Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages

Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that control fatty acid and cholesterol metabolism. As the major SREBP isoform in macrophages, SREBP1a is also required for inflammatory and phagocytotic functions. However, it is insufficiently understood how SREBP1a is activated by the innate immune response in macrophages. Here, we show that mouse caspase-11 is a novel inflammatory activator of SREBP1a in macrophages. Upon LPS treatment, caspase-11 was found to promote the processing of site-1 protease (S1P), an enzyme that mediates the cleavage and activation of SREBP1. We also determined that caspase-11 directly associates with S1P and cleaves it at a specific site. Furthermore, deletion of the Casp4 gene, which encodes caspase-11, impaired the activation of S1P and SREBP1 as well as altered the expression of genes regulated by SREBP1 in macrophages. These results demonstrate that the caspase-11/S1P pathway activates SREBP1 in response to LPS, thus regulating subsequent macrophage activation

Pachychoroid neovasculopathy and age-related macular degeneration.

Pachychoroid neovasculopathy is a recently proposed clinical entity of choroidal neovascularization (CNV). As it often masquerades as neovascular age-related macular degeneration (AMD), it is currently controversial whether pachychoroid neovasculopathy should be distinguished from neovascular AMD. This is because its characteristics have yet to be well described. To estimate the relative prevalence of pachychoroid neovasculopathy in comparison with neovascular AMD and to investigate the phenotypic/genetic differences of the two diseases, we evaluated 200 consecutive Japanese patients who agreed to participate in the genetic study and diagnosed with pachychoroid neovasculopathy or neovascular AMD. Pachychoroid neovasculopathy was observed in 39 individuals (19. 5%), which corresponds to one fourth of neovascular AMD. Patients with pachychoroid neovasculopathy were significantly younger (p = 5. 1 × 10[−5]) and showed a greater subfoveal choroidal thickness (p = 3. 4 × 10[−14]). Their genetic susceptibility to AMD was significantly lower than that of neovascular AMD; ARMS2 rs10490924 (p = 0. 029), CFH rs800292 (p = 0. 013) and genetic risk score calculated from 11 AMD susceptibility genes (p = 3.8 × 10[−3]). Current results implicate that the etiologies of the two conditions must be different. Thus, it will be necessary to distinguish these two conditions in future studie

乳房切断術患者の術後遠隔期におけるQOLに関する研究

根治的乳房切断術を受けた乳癌患者137例について，術後遠隔時のQOLをアンケート調査票を送付して行った．QOLの構成因子を患側上肢の機能障害，Activity　of　Daily　Life（以下ADL），State of　Daily　Life（以下SDL），就労状況，身体的活動意欲，精神的活動意欲，手術満足度，癌再発不安度，ボディ・イメージの変容とした．患側上肢の自覚症状として，腫脹32％，筋力低下25％，疼痛14％，可動域制限14％，知覚異常7％が認められた．ADLを各項目別に検討すると，過半数の例に何らかの支障を認めた．これら機能障害の高度な例では，身体的・精神的活動意欲などの他のQOL因子も有意に不良であった．SDLが術前と不変と回答した例は108例中79％であった．手術不満例は16％であり，上肢の高度機能障害例に多かった．癌再発不安は，65歳以上の高齢者群に比し，65歳未満の若年者群に有意に高く，長期経過例であっても不安は解消されていなかった．乳房喪失というボディ・イメージの変容に対して，大多数の症例がブラジャー，衣服の工夫を行っていた．　以上により種々の程度の上肢の機能障害に対し，各人に適合した補整具の開発やアフタケアを含めた指導や，癌再発不安などに対する継続的な看護が重要であると考えられた．We conducted a questionnaire survey to evaluate the long-term quality of life (QOL) in 137 patients with breast cancer who underwent radical mastectomy. QOL factors consist functional impairment in the upper limb on the affected side, activity of daily life (ADL), state of daily life (SDL), the status of postoperative rehabilitation, mental activities, physical activities, satisfaction of the surgery, anxiety for recurrence of cancer, cosmetic factor (changes in the body image). In the upper limb on the affected side, swelling was observed in 32％, decreased muscle strength in 25％, pain in 14％, limitation in the range of motion in 14％, and sensory impairment in 7％. However, evaluation of the items of the ADL questionnaire revealed specific disturbance in daily life in more than 50％ of respondents. Patients who showed marked functional impairment in this limb had other QOL factors, such as the desire to do mental and physical activiies which were also significantly poor. Of these patients, 108 (79％) replied that state of daily living (SDL) did not change after the survey. Sixteen percent of the patients were not satisfied with the results of their surgery, and they often noted marked functional impairment in the upper limb. Anxiety about recurrence of cancer was more in the middle aged group (65 years or more) than in the aged group (less than 65 old). Anxiety persisted even in patients showing a long survival without regard to aging. Against changes in the body image, ie., loss of the breast, most patients used prosthetic devices in a brassiere and clothes. These results suggested the need to develop prosthetic consultation for each patient, and instruction in post operative care to help prevent functional impairment in the upper limb, continuous nursing intervention to the anxiety about recurrence of cancer might be needed. to various level of the functional impairment in the upper limb

Focal choroidal excavation in eyes with central serous chorioretinopathy.

[Purpose]To study the prevalence and 3-dimensional (3-D) tomographic features of focal choroidal excavations in eyes with central serous chorioretinopathy (CSC) using swept-source optical coherence tomography (OCT). [Design]Prospective, cross-sectional study. [Methods]We examined 116 consecutive eyes with CSC with a prototype 3-D swept-source OCT. 3-D images of the shape of the macular area, covering 6 × 6 mm2, were reconstructed by segmentation of the outer surface of the retinal pigment epithelium (RPE). [Results]The 3-D swept-source OCT detected focal choroidal excavations in 9 eyes (7.8%). The 3-D scanning protocol, coupled with en face scans, allowed for clear visualization of the excavation morphology. In 5 eyes with focal excavations, unusual choroidal tissue was found beneath the excavation, bridging the bottom of the excavation and the outer choroidal boundary. Additionally, 3 of those 5 eyes showed a suprachoroidal space below the excavation, as if the outer choroidal boundary is pulled inward by this bridging tissue. The focal choroidal excavations were located within fluorescein leakage points and areas of choroidal hyperpermeability. Eyes with focal choroidal excavations were more myopic (−4.42 ± 2.92 diopters) than eyes without excavations (−0.27 ± 1.80 diopters, P = .001). Subfoveal choroidal thickness was significantly thinner (301.3 ± 60.1 μm) in eyes with focal excavations than in eyes without the excavations (376.6 ± 104.8 μm, P = .036). [Conclusions]Focal choroidal excavations were present in 7.8% of eyes with CSC. In these eyes, focal choroidal excavations may have formed from RPE retraction caused by focal scarring of choroidal connective tissue

Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis

Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response

Clinical and MRI Characteristics of Uterine Cervical Adenocarcinoma: Its Variants and Mimics

Adenocarcinoma currently accounts for 10–25% of all uterine cervical carcinomas and has a variety of histopathological subtypes. Among them, mucinous carcinoma gastric type is not associated with high-risk human papillomavirus (HPV) infection and a poor prognosis, while villoglandular carcinoma has an association with high-risk HPV infection and a good prognosis. They show relatively characteristic imaging findings which can be suggested by magnetic resonance imaging (MRI), though the former is sometimes difficult to be distinguished from lobular endocervical glandular hyperplasia. Various kinds of other tumors including squamous cell carcinoma should be also differentiated on MRI, while it is currently difficult to distinguish them on MRI, and HPV screening and pathological confirmation are usually necessary for definite diagnosis and further patient management

Krüppel-Like Factors in Metabolic Homeostasis and Cardiometabolic Disease

Members of the Krüppel-like factor (KLF) family of transcription factors, which are characterized by the presence of three conserved Cys2/His2 zinc-fingers in their C-terminal domains, control a wide variety of biological processes. In particular, recent studies have revealed that KLFs play diverse and essential roles in the control of metabolism at the cellular, tissue and systemic levels. In both liver and skeletal muscle, KLFs control glucose, lipid and amino acid metabolism so as to coordinate systemic metabolism in the steady state and in the face of metabolic stresses, such as fasting. The functions of KLFs within metabolic tissues are also important contributors to the responses to injury and inflammation within those tissues. KLFs also control the function of immune cells, such as macrophages, which are involved in the inflammatory processes underlying both cardiovascular and metabolic diseases. This review focuses mainly on the physiological and pathological functions of KLFs in the liver and skeletal muscle. The involvement of KLFs in inflammation in these tissues is also summarized. We then discuss the implications of KLFs' control of metabolism and inflammation in cardiometabolic diseases