of colchicine in cardiovascular medicine: a pharmacological review.

Colchicine is an ancient herbal drug derived from Colchicum autumnale. It was first used to treat familial Mediterranean fever and gout. Based on its unique efficacy as an anti-inflammatory agent, colchicine has been used in the therapy of cardiovascular diseases including coronary artery disease, atherosclerosis, recurrent pericarditis, vascular restenosis, heart failure, and myocardial infarction. More recently, colchicine has also shown therapeutic efficacy in alleviating cardiovascular complications of COVID-19. COLCOT and LoDoCo2 are two milestone clinical trials that confirm the curative effect of long-term administration of colchicine in reducing the incidence of cardiovascular events in patients with coronary artery disease. There is growing interest in studying the anti-inflammatory mechanisms of colchicine. The anti-inflammatory action of colchicine is mediated mainly through inhibiting the assembly of microtubules. At the cellular level, colchicine inhibits the following: (1) endothelial cell dysfunction and inflammation; (2) smooth muscle cell proliferation and migration; (3) macrophage chemotaxis, migration, and adhesion; (4) platelet activation. At the molecular level, colchicine reduces proinflammatory cytokine release and inhibits NF-κB signaling and NLRP3 inflammasome activation. In this review, we summarize the current clinical trials with proven curative effect of colchicine in treating cardiovascular diseases. We also systematically discuss the mechanisms of colchicine action in cardiovascular therapeutics. Altogether, colchicine, a bioactive constituent from an ancient medicinal herb, exerts unique anti-inflammatory effects and prominent cardiovascular actions, and will charter a new page in cardiovascular medicine.

A Novel PIFA/KOH Promoted Approach to Synthesize C2-arylacylated Benzothiazoles as Potential Drug Scaffolds.

To discover an efficient and convenient method to synthesize C2-arylacylated benzothiazoles as potential drug scaffolds, a novel [bis(trifluoroacetoxy)iodo]benzene(PIFA)/KOH synergistically promoted direct ring-opening C2-arylacylation reaction of 2H-benzothiazoles with aryl methyl ketones has been developed. Various substrates were tolerated under optimized conditions affording the C2-arylacylation products in 70-95% yields for 38 examples. A plausible mechanism was also proposed based on a series of controlled experiments.

Design, Synthesis and Cytotoxicity of Thiazole-Based Stilbene Analogs as Novel DNA Topoisomerase IB Inhibitors.

A series of new thiazole-based stilbene analogs were designed, synthesized and evaluated for DNA topoisomerase IB (Top1) inhibitory activity. Top1-mediated relaxation assays showed that the synthesized compounds possessed variable Top1 inhibitory activity. Among them, (E)-2-(3-methylstyryl)-4-(4-fluorophenyl)thiazole (8) acted as a potent Top1 inhibitor with high Top1 inhibition of ++++ which is comparable to that of CPT. A possible binding mode of compound 8 with Top1-DNA complex was further provided by molecular docking. An MTT assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines revealed that the majority of these compounds showed high cytotoxicity, with IC50 values at micromolar concentrations. Compounds 8 and (E)-2-(4-tert-butylstyryl)-4-(4-fluorophenyl)thiazole (11) exhibited the most potent cytotoxicity with IC50 values of 0.78 and 0.62 µM against MCF-7 and HCT116, respectively. Moreover, the preliminary structure-activity relationships of thiazole-based stilbene analogs was also discussed.

Synthesis and Pesticidal Activity of New Niacinamide Derivatives Containing a Flexible, Chiral Chain.

Natural products are a source for pesticide or drug discovery. In order to discover lead compounds with high fungicidal or herbicidal activity, new niacinamide derivatives derived from the natural product niacinamide, containing chiral flexible chains, were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR and HRMS analysis. The fungicidal and herbicidal activities of these compounds were tested. The fungicidal activity results demonstrated that the compound (S)-2-(2-chloronicotinamido)propyl-2-methylbenzoate (3i) exhibited good fungicidal activity (92.3% inhibition) against the plant pathogen Botryosphaeria berengriana at 50 µg/mL and with an EC50 of 6.68 ± 0.72 µg/mL, which is the same as the positive control (fluxapyroxad). Compound 3i was not phytotoxic and could therefore be used as a fungicide on crops. Structure-activity relationships (SAR) were studied by molecular docking simulations with the succinate dehydrogenase of the fungal mitochondrial respiratory chain.

The prognostic value of MELD-XI in elderly patients with ST-segment elevation myocardial infarction: an observational study.

BACKGROUND: The model for end-stage liver disease excluding international normalized ratio (MELD-XI) is a simple score for risk assessment. However, the prognostic role of MELD-XI and its additional value to current risk assessment in elderly patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) is uncertain. METHODS: In all, 1029 elderly patients with STEMI undergoing PCI were consecutively included and classified into three groups according to the TIMI risk score: low-risk (≤ 3, n = 251); moderate-risk (4-6, n = 509); and high-risk (≥ 7, n = 269) groups. Multivariate analysis was performed to identify risk factors for adverse events. RESULTS: The overall in-hospital mortality was 5.3% and was significantly higher in the high-risk group (1.2% vs. 3.3% vs. 13.0%, p < 0.001). The optimal cut-off of the TIMI risk score and MELD-XI for in-hospital death was 7 and 13, respectively. MELD-XI was associated with in-hospital (adjusted odds ratio = 1.09, 95% CI = 1.04-1.14, p = 0.001) and one-year (adjusted hazard ratio = 1.05, 95% CI = 1.01-1.08, p = 0.005) mortality independently of the TIMI risk score. Combining TIMI risk score and MELD-XI exhibited better predictive power for in-hospital death than TIMI risk score (area under the curve [AUC] = 0.810 vs. 0.753, p = 0.008) or MELD-XI alone (AUC = 0.810 vs. 0.750, p = 0.018). Patients with TIMI risk score ≥ 7 and MELD-XI ≥ 13 had the worst prognosis. CONCLUSION: MELD-XI could be considered as a risk-stratified tool for elderly patients with STEMI undergoing PCI. It had an additive prognostic value to TIMI risk score.

The clinical, radiological, and immunohistochemical characteristics and outcomes of primary intracranial gliosarcoma: a retrospective single-centre study.

Primary intracranial gliosarcoma is a rare malignant brain tumour, and the most effective treatment for gliosarcoma remains unclear. This study aimed to identify risk factors for progression-free survival (PFS) and overall survival (OS) in these cases. This retrospective single-centre study evaluated 103 patients (median age, 51 years; 67 men [65%]) with primary intracranial gliosarcoma between 2006 and 2017. Treatments included surgery (GTR, 63 patients; STR, 39 patients; biopsy, 1 patient), radiotherapy (adjuvant, 76 patients; exclusive treatment, 1 patient), and chemotherapy (adjuvant temozolomide, 52 patients; adjuvant nimustine/teniposide, 19 patients; adjuvant bevacizumab, 1 patient; exclusive nimustine/teniposide treatment, 1 patient). The median OS was 13.3 months, and the median PFS was 9.1 months. In the multivariate analyses, the poor prognostic factors were ependymal lining enhancement of the lateral ventricle (PFS, HR 2.406, p = 0.005; OS, HR 2.946, p = 0.009) and enhancement in the motor functional cortex (PFS, HR 2.892, p = 0.002; OS, HR 2.639, p = 0.009). Good OS was predicted by adjuvant radiotherapy alone (HR 0.071, p < 0.001), adjuvant temozolomide-based chemotherapy alone (HR 0.063, p = 0.005), adjuvant temozolomide-based chemotherapy with concurrent radiotherapy (HR 0.056, p < 0.001), and salvage surgery at recurrence (HR 0.449, p = 0.031). The present study revealed that, in patients with primary intracranial gliosarcoma, enhancement in the functional motor cortex and ependymal lining enhancement of the lateral ventricle were both poor prognostic factors. Survival was optimized in cases treated using maximal safe resection followed by adjuvant temozolomide-based chemotherapy with concurrent radiotherapy. Furthermore, salvage surgery provided meaningful therapeutic benefits for recurrent gliosarcoma.