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Acute myocardial infarction (AMI) remains a dominant origin of morbidity, mortality and disability worldwide. Increases in reactive oxygen species (ROS) are key contributor to excessive cardiac injury after AMI. Here we developed an immobilized enzyme with Superoxide Dismutase (SOD) activity cross-link with Zr-based metal-organic framework (ZrMOF) (SOD-ZrMOF) for mitigate ROS-caused injury. In vitro and in vivo evidence indicates that SOD-ZrMOF exhibits excellent biocompatibility. By efficiently scavenging ROS and suppressing oxidative stress, SOD-ZrMOF can protect the function of mitochondria, reduce cell death and alleviate inflammation. More excitingly, long-term study using an animal model of AMI demonstrated that SOD-ZrMOF can reduce the infarct area, protect cardiac function, promote angiogenesis and inhibit pathological myocardial remodeling. Therefore, SOD-ZrMOF holds great potential as an efficacious and safe nanomaterial treatment for AMI., Graphical abstract Image 1, Highlights • We synthesized a superoxide dismutase immobilized nanocomposite with enhanced stability. • We tested the biocompatibility of SOD-ZrMOF and found it could promote the cell viability and proliferation of H9c2 cells. • SOD-ZrMOF shows excellent performance in protecting mitochondrial function of CMs by eliminating excessive ROS under hypoxia. • SOD-ZrMOF exhibited therapeutic effects on MI heart through inhibiting oxidative stress injury by NF-κB/HIF-1α pathway.

Supplemental material, sj-docx-1-imj-10.1177_10815589221150644 for Predictors of adverse outcomes in aged patients critically ill with COVID-19: a retrospective study by Matthew Rockstrom, Eric Balaban, Shoaib Fakhri, Ryan A Peterson, Ying Jin, Sarah E Jolley, Kristine M Erlandson and Joseph A Hippensteel in Journal of Investigative Medicine

Amorphous solid dispersions (ASD) are one of most commonly used supersaturating drug delivery systems (SDDS) to formulate insoluble active pharmaceutical ingredients. However, the development of polymer-guided stabilization of ASD systems faces many obstacles. To overcome these shortcomings, co-amorphous supersaturable formulations have emerged as an alternative formulation strategy for poorly soluble compounds. Noteworthily, current researches around co-amorphous system (CAS) are mostly focused on preparation and characterization of these systems, but more detailed investigations of their supersaturation (“spring-parachute“ process), stability, in vivo bioavailability and molecular mechanisms are inadequate and need to be clarified. In present study, we chose pharmacological relevant BCS II drugs to fabricate and characterize “felodipine-indomethacin” CAS. To enrich the current inadequate but key knowledge on CAS studies, we carried out following highlighted investigations including dissolution/solubility, semi-continuous “spring-parachute” process, long-term stability profile of amorphous state, in vivo bioavailability and underlying molecular mechanisms (molecular interaction, molecular miscibility and crystallization inhibition). Generally, the research provides some key information in the field of current “drug-drug” CAS supersaturable formulations.

Context A personalized antiplatelet therapy guided by a novel platelet function testing (PFT), PL-12, is considered an optimized treatment strategy in stable coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). However, the safety and efficacy of any dual-antiplatelet therapy (DAPT) strategy may differ in relation to diabetes status. Objective The aim of this study was to compare the outcomes of PFT-guided personalized DAPT in stable CAD patients with and without diabetes mellitus. Methods The PATH-PCI trial randomly assigned 2285 stable CAD patients to either personalized antiplatelet therapy or standard antiplatelet treatment. We investigated the association and interaction of diabetes on clinical outcomes across 2 treatment groups. Results We did not find a significant difference between the personalized group and the standard group in net adverse clinical events in either diabetes patients (10.3% vs 13.4%, P = .224) or in the nondiabetic group (3.1% vs 5.0%, P = .064). In diabetes patients (n = 646, 28.3%), the overall ischemic event rates were significantly low (6.8% vs 11.3%, HR = 0.586, 95% CI, 0.344-0.999, P = .049) and the bleeding event rates did not differ between the 2 groups (3.5% vs 3.3%, HR = 1.066, 95% CI, 0.462-2.458, P = .882). Similarly, in nondiabetic patients, the overall ischemic event rates were significantly low (1.8% vs 4.2%, HR = 0.428, 95% CI, 0.233-0.758, P = .006) and the bleeding event rates did not differ between the 2 groups (1.6% vs 0.9%, HR = 1.802, 95% CI: 0.719-4.516, P = .209). Conclusion The present study suggests that personalized antiplatelet therapy according to PFT can reduce ischemic events but not increase bleedings in stable CAD patients with or without diabetes who have undergone PCI.

Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation underwent various physicochemical characterization experiments, an in vitro release study, molecular simulations and was evaluated for in vitro anti-inflammatory activity. Results: Results showed that Nio-Curc had a mean particle size of 284.93 ± 14.27 nm, zeta potential of -46.93 and encapsulation efficacy of 99.62%, which demonstrates optimized physicochemical characteristics. Curcumin release in vitro could be sustained for up to 24 h. Additionally, Nio-Curc effectively reduced mRNA transcript expression of pro-inflammatory markers; IL-6, IL-8, IL-1β and TNF-α in immortalized human airway basal cell line (BCi-NS1.1). Conclusion: In this study, we have demonstrated that Nio-Curc mitigated the mRNA expression of pro-inflammatory markers in an in vitro study, which could be applied to treatment of asthma with further studies.

Circulating exosomes delivering microRNAs are involved in the occurrence and development of cardiovascular diseases. How are the circulating exosomes involved in the repair of endothelial injury in acute myocardial infarction (AMI) convalescence (3‐7 days) was still not clear. In this study, circulating exosomes from AMI patients (AMI‐Exo) and healthy controls (Normal‐Exo) were extracted. In vitro and in vivo, our study showed that circulating exosomes protected endothelial cells (HUVECs) from oxidative stress damage; meanwhile, Normal‐Exo showed better protective effects. Through the application of related inhibitors, we found that circulating exosomes shuttled between HUVECs via dynamin. Microarry analysis and qRT‐PCR of circulating exosomes showed higher expression of miR‐193a‐5p in Normal‐Exo. Our study showed that miR‐193a‐5p was the key factor on protecting endothelial cells in vitro and in vivo. Bioinformatics analyses found that activin A receptor type I (ACVR1) was the potential downstream target of miR‐193a‐5p, which was confirmed by ACVR1 expression and dual‐luciferase report. Inhibitor of ACVR1 showed similar protective effects as miR‐193a‐5p. While overexpression of ACVR1 could attenuate protective effects of miR‐193a‐5p. To sum up, these findings suggest that circulating exosomes could shuttle between cells through dynamin and deliver miR‐193a‐5p to protect endothelial cells from oxidative stress damage via ACVR1.

IgE-mediated activation of Nhe1 (Na + -H + exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)–induced AAA in Nhe1-insufficient Apoe −/− Nhe1 +/− mice and Apoe −/− Nhe1 +/+ littermates tested Nhe1 activity in experimental AAA, because Nhe1 −/− mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from Apoe −/− Nhe1 +/+ mice, such acidic areas were much smaller in lesions from Apoe −/− Nhe1 +/− mice. Nhe1-FcεR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.

Radiation enteritis is a common side effect of radiotherapy for abdominal and pelvic malignancies, which can lead to a decrease in patients’ tolerance to radiotherapy and the quality of life. It has been demonstrated that glycyrrhizin (GL) possesses significant anti-inflammatory activity. However, little is known about its anti-inflammatory effect in radiation enteritis. In the present study, we aimed to investigate the potential anti-inflammatory effects of GL on radiation enteritis and elucidate the possible underlying molecular mechanisms involved. The C57BL/6 mice were subjected to 6.5 Gy abdominal X-ray irradiation to establish a model of radiation enteritis. Hematoxylin and eosin staining was performed to analyze the pathological changes in the jejunum. The expression of TNF-α in the jejunum was analyzed by immunochemistry. The levels of inflammatory cytokines, such as TNF-α, IL-6, IL-1β, and HMGB1 in the serum were determined by enzyme-linked immunosorbent assay. The intestinal absorption capacity was tested using the D-xylose absorption assay. The levels of HMGB1 and TLR4 were analyzed by western blotting and immunofluorescence staining. We found that GL significantly alleviated the intestinal damage and reduced the levels of inflammatory cytokines, such as TNF-α, IL-6, IL-1β, and HMGB1 levels. Furthermore, the HMGB1/TLR4 signaling pathway was significantly downregulated by GL treatment. In conclusion, these findings indicate that GL has a protective effect against radiation enteritis through the inhibition of the intestinal damage and the inflammatory responses, as well as the HMGB1/TLR4 signaling pathway. Thereby, GL might be a potential therapeutic agent for the treatment of radiation enteritis.

To assess the safety and efficacy of local intra-gestational sac methotrexate injection followed by dilation and curettage (D&C) in treating cesarean scar pregnancies (CSP). Medical records of CSP patients treated with local intra-gestational sac methotrexate injection followed by dilation and curettage were analyzed at the Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, China. Thirty-one patients were included in this study. The mean gestational age, sac diameter and thickness of the uterine scar were 49.6 ± 7.7 days, 1.8 ± 0.6 cm and 0.30 ± 0.15 cm, respectively. The median pretreatment serum β-human chorionic gonadotropin (β-HCG) level was 40,887 mIU/mL, with the 25th and 75th percentiles at 19,852 and 74,552, respectively. The median blood loss during D&C was 20 mL with the 25th and 75th percentiles at 10 mL and 50 mL. Following D&C, a Foley’s balloon catheter compression was implanted in 26 (83.9%) patients due to active uterine bleeding. All patients had a β-HCG regression time of ≤ 4 weeks after D&C. While 30 patients (96.8%) had a uterine recovery time of ≤ 4 weeks, and 29 patients (93.5%) had resumption of menstruation of less than 6 weeks. Three patients (9.7%) had complications. One of them suffered from massive vaginal bleeding and underwent s blood transfusion. There were no other complications, such as pelvic infection and uterine rupture during the procedures. And no patient was converted to surgical resection or uterine artery embolization. Overall, 30 patients (96.8%) were treated successfully. Local intra-gestational sac methotrexate injection followed by D&C with the aid of a Foley’s balloon catheter compression appears to be a safe and effective treatment for CSP. Further randomized controlled trials are suggested to confirm these findings.

Lipopolysaccharide (LPS)-induced inflammation causes massive threatening diseases, such as sepsis, acute lung injury and multiple organ dysfunction syndrome. Efficient treatment to prevent inflammation is crucial in LPS-induced inflammatory diseases. Heat-clearing Chinese medicines (CMs) have been used to ameliorate LPS-induced inflammation in China for centuries. Heat-clearing CMs regulate inflammatory pathways, thereby inhibiting the release of inflammatory factors. This review aimed to introduce promising heat-clearing CMs countering LPS-induced inflammation in the last 5 years, exploring the underlying molecular mechanisms.

OBJECTIVES To determine whether gamma-glutamyl transferase (GGT) to albumin ratio (GAR) independently predicts mortality and bleeding events in coronary artery disease (CAD) patients who undergo percutaneous coronary intervention (PCI). BACKGROUND Serum GGT and albumin levels have been associated with CAD risk and mortality. However, more analysis is needed to determine their predictive relationship with adverse outcomes. METHODS In total, 5,638 patients from a large retrospective cohort study were enrolled from January 2008 to December 2016 and divided into two groups (GAR

OBJECTIVE The study mainly aimed to determine the bioequivalence of two branded ciprofloxacin hydrochloride tablets (250 mg) under fasting and fed conditions. MATERIALS AND METHODS The study was carried out in 48 healthy Chinese subjects under fasting and fed conditions with a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design. In each period of the study, the subjects were assigned to receive a single oral dose of 250 mg ciprofloxacin hydrochloride. Blood samples were collected from 1 hour before dosing to 36 hours after administration with 16 timepoints in total. The bioequivalence analysis was performed after ln-transformation of the ciprofloxacin pharmacokinetic parameters including Cmax, AUC0-t, and AUC0-∞. RESULTS A total of 48 subjects were enrolled in the fasting and fed studies, and 1 of the subjects was excluded before drug administration. In the fasting study, the 90% CIs for the test/reference geometric mean ratios (GMRs) of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 85.41 - 100.97%, 95.40 - 100.27%, and 95.48 - 100.30%, respectively. For the fed study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 90.15 - 113.75%, 99.10 - 103.77%, and 99.11 - 103.80%, respectively. These values all fell within the standard acceptance range of 80 - 125%. CONCLUSION In the study, the generic (test) product of ciprofloxacin hydrochloride 250 mg was bioequivalent to the innovator (reference) product after single-, oral-dose administration under fasting and fed conditions.

Background & aims Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance (IR), obesity and hyperlipidemia. Nonalcoholic steatohepatitis (NASH) is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor (OTU) domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases (DUBs), regulates many metabolism-associated signaling pathways. However, the role of OTUB1 in NASH is unclarified. Methods & results We demonstrated that mice with Otub1 deficiency exhibited aggravated high-fat diet (HFD)- and high-fat high-cholesterol (HFHC) diet-induced hyperinsulinemia and liver steatosis. Notably, hepatocyte-specific overexpression of Otub1 markedly alleviated HFHC diet-induced hepatic steatosis, inflammatory responses and liver fibrosis. Mechanistically, we identified apoptosis signal-regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA-seq analysis and immunoblot analysis. Through immunoprecipitation-mass spectrometry (IP-MS) analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppressed its lysine 63 (K63)-linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway. Conclusion OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6-mediated ASK1 activation. Targeting the OTUB1-TRAF6-ASK1 axis may be a promising novel therapeutic strategy for NASH.

The change in tissue stiffness caused by pathological changes in the tissue’s structure could be detected earlier, prior to the manifestation of their clinical features. Magnetic resonance elastography (MRE) is a noninvasive imaging technique that uses low-frequency vibrations to quantitatively measure the elasticity or stiffness of tissues. In tumor tissue, stiffness is directly related to tumor development, invasion, metastasis, and chemoradiotherapy resistance. It also dictates the choice of surgical method. At present, MRE is widely used in assessing different human organs, such as the liver, brain, breast, prostate, uterus, gallbladder, and colon stiffness. In the field of oncology, MRE’s value lies in tumor diagnosis (especially early diagnosis), selection of treatment method, and prognosis evaluation. This article summarizes the principle of MRE and its research and application progress in tumor diagnosis and treatment.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have well-documented effects on reducing hospitalization for heart failure and cardiovascular mortality, although the effect on atrial fibrillation (AF) has not been comprehensively investigated. Therefore, we performed a meta-analysis to assess the association between SGLT2 inhibitors and AF risk by systematically searching PubMed, Embase, and ClinicalTrials.gov. Two investigators independently identified randomized controlled trials, which compared SGLT2 inhibitors with control in patients with type 2 diabetes, heart failure, or chronic kidney disease. Primary outcomes were incident AF and stroke. We included 20 randomized trials involving 63,604 patients. The SGLT2 inhibitors used were dapagliflozin (7 studies, 28,834 patients), canagliflozin (7 studies, 17,440 patients), empagliflozin (5 studies, 9082 patients), and ertugliflozin (1 study, 8246 patients). Follow-up ranged from 24 weeks to 202 weeks. SGLT2 inhibitors treatment was associated with a significant attenuation in the risk of incident AF (odds ratio = 0.82; 95% confidence interval, 0.72-0.93; P = 0.002) compared with control. No significant difference in stroke between SGLT2 inhibitors and control groups was found (odds ratio = 0.99; 95% confidence interval, 0.85-1.15; P = 0.908). This present meta-analysis indicates that SGLT2 inhibitors are associated with a lower risk of incident AF and do not significantly affect stroke risk for patients with and without type 2 diabetes.

BackgroundThere have been reports of increasing azole resistance in Candida tropicalis, especially in the Asia-Pacific region. Here we report on the epidemiology and antifungal susceptibility of C. tropicalis causing invasive candidiasis in China, from a 9-year surveillance study.MethodsFrom August 2009 to July 2018, C. tropicalis isolates (n = 3702) were collected from 87 hospitals across China. Species identification was carried out by mass spectrometry or rDNA sequencing. Antifungal susceptibility was determined by Clinical and Laboratory Standards Institute disk diffusion (CHIF-NET10–14, n = 1510) or Sensititre YeastOne (CHIF-NET15–18, n = 2192) methods.ResultsOverall, 22.2% (823/3702) of the isolates were resistant to fluconazole, with 90.4% (744/823) being cross-resistant to voriconazole. In addition, 16.9 (370/2192) and 71.7% (1572/2192) of the isolates were of non-wild-type phenotype to itraconazole and posaconazole, respectively. Over the 9 years of surveillance, the fluconazole resistance rate continued to increase, rising from 5.7 (7/122) to 31.8% (236/741), while that for voriconazole was almost the same, rising from 5.7 (7/122) to 29.1% (216/741), with no significant statistical differences across the geographic regions. However, significant difference in fluconazole resistance rate was noted between isolates cultured from blood (27.2%, 489/1799) and those from non-blood (17.6%, 334/1903) specimens (P-value < 0.05), and amongst isolates collected from medical wards (28.1%, 312/1110) versus intensive care units (19.6%, 214/1092) and surgical wards (17.9%, 194/1086) (Bonferroni adjusted P-value < 0.05). Although echinocandin resistance remained low (0.8%, 18/2192) during the surveillance period, it was observed in most administrative regions, and one-third (6/18) of these isolates were simultaneously resistant to fluconazole.ConclusionThe continual decrease in the rate of azole susceptibility among C. tropicalis strains has become a nationwide challenge in China, and the emergence of multi-drug resistance could pose further threats. These phenomena call for effective efforts in future interventions.

Background It has been confirmed that the triglyceride to high-density lipoprotein cholesterol ratio (THR) is associated with insulin resistance and metabolic syndrome. However, to the best of our knowledge, only a few studies with small sample sizes have investigated the relationship between THR and coronary artery disease (CAD). Therefore, we aimed to assess the correlation between the THR and long-term mortality in patients with CAD after undergoing percutaneous coronary intervention (PCI) in our study that enrolled a large number of patients. Methods A total of 3269 post-PCI patients with CAD were enrolled in the CORFCHD-ZZ study from January 2013 to December 2017. The mean follow-up time was 37.59 ± 22.24 months. Patients were divided into two groups according to their THR value: the lower group (THR n = 1232) and the higher group (THR ≥ 2.84, n = 2037). The primary endpoint was long-term mortality, including all-cause mortality (ACM) and cardiac mortality (CM). The secondary endpoints were major adverse cardiac events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs). Results In our study, ACM occurred in 124 patients: 30 (2.4%) in the lower group and 94 (4.6%) in the higher group (P = 0.002). MACEs occurred in 362 patients: 111 (9.0%) in the lower group and 251 (12.3%) in the higher group (P = 0.003). The number of MACCEs was 482: 152 (12.3%) in the lower group and 320 (15.7%) in the higher group (P = 0.008). Heart failure occurred in 514 patients: 89 (7.2%) in the lower group and 425 (20.9%) in the higher group (P P = 0.044) and the occurrence of heart failure (log-rank, P P = 0.004) and heart failure (adjusted HR = 1.700 [1.347–2.147], P Conclusions An increased THR is an independent predictor of long-term ACM and heart failure in post-PCI patients with CAD.

Rampant use of tetracycline in animal feed is a threat to food security, the environment, and human health because of the risk of drug residues. Therefore, it is necessary to establish a sensitive, efficient, and reliable method for qualitative and quantitative detection of tetracycline. In this paper, we synthesized fluorescent carbon dots (FCDs) by thermal cracking of crab shell waste, and obtained a fluorescence quantum yield of 30%. Characterization of the FCDs by transmission electron microscopy, Fourier-transform infrared spectroscopy, ultraviolet visible absorption spectroscopy, and photoluminescence spectroscopy showed that they were fluorescent and evenly distributed with an average size of approximately 10 nm. We designed a sensitive probe for detecting tetracycline using the fluorescence intensity change of the FCDs. This method is sensitive, inexpensive, and environmentally friendly. The concentration of tetracycline was examined by comparing the fluorescence intensities of the FCDs before and after tetracycline addition. The limit of detection for tetracycline was 0.005 mg/L (signal-to-noise ratio = 3), which is promising for method development.

The mechanism of rabies virus (RABV) infection still needs to be further characterized. RABV particle with self-fluorescent is a powerful viral model to visualize the viral infection process in cells. Herein, based on a reverse genetic system of the Evelyn-Rokitnicki-Abelseth (rERA) strain, we generated a recombinant RABV rERA-N/mCherry strain that stably expresses an additional ERA nucleoprotein that fuses with the red fluorescent protein mCherry (N/mCherry). The rERA-N/mCherry strain retained growth property similar to the parent strain rERA in vitro. The N/mCherry expression showed genetic stability during passage into mouse neuroblastoma (NA) cells and did not change the virulence of the vector. The rERA-N/mCherry strain was then utilized as a visual viral model to study the RABV-cell binding and internalization. We directly observed the red self-fluorescence of rERA-N/mCherry particles binding to the cell surface, and further co-localizing with clathrin in the early stage of infection in NA cells by fluorescence microscopy. Our results showed that the rERA-N/mCherry strain uses clathrin-dependent endocytosis to enter cells, which is consistent with the well-known mechanism of RABV invasion. The recombinant RABV rERA-N/mCherry thus appears to have the potential to be an effective viral model to further explore the fundamental molecular mechanism of rabies neuropathogenesis.

Polysaccharide is a key bioactive component of Schisandra chinensis and has significant pharmacological activities. The aim of this study was to evaluate the anti-diabetic effect of acidic polysaccharide from Schisandra chinensis (SCAP). Type 2 diabetic (T2D) rats were developed by giving a high-fat diet (HFD) combined with low-dose streptozotocin (STZ), and administered orally with SCAP (25, 50 mg/kg) for 8 weeks. Fasting blood glucose (FBG), fasting insulin (FINS), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), malondialdehyde (MDA), and superoxide dismutase (SOD) in the rat's serum were measured. Oral glucose tolerance test (OGTT) and pathological changes of pancreas were observed. Furthermore, expressions of c-Jun N-terminal kinase (JNK), B-cell lymphoma 2-associated X protein (BAX), B-cell lymphoma 2 (Bcl-2), and Cleaved Caspase-3 in pancreatic islet were detected. The results showed that SCAP decreased FBG, TG, TC, LDL-C and MDA levels, increased insulin, HDL-C levels and SOD activity, improved the pathological changes in pancreatic islet. Furthermore, SCAP inhibited the up-regulation of phosphorylated JNK, BAX and Cleaved Caspase-3 proteins, and increased Bcl-2 protein expression. These data indicate that SCAP has a therapeutic effect in T2D rats, and the mechanism may be related to its protection against β-cells apoptosis by regulating apoptosis-related proteins expression to alleviate the injury caused by the oxidative stress.

Interleukin 33 (IL33) has been found to be cardioprotective on various cardiovascular pathologies. However, it is not clear whether IL33 may inhibit myocardial infarction-related ventricular remodeling through inducing macrophage polarization. The objective of present study is to assess whether IL33 can improve ventricular remodeling after myocardial infarction by inducing macrophage polarization. In this study, the direct influence of IL33 on the polarization of macrophages and its mechanism in vitro were investigated. The potential protective effects of IL33 on acute and chronic myocardial infarction (MI) in vivo as well as its underlying mechanism through macrophage polarization were also determined. We found that IL33 significantly enhanced M2 macrophage and decreased the proportion of M1 macrophage. Importantly, IL33 induced M2 macrophage polarization by activating the JAK/STAT signaling pathway. In vivo, IL33 weaken the inflammatory level and myocardial apoptosis after MI and improved the systolic and diastolic function of the heart. Furthermore, IL33 significantly reduced infarct area and prevented the progression of fibrosis by inducing M2 macrophage polarization. The protective effects of IL33 were suppressed by JAK/STAT signaling pathway inhibitor. Our findings highlighted that IL33 not only reduced the early inflammatory response and inhibited myocardial apoptosis, but also increased the number of M2 macrophage in the infarcted area, significantly reduced infarct area and prevented the progression of fibrosis by activating JAK/STAT pathway. Therefore, IL33 may be a novel cardiac protective cytokine for myocardial infarction.

Schisandra chinensis is a hepatoprotective herb that has been used for centuries in China. Polysaccharide is one of the major active components in S. chinensis, which has been reported to improve liver injuries induced by carbon tetrachloride, alcohol, or high-fat diet. In this study, we observed the effects and corresponding mechanisms of the secondary component of Schisandra polysaccharide (acidic polysaccharide, SCAP) on a murine model of severe acute liver injury induced by acetaminophen (APAP). SCAP significantly decreased the serum alanine aminotransferase (ALT), aspartate aminotransferas (AST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels, and was found to alleviate hepatic pathological alterations in the mouse model. Meanwhile, SCAP revealed a protective effects on the liver injury-related enzymes and factors, such as significantly diminished malondialdehyde (MDA) levels and glutathione (GSH) depletion, reduced ratio of B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax)/Bcl-2, prohibited cleaved caspase-3 expression, and elevated the expression of p-AMPK, p-Akt, p-glycogen synthase kinase 3β (GSK 3β), nuclear factor erythroid 2–derived-like 2 (Nrf 2) and heme oxygenase-1 (HO-1) proteins in the liver tissues of the mouse model. In conclusion, we speculated that the protective activities of SCAP on the APAP-induced mouse model of acute liver injury might be related to its antioxidation, anti-inflammation and anti-apoptosis properties. Keywords: Schisandra chinensis, Polysaccharide, Hepatoprotection, Antioxidation

Sodium (±)‐5‐bromo‐2‐(a‐hydroxypentyl) benzoate (generic name: brozopine, BZP) has been reported to protect against stroke‐induced brain injury and was approved for Phase II clinical trials for treatment of stroke‐related brain damage by the China Food and Drug Administration (CFDA). However, the role of BZP in cardiac diseases, especially in pressure overload‐induced cardiac hypertrophy and heart failure, remains to be investigated. In the present study, angiotensin II stimulation and transverse aortic constriction were employed to induce cardiomyocyte hypertrophy in vitro and in vivo, respectively, prior to the assessment of myocardial cell autophagy. We observed that BZP administration ameliorated cardiomyocyte hypertrophy and excessive autophagic activity. Further results indicated that AMP‐activated protein kinase (AMPK)‐mediated activation of the mammalian target of rapamycin (mTOR) pathway likely played a role in regulation of autophagy by BZP after Ang II stimulation. The activation of AMPK with metformin reversed the BZP‐induced suppression of autophagy. Finally, for the first time, we demonstrated that BZP could protect the heart from pressure overload‐induced hypertrophy and dysfunction, and this effect is associated with its inhibition of maladaptive cardiomyocyte autophagy through the AMPK‐mTOR signalling pathway. These findings indicated that BZP may serve as a promising compound for treatment of pressure overload‐induced cardiac remodelling and heart failure.

Aims/Introduction Diabetes is an important risk factor for atherosclerotic disease. The initiating factor of atherosclerosis is local endothelial cell injury. The arachidonic acid metabolite, 12(S)‐hydroxyeicosatetraenoic acid (12[S]‐HETE), might be involved in this process. In recent years, some studies have discussed the effect of 12(S)‐HETE on vascular endothelial cell function. In the present study, we investigated the effect of 12(S)‐HETE on vascular endothelial cell function in high‐glucose conditions and the mechanisms involved. Materials and Methods Human umbilical vein endothelial cells were cultured in conventional M199 medium and high‐glucose M199 medium. Human umbilical vein endothelial cells were stimulated with 12(S)‐HETE and cinnamyl‐3,4‐dihydroxy‐α‐cyanocinnamate (a 12/15‐lipoxygenases inhibitor). A type 1 diabetes mellitus model was established in C57BL/6 or 12/15‐lipoxygenases knockout mice with streptozotocin. Aortic tissue was harvested for subsequent testing. The transmembrane transport of dextran and human acute monocytic leukaemia cell line (THP‐1) cells was measured. The adherens junction protein, IkBα, nuclear factor kappa Bp65 (P65), intercellular adhesion molecule 1 and vascular cell adhesion protein 1 expression and phosphorylation, and the binding/dissociation of endothelial cell components were observed. Results Transendothelial migration of dextran and THP‐1 cells was significantly increased by stimulation of human umbilical vein endothelial cell monolayers with high glucose and 12(S)‐HETE (P

We assessed the effects of the sacubitril/valsartan combination drug (LCZ696), in comparison to valsartan alone, on the progression of atherosclerotic plaque formation and inflammatory gene expression in apolipoprotein E- deficient mice (apoE−/− mice). Seventy-two apoE−/− mice were fed a western diet and a constrictive silastic tube was used to elicit carotid lesion formation. The animals were separated into a control group, a valsartan group or an LCZ696 group (n = 24 in each group). Plaques in the carotid artery were harvested 12 weeks later for histological examination. The levels of pro-inflammatory genes in the plasma and lesions were detected using real-time PCR and ELISA. Valsartan or LCZ696 treatment remarkably inhibited the expression of pro-inflammatory genes, including interleukin-6, matrix metalloproteinase-8 and monocyte chemotactic protein-1, in comparison with the control group. Meanwhile, both valsartan and LCZ696 suppressed the formation of atherosclerotic plaques by decreasing plaque lipid content and cross-sectional plaque area and increasing the content of plaque collagen and fibrous cap thickness. In particular, LCZ696 performed the best in suppressing atherosclerosis and inhibiting the level of pro-inflammatory genes. LCZ696 significantly ameliorated atherosclerosis and inflammation in apoE−/− mice compared with valsartan.

Immune checkpoint blockade-based immunotherapy is a new modality of cancer treatment with a unique mechanism that has gained increased numbers of indication and is now used in several cancer types. However, immune-related adverse events (irAEs) emerge as a new entity of diseases involving one or multiple organ systems. irAEs could result in interruption of immunotherapy, morbidities or even death. Among various manifestations of irAEs, immune-mediated hypophysitis is rare but important, requiring prompt diagnosis and treatment to avoid life-threatening conditions. We report seven cases of immune-mediated hypophysitis in Taiwan. They suffered from various types of advanced cancer and received different regimens of immune checkpoint inhibitors. The time of onset after initiation of immunotherapy ranged from 5 to 36 weeks. All seven subjects were diagnosed of central adrenal insufficiency, while four of them had primary hypothyroidism. There was no typical finding of infiltrative hypophysitis on the pituitary MRI. There was no documented hormone recovery after diagnosis of hypophysitis, and the tumor responses to immunotherapy were variable in these seven patients. In conclusion, immune-mediated hypophysitis is often irreversible. Fortunately, it can be managed adequately with hormone replacements. Further investigations are warranted to unveil underlying mechanisms and ethnic differences to guide the solutions. Keywords: Endocrine system diseases, hypophysitis, immunotherapy

Background: Monocyte count and serum albumin (Alb) have been proven to be involved in the process of systemic inflammation. Therefore, we investigated the prognostic value of monocyte-to-albumin ratio (MAR) in patients who underwent percutaneous coronary intervention (PCI). Methods: We enrolled a total of 3561 patients in the present study from January 2013 to December 2017. They were divided into two groups according to MAR cut-off value (MAR < 0.014, n=2220; MAR ≥ 0.014, n=1119) as evaluated by receiver operating characteristic (ROC) curve. The average follow-up time was 37.59 ± 22.24 months. Results: The two groups differed significantly in the incidences of all-cause mortality (ACM; P Conclusion: The findings of the present study suggested that MAR was a novel independent predictor of long-term mortality in patients who underwent PCI.

Background: Alkaline phosphatase (ALP) and albumin (ALB) have been shown to be associated with coronary artery disease (CAD), and it has been reported that alkaline phosphatase-to-albumin ratio (AAR) is associated with the liver damage and poorer prognosis of patients with digestive system malignancy. Moreover, several previous studies showed that there was a higher incidence of malignancy in CAD patients. However, to our knowledge, the relationship between AAR and long-term adverse outcomes in CAD patients after undergoing percutaneous coronary intervention (PCI) has not been investigated. Therefore, we aim to access the relation between AAR and long-term adverse outcomes in post-PCI patients with CAD. Methods: A total of 3378 post-PCI patients with CAD were enrolled in the retrospective Clinical Outcomes and Risk Factors of Patients with Coronary Heart Disease after PCI (CORFCHD-ZZ) study from January 2013 to December 2017. The median duration of follow-up was 37.59 ± 22.24 months. The primary end point was long-term mortality including all-cause mortality (ACM) and cardiac mortality (CM). The secondary end points were major adverse cardiac events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs). Results: Kaplan–Meier analyses showed that an increased AAR was positively correlated with incidences of long-term ACM (log-rank, P=0.014), CM (log-rank, P=0.011), MACEs (log-rank, P=0.013) and MACCEs (log-rank, P=0.006). Multivariate Cox regression analyses showed that the elevated AAR was an independent predictor of long-term ACM (adjusted HR = 1.488 [1.031–2.149], P=0.034), CM (adjusted HR = 1.837 [1.141–2.959], P=0.012), MACEs (adjusted HR = 1.257 [1.018–1.551], P=0.033) and MACCEs (adjusted HR = 1.237 [1.029–1.486], P=0.024). Conclusion: An elevated AAR is a novel independent predictor of long-term adverse outcomes in CAD patients following PCI.

Purpose: Irritable bowel syndrome with diarrhea (IBS-D) is a common functional gastrointestinal disorder around the world. However, the molecular mechanisms of IBS-D are still not well understood. This study was designed to identify key biomarkers and immune infiltration in the rectal mucosa of IBS-D by bioinformatics analysis. Methods: The gene expression profiles of GSE36701 were downloaded from the GEO database. The differentially expressed genes (DEGs) were identified and functional enrichment and pathway analyses were performed. Using STRING and Cytoscape, protein-protein interaction (PPI) networks were constructed and core genes were identified. Subsequently, 22 immune cell types of IBS-D tissues were explored by the Cell type Identification by Estimating Relative Subsets of RNA Transcripts. Finally, the co-expression network of DEGs was estimated by the weigh gene co-expression network analysis method to identify IBS-D-related modules and deeply hub genes. Results: 224 up-regulated and 171 down-regulated genes in IBS-D patients: Our analysis indicated that several DEGs might play crucial roles in IBS-D, such as CDC20, UBE2C, AURKA, CDC26, CKS1B and PSMB3. Later, we found that immune infiltrating cells such as T cells CD4 memory resting, M2 macrophages are crucial in IBS-D progression. In the end, a total of 9 co-expression gene modules were calculated and the black module was found to have the highest correlation. 15 hub genes were identified both in DEGs and the black module. Conclusions: This study identified molecular mechanisms and a series of candidate genes as well as significant pathways from the bioinformatics network, which may provide a diagnostic method and therapeutic targets for IBS-D.

Acute myocardial infarction has a high clinical mortality rate. The initial exclusion or diagnosis is important for the timely treatment of patients with acute myocardial infarction. As a marker, cardiac troponin I (cTnI) has a high specificity, high sensitivity to myocardial injury and a long diagnostic window. Therefore, its diagnostic value is better than previous markers of myocardial injury. In this work, we propose a novel aptamer electrochemical sensor. This sensor consists of silver nanoparticles/MoS2/reduced graphene oxide. The combination of these three materials can provide a synergistic effect for the stable immobilization of aptamer. Our proposed aptamer electrochemical sensor can detect cTnl with high sensitivity. After optimizing the parameters, the sensor can provide linear detection of cTnl in the range of 0.3 pg/ml to 0.2 ng/ml. In addition, the sensor is resistant to multiple interferents including urea, glucose, myoglobin, dopamine and hemoglobin.