Autopsy analysis reveals increased macrophage infiltration and cell apoptosis in COVID-19 patients with severe pulmonary fibrosis.

Clinical data indicates that SARS-CoV-2 infection-induced respiratory failure is a fatal condition for severe COVID-19 patients. However, the pathological alterations of different types of respiratory failure remained unknown for severe COVID-19 patients. This study aims to evaluate whether there are differences in the performance of various types of respiratory failure in severe COVID-19 patients and investigate the pathological basis for these differences. The lung tissue sections of severe COVID-19 patients were assessed for the degree of injury and immune responses. Transcriptome data were used to analyze the molecular basis in severe COVID-19 patients. Severe COVID-19 patients with combined oxygenation and ventilatory failure presented more severe pulmonary fibrosis, airway obstruction, and prolonged disease course. The number of M2 macrophages increased with the degree of fibrosis in patients, suggesting that it may be closely related to the development of pulmonary fibrosis. The co-existence of pro-inflammatory and anti-inflammatory cytokines in the pulmonary environment could also participate in the progression of pulmonary fibrosis. Furthermore, the increased apoptosis in the lungs of COVID-19 patients with severe pulmonary fibrosis may represent a critical factor linking sustained inflammatory responses to fibrosis. Our findings indicate that during the extended phase of COVID-19, antifibrotic and antiapoptotic treatments should be considered in conjunction with the progression of the disease.

A retrospective study of Kaposi's sarcoma in Hotan region of Xinjiang, China.

Kaposi sarcoma (KS) is the most common cancer in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (AIDS). In 1994, Chang and Moore discovered Kaposi sarcoma associated herpesvirus for the first time in KS lesions in AIDS patients. KS is a low-grade mesenchymal neoplasm of blood and lymphatic vessels that primarily affects the skin, although the disease may become disseminated to the lymphatic system, lungs, airways, or abdominal viscera. In this research, clinical characteristics and treatment of patients of Kaposi sarcoma were retrospectively analyzed in Hotan District, Xinjiang China. We look into the clinical traits, prognosis, and therapy of Kaposi sarcoma. From May 2017 to August 2022, 32 patients were treated in the People's Hospital of Hotan District, Xinjiang Uygur Autonomous Region, China. Twenty-two of these were classic Kaposi sarcomas (cKS), and 10 of these were Kaposi sarcomas linked to AIDS (AIDS-KS). The majority of KS patients were Uyghur. In terms of age at onset, AIDS-KS patients were younger than cKS patients. cKS and AIDS-KS are most frequently manifested in the feet and lower limbs. Ten patients with AIDS-KS have treated with combination antiretroviral therapy (combination antiretroviral therapy) combination chemotherapy, 5 of 10 patients had a complete response, 2 patients achieved partial response, the overall effective rate was 70%, and CD4 + T cells were greater than before. For cKS and AIDS-KS, the median overall survival was 56 and 50.8 months, respectively (P > .05). As a result, antiviral combination chemotherapy can also improve the prognosis of AIDS-KS patients.

Collagen for neural tissue engineering: Materials, strategies, and challenges.

Neural tissue engineering (NTE) has made remarkable strides in recent years and holds great promise for treating several devastating neurological disorders. Selecting optimal scaffolding material is crucial for NET design strategies that enable neural and non-neural cell differentiation and axonal growth. Collagen is extensively employed in NTE applications due to the inherent resistance of the nervous system against regeneration, functionalized with neurotrophic factors, antagonists of neural growth inhibitors, and other neural growth-promoting agents. Recent advancements in integrating collagen with manufacturing strategies, such as scaffolding, electrospinning, and 3D bioprinting, provide localized trophic support, guide cell alignment, and protect neural cells from immune activity. This review categorises and analyses collagen-based processing techniques investigated for neural-specific applications, highlighting their strengths and weaknesses in repair, regeneration, and recovery. We also evaluate the potential prospects and challenges of using collagen-based biomaterials in NTE. Overall, this review offers a comprehensive and systematic framework for the rational evaluation and applications of collagen in NTE.

Cartilage Lacuna-Inspired Microcarriers Drive Hyaline Neocartilage Regeneration.

Cartilage equivalents from hydrogels containing chondrocytes exhibit excellent potential in hyaline cartilage regeneration, yet current approaches have limited success at reconstituting the architecture to culture nondifferentiated chondrocytes in vitro. In this study, specially designed lacunar hyaluronic acid microcarriers (LHAMCs) with mechanotransductive conditions that rapidly form stable hyaluronic acid (HA) N-hydroxy succinimide ester (NHS-ester) are reported. Specifically, carboxyl-functionalized HA is linked to collagen type I via amide-crosslinking, and gas foaming produced by ammonium bicarbonate forms concave surface of the microcarriers. The temporal 3D culture of chondrocytes on LHAMCs uniquely remodels the extracellular matrix to induce hyaline cartilaginous microtissue regeneration and prevents an anaerobic-to-aerobic metabolism transition in response to the geometric constraints. Furthermore, by inhibiting the canonical Wnt pathway, LHAMCs prevent ß-catenin translocation to the nucleus, repressing chondrocyte dedifferentiation. Additionally, the subcutaneous implantation model indicates that LHAMCs display favorable cytocompatibility and drive robust hyaline chondrocyte-derived neocartilage formation. These findings reveal a novel strategy for regulating chondrocyte dedifferentiation. The current study paves the way for a better understanding of geometrical insight clues into mechanotransduction interaction in regulating cell fate, opening new avenues for advancing tissue engineering.

Investigation of Factors Influencing the Fear of Cancer Recurrence in Breast Cancer Patients Using Structural Equation Modeling: A Cross-Sectional Study.

Objective: This study aimed to investigate the fear of cancer recurrence (FCR) in breast cancer patients and develop a structural equation model of influencing factors to help formulate clinical intervention strategies. Methods: A convenience sample of 325 patients was surveyed using a general and disease-related data questionnaire, which combined the Fear of Progression Questionnaire-Short Form, Mishel Uncertainty in Illness Scale, Perceived Social Support Scale, and Medical Coping Modes Questionnaire. Results: The total score of FCR in breast cancer patients was 35.06 ± 10.83, and 53.8% of patients reached the clinical level. The structural equation model demonstrated that illness uncertainty had a direct positive impact on FCR (ß = 0.275, p < 0.05), and it could have an indirect impact through social support and resignation coping methods (ß = 0.254, p < 0.05). Conclusion: The fear of cancer recurrence in breast cancer patients needs further understanding. Medical staff can reduce or buffer FCR in breast cancer patients by strengthening positive influences, such as social support, or weakening negative influences, such as illness uncertainty and resignation coping.

Spatial region-resolved proteome map reveals mechanism of COVID-19-associated heart injury.

Direct myocardial and vascular injuries due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-driven inflammation is the leading cause of acute cardiac injury associated with coronavirus disease 2019 (COVID-19). However, in-depth knowledge of the injury characteristics of the heart affected by inflammation is lacking. In this study, using a quantitative spatial proteomics strategy that combines comparative anatomy, laser-capture microdissection, and histological examination, we establish a region-resolved proteome map of the myocardia and microvessels with obvious inflammatory cells from hearts of patients with COVID-19. A series of molecular dysfunctions of myocardia and microvessels is observed in different cardiac regions. The myocardia and microvessels of the left atrial are the most susceptible to virus infection and inflammatory storm, suggesting more attention should be paid to the lesion and treatment of these two parts. These results can guide in improving clinical treatments for cardiovascular diseases associated with COVID-19.

HOXA5 is amplified in glioblastoma stem cells and promotes tumor progression by transcriptionally activating PTPRZ1.

Although the tumorigenic potential of glioma stem cells (GSCs) is associated with multiple molecular alterations, the gene amplification status of GSCs has not been elucidated. Overexpression of HomeoboxA5 (HOXA5) is associated with increased glioma malignancy. In this study, we identify the gene amplification and protein overexpression of HOXA5 in GSCs and its function in regulating GSC maintenance and the downstream transcriptional effector, to explore the significance of HOXA5 amplification/overexpression for GSC identification and prognostic determination. The HOXA5 gene is significantly amplified in glioblastoma (GBM) and is an independent prognostic factor for predicting worse patient outcomes. Specifically, HOXA5 gene amplification and the resultant protein overexpression are correlated with increased proportions of GSCs and enhanced self-renewal/invasiveness of these cells. Disruption of HOXA5 expression impairs GSC survival and GBM tumor propagation. Mechanistically, HOXA5 directly binds to the promoter region of protein tyrosine phosphatase receptor type Z1 (PTPRZ1), thereby upregulating this gene for GSC maintenance. Suppression of PTPRZ1 largely compromises the pro-tumoral effect of HOXA5 on GSCs. In summary, HOXA5 amplification serves as a genetic biomarker for predicting worse GBM outcome, by enhancing PTPRZ1-mediated GSC survival.

Complete mitogenome of Treron sphenurus (Aves, Columbiformes): the first representative from the genus Treron, genomic comparisons and phylogenetic analysis of Columbidae.

The wedge-tailed green pigeon (Treron sphenurus) has a protective value in the evolution of the family Columbidae. In this study, the complete mitogenome of T. sphenurus from Baise City, China, which represents the first sequenced species of the genus Treron in Tribe Treronini, is reported. This was accomplished using PCR-based methods and a primer-walking sequencing strategy with genus-specific primers. The mitogenome was found to be 18,919 bp in length comprising 37 genes, including 13 protein-coding genes, two rRNA genes, 22 tRNA genes, and one control region. In terms of structure and composition, many similarities were found between the T. sphenurus and Hemiphaga novaeseelandiae (New Zealand pigeon) mitogenomes. This was further supported by phylogenetic analysis showing that T. sphenurus has a close evolutionary relationship with H. novaeseelandiae. The complete mitogenome of T. sphenurus reported here is expected to provide valuable molecular information for further studies on the phylogeny of the genus Treron and for analyses of the taxonomic status of the family Columbidae.

Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling.

Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.

Effects of astaxanthin on plasma membrane function and fertility of boar sperm during cryopreservation.

Mammalian sperm is highly susceptible to reactive oxygen species (ROS) during the cryopreservation process. Astaxanthin (AST), a red pigment of the carotenoid family, is recognized as having a variety of beneficial biological activities and effects, including antioxidant, anticancer, anti-diabetic, and anti-inflammatory. The present study aimed to investigate whether the presence of AST protected boar sperm from ROS stress during cryopreservation. Boar sperm was diluted with a freezing medium supplemented with different concentrations of AST (0, 0.5, 1, 2, or 5 µM). The addition of AST, especially at a concentration of 2 µM, exerted positive effects on post-thaw sperm motility parameters. Meanwhile, sperm plasma membrane integrity and acrosome integrity of post-thaw sperm were significantly increased, while lipid peroxidation was inhibited in response to 2 µM AST treatment. Interestingly, compared to the control, supplementation with 2 µM AST increased unsaturated fatty acids (UFAs) levels and decreased saturated fatty acids (SFAs) content in post-thaw sperm, leading to a decreased ratio of SFAs/UFAs in the AST group. In conclusion, the addition of AST to freezing extenders inhibited lipid peroxidation and regulated fatty acid composition of the sperm membrane, improved post-thaw sperm quality, and had no adverse effect on boar sperm in vitro fertilization (IVF) capacity and potential for embryonic development. Our data provide a novel insight into understanding the mechanisms of AST concerning protecting boar sperm quality against ROS damage during cryopreservation.

Effect of L-carnitine on sperm quality during liquid storage of boar semen.

OBJECTIVE: This study was conducted to investigate the effect of L-carnitine on the pig semen characteristics during storage. METHODS: Spermatozoa samples were examined for spermatozoa quality and then randomly divided into 5 groups: 0 (control), 12.5, 25, 50, and 100 mM L-carnitine. Sperm motility, plasma membrane integrity and antioxidant parameters (total reactive oxygen species, total antioxidant capacity, and malondialdehyde) were evaluated after 0, 3, 5, and 10 day cooledstorage at 17°C. Moreover, ATP content, mitochondria activity as well as sperm-binding and in vitro fertilizing ability of preserved boar sperm were also investigated. RESULTS: Supplementation with 50 mM L-carnitine could effectively maintain boar sperm quality parameters such as sperm motility and membrane integrity. Besides, we found that L-carnitine had positive effects on boar sperm quality mainly through improving antioxidant capacities and enhancing ATP content and mitochondria activity. Interestingly, by assessing the effect of L-carnitine on sperm fertility and developmental potential, we discovered that the extender containing L-carnitine could improve sperm quality and increase the number of sperms bounding to zona pellucida, without improving in vitro fertility and development potential. CONCLUSION: These findings suggested that the proper addition of L-carnitine to the semen extender improved boar sperm quality during liquid storage at 17°C.

Protective influence of rosiglitazone against time-dependent deterioration of boar spermatozoa preserved at 17°C.

Spermatozoa are highly specialized cells, and energy metabolism plays an important role in modulating sperm viability and function. Rosiglitazone is an antidiabetic drug in the thiazolidinedione class that regulates metabolic flexibility and glucose uptake in various cell types, but its effects on boar sperm metabolism are unknown. In this study, we investigated the potential effect of rosiglitazone against time-dependent deterioration of boar spermatozoa during liquid preservation at 17°C. Freshly ejaculated semen was diluted with Beltsville Thawing Solution (BTS) containing different concentrations of rosiglitazone, and the motility, membrane and acrosome integrity of sperm were detected. Besides, we measured glucose uptake capacity, l-lactate production level, mitochondrial membrane potential, adenosine triphosphate (ATP) content and mitochondrial reactive oxygen species (mROS) production of sperm after boar semen had been incubated with or without rosiglitazone, iodoacetate (glycolysis inhibitor) and rotenone (electron transport chain inhibitor) for 5 days. The addition of rosiglitazone significantly enhanced sperm quality and had a strong protective effect on the sperm membrane and acrosome integrity during storage. BTS containing 50 µM rosiglitazone maintained the total motility of liquid-preserved sperm above 60% for 7 days. Rosiglitazone improved sperm quality by regulating energy metabolism manner of preserved sperm, protected the sperm mitochondrial membrane potential, enhanced sperm ATP production and in the meanwhile reduced mROS through enhancing glycolysis but not oxidative phosphorylation. The data suggested the practical feasibility of using rosiglitazone for improving boar spermatozoa quality during semen preservation.

The complete mitochondrial genome sequence of Yarkand hare (Lepus yarkandensis).

We first reported the mitochondrial genome of Lepus yarkandensis. The mitogenome of L. yarkandensis contains 17,011 base pairs. The overall base composition of complete mitogenome is 28.13% A, 27.67% T, 22.02% C, and 22.17% G, with 44.20% of the GC content. All genes exhibit the typical mitochondrial gene arrangement and transcribing directions. Phylogenetic analysis of 9 Lepus species was performed based on the sequence of cytochrome b gene using the Maximum Likelihood method in MEGA 7.0. The results suggested that L. yarkandensis is closely related to Lepus timidus. The results are helpful to future studies on molecular evolution, population genetics, and wildlife protection of L. yarkandensis.

Knowledge mapping visualization analysis of the military health and medicine papers published in the web of science over the past 10 years.

BACKGROUND: Military medicine is a research field that seeks to solve the medical problems that occur in modern war conditions based on public medicine theory. METHODS: We explore the main research topics of military health and medical research in the web of science™ core collection (WoSCC) from 2007 to 2016, and the goal of this work is to serve as a reference for orientation and development in military health and medicine. Based on CiteSpace III, a reference co-citation analysis is performed for 7921 papers published in the WoSCC from 2007 to 2016. In addition, a cluster analysis of research topics is performed with a comprehensive analysis of high-yield authors, outstanding research institutions and their cooperative networks. RESULTS: Currently, the research topics in military health and medicine mainly focus on the following seven aspects: mental health diagnoses and interventions, an army study to assess risk and resilience in service members (STARRS), large-scale military action, brain science, veterans, soldier parents and children of wartime, and wound infection. We also observed that the annual publication rate increased with time. Wessely S, Greenberg N, Fear NT, Smith TC, Smith B, Jones N, Ryan MAK, Boyko EJ, Hull L, and Rona RJ were the top 10 authors in military health and medicine research. The top 10 institutes were the Uniformed Services University of the Health Sciences, the United States Army, the United States Navy, Kings College London, Walter Reed National Military Medical Center, Boston University, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Naval Health Research Center, and the VA Boston Healthcare System. CONCLUSIONS: We are able to perform a comprehensive analysis of studies in military health and medicine research and summarize the current research climate and the developmental trends in the WoSCC. However, further studies and collaborations are needed worldwide. Overall, our findings provide valuable information and new perspectives and shape future research directions for further research in the area of military health and medicine.

κ-Opioid Receptor Stimulation Improves Endothelial Function via Akt-stimulated NO Production in Hyperlipidemic Rats.

This study was designed to investigate the effect of U50,488H (a selective κ-opioid receptor agonist) on endothelial function impaired by hyperlipidemia and to determine the role of Akt-stimulated NO production in it. Hyperlipidemic model was established by feeding rats with a high-fat diet for 14 weeks. U50,488H and nor-BNI (a selective κ-opioid receptor antagonist) were administered intraperitoneally. In vitro, the involvement of the PI3K/Akt/eNOS pathway in the effect of U50,488H was studied using cultured endothelial cells subjected to artificial hyperlipidemia. Serum total cholesterol and low-density lipoprotein cholesterol concentrations dramatically increased after high-fat diet feeding. Administration of U50,488H significantly alleviated endothelial ultrastructural destruction and endothelium-dependent vasorelaxation impairment caused by hyperlipidemia. U50,488H also increased Akt/eNOS phosphorylation and serum/medium NO level both in vivo and in vitro. U50,488H increased eNOS activity and suppressed iNOS activity in vivo. The effects of U50,488H were abolished in vitro by siRNAs targeting κ-opioid receptor and Akt or PI3K/Akt/eNOS inhibitors. All effects of U50,488H were blocked by nor-BNI. These results demonstrate that κ-opioid receptor stimulation normalizes endothelial ultrastructure and function under hyperlipidemic condition. Its mechanism is related to the preservation of eNOS phosphorylation through activation of the PI3K/Akt signaling pathway and downregulation of iNOS expression/activity.

Inhibition of CYP2E1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction and apoptosis.

Alcohol intake is associated with myocardial contractile dysfunction and apoptosis although the precise mechanism is unclear. This study was designed to examine the effect of the cytochrome P450 enzyme CYP2E1 inhibition on ethanol-induced cardiac dysfunction. Adult male mice were fed a 4% ethanol liquid or pair-fed control diet for 6weeks. Following 2weeks of diet feeding, a cohort of mice started to receive the CYP2E1 inhibitor diallyl sulfide (100mg/kg/d, i.p.) for the remaining feeding duration. Cardiac function was assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate CYP2E1, heme oxygenase-1 (HO-1), iNOS, the intracellular Ca(2+) regulatory proteins sarco(endo)plasmic reticulum Ca(2+)-ATPase, Na(+)Ca(2+) exchanger and phospholamban, pro-apoptotic protein cleaved caspase-3, Bax, c-Jun-NH(2)-terminal kinase (JNK) and apoptosis signal-regulating kinase (ASK-1). Ethanol led to elevated levels of CYP2E1, iNOS and phospholamban, decreased levels of HO-1 and Na(+)Ca(2+) exchanger, cardiac contractile and intracellular Ca(2+) defects, cardiac fibrosis, overt O(2)(-) production, and apoptosis accompanied with increased phosphorylation of JNK and ASK-1, the effects were significantly attenuated or ablated by diallyl sulfide. Inhibitors of JNK and ASK-1 but not HO-1 inducer or iNOS inhibitor obliterated ethanol-induced cardiomyocyte contractile dysfunction, substantiating a role for JNK and ASK-1 signaling in ethanol-induced myocardial injury. Taken together, these findings suggest that ethanol metabolism through CYP2E1 may contribute to the pathogenesis of alcoholic cardiomyopathy including myocardial contractile dysfunction, oxidative stress and apoptosis, possibly through activation of JNK and ASK-1 signaling.

κ-opioid receptor activation prevents against arrhythmias by preserving Cx43 protein via alleviation of intracellular calcium.

κ-opioid receptor (κ-OR) activation with U50,488H, a selective κ-OR agonist, has been previously demonstrated to prevent against cardiac arrhythmias via stabilizing the synthesis and degradation of an integral membrane protein, Cx43, in gap junctions. However, the exact prevention mechanism remains unclear. The present study tested the hypothesis that the kappa OR agonist U50,488H mediates the prevention of arrhythmia through the regulation of intracellular calcium leading to the preservation of Cx43 protein. By performing electrocardiogram monitoring and immunoblotting in isolated Langendorff-perfused rat hearts, high concentrations of calcium-perfused rat hearts exhibited increased cardiac arrhythmias. Diminished expression of Cx43 protein was observed. The utilization of a whole-cell patch clamp technique revealed that U50,488H inhibited L-type calcium current in single ventricular myocytes in a dose-dependent manner. These effects were blocked by nor-binaltorphimine, potent and selective κ-OR antagonists. Administration of U50,488H before myocardial ischemia resulted in an attenuated of total arrhythmia scores. The attenuation effect was blocked by nor-binaltorphimine. The attenuation effect was antagonized both by Bay K8644, a L-type calcium channel agonist, and also by the Cx43 uncoupler heptanol. Finally, immunoblotting data demonstrated that the preservation of Cx43 protein conferred by U50,488H was reversed in the presence of Bay K8644. In summary, the present study demonstrates κ-OR activation with U50,488H may confer antiarrhythmic effects via modulation of the calcium-Cx43 pathway.

Vasculoprotective effect of U50,488H in rats exposed to chronic hypoxia: role of Akt-stimulated NO production.

Impairment of pulmonary endothelium function in the pulmonary artery is a direct result of chronic hypoxia. This study is to investigate the vasculoprotective effects of U50,488H (a selective κ-opioid receptor agonist) and its underlying mechanism in hypoxia-induced pulmonary artery endothelial functional injury. Chronic hypoxia was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. The pulmonary vascular dysfunction, effect of nitric oxide synthase inhibitor (l-NAME) on the relaxation of U50,488H, and level of nitric oxide (NO) were determined. In vitro, the signaling pathway involved in the anti-apoptotic effect of U50,488H was investigated. Cultured endothelial cells were subjected to simulated hypoxia, and cell apoptosis was determined by TUNEL staining. U50,488H (1.25 mg/kg) significantly reduced RVP and RVHI in hypoxia. U50,488H markedly improved both pulmonary endothelial function (maximal vasorelaxation in response to ACh: 74.9 ± 1.8%, n = 6, P <0.01 vs. hypoxia for 2 wk group) and increased total NO production (1.65 fold). U50,488H relaxed the pulmonary artery rings of the hypoxic rats. This effect was partly abolished by l-NAME. In cells, U50,488H both increased NO production and reduced hypoxia-induced apoptosis. Moreover, pretreatment with nor-binaltorphimine (nor-BNI, a selective κ-opioid receptor antagonist), PI3K inhibitor, Akt inhibitor or l-NAME almost abolished anti-apoptotic effect exerted by U50,488H. U50,488H resulted in increases in Akt and eNOS phosphorylation. These results demonstrate that pretreatment with U50,488H attenuates hypoxia-induced pulmonary vascular endothelial dysfunction in an Akt-dependent and NO-mediated fashion.

Deletion of RBP-J in adult mice leads to the onset of aortic valve degenerative diseases.

Transcription factor RBP-J-mediated Notch signaling has been implicated in several inherited cardiovascular diseases including aortic valve diseases (AVD). But whether Notch signal plays a role in AVD in adults has been unclear. This study aims to test whether the deletion of RBP-J in adult mice would lead to AVD and to investigate the underlying mechanisms. Cre-LoxP-mediated gene deletion was employed to disrupt Notch signal in adult mice. Immunofluorescence and electron microscope observations showed that deletion of RBP-J in adult mice led to early morphological changes of AVD. The size of aortic valve was enlarged. The endothelial homeostasis was perturbed, probably due to the up-regulation of VEGFR2. The endothelial cells exhibited increased proliferation and loose endothelial junctions. The valvular mesenchyme displayed significant fibrosis, consistent with the up-regulation of TGF-ß1 and activation of endothelial-mesenchymal transition. We observed melanin-producing cells in aortic valves. The number of melanin-producing cells increased significantly, and their location changed from the mesenchyme to subendothelial layer of valve cusps in RBP-J deficient mice. These results suggest that RBP-J-mediated Notch signaling in aortic valves may be critically involved in valve homeostasis and valve diseases as well. These findings will be helpful for the understanding of the molecular mechanisms of AVD in adults.

Resveratrol attenuates ischemia/reperfusion injury in neonatal cardiomyocytes and its underlying mechanism.

This study was designed to investigate whether Resveratrol (Res) could be a prophylactic factor in the prevention of I/R injury and to shed light on its underlying mechanism. Primary culture of neonatal rat cardiomyocytes were randomly distributed into three groups: the normal group (cultured cardiomyocytes were in normal conditions), the I/R group (cultured cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion), and the Res+I/R group (100 µmol/L Res was administered before cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion). To test the extent of cardiomyocyte injury, several indices were detected including cell viability, LDH activity, Na(+)-K(+)-ATPase and Ca(2+)-ATPase activity. To test apoptotic cell death, caspase-3 activity and the expression of Bcl-2/Bax were detected. To explore the underlying mechanism, several inhibitors, intracellular calcium, SOD activity and MDA content were used to identify some key molecules involved. Res increased cell viability, Na(+)-K(+)-ATPase and Ca(2+)-ATPase activity, Bcl-2 expression, and SOD level. While LDH activity, capase-3 activity, Bax expression, intracellular calcium and MDA content were decreased by Res. And the effect of Res was blocked completely by either L-NAME (an eNOS inhibitor) or MB (a cGMP inhibitor), and partly by either DS (a PKC inhibitor) or Glybenclamide (a K(ATP) inhibitor). Our results suggest that Res attenuates I/R injury in cardiomyocytes by preventing cell apoptosis, decreasing LDH release and increasing ATPase activity. NO, cGMP, PKC and K(ATP) may play an important role in the protective role of Res. Moreover, Res enhances the capacity of anti-oxygen free radical and alleviates intracellular calcium overload in cardiomyocytes.