A massive pulmonary arteriovenous fistula complicated with coronary atherosclerotic heart disease treated by interventional therapy: a case report.

BACKGROUND: Pulmonary arteriovenous fistula (PAVF) is a rare disease, and its symptoms lack specificity. For patients with coronary heart disease(CHD), hypertension and other common cardiovascular diseases, PAVF is easy to be ignored. We presented a case of massive PAVF complicated with coronary atherosclerotic heart disease by interventional treatment to improve the understanding of this complex disease. CASE PRESENTATION: A 77-year-old female patient was admitted to the hospital due to chest tightness and shortness of breath following activities, which was diagnosed with CHD and hypoxemia in other hospitals. Coronary angiography showed that the patient had severe stenosis of coronary artery while pulmonary vascular DSA showing the patient had PAVF. After interventional therapy of both coronary artery and PAVF, the patient's symptoms were significantly improved. CONCLUSION: We presented a case of massive PAVF complicated with CHD by interventional treatment. For patients with unexplained hypoxemia and symptoms similar with CHD, the possibility of PAVF often leads to oversight, and various auxiliary examinations should be improved to avoid missed diagnosis. And intervention treatment should be carried out to improve the prognosis of patients as much as possible.

Glutathione-responsive CD-MOFs co-loading honokiol and indocyanine green biomimetic active targeting to enhance photochemotherapy for breast cancer.

Breast cancer has now replaced lung cancer as the most prevalent malignant tumor worldwide, posing a serious health risk to women. We have recently designed a promising option strategy for the treatment of breast cancer. In this work, cyclodextrin metal-organic frameworks with high drug-carrying properties were endo-crosslinked by 3,3'dithiodipropionyl chloride to form cubic phase gel nanoparticles, which were drug-loaded and then coated by MCF-7 cell membranes. After intravenous injection, this multifunctional nanomedicine achieved dramatically homologous targeting co-delivery of honokiol and indocyanine green to the breast tumor. Further, the disulfide bonds in the nanostructures achieved glutathione-responsive drug release, induced tumor cells to produce reactive oxygen species and promoted apoptosis, resulting in tumor necrosis, and at the same time, inhibited Ki67 protein expression, which enhanced photochemotherapy, and resulted in a 94.08 % in vivo tumor suppression rate in transplanted tumor-bearing mice. Thereby, this nanomimetic co-delivery system may have a place in breast cancer therapy due to its simple fabrication process, excellent biocompatibility, efficient targeted delivery of insoluble drugs, and enhanced photochemotherapy.

The Efficacy of Dietary Intake, Supplementation, and Blood Concentrations of Carotenoids in Cancer Prevention: Insights from an Umbrella Meta-Analysis.

Previous meta-analyses of multiple studies have suggested that dietary intake and blood concentrations of carotenoids, as well as dietary supplement of certain carotenoids, play a role in reducing the risk of cancer. However, the conclusions of these studies have been subject to controversy. We conducted an umbrella review of meta-analyses to comprehensively analyze and evaluate the evidence pertaining the association between carotenoids and cancer outcomes. We searched PubMed, Web of Science, Embase, and Cochrane Library databases of meta-analyses and systematic reviews up to June 2023. Our selection criteria encompassed meta-analyses of cohort and case-control studies, as well as randomized controlled clinical trials, which investigated the associations between carotenoids and cancer risk. We also determined the levels of evidence for these associations with AMSTAR 2 criteria. We included 51 eligible articles, including 198 meta-analyses for qualitative synthesis in the umbrella review. Despite the presence of moderate to high heterogeneity among the studies, dietary intake, supplementation, and blood concentrations of carotenoids were inversely associated with the risk of total cancer, and certain specific cancers of lung, digestive system, prostate, breast, head and neck, and others. Subgroup analysis also showed that individual carotenoids (α-carotene, ß-carotene, ß-cryptoxanthin, lutein, zeaxanthin, and lycopene) offer certain protection against specific types of cancers. However, high doses of carotenoid supplements, especially ß-carotene, significantly increased the risk of total cancer, lung cancer, and bladder cancer. Our umbrella meta-analysis supported that high intake of dietary carotenoids as a whole food approach could be more beneficial in reducing cancer risk. Concurrently, the findings suggest that the efficacy of single-carotenoid supplementation in cancer prevention remains a subject of controversy.

Platelet-derived microparticles and their cargos: The past, present and future.

All eukaryotic cells can secrete extracellular vesicles, which have a double-membrane structure and are important players in the intercellular communication involved in a variety of important biological processes. Platelets form platelet-derived microparticles (PMPs) in response to activation, injury, or apoptosis. This review introduces the origin, pathway, and biological functions of PMPs and their importance in physiological and pathological processes. In addition, we review the potential applications of PMPs in cancer, vascular homeostasis, thrombosis, inflammation, neural regeneration, biomarkers, and drug carriers to achieve targeted drug delivery. In addition, we comprehensively report on the origin, biological functions, and applications of PMPs. The clinical transformation, high heterogeneity, future development direction, and limitations of the current research on PMPs are also discussed in depth. Evidence has revealed that PMPs play an important role in cell-cell communication, providing clues for the development of PMPs as carriers for relevant cell-targeted drugs. The development history and prospects of PMPs and their cargos are explored in this guidebook.

GAS5, a long noncoding RNA, contributes to annulus fibroblast osteogenic differentiation and apoptosis in intervertebral disk degeneration via the miR-221-3p/SOX11 axis.

miR-221-3p has been reported to attenuate the osteogenic differentiation of annulus fibrosus cells (AFs), which has been implicated in intervertebral disk degeneration (IVDD) development. This study aimed to elucidate miR-221-3p's role in osteogenic differentiation and apoptosis of AFs in an IVDD model. After successfully establishing an IVDD rat model by annulus fibrosus needle puncture, AFs were isolated. Bioinformatics, dual-luciferase reporter, and AGO2-RNA immunoprecipitation (RIP) assays predicted and confirmed the potential miR-221-3p lncRNA and gene target. Functional analyses were performed after AF transfection to explore the roles of the identified lncRNA and gene. Western blotting, Alkaline phosphatase (ALP), and Alizarin red and TUNEL staining were performed to investigate AF apoptosis and osteogenic differentiation with different transfections. Compared with AFs isolated from sham rats, IVDD-isolated Afs exhibited stronger osteogenic potential and higher apoptosis rates accompanied by miR-221-3p downregulation. The growth arrest-specific transcript 5 (GAS5) was identified as miR-221-3p's target lncRNA, which was highly expressed in IVDD. GAS5 overexpression facilitated AF apoptosis and osteogenic differentiation, whereas silencing GAS5 had the opposite effect. SRY box-related11 (SOX11) was identified as a downstream miR-221-3p target gene in IVDD. GASS silencing-induced suppression of AF apoptosis and osteogenic differentiation could be reversed by SOX11 overexpression. Our findings uncovered a lncRNA GAS5/miR-221-3p/SOX11 axis in Afs under IVDD, which may help implement novel IVDD therapeutic strategies.

Effect of GRK4 on renal gastrin receptor regulation in hypertension.

OBJECTIVE: To investigate whether GRK4 regulates the phosphorylation and function of renal CCKBR. METHODS: GRK4 A142V transgenic mice were used as an animal model of enhanced GRK4 activity, and siRNA was used to silence the GRK4 gene to investigate the regulatory effect of GRK4 on CCKBR phosphorylation and function. Finally, the co-localization and co-connection of GRK4 and CCKBR in RPT cells were observed by laser confocal microscopy and immunoprecipitation to explore the mechanism of GRK4 regulating CCKBR. RESULTS: Gastrin infusion significantly increased urinary flow and sodium excretion rates in GRK4 WT mice (P < .05). GRK4 siRNA did not affect CCKBR protein expression in WKY RPT cells and SHR RPT cells, but remarkably reduced CCKBR phosphorylation in WKY and SHR RPT cells (P < .05). The inhibitory effect of gastrin on Na+-K+ -ATPase activity in WKY RPT cells was further enhanced by the reduction of GRK4 expression (P < .05), while GRK4 siRNA restored the inhibitory effect of gastrin on Na+-K+ -ATPase activity in SHR RPT cells. Laser confocal and Co-immunoprecipitation results showed that GRK4 and CCKBR co-localized in cultured RPT cells' cytoplasm. CONCLUSION: GRK4 participates in the development of hypertension by regulating the phosphorylation of renal CCKBR leading to impaired CCKBR function and water and sodium retention. Knockdown of GRK4 restored the function of CCKBR. The enhanced co-connection between GRK4 and CCKBR may be an important reason for the hyperphosphorylation of GRK4 and CCKBR involved in the pathogenesis of hypertension.

Evaluation of the Antioxidant Activities and Phenolic Profile of Shennongjia Apis cerana Honey through a Comparison with Apis mellifera Honey in China.

This study evaluates the phenolic profile as well as the antioxidant properties of Shennongjia Apis cerana honey through a comparison with Apis mellifera honey in China. The total phenolic content (TPC) ranges from 263 ± 2 to 681 ± 36 mg gallic acid/kg. The total flavonoids content (TFC) ranges from 35.9 ± 0.4 to 102.2 ± 0.8 mg epicatechin/kg. The correlations between TPC or TFC and the antioxidant results (FRAP, DPPH, and ABTS) were found to be statistically significant (p < 0.01). Furthermore, the phenolic compounds are quantified and qualified by high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS), and a total of 83 phenolic compounds were tentatively identified in this study. A metabolomics analysis based on the 83 polyphenols was carried out and subjected to principal component analysis and orthogonal partial least squares-discriminant analysis. The results showed that it was possible to distinguish Apis cerana honey from Apis mellifera honey based on the phenolic profile.

Diethylene glycol monoethyl ether-mediated nanostructured lipid carriers enhance trans-ferulic acid delivery by Caco-2 cells superior to solid lipid nanoparticles.

This work aimed to compare the performance of trans-ferulic acid-encapsulated nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) for transport by Caco-2 cells. The NLC particles (diameter: 102.6 nm) composed of Compritol® 888 ATO, ethyl oleate, Cremophor® EL, and Transcutol® P were larger than the SLNs (diameter: 86.0 nm) formed without liquid lipid (ethyl oleate), and the former had a higher encapsulation efficiency for trans-ferulic acid (p < 0.05). In vitro cultured Caco-2 cell transport was used to simulate intestinal absorption, and the cellular uptake of NLCs was higher than that of SLNs (p < 0.05). Compared to SLNs, NLCs greatly enhanced trans-ferulic acid permeation through the MillicellTM membrane (p < 0.05). This work confirms that NLCs have better properties than SLNs in terms of increasing drug transport by Caco-2 cells. This helps to comprehend the approach by which NLC-mediated oral bioavailability of trans-ferulic acid is better than that mediated by SLNs, as shown in our previous report.

Low-dose dexmedetomidine as a perineural adjuvant for postoperative analgesia: a randomized controlled trial.

PURPOSE: Dexmedetomidine has been proposed as an additive to local anesthetics to prolong peripheral nerve block duration; however, perineural dexmedetomidine has been associated with an increased risk of bradycardia and hypotension This randomized controlled study investigated the effects of low-dose dexmedetomidine as a perineural adjuvant for postoperative analgesia. METHODS: Fifty-five patients who had undergone elective upper extremity surgery were randomized to receive an ultrasound-guided supraclavicular brachial plexus block with 20 mL 0.5% ropivacaine with or without 30 µg dexmedetomidine. The primary outcome was the duration of analgesia. Secondary outcomes included the onset time and duration of the motor and sensory blocks, incidence of hypotension and bradycardia, total postoperative analgesics, and safety assessment during the 24 h after surgery. RESULTS: Dexmedetomidine significantly prolonged the duration of analgesia (887 ± 92 min vs 661 ± 83 min, P < 0.0001). The onset time and the duration of motor and sensory block were significantly different between the groups (all P < 0.001). No episodes of hypotension or bradycardia were detected in the dexmedetomidine group. The total postoperative analgesic use and side effect profiles in the first 24 h postoperative period were similar for both groups. CONCLUSIONS: Low-dose dexmedetomidine (30 µg) as a perineural adjuvant significantly prolonged the analgesic duration of a brachial plexus block without inducing hemodynamic instability. TRIAL REGISTRATION: This trial was registered at ClinicalTrial.gov (NCT02630290).

The Burden of Trachea, Bronchus, and Lung Cancer Attributable to Occupational Exposure From 1990 to 2019.

Objectives: Occupational exposure to carcinogens is associated with trachea, bronchus, and lung (TBL) cancer. The objective of this study was to provide global and regional estimates of the burden of TBL cancer associated with occupational carcinogens (OCs) between 1990 and 2019. Methods: Age-standardized mortality rates (ASMR) and age-standardized disability-adjusted life years (DALYs) rates (ASDR) of TBL cancer related to exposure to OCs at the global and regional levels were extracted for 1990-2019 from the Global Burden of Disease 2019. Joinpoint regression was used to analyze trends in the ASMR and ASDR of TBL cancer burden related to OCs, and the annual percent change and the average annual percent change (AAPC) were recorded. Results: The mortality from TBL cancer related to exposure to OCs increased globally. The ASMR and ASDR decreased in both sexes and in men between 1990 and 2019. The AAPC of ASMR and ASDR decreased in men between 1990 and 2019, but increased in women. Asbestos accounted for the highest death number and beryllium accounted for the lowest; diesel engine exhaust caused the largest percentage change in death number (145.3%), in ASDR (14.9%), and in all ages DALY rates (57.6%). Asbestos accounted for the largest death number in high social development index (SDI) countries, whereas low-middle SDI countries had the largest percent change (321.4%). Asbestos was associated with decreased ASDR in high SDI countries and increased ASDR in low-middle SDI countries, and similar changes were observed for other OCs. Conclusions: The overall mortality and DALYs of TBL cancer burden related to OCs showed a decreasing trend between 1990 and 2019, whereas death number increased. Asbestos accounted for the highest death number. TBL cancer burden related to OCs decreased to different degrees in high, low, low-middle, and middle SDI countries, which showed variable levels of TBL cancer burden related to exposure to OCs (except asbestos).

B16F10 Cell Membrane-Based Nanovesicles for Melanoma Therapy Are Superior to Hyaluronic Acid-Modified Nanocarriers.

Some cancer cell membrane (CCM)-derived nanovesicles show strong homing effects and are used for targeted cancer therapy. By co-constructing the B16F10 cell membrane with a PEGylated phospholipid membrane, a new nanocarrier with a composite nanocrown structure was developed, which can evade immune recognition and actively target homologous melanoma. The nanocrowns have an encapsulation efficiency of more than 90% for paclitaxel and showed no significant difference (p > 0.05) from the PEGylated phospholipid membrane vesicles. Compared with the hyaluronic acid-modified PEGylated phospholipid membrane vesicles, the biomimetic nanocrowns enhanced the escape of nanovesicles from reticuloendothelial cells in vitro and extended the circulation time in vivo; moreover, the nanocrowns showed superior melanoma-targeted drug delivery capability and improved anticancer effects of paclitaxel as demonstrated by the inhibition of B16F10 cell proliferation and induction of apoptosis by interfering with microtubule formation. In contrast, the modification of hyaluronic acid did not increase the targeting capacity or antitumor effects of the nanocrowns, confirming that the superior targeting capacity was mediated by the exposed homologous CCMs rather than by hyaluronic acid. Our results demonstrate the potential of using biomimetic nanocrowns for active melanoma-targeted therapy.

Role of Outer Membrane Vesicles From Helicobacter pylori in Atherosclerosis.

Infection is thought to be involved in the pathogenesis of atherosclerosis. Studies have shown the association between helicobacter pylori (H. pylori) and coronary artery disease. It is interesting to find H. pylori DNA and cytotoxin-associated gene A (CagA) protein in atherosclerotic plaque. Outer membrane vesicles (OMVs), secreted by H. pylori, exert effects in the distant organ or tissue. However, whether or not OMVs from H. pylori are involved in the pathogenesis of atherosclerosis remains unknown. Our present study found that treatment with OMVs from CagA-positive H. pylori accelerated atherosclerosis plaque formation in ApoE-/- mice. H. pylori-derived OMVs inhibited proliferation and promoted apoptosis of human umbilical vein endothelial cells (HUVECs), which was also reflected in in vivo studies. These effects were normalized to some degree after treatment with lipopolysaccharide (LPS)-depleted CagA-positive OMVs or CagA-negative OMVs. Treatment with H. pylori-derived OMVs increased reactive oxygen species (ROS) levels and enhanced the activation of nuclear factor-κB (NF-κB) in HUVECs, which were reversed to some degree in the presence of a superoxide dismutase mimetic TEMPOL and a NF-κB inhibitor BAY11-7082. Expressions of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), two inflammatory factors, were augmented after treatment with OMVs from H. pylori. These suggest that H. pylori-derived OMVs accelerate atherosclerosis plaque formation via endothelium injury. CagA and LPS from H. pylori-OMVs, at least in part, participate in these processes, which may be involved with the activation of ROS/NF-κB signaling pathway. These may provide a novel strategy to reduce the incidence and development of atherosclerosis.

Galectin-3 Induces Atrial Fibrosis by Activating the TGF-ß1/Smad Pathway in Patients with Atrial Fibrillation.

BACKGROUND: Atrial fibrosis plays a critical role in the occurrence and maintenance of atrial fibrillation. The role of TGF-ß1 in mediating atrial fibrosis is well documented. The ß-galactoside-binding lectin galectin-3 (Gal-3) is mainly produced by macrophages in biological events such as inflammation and angiogenesis. Previous studies have shown that Gal-3 is associated with atrial fibrosis, but the relationship between TGF-ß1 and Gal-3 in atrial fibrosis remains unclear. OBJECTIVE: To determine whether Gal-3 induces atrial fibrosis and atrial fibrillation by activating the TGF-ß1/Smad pathway and whether the expression of Gal-3 is mediated by TGF-ß1, which can enable assessing the relationship between Gal-3 and TGF-ß1 in atrial fibrosis. METHODS: In this study, 30 patients' right atrial appendages were collected and divided into 3 groups: congenital heart disease sinus rhythm group (n = 10, as a control group), rheumatic heart disease sinus rhythm group (n = 10), and rheumatic heart disease atrial fibrillation group (n = 10). Rat atrial fibroblasts were cultured in vitro, and recombinant Gal-3 and recombinant TGF-ß1 proteins were added to the cell culture. The expression of Gal-3, TGF-ß1, Smad2, and collagen I was detected by Western blotting and quantitative real-time PCR. Atrial tissues were stained with Masson's trichrome stain to evaluate the extent of atrial fibrosis. The expression of Gal-3 and TGF-ß1 was detected by immunohistochemical staining and immunofluorescence staining. Gal-3 and TGF-ß1 interaction was demonstrated by immunoprecipitation. RESULTS: The expression levels of Gal-3, TGF-ß1, Smad2, and collagen I were elevated in the rheumatic heart disease atrial fibrillation group compared with the congenital heart disease sinus rhythm group and the rheumatic heart disease sinus rhythm group. In cultured atrial fibroblasts, there is a synergistic interaction between Gal-3 and TGF-ß1. Gal-3 stimulated the TGF-ß1/Smad pathway, and overexpression of TGF-ß1 induced Gal-3 expression. CONCLUSIONS: Gal-3 and TGF-ß1 interact with each other and stimulate the downstream TGF-ß1/Smad pathway. This finding suggests that Gal-3 could be an important factor in TGF-ß1-induced fibrosis in atrial fibrillation.

Activation of a gamma-cyclodextrin-based metal-organic framework using supercritical carbon dioxide for high-efficient delivery of honokiol.

A facile method for the activation of γ-cyclodextrin metal-organic framework (CD-MOF) without channel blockage and framework collapse was first developed using supercritical carbon dioxide (scCO2), which enabled higher surface area and larger pore volume. The scCO2-assisted impregnation method was also applied to introduce the insoluble drug, honokiol (HNK), into the pores of CD-MOF with higher cargo loading compared to the conventional liquid phase incorporation in ethanol. Notably, the resulting HNK-loaded CD-MOF (HNK@CD-MOF) had improved apparent solubility and enhanced dissolution rate. The intestinal cellular uptake and transport experiments demonstrated that CD-MOF could enhance cellular uptake and increase drug transport across the intestinal epithelial cells compared to the cyclodextrin inclusion complex. Moreover, the in vivo pharmacokinetic studies further confirmed that CD-MOF could significantly improve the oral absorption and bioavailability of HNK. Overall, the scCO2 activation and scCO2-assisted impregnation approaches were demonstrated as promising strategies to maximize the potential capability of CD-MOF.

N-Acetylcysteine Attenuates Lipopolysaccharide-Induced Osteolysis by Restoring Bone Remodeling Balance via Reduction of Reactive Oxygen Species Formation During Osteoclastogenesis.

Chronic inflammatory diseases affect bone and teeth health tremendously. Characterized by osteolytic lesion and hyperactive osteoclastogenesis, inflammatory bone diseases are short of effective therapeutics and therefore highlight the importance of understanding pathogenesis and developing ideal medications. Reactive oxygen species (ROS) play a prominent role in the innate immune response of activated macrophages, as well as in the physiological signaling of osteoclasts (OCs) differentiation. N-acetylcysteine (NAC) is a potent ROS scavenger and a potential option for treating diseases characterized by excessive ROS generation. However, whether NAC can protect physiological bone remodeling from in vivo inflammatory conditions is largely undefined. We applied NAC treatment on lipopolysaccharide (LPS)-induced inflammatory osteolysis mice model and found that NAC could attenuate bone erosion and protect mice against LPS-induced osteolysis, due to the suppressive effect on osteoclastogenesis and stimulated effect on osteogenesis. Moreover, in vitro study demonstrated that, in OC precursors (pre-OCs), LPS-stimulated expressions of OC marker genes, such as tartrate-resistant acid phosphatase type 5 (Acp5), cathepsin K (Ctsk), OC stimulatory transmembrane protein (Oc-stamp), dendritic cell-specific transmembrane protein (Dc-stamp), and nuclear factor of activated T cells 1 (NFATc1), were all reduced because of the NAC pretreatment, thereby adversely affecting OC function including F-actin ring formation and bone resorption. Further mechanism study showed that NAC blocked LPS-induced ROS formation in both macrophages and pre-OCs, cutting off the LPS-stimulated autocrine/paracrine mechanism during inflammatory osteolysis. Our findings reveal that NAC attenuates inflammatory osteolysis via the elimination of ROS formation during LPS-stimulated osteoclastogenesis, and provide a potential therapeutic approach to treat inflammatory bone disease.

Molecular characterization of a RNA polymerase (RNAP) II (DNA directed) polypeptide H (POLR2H) in Pacific white shrimp (Litopenaeus vannamei) and its role in response to high-pH stress.

RNA polymerase (RNAP) II (DNA-directed) (POLR2) genes are essential for cell viability under environmental stress and for the transfer of biological information from DNA to RNA. However, the function and characteristics of POLR2 genes in crustaceans are still unknown. In the present study, a POLR2H cDNA was isolated from Pacific white shrimp (Litopenaeus vannamei) and designated as Lv-POLR2H. The full-length Lv-POLR2H cDNA is 772 bp in length and contains a 32-bp 5'- untranslated region (UTR), a 284-bp 3'- UTR with a poly (A) sequence, and an open reading frame (ORF) of 456 bp encoding an Lv-POLR2H protein of 151 amino acids with a deduced molecular weight of 17.21 kDa. The Lv-POLR2H protein only contains one functional domain, harbors no transmembrane domains and mainly locates in the nucleus. The expression of the Lv-POLR2H mRNA was ubiquitously detected in all selected tissues, with the highest level in the gills. In situ hybridization (ISH) analysis showed that Lv-POLR2H was mainly located in the secondary gill filaments, the transcript levels of Lv-POLR2H in the gills were found to be significantly affected after challenge by pH, low salinity and high concentrations of NO2- and NH4+, indicating that Lv-POLR2H in gill tissues might play roles under various physical stresses. Specifically, under high-pH stress, knockdown of Lv-POLR2H via siRNA significantly decreased the survival rate of the shrimp, indicating its key roles in the response to high-pH stress. Our study may provide the first evidence of the role of POLR2H in shrimp responding to high-pH stress and provides new insight into molecular regulation in response to high pH in crustaceans.

Design, synthesis, and discovery of ocotillol-type amide derivatives as orally available modulators of P-glycoprotein-mediated multidrug resistance.

Multidrug resistance (MDR) is a major cause of failure in cancer treatment, in which the overexpression of P-glycoprotein (Pgp) plays a crucial role. Herein, a novel class of ocotillol-type amide derivatives has been designed, synthesized, and evaluated for their ability to reverse MDR. The structure-activity relationship of the reversal activity was analyzed. Ten compounds showed promising chemo-reversal ability, among which the 24R-ocotillol-type amide derivative 6c with an N-Boc-hexanoyl unit exhibited the most potency in reversing paclitaxel resistance in KBV cells. Compound 6c could inhibit Pgp-mediated rhodamine123 efflux function via stimulating Pgp-ATPase activity and exhibited high binding affinity with Pgp in molecular docking studies. Importantly, compound 6c enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice after oral administration. These results indicate that ocotillol-type amide derivatives are promising lead compounds for overcoming MDR in cancer.

Relaxin ameliorates high glucose-induced cardiomyocyte hypertrophy and apoptosis via the Notch1 pathway.

The present study aimed to investigate the role of relaxin (RLX) on high glucose (HG)-induced cardiomyocyte hypertrophy and apoptosis, as well as the possible molecular mechanism. H9c2 cells were exposed to 33 mmol/l HG with or without RLX (100 nmol/ml). Cell viability, apoptosis, oxidative stress, cell hypertrophy and the levels of Notch1, hairy and enhancer of split 1 (hes1), atrial natriuretic polypeptide (ANP), brain natriuretic peptide (BNP), manganese superoxide dismutase (MnSOD), cytochrome C and caspase-3 were assessed in cardiomyocytes. Compared with the HG group, the viability of H9c2 cells was increased by RLX in a time- and dose-dependent manner, and was accompanied with a significant reduction in apoptosis. Furthermore, RLX significantly suppressed the formation of reactive oxygen species and malondialdehyde, and enhanced the activity of SOD. In addition, the levels of ANP, BNP, cytochrome C and caspase-3 were increased and Notch1, hes1 and MnSOD were inhibited in the HG group compared with those in the normal group. However, the Notch inhibitor DAPT almost abolished the protective effects of RLX. These results suggested that RLX protected cardiomyocytes from HG-induced hypertrophy and apoptosis partly through a Notch1-dependent pathway, which may be associated with reducing oxidative stress.

Potential role of MG53 in the regulation of transforming-growth-factor-ß1-induced atrial fibrosis and vulnerability to atrial fibrillation.

Atrial fibrosis plays a critical role in atrial fibrillation (AF) by the transforming growth factor (TGF)-ß1/Smad pathway. The disordered differentiation, proliferation, migration and collagen deposition of atrial fibroblasts play significant roles in atrial fibrosis. Mitsugumin (MG)53 is predominantly expressed in myocardium of rodents and has multiple biological functions. However, the role of MG53 in cardiac fibrosis remains unclear. This study provided clinical and experimental evidence for the involvement of MG53 in atrial fibrosis in humans and atrial fibrosis phenotype in cultured rat atrial fibroblasts. In atrial tissue from patients we demonstrated that MG53 was expressed in human atrium. Expression of MG53 increased with the extent of atrial fibrosis, which could induce AF. In cultured atrial fibroblasts, depletion of MG53 by siRNA caused down-regulation of the TGF-ß1/Smad pathway, while overexpression of MG53 by adenovirus up-regulated the pathway. MG53 regulated the proliferation and migration of atrial fibroblasts. Besides, exogenous TGF-ß1 suppressed expression of MG53. In conclusion, we demonstrated that MG53 was expressed in human atrium, and may be a potential upstream of the TGF-ß1/Smad pathway in human atrium and rat atrial fibroblasts. This suggests that MG53 is a potential regulator of atrial fibrosis induced by the TGF-ß1/Smad pathway in patients with AF.

Erythrocyte membrane-encapsulated celecoxib improves the cognitive decline of Alzheimer's disease by concurrently inducing neurogenesis and reducing apoptosis in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is characterized by the loss of neurogenesis and excessive induction of apoptosis. The induction of neurogenesis and inhibition of apoptosis may be a promising therapeutic approach to combating the disease. Celecoxib (CB), a cyclooxygenase-2 specific inhibitor, could offer neuroprotection. Specifically, the CB-encapsulated erythrocyte membranes (CB-RBCMs) sustained the release of CB over a period of 72 h in vitro and exhibited high brain biodistribution efficiency following intranasal administration, which resulted in the clearance of aggregated ß-amyloid proteins (Aß) in neurons. The high accumulation of the CB-RBCMs in neurons resulted in a decrease in the neurotoxicity of CB and an increase in the migratory activity of neurons, and alleviated cognitive decline in APP/PS1 transgenic (Tg) mice. Indeed, COX-2 metabolic products including prostaglandin E2 (PGE2) and PGD2, PGE2 induced neurogenesis by enhancing the expression of SOD2 and 14-3-3ζ, and PGD2 stimulated apoptosis by increasing the expression of BIK and decreasing the expression of ARRB1. To this end, the CB-RBCMs achieved better effects on concurrently increasing neurogenesis and decreasing apoptosis than the phospholipid membrane-encapsulated CB liposomes (CB-PSPD-LPs), which are critical for the development and progression of AD. Therefore, CB-RBCMs provide a rational design to treat AD by promoting the self-repairing capacity of the brain.