ABCG1

A groundbreaking study presents crucial insights into the ocular effects of Zika virus infection during pregnancy and offers promising avenues for therapeutic intervention. A groundbreaking study published in the journal iScience presents crucial insights into the ocular effects of Zika virus infection during pregnancy and offers promising avenues for therapeutic intervention. Produced by a team of researchers in the Department of Ophthalmology, Visual and Anatomical Sciences at the Wayne State University School of Medicine, the paper, "Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology," provides compelling evidence of the involvement of cholesterol metabolism in ZIKV-related eye abnormalities. Zika virus, or ZIKV, has emerged as a public health threat and poses significant challenges to reproductive health worldwide. While congenital ZIKV infection has been shown to cause neurological disorders, primarily microcephaly -- abnormal shrinking of the head circumference -- several clinical studies have linked ZIKV to ocular deformities in infants. These include retinal lesions, microphthalmia, hemorrhagic retinopathy, retinal pigmented epithelium mottling, optic neuritis and hypoplasia of the optic nerve. Despite the ZIKV infection causing severe neurological and ocular abnormalities in infants, no specific vaccines or antiviral treatments are available. In their research, the team conducted a transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells, revealing significant alterations in the cholesterol pathway. "Our study aimed to uncover the molecular mechanisms underlying ZIKV-related eye abnormalities, with a focus on cellular metabolism," said Ashok Kumar, Ph.D., professor of ophthalmology, visual and anatomical sciences, and senior author of the study. "By elucidating the roles of key players in cholesterol metabolism, we sought to identify potential targets for therapeutic intervention." The researchers investigated the functional roles of ATP-binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREBP-2), two critical regulators of cholesterol metabolism, during ocular ZIKV infection. Their cell culture experiments demonstrated that increased ABCG1 activity, mediated via liver X receptors (LXRs), led to reduced ZIKV replication, while inhibition of SREBP-2 reduced viral replication by lowering cholesterol levels. In vivo studies using mouse models of ZIKV-induced chorioretinal lesions revealed that treatment with an LXR agonist or SREBP-2 inhibitor mitigated ocular abnormalities associated with ZIKV infection. These treatments were accompanied by decreased expression of inflammatory mediators and increased activation of antiviral response genes. "This study highlights the intricate interplay between cholesterol metabolism and ZIKV infection in the eye," explained Sneha Singh, Ph.D., a postdoctoral fellow in Kumar's lab. "Our findings suggest that targeting cholesterol pathway components, such as ABCG1 and SREBP-2, could offer promising therapeutic strategies for mitigating ZIKV-induced ocular complications." "The implications of our study extend beyond Zika virus, as the mechanisms uncovered can potentially apply to other enveloped viruses such as West Nile virus, Japanese encephalitis virus and Dengue virus," Kumar said. Kumar's team is utilizing a lipidomics approach to pinpoint lipid molecules possessing both proviral and antiviral properties, with the overarching goal of unearthing novel antiviral therapeutics. The publication of this paper underscores Wayne State's commitment to advancing scientific knowledge and addressing pressing global health challenges. The interdisciplinary collaboration and innovative methodologies employed in this research exemplify the institution's dedication to excellence in scientific inquiry. "Through the innovative research team that Dr. Kumar has established, they are at the forefront of developing breakthroughs that will play a vital role in therapeutic interventions in eye abnormalities caused by the Zika virus," said Ezemenari M. Obasi, Ph.D., vice president for research at Wayne State. "This study is an excellent example of how Wayne State's research is making discoveries that can impact lives in Detroit and around the world." This research was made possible through funding from the National Institutes of Health's National Eye Institute (Grants: R21AI135583, R01EY026964, 1R01EY032149-01 and R01 EY027381).

非酒精性脂肪性肝病(NAFLD)目前是一种日益增长的慢性流行病，并与心血管疾病(CVD)相关。然而，NAFLD如何影响CVD的发生和进展仍然不清楚。2023年9月4日，中山大学凌文华及广州医科大学Xue Hongliang共同通讯在Journal of Hepatology（IF=26）在线发表题为“Hepatic steatosis aggravates atherosclerosis via small extracellular vesicle-mediated inhibition of cellular cholesterol efflux”的研究论文，该研究表明肝脂肪变性通过小细胞外囊泡介导的抑制细胞胆固醇外排加重动脉粥样硬化。来自脂肪变性肝细胞的sEVs通过抑制ABCA在动脉粥样硬化进展中的作用。此外，肝细胞特异性缺失Rab27a可显著改善ApoE-/-小鼠高脂高胆固醇(HFHC)诱导的AS进展。Rab27a是调节sEVs释放的关键GTPase。miRNA深度测序结果显示，脂肪变性肝细胞的sEVs中富集了miR-30a-3p。miR-30a-3p直接靶向ABCA1 3'UTR抑制ABCA1表达和胆固醇外排。anagomiR-30a-3p治疗显著减轻HFHC喂养的ApoE-/-小鼠的动脉粥样硬化进展。此外，NAFLD患者血清sEVs降低了泡沫细胞中的胆固醇外排水平。sEV-miRNA-30a-3p相对含量与泡沫细胞胆固醇外排水平变化呈负相关。总之，脂肪变性肝细胞衍生的sEVs通过miR-30a-3p/ABCA1轴促进泡沫细胞形成和动脉粥样硬化。靶向和减少肝脏脂肪变性sEVs分泌或miR-30a-3p可能是减缓NAFLD驱动的AS进展的潜在治疗方法。久坐不动的生活方式和高热量食物的过度消费导致非酒精性脂肪性肝病(NAFLD)成为全球最普遍的肝病。有证据表明，NAFLD可影响包括心血管疾病(CVDs)在内的主要肝外代谢。肝脂肪变性与CVD和CVD相关事件的风险密切相关。动脉粥样硬化(AS)的发展和进展是心血管疾病的病理生理基础。然而，肝脂肪变性加速AS发展和进展的确切机制尚不清楚。细胞外囊泡(Extracellular vesicles，简称EVs)是源自供体细胞的膜状颗粒，可将其载货蛋白或miRNA运送到受体细胞，在代谢信号的器官间传递中发挥重要作用。作为细胞内通信的载体，EVs载货量可随着供体细胞受到的刺激而改变。小EVs通常指直径小于200 nm的EVs，其中包括外泌体和微泡。脂质超载后，肝细胞来源的sEVs在释放sEVs的数量和组成方面显示出巨大的变化。来自脂肪变性肝细胞的小EVs可加重肝脏炎症和NAFLD进展。然而，来自脂肪性肝细胞的sEVs是否会影响肝外代谢状况，尤其是AS，以及来自肝脂肪变性的细胞特异性信号如何调节AS进展仍然是悬而未决的问题。机理模式图（图源自Journal of Hepatology）动脉内膜中富含胆固醇的泡沫细胞是动脉粥样硬化进展的标志。动脉粥样硬化中泡沫细胞的主要细胞类型是巨噬细胞，巨噬细胞可以通过逆向胆固醇转运降低过量的细胞胆固醇水平 (RCT)。RCT的第一步是HDL通过ABCA1、ABCG1或SR-BI转运蛋白促进巨噬细胞的胆固醇外排，然后HDL-胆固醇被转运到肝脏排泄。越来越多的证据表明，巨噬细胞的RCT损伤会加剧AS的进展。该研究从脂肪变性肝细胞中分离了sEVs，并分析了这些sEVs在泡沫细胞形成和AS进展中的作用。研究结果表明，脂肪变性肝细胞来源的sEVs通过miR-30a-3p/ABCA1途径抑制巨噬细胞RCT，从而加剧泡沫细胞的形成和AS的进展，这表明抑制脂肪变性肝细胞的sEVs分泌或靶向miR-30a-3p可能能够改善NAFLD驱动的AS。此外，该研究肝脂肪变性在AS进展中的因果作用提供了概念验证的实验证据。总之，该研究揭示了肝脂肪变性通过sEVs在AS进展中的因果作用。来自脂肪变性肝细胞的sEVs可通过miR-30a-3p/ABCA1轴促进泡沫细胞形成。靶向和抑制sEVs分泌或miR-30a-3p可能是减轻NAFLD驱动的AS发展和进展的新治疗方法。文章来源“iNture”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

LA JOLLA, Calif., Dec. 06, 2022 (GLOBE NEWSWIRE) -- MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), today announced that MediciNova’s Chief Medical Officer, Kazuko Matsuda, MD PhD MPH, presented positive results from a subgroup analysis of the completed Phase 2 clinical trial which evaluated MN-001 (tipelukast) for the treatment of hypertriglyceridemia at the International Diabetes Federation (IDF) World Diabetes Congress 2022 held online December 5 - 8, 2022. In the completed Phase 2 study, MN-001 (tipelukast) significantly reduced serum triglycerides in participants with non-alcoholic fatty liver disease (NAFLD) and hypertriglyceridemia (HTG). Subsequent in vitro results revealed that MN-001 (tipelukast) downregulated CD36 and upregulated ABCG1 mRNA expression, both of which are highly associated with Type 2 diabetes mellitus (T2DM). Hypothesizing that MN-001 (tipelukast) might be more effective at reducing serum triglycerides in participants with a dual diagnosis of NAFLD and Type 2 diabetes mellitus (T2DM), a subgroup analysis was conducted in participants with and without T2DM. In the presentation entitled, “Improvement of Serum Lipid Panel by Tipelukast (MN-001) in Type 2 Diabetes Mellitus and Non-alcoholic Fatty Liver Disease Patients" (Abstract #LI2022-1192) the following results were announced: Compared to subjects without T2DM, the T2DM group showed a greater reduction in serum triglyceride levels at Week 8 (50.8% reduction for with T2DM versus 17.8% reduction for without T2DM, p=0.098).Mean HDL increase was significantly greater in subjects with T2DM than subjects without T2DM at Week 8 (15.8% versus 1.0%, p<0.0002). In comparison to subjects without T2DM, the T2DM group showed a greater reduction in serum LDL levels at Week 8 (15.4% versus 6.7%). Kazuko Matsuda, M.D. Ph.D., M.P.H., Chief Medical Officer, MediciNova, Inc., commented, “We are very pleased to present this subgroup analysis of the results of our completed Phase 2 trial in individuals diagnosed with NAFLD and hypertriglyceridemia. Those participants with T2DM/prediabetes showed greater improvement in the serum lipid profile than participants without T2DM. These findings suggest that MN-001 is a potential treatment for patients with dyslipidemia and NAFLD due to T2DM. A trial to evaluate the efficacy and safety of MN-001 in patients with T2DM, NAFLD, and HTG is currently ongoing.” About NAFLD, Type 2 Diabetes Mellitus (T2DM), and Hypertriglyceridemia NAFLD is considered the hepatic manifestation of metabolic syndrome; studies have reported that 50% of patients with metabolic syndrome also have NAFLD. There is sufficient clinical and epidemiological evidence supporting the assertion that NAFLD is strongly associated with an increased prevalence and incidence of cardiovascular disease, T2DM, chronic kidney disease, and malignancy. The presence of dyslipidemia (hypercholesterolemia, hypertriglyceridemia, or both) is reported in 20 - 80% of NAFLD cases. About MN-001 MN-001 (tipelukast) is a novel, orally bioavailable, small molecule compound thought to exert its effects through several mechanisms to produce its anti-inflammatory and anti-fibrotic activity in preclinical models, including leukotriene (LT) receptor antagonism, inhibition of phosphodiesterases (PDE) (mainly 3 and 4), and inhibition of 5-lipoxygenase (5-LO). The 5-LO/LT pathway has been postulated as a pathogenic factor in fibrosis development, and MN-001's inhibitory effect on 5-LO and the 5-LO/LT pathway is a novel approach to treat fibrosis. MN-001 has been shown to down-regulate expression of genes that promote fibrosis including LOXL2, Collagen Type 1 and TIMP-1. MN-001 has also been shown to down-regulate expression of genes that promote inflammation including CCR2 and MCP-1. In addition, MN-001 was found to inhibit triglyceride synthesis in hepatocytes by inhibiting arachidonic acid uptake. About MediciNova MediciNova, Inc. is a clinical-stage biopharmaceutical company developing a broad late-stage pipeline of novel small molecule therapies for inflammatory, fibrotic, and neurodegenerative diseases. Based on two compounds, MN-166 (ibudilast) and MN-001 (tipelukast), with multiple mechanisms of action and strong safety profiles, MediciNova has 11 programs in clinical development. MediciNova’s lead asset, MN-166 (ibudilast), is currently in Phase 3 for amyotrophic lateral sclerosis (ALS) and degenerative cervical myelopathy (DCM) and is Phase 3-ready for progressive multiple sclerosis (MS). MN-166 (ibudilast) is also being evaluated in Phase 2 trials in glioblastoma and substance dependence. MN-001 (tipelukast) was evaluated in a Phase 2 trial in idiopathic pulmonary fibrosis (IPF) and a second Phase 2 trial in non-alcoholic fatty liver disease (NAFLD) is ongoing. MediciNova has a strong track record of securing investigator-sponsored clinical trials funded through government grants. Statements in this press release that are not historical in nature constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding the future development and efficacy of MN-166, MN-001, MN-221, and MN-029. These forward-looking statements may be preceded by, followed by, or otherwise include the words "believes," "expects," "anticipates," "intends," "estimates," "projects," "can," "could," "may," "will," "would," “considering,” “planning” or similar expressions. These forward-looking statements involve a number of risks and uncertainties that may cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Factors that may cause actual results or events to differ materially from those expressed or implied by these forward-looking statements include, but are not limited to, risks of obtaining future partner or grant funding for development of MN-166, MN-001, MN-221, and MN-029 and risks of raising sufficient capital when needed to fund MediciNova's operations and contribution to clinical development, risks and uncertainties inherent in clinical trials, including the potential cost, expected timing and risks associated with clinical trials designed to meet FDA guidance and the viability of further development considering these factors, product development and commercialization risks, the uncertainty of whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, risks associated with the reliance on third parties to sponsor and fund clinical trials, risks regarding intellectual property rights in product candidates and the ability to defend and enforce such intellectual property rights, the risk of failure of the third parties upon whom MediciNova relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials, and the timing of expected filings with the regulatory authorities, MediciNova's collaborations with third parties, the availability of funds to complete product development plans and MediciNova's ability to obtain third party funding for programs and raise sufficient capital when needed, and the other risks and uncertainties described in MediciNova's filings with the Securities and Exchange Commission, including its annual report on Form 10-K for the year ended December 31, 2021 and its subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Undue reliance should not be placed on these forward-looking statements, which speak only as of the date hereof. MediciNova disclaims any intent or obligation to revise or update these forward-looking statements. INVESTOR CONTACT: Geoff O'Brien Vice President MediciNova, Inc. info@medicinova.com