Statins, Competitive Inhibitors of HMG-Co Reductase Integral to Cholesterol Biosynthesis, as Immune Modulators

Rema Naskar, Inkyu Hwang 충남대학교 약학대학 의약품개발연구소 2021 藥學論文集 Vol.36 No.-

Statins are cholesterol-lowering agents extensively used for the prevention of cardiovascular dis- eases related to hypercholesterolemia. They are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) to catalyze the conversion of HMG-CoA to mevalonate, a rate-limiting reaction in the mevalonate pathway for cholesterol biosynthesis. The inhibition of HMGCR causes a decrease in the rates of syntheses of cholesterol and other intermediates such as farnesyl pyrophosphates and geranylgeranyl pyrophosphate, which are necessary for anchoring GTP-binding proteins to the plasma membrane. While statins were originally developed as cholesterol-lowering drugs, many studies have also unveiled their im- mune-regulatory properties, implying the possibilities for repositioning statins to treat various immune disorders. Mechanisms for the immune regulation by statins have also been investigated, highlighting the im- portance of both cholesterol and isoprenoid pyrophosphates in the activation and survival of immune cells and the production of cytokines and other inflammatory mediators. This review summarizes the anti-inflammatory and immunomodulatory effects of statins and the underlying mechanisms.

Segmentation of Human Intestinal Parasites from Microscopy Images Using Localized Mean-Separation Based Active Contour Model

Madhu S. Nair,Rema M. 대한의용생체공학회 2013 Biomedical Engineering Letters (BMEL) Vol.3 No.3

Purpose Identification of human intestinal parasites from microscopy images of fecal sample is an important and time consuming process in the diagnosis of intestinal parasitosis. Automatic image processing can be applied to segment and identify the parasite but the presence of fecal impurities makes this process a challenging one. This paper presents a framework for segmentation of bright field microscopy images of fecal sample that contain both parasites and impurities. Methods The proposed framework uses thresholding,morphological opening and Active Contour Model (ACM). Contour is initialized using thresholding and morphological opening and the contour is evolved using Localized Mean-Separation based Active Contour Model (LMS-ACM). Results This framework is simple, fast and yields good results even when the parasites are overlapped with impurities. The accuracy of the method is tested by comparing the results with manually segmented images. Conclusions As accurate segmentation of the objects is the first and important step in identification process, this work is a promising approach towards the automatic diagnosis of human intestinal parasitosis.

Clinical characteristics and treatment outcomes of primary autoimmune hemolytic anemia: a single center study from South India

Raghuveer Prabhu,Renjitha Bhaskaran,Veena Shenoy,Rema G,Neeraj Sidharthan 대한혈액학회 2016 Blood Research Vol.51 No.2

BackgroundAutoimmune hemolytic anemia (AIHA) is a less recognized, potentially fatal condition. There is a scarcity of data on clinicoserological characteristics and response to therapy concerning this disease from South India.MethodsData for 33 patients with primary AIHA recorded from July 2009 to June 2015 were retro-spectively analyzed for clinical presentation, response to frontline therapy, durability of response, time to next treatment (TTNT), and response to second-line agents.ResultsThe median follow-up period was 50 months. Among 33 patients, 48% of the cases were warm autoimmune hemolytic anemia (WAIHA), 46% were cold agglutinin disease (CAD), and 6% were atypical. Three-fourth of patients had severe anemia (<8 g/dL hemoglobin [Hb]) at onset; younger patients (age <40 yr) had more severe anemia. All of the patients who required treatment received oral prednisolone at 1.5 mg/kg/d as a frontline therapy, and the response rate was 90% (62% complete response [CR] and 28% partial response [PR]). The overall response to corticosteroids in WAIHA and CAD was 87% and 92%, respectively. The median corticosteroid duration was 14 months, and 50% of the patients required second-line agents. Fourteen patients received azathioprine as a second-line agent, and 11 of these patients responded well, with half of them not requiring a third agent. Four patients developed severe infections (pneumonia, sepsis, and soft tissue ab-scess) and two had life-threatening venous thrombosis. One case of death was recorded.ConclusionAIHA is a heterogeneous disease that requires care by physicians experienced in treating these patients.

Infusing the axioms of clinical reasoning while designing clinical anatomy case vignettes teaching for novice medical students: a randomised cross over study

Dinesh Kumar,V,Rajprasath R,N,A,Priyadharshini,Magi Murugan,Rema Devi 대한해부학회 2020 Anatomy & Cell Biology Vol.53 No.2

The clinical reasoning skills is often gained when the biomedical knowledge is broadened and deepened alongside exposure to patients. The ‘ideal’ blend of axioms of clinical reasoning and case based learning would establish the pedagogical bridges right from the first year of medical education. So this study aimed to investigate the perceived importance and efficacy of teaching clinical reasoning skills among first year medical students, as this has not previously been described. As a priori, two clinical reasoning skill sessions were conducted using clinico-anatomical case vignettes designed according to the literature regarding clinical reasoning (‘serial cue’ approach and hypothetico-deduction). Students were divided into intervention and control group and crossed over in subsequent sessions. Analysis was done by mixed method approach including measuring proof of benefit using post-test comparison, quantitative survey and qualitative analysis by nominal group discussion. Post test scores were compared using student’s t-test. Feedbacks were analysed using descriptive statistics. The results showed that post test scores were significantly higher in intervention group than the control group in both sessions (P<0.001, 0.016). A total of 66% students felt, diagnostic skills and lateral thinking abilities were improved and It helped in developing problem-solving abilities for 67% students. clinico-anatomical case vignettes helped in understanding anatomical basis of clinical conditions for 61% students. To conclude, introducing clinical reasoning has considerable effect in improving the decision making ability of the students and if incorporated right from the first year, would better prepare the students in successful transition to clinical learning environment.

RAP80 binds p32 to preserve the functional integrity of mitochondria

Chung, Hee Jin,Korm, Sovannarith,Lee, Se-in,Phorl, Sophors,Noh, Solhee,Han, Miae,Naskar, Rema,Kim, Hongtae,Lee, Joo-Yong Academic Press 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>RAP80, a member of the BRCA1-A complex, is a well-known crucial regulator of cell cycle checkpoint and DNA damage repair in the nucleus. However, it is still unclear whether Rap80 localizes to another region outside the nucleus and plays different roles with its partners. Here, we found mitochondrial p32 as a novel binding partner of RAP80 by using yeast two-hybrid screening. RAP80 directly binds the internal region of p32 through its arginine rich C-terminal domain. Based on the interaction, we showed that a subset of RAP80 localizes to mitochondria where p32 exists. Loss of function study revealed that RAP80 deficiency reduces the protein level of p32 and p32 dependent mitochondrial translating proteins such as Rieske and COX1. As a result, mitochondrial membrane potential and oxygen consumption are reduced in RAP80 knockdown cells, indicating mitochondrial dysfunction. Our study identifies a novel interaction between RAP80 and p32, which is important for preserving intact mitochondrial function.</P> <P><B>Highlights</B></P> <P> <UL> <LI> RAP80 binds p32 through its arginine rich C-terminal region. </LI> <LI> The loss of RAP80 expression reduces the protein level of p32. </LI> <LI> The RAP80-p32 interaction is essential for maintaining the integrity of mitochondrial function. </LI> </UL> </P>

HDAC6 deficiency induces apoptosis in mesenchymal stem cells through p53 K120 acetylation

Park, Song-Yi,Phorl, Sophors,Jung, Suna,Sovannarith, Korm,Lee, Se-in,Noh, Solhee,Han, Miae,Naskar, Rema,Kim, Jae-Young,Choi, Yun-Jaie,Lee, Joo-Yong Academic Press 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>The acetylation of p53 is critical in modulating its pro-apoptotic roles. However, its regulatory mechanism and physiological significance are unclear. Here, we show HDAC6 negatively regulates pro-apoptotic acetylation of p53 at lysine residue 120 (K120) in mesenchymal stem cells (MSCs). The loss of HDAC6 expression in MSCs increases K120 acetylation of p53, which is successfully reversed by the wild-type but not by catalytically dead HDAC6. Deletion of HDAC6 induces caspase-dependent apoptosis by promoting transactivation of Bax and suppression of Bcl-2. Moreover, HDAC6 deficiency leads to mitochondrial dysfunction characterized by aberrant reactive oxygen species production and defective oxidative phosphorylation, which is reversed by ectopic expression of wild-type or acetylation mimetic p53. This study demonstrates that HDAC6 is a critical regulator of a pro-apoptotic p53 K120 acetylation and mitochondrial function in MSCs, suggesting that the modulation of HDAC6 activity could be a novel approach to improve MSC- based therapies.</P>

HDAC6 regulates thermogenesis of brown adipocytes through activating PKA to induce UCP1 expression

Jung, Suna,Han, Miae,Korm, Sovannarith,Lee, Se-in,Noh, Solhee,Phorl, Sophors,Naskar, Rema,Lee, Kye-Sung,Kim, Geon-Hee,Choi, Yun-Jaie,Lee, Joo-Yong Elsevier 2018 Biochemical and biophysical research communication Vol.503 No.1

<P><B>Abstract</B></P> <P>Mitochondrial uncoupling protein 1 (UCP1) is responsible for nonshivering thermogenesis in brown adipose tissue (BAT). UCP1 increases the conductance of the inner mitochondrial membrane (IMM) for protons to make BAT mitochondria generate heat rather than ATP. HDAC6 is a cytosolic deacetylase for non-histone substrates to regulate various cellular processes, including mitochondrial quality control and dynamics. Here, we showed that the body temperature of HDAC6 knockout mice is slightly decreased in normal hosing condition. Interestingly, UCP1 was downregulated in BAT of HDAC6 knockout mice, which extensively linked mitochondrial thermogenesis. Mechanistically, we showed that cAMP-PKA signaling plays a key role in HDAC6-dependent UCP1 expression. Notably, the size of brown adipocytes and lipid droplets in HDAC6 knockout BAT is increased. Taken together, our findings suggested that HDAC6 contributes to mitochondrial thermogenesis in BAT by increasing UCP1 expression through cAMP-PKA signaling pathway.</P> <P><B>Highlights</B></P> <P> <UL> <LI> HDAC6 regulates thermogenesis of brown adipose tissue. </LI> <LI> cAMP-PKA signaling is responsible for HDAC6-dependent thermogenic regulation to control UCP1 expression. </LI> <LI> HDAC6-dependent regulation of UCP1 affects lipid metabolism in brown adipose tissue. </LI> </UL> </P>