Cardiac-Specific Suppression of Valosin-Containing Protein Induces Progressive Heart Failure and Premature Mortality Correlating with Temporal Dysregulations in mTOR Complex 2 and Protein Phosphatase 1.

Valosin-containing protein (VCP), an ATPase-associated protein, is emerging as a crucial regulator in cardiac pathologies. However, the pivotal role of VCP in the heart under physiological conditions remains undetermined. In this study, we tested a hypothesis that sufficient VCP expression is required for cardiac development and physiological cardiac function. Thus, we generated a cardiac-specific VCP knockout (KO) mouse model and assessed the consequences of VCP suppression on the heart through physiological and molecular studies at baseline. Our results reveal that homozygous KO mice are embryonically lethal, whereas heterozygous KO mice with a reduction in VCP by ~40% in the heart are viable at birth but progressively develop heart failure and succumb to mortality at the age of 10 to 12 months. The suppression of VCP induced a selective activation of the mammalian target of rapamycin complex 1 (mTORC1) but not mTORC2 at the early age of 12 weeks. The prolonged suppression of VCP increased the expression (by ~2 folds) and nuclear translocation (by >4 folds) of protein phosphatase 1 (PP1), a key mediator of protein dephosphorylation, accompanied by a remarked reduction (~80%) in AKTSer473 phosphorylation in VCP KO mouse hearts at a later age but not the early stage. These temporal molecular alterations were highly associated with the progressive decline in cardiac function. Overall, our findings shed light on the essential role of VCP in the heart under physiological conditions, providing new insights into molecular mechanisms in the development of heart failure.

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database.

AIMS: Avapritinib was first approved by the FDA in January 2020 and represents the first precision-targeted drug for gastrointestinal stromal tumours. However, there is a lack of large-scale data relating to adverse events (AEs) related to its use. We aimed to explore the avapritinib-related AEs in real-world practice based on the post-marketing data. METHODS: We extracted all avapritinib-related reports submitted to the FDA Adverse Event Reporting System (FAERS) by June 2022. Based on disproportionality analysis and Bayesian analysis, we then calculated the reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC) and empirical Bayes geometric mean (EBGM) to evaluate whether there is a significant association between avapritinib and AEs. Gender, age and time to onset were comparable between haemorrhage/non-haemorrhage, serious/non-serious, death/non-death AEs, respectively. RESULTS: In total, 3120 cases related to avapritinib were documented in the FAERS database, and 44% were reported within 30 days of commencing avapritinib. A total of 331 different AE signals were detected, and no significant differences between males and females was identified. Although the number of AEs associated with an abnormal skin texture and executive dysfunction was small, the signal intensity is high, suggesting that these events are strongly correlated with avapritinib. Subgroup analysis showed that elderly male patients were more likely to suffer from serious AEs compared to females (P < .01), but there was no significant difference between the haemorrhage group and the non-haemorrhage group. Analysis of fatalities due to avapritinib-related AEs indicated that sex, age and time-to-onset were all significantly related to death (P < .05). CONCLUSION: Our study provides a more precise description of the incidence and characteristics of AEs after using avapritinib, clinicians should be particularly careful when prescribing avapritinib to elderly male patients, especially within the 30 days.

Thrombotic thrombocytopenic purpura in a patient on long-term alpha-interferon therapy for essential thrombocythemia: a case report.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is rare and severe thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and renal dysfunction. In contrast, essential thrombocythemia (ET) is a myeloproliferative disease associated with an abnormal increase in platelet numbers. Previous studies reported several cases of the development of ET in patients with TTP. However, the case of an ET patient complicated with TTP has not been previously reported. In this case study, we present a patient with TTP who was previously diagnosed with ET. Therefore, to the best of our knowledge, this is the first report of TTP in ET. CASE PRESENTATION: A 31-year-old Chinese female who was previously diagnosed with ET presented with anemia and renal dysfunction. The patient had been on long-term treatment with hydroxyurea, aspirin, and alpha interferon (INF-α) for ten years. The diagnosis of TTP was confirmed by clinical features, schistocytes noted on the peripheral blood smear, and lower ADAMTS13 activity (8.5%), together with the renal biopsy results. INF-α was discontinued, and the patient was then treated with plasma exchange and corticosteroids. After one year of follow-up, the patient had a normal hemoglobin level and platelet numbers, and her ADAMTS13 activity had improved. However, the patient's renal function remains impaired. CONCLUSIONS: We report a case of an ET patient complicated with TTP that was possibly due to INF-α, highlighting the potential complications associated with long-term ET therapy. The case also highlights the importance of considering TTP in patients with pre-existing ET who present with anemia and renal dysfunction, extending the spectrum of known studies.

Prevalence of Theileria in cattle in China: A systematic review and meta-analysis.

Theileria, one of the causative agents of blood protozoan, has brought a huge economic loss to the cattle industry worldwide. However, the epidemiology of Theileria in Chinese cattle has not been systematically investigated. This comprehensive review aimed at investigating the prevalence of Theileria infection in cattle in China. A total of 48 published papers on Theileria infection in cattle in China (including data from 21,366 animals) from inception to October 8, 2021 met the inclusion standard after searching in five databases (Technology Periodical Database, Wan Fang Database, China National Knowledge Infrastructure, PubMed, and ScienceDirect). The pooled prevalence of Theileria in cattle in China was 32.4% identified by using a random effects model. The prevalence in Northeastern China (45.3%) was higher than that in other regions. In the sex subgroup, the prevalence of Theileria was higher in females (48.9%) than that in males (45.8%). The prevalence of Theileria was higher in cattle of free range (34.4%) compared with that of intensive farming (22.3%). The prevalence prior to 2013 (36.1%) was higher than that after 2013 (33.6%). Among three cattle species, dairy cows had the lowest prevalence (21.5%). The prevalence of Theileria (T.) annulata (22.2%) and T. sergenti (26.2%) was higher than other species of Theileria (T. buffeli: 17.5%, T. luwenshuni: 0.9%, T. orientalis: 15.5%, T. ovis: 0.21%, T. sinensis: 20.2%, T. uilenbergi: 6.2%, Others: 0.9%). We also analyzed the impact of different geographic factor subgroups (longitude, latitude, precipitation, temperature, humidity, and altitude) on the prevalence of Theileria in cattle. Among them, climatic factors of longitude, latitude, precipitation, humidity, temperature were associated with the prevalence of Theileria. These analyses suggested that Theileria was common in cattle in China. Targeted prevention programs based on geographic and climatic conditions in different areas may play an important role in reducing Theileria infection among cattle.

Ablation of Sam68 in adult mice increases thermogenesis and energy expenditure.

Genetic deletion of Src associated in mitosis of 68kDa (Sam68), a pleiotropic adaptor protein prevents high-fat diet-induced weight gain and insulin resistance. To clarify the role of Sam68 in energy metabolism in the adult stage, we generated an inducible Sam68 knockout mice. Knockout of Sam68 was induced at the age of 7-10 weeks, and then we examined the metabolic profiles of the mice. Sam68 knockout mice gained less body weight over time and at 34 or 36 weeks old, had smaller fat mass without changes in food intake and absorption efficiency. Deletion of Sam68 in mice elevated thermogenesis, increased energy expenditure, and attenuated core-temperature drop during acute cold exposure. Furthermore, we examined younger Sam68 knockout mice at 11 weeks old before their body weights deviate, and confirmed increased energy expenditure and thermogenic gene program. Thus, Sam68 is essential for the control of adipose thermogenesis and energy homeostasis in the adult.

What is the prognosis of ANCA-associated glomerulonephritis with immune deposition?

OBJECTIVES: This study aimed to analyze histological and clinical characteristics of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) showing renal involvement to investigate the associations between immune complexes (IC) and clinicopathological indicators, and explore the renal outcomes of AAV. METHODS: We retrospectively evaluated the histopathological features and clinical characteristics of 80 renal biopsies of patients with AAV with renal involvement. Renal morphology was classified into two (with and without the presence of IC and complement deposition). Endpoints included end-stage kidney disease (ESKD) and death. RESULTS: Compared with patients without IC, patients with immune deposition had lower complement C3 (0.80 ± 0.27 vs. 0.93 ± 0.20, p = 0.024), more severe hematuria [133 (46-299) vs. 33 (15-115), p = 0.001] but had milder chronic pathology, including chronic tubular atrophy (p = 0.03), chronic interstitial fibrosis (p = 0.049). Patients in the immune deposition group showed a tendency to have more severe crescent formation and less glomerulosclerosis, but the difference was not statistically significant. Endpoints such as death and ESKD were not significantly different between the two groups. CONCLUSIONS: Immune deposition may indicate lower complement C3, more severe hematuria and glomerular lesions, milder tubular atrophy, and interstitial fibrosis, but it cannot predict the renal outcome.

Simple and efficient registration of 3D point cloud and image data for an indoor mobile mapping system.

Registration of 3D lidar point clouds with optical images is critical in the combination of multisource data. Geometric misalignment originally exists in the pose data between lidar point clouds and optical images. To improve the accuracy of the initial pose and the applicability of the integration of 3D points and image data, we develop a simple but efficient registration method. We first extract point features from lidar point clouds and images: point features are extracted from single-frame lidar and point features are extracted from images using a classical Canny operator. The cost map is subsequently built based on Canny image edge detection. The optimization direction is guided by the cost map, where low cost represents the desired direction, and loss function is also considered to improve the robustness of the proposed method. Experiments show positive results.

Molecular detection of Blastocystis in black bears and sika deer in northern China.

Protists of the Blastocystis genus are distributed worldwide and can infect a range of hosts. However, data concerning Blastocystis infection are limited for sika deer and are not available for black bears. Therefore, in the present study, a total of 312 black bears (Ursus thibetanus) from Heilongjiang Province and 760 sika deer (Cervus nippon) from four different northern Chinese provinces were investigated. Blastocystis infection in these animals was detected via PCR amplification of the small subunit rRNA gene in fecal samples. The prevalence of Blastocystis infection in black bears and sika deer was 14.4% (45/312 positive samples) and 0.8% (6/760 positive samples), respectively. Young black bears (18.3%) had a significantly higher Blastocystis prevalence than adult bears (9.1%). The prevalence of Blastocystis was significantly higher in black bears raised outdoors (24.6%) than in bears raised indoors (12.2%). Blastocystis-positive sika deer were only found in Jilin Province (1.3%, 6/480). Female sika deer (0%, 0/61) had a significantly lower Blastocystis prevalence than males (0.9%, 6/699). Sanger sequencing was used to determine the small subunit rRNA gene sequences of the Blastocystis-positive PCR products. A neighbor-joining phylogenetic tree based on the small subunit rRNA gene sequences showed that only Blastocystis subtype (ST)1 was identified in black bears, whereas ST10 and ST14 were found in sika deer. This is the first report of Blastocystis ST1 infection in black bears. These findings also extend the distribution information of Blastocystis subtypes, which will provide a foundation for further study of Blastocystis in different hosts in China.

Interleukin-1ß in Multifactorial Hypertension: Inflammation, Vascular Smooth Muscle Cell and Extracellular Matrix Remodeling, and Non-Coding RNA Regulation.

The biological activities of interleukins, a group of circulating cytokines, are linked to the immuno-pathways involved in many diseases. Mounting evidence suggests that interleukin-1ß (IL-1ß) plays a significant role in the pathogenesis of various types of hypertension. In this review, we summarized recent findings linking IL-1ß to systemic arterial hypertension, pulmonary hypertension, and gestational hypertension. We also outlined the new progress in elucidating the potential mechanisms of IL-1ß in hypertension, focusing on it's regulation in inflammation, vascular smooth muscle cell function, and extracellular remodeling. In addition, we reviewed recent studies that highlight novel findings examining the function of non-coding RNAs in regulating the activity of IL-1ß and its associated proteins in the setting of hypertension. The information collected in this review provides new insights into understanding the pathogenesis of hypertension and could lead to the discovery of new anti-hypertensive therapies to combat this highly prevalent disease.

Structural and Functional Remodeling of Mitochondria in Cardiac Diseases.

Mitochondria undergo structural and functional remodeling to meet the cell demand in response to the intracellular and extracellular stimulations, playing an essential role in maintaining normal cellular function. Merging evidence demonstrated that dysregulation of mitochondrial remodeling is a fundamental driving force of complex human diseases, highlighting its crucial pathophysiological roles and therapeutic potential. In this review, we outlined the progress of the molecular basis of mitochondrial structural and functional remodeling and their regulatory network. In particular, we summarized the latest evidence of the fundamental association of impaired mitochondrial remodeling in developing diverse cardiac diseases and the underlying mechanisms. We also explored the therapeutic potential related to mitochondrial remodeling and future research direction. This updated information would improve our knowledge of mitochondrial biology and cardiac diseases' pathogenesis, which would inspire new potential strategies for treating these diseases by targeting mitochondria remodeling.

Molecular detection of Cryptosporidium spp. and Enterocytozoon bieneusi in Longjiang Wagyu cattle in Northeastern China.

Cryptosporidium spp. and Enterocytozoon bieneusi are two important zoonotic pathogens that can cause diarrhea and other gastrointestinal illnesses in humans and animals. However, the prevalence and genotype of the parasites in Longjiang Wagyu cattle in Heilongjiang Province, Northeast China have not been reported. In the present study, a total of 423 fecal samples of Longjiang Wagyu cattle collected from different farms in Heilongjiang Province, Northeast China, were examined for Cryptosporidium spp. and E. bieneusi using nested PCR. The overall infection rates for Cryptosporidium spp. and E. bieneusi were 6.38% (n = 27) and 7.09% (n = 30), respectively. The prevalence in different age groups ranged from 3.80% (95% confidence interval (CI) 1.01-6.59) to 8.36% (95% CI 4.83-11.90) for Cryptosporidium spp. and 5.97% (95% CI 2.52-9.43) to 7.94% (95% CI 4.49-11.40) for E. bieneusi. By analyzing the DNA sequences of the small subunit (SSU) rRNA gene, two Cryptosporidium species were detected in this study, namely C. parvum (n = 25) and C. ryanae (n = 2). The IIdA20G1 subtype was further identified by using the 60-kDa glycoprotein (gp60) gene of C. parvum. E. bieneusi was identified using three known sequences through the analysis of internal transcribed spacer (ITS) sequences: J (n = 23), I (n = 5), and BEB4 (n = 2), and all belonged to group 2. The results indicated that some of the Cryptosporidium species and E. bieneusi genotypes identified in Longjiang Wagyu cattle in the study areas might have zoonotic potential.

E2F1 Suppresses Oxidative Metabolism and Endothelial Differentiation of Bone Marrow Progenitor Cells.

RATIONALE: The majority of current cardiovascular cell therapy trials use bone marrow progenitor cells (BM PCs) and achieve only modest efficacy; the limited potential of these cells to differentiate into endothelial-lineage cells is one of the major barriers to the success of this promising therapy. We have previously reported that the E2F transcription factor 1 (E2F1) is a repressor of revascularization after ischemic injury. OBJECTIVE: We sought to define the role of E2F1 in the regulation of BM PC function. METHODS AND RESULTS: Ablation of E2F1 (E2F1 deficient) in mouse BM PCs increases oxidative metabolism and reduces lactate production, resulting in enhanced endothelial differentiation. The metabolic switch in E2F1-deficient BM PCs is mediated by a reduction in the expression of pyruvate dehydrogenase kinase 4 and pyruvate dehydrogenase kinase 2; overexpression of pyruvate dehydrogenase kinase 4 reverses the enhancement of oxidative metabolism and endothelial differentiation. Deletion of E2F1 in the BM increases the amount of PC-derived endothelial cells in the ischemic myocardium, enhances vascular growth, reduces infarct size, and improves cardiac function after myocardial infarction. CONCLUSION: Our results suggest a novel mechanism by which E2F1 mediates the metabolic control of BM PC differentiation, and strategies that inhibit E2F1 or enhance oxidative metabolism in BM PCs may improve the effectiveness of cell therapy.

Prevalence of Clonorchis sinensis infection in fish in South-East Asia: A systematic review and meta-analysis.

Clonorchis sinensis, an important fish-borne zoonotic trematode, is widely distributed in South-East Asia, especially in China. Infections from human and animal reservoir hosts occur due to the consumption of raw or undercooked fish with C. sinensis metacercariae. This study aimed to evaluate the prevalence of C. sinensis metacercariae in fish in South-East Asia via systematic review and meta-analysis. We searched PubMed, ScienceDirect, China National Knowledge Infrastructure, Wanfang and Chongqing VIP databases for studies published between 1976 and 2020 that are related to the prevalence of C. sinensis metacercariae in fish. Studies were screened with keywords based on inclusion and exclusion criteria. Seventy-one eligible articles were identified, covering three countries: China, Korea and Vietnam. The pooled prevalence of C. sinensis metacercariae in fish from South-East Asia was 30.5%, with 35.1% in China, 29.7% in Korea and 8.4% in Vietnam. In subgroup analyses of climate, season, water source and publication date, the highest prevalence was identified in the Dwb climate type (43.3%), summer (70.2%), river (34.5%) and pre-2001 publications (38.9%), respectively. In comparison, the lowest prevalence was found in the Dfa climate type (14.5%), winter (19.5%), lake (8.0%) and post-2001 publications (23.8%). Meta-regression results indicated that country (p = .009), the published time (p = .035) and water source subgroups (p = .003) may be the source of heterogeneity. Overall, our study indicates that a high prevalence of C. sinensis infections occurs in fish in China, Korea and Vietnam, illuminating a significant public health concern in these countries.

Molecular detection of Cryptosporidium and Enterocytozoon bieneusi in dairy calves and sika deer in four provinces in Northern China.

The protistan pathogens Cryptosporidium and Enterocytozoon bieneusi can cause significant intestinal diseases in animals and humans. However, limited information is available regarding prevalence and molecular characterization of Cryptosporidium and E. bieneusi in ruminants in Northern China. In this study, the overall prevalence of Cryptosporidium and E. bieneusi was 19.3% (62/321) and 28.97% (93/321) in dairy calves and 1.10% (9/818) and 13.57% (111/818) in sika deer (Cervus nippon) in four provinces in Northern China, respectively. The prevalence of Cryptosporidium and E. bieneusi in different factor groups was various. Five Cryptosporidium species/genotypes were identified, of which C. parvum, C. ryanae, C. bovis, and C. andersoni were only found in dairy calves, and only Cryptosporidium deer genotype was found in sika deer. Moreover, J, I, and BEB4 ITS genotypes of E. bieneusi were found in dairy calves, and six known genotypes (JLD-III, JLD-IX, JLD-VII, EbpC, BEB6, and I) and ten novel genotypes (namely LND-I and JLD-XV to JLD-XXIII) were found in sika deer in this study. Cryptosporidium parvum and E. bieneusi genotype J were identified as the predominant species/genotypes in dairy calves, whereas the predominance of Cryptosporidium spp. and E. bieneusi in sika deer was Cryptosporidium deer genotype and BEB6, respectively. The present study reported the prevalence and genotypes of Cryptosporidium and E. bieneusi in dairy calves and sika deer in four provinces in northern China. The present findings also suggest that investigated dairy calves and sika deer may play an important role in the transmission of E. bieneusi and Cryptosporidium to humans and other animals, and also in an effort to better understand the epidemiology of these enteric pathogens in China.

The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart.

Calcium ion (Ca2+) plays a critical role in the cardiac mitochondria function. Ca2+ entering the mitochondria is necessary for ATP production and the contractile activity of cardiomyocytes. However, excessive Ca2+ in the mitochondria results in mitochondrial dysfunction and cell death. Mitochondria maintain Ca2+ homeostasis in normal cardiomyocytes through a comprehensive regulatory mechanism by controlling the uptake and release of Ca2+ in response to the cellular demand. Understanding the mechanism of modulating mitochondrial Ca2+ homeostasis in the cardiomyocyte could bring new insights into the pathogenesis of cardiac disease and help developing the strategy to prevent the heart from damage at an early stage. In this review, we summarized the latest findings in the studies on the cardiac mitochondrial Ca2+ homeostasis, focusing on the regulation of mitochondrial calcium uptake, which acts as a double-edged sword in the cardiac function. Specifically, we discussed the dual roles of mitochondrial Ca2+ in mitochondrial activity and the impact on cardiac function, the molecular basis and regulatory mechanisms, and the potential future research interest.

Valosin-Containing Protein, a Calcium-Associated ATPase Protein, in Endoplasmic Reticulum and Mitochondrial Function and Its Implications for Diseases.

Endoplasmic reticulum (ER) and mitochondrion are the key organelles in mammal cells and play crucial roles in a variety of biological functions in both physiological and pathological conditions. Valosin-containing protein (VCP), a newly identified calcium-associated ATPase protein, has been found to be involved in both ER and mitochondrial function. Impairment of VCP, caused by structural mutations or alterations of expressions, contributes to the development of various diseases, through an integrating effect on ER, mitochondria and the ubiquitin-proteasome system, by interfering with protein degradation, subcellular translocation and calcium homeostasis. Thus, understanding the role and the molecular mechanisms of VCP in these organelles brings new insights to the pathogenesis of the associated diseases, and leads to the discovery of new therapeutic strategies. In this review, we summarized the progress of studies on VCP, in terms of its regulation of ER and mitochondrial function and its implications for the associated diseases, focusing on the cancers, heart disease, and neurodegenerative disorders.

Interleukin-36 Cytokine/Receptor Signaling: A New Target for Tissue Fibrosis.

Tissue fibrosis is a major unresolved medical problem, which impairs the function of various systems. The molecular mechanisms involved are poorly understood, which hinders the development of effective therapeutic strategies. Emerging evidence from recent studies indicates that interleukin 36 (IL-36) and the corresponding receptor (IL-36R), a newly-characterized cytokine/receptor signaling complex involved in immune-inflammation, play an important role in the pathogenesis of fibrosis in multiple tissues. This review focuses on recent experimental findings, which implicate IL-36R and its associated cytokines in different forms of organ fibrosis. Specifically, it outlines the molecular basis and biological function of IL-36R in normal cells and sums up the pathological role in the development of fibrosis in the lung, kidney, heart, intestine, and pancreas. We also summarize the new progress in the IL-36/IL-36R-related mechanisms involved in tissue fibrosis and enclose the potential of IL-36R inhibition as a therapeutic strategy to combat pro-fibrotic pathologies. Given its high association with disease, gaining new insight into the immuno-mechanisms that contribute to tissue fibrosis could have a significant impact on human health.

The Role of Cell Cycle Regulators in Cell Survival-Dual Functions of Cyclin-Dependent Kinase 20 and p21Cip1/Waf1.

The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies.

Sam68 impedes the recovery of arterial injury by augmenting inflammatory response.

OBJECTIVE: The role of Src-associated-in-mitosis-68-kDa (Sam68) in cardiovascular biology has not been studied. A recent report suggests that Sam68 promotes TNF-α-induced NF-κB activation in fibroblasts. Here we sought to dissect the molecular mechanism by which Sam68 regulates NF-κB signaling and its functional significance in vascular injury. APPROACH AND RESULTS: The endothelial denudation injury was induced in the carotid artery of Sam68-null (Sam68-/-) and WT mice. Sam68-/- mice displayed an accelerated re-endothelialization and attenuated neointima hyperplasia, which was associated with a reduced macrophage infiltration and lowered expression of pro-inflammatory cytokines in the injured vessels. Remarkably, the ameliorated vascular remodeling was recapitulated in WT mice after receiving transplantation of bone marrow (BM) from Sam68-/- mice, suggesting the effect was attributable to BM-derived inflammatory cells. In cultured Raw264.7 macrophages, knockdown of Sam68 resulted in a significant reduction in the TNF-α-induced expression of TNF-α, IL-1ß, and IL-6 and in the level of nuclear phospho-p65, indicating attenuated NF-κB activation; and these results were confirmed in peritoneal and BM-derived macrophages of Sam68-/- vs. WT mice. Furthermore, co-immunoprecipitation and mass-spectrometry identified Filamin A (FLNA) as a novel Sam68-interacting protein upon TNF-α treatment. Loss- and gain-of-function experiments suggest that Sam68 and FLNA are mutually dependent for NF-κB activation and pro-inflammatory cytokine expression, and that the N-terminus of Sam68 is required for TRAF2-FLNA interaction. CONCLUSIONS: Sam68 promotes pro-inflammatory response in injured arteries and impedes recovery by interacting with FLNA to stabilize TRAF2 on the cytoskeleton and consequently potentiate NF-κB signaling.

Non-Coding RNA in the Pathogenesis, Progression and Treatment of Hypertension.

Hypertension is a complex, multifactorial disease that involves the coexistence of multiple risk factors, environmental factors and physiological systems. The complexities extend to the treatment and management of hypertension, which are still the pursuit of many researchers. In the last two decades, various genes have emerged as possible biomarkers and have become the target for investigations of specialized drug design based on its risk factors and the primary cause. Owing to the growing technology of microarrays and next-generation sequencing, the non-protein-coding RNAs (ncRNAs) have increasingly gained attention, and their status of redundancy has flipped to importance in normal cellular processes, as well as in disease progression. The ncRNA molecules make up a significant portion of the human genome, and their role in diseases continues to be uncovered. Specifically, the cellular role of these ncRNAs has played a part in the pathogenesis of hypertension and its progression to heart failure. This review explores the function of the ncRNAs, their types and biology, the current update of their association with hypertension pathology and the potential new therapeutic regime for hypertension.