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아나볼릭 스테로이드, 선택적 아드로겐 수용체 조절인자, 그리고 마이오스타틴 억제제의 기전에 관한 연구
Jeremy Park,Vera Mcllvain,Jared Rosenberg,Lorin Donovan,Priya Desai,김준영 대한스포츠의학회 2022 대한스포츠의학회지 Vol.40 No.2
In the clinical setting, anabolic agents serve to ameliorate muscle- and bone-wasting diseases. However, many of these anabolic agents are also used by bodybuilders to surpass natural limits of body composition as performance- enhancing drugs (PEDs). The first generation of PEDs comprises testosterone-derived anabolic-androgenic steroids (AAS) which have demonstrated significant myotropic effects. However, AAS lack optimal tissue-selectively and thus, are prone to numerous adverse health consequences. Hence, a newer generation of PEDs, selective androgen receptor modulators (SARMs), was developed with the goal of achieving superior tissue-selectivity (i.e., exerting anabolic effects only in muscle and bone tissue, while minimally affecting other body systems). In general, AAS and SARMs enhance muscle growth primarily through androgen receptor (AR) agonism in target tissues. Despite multiple attempts, no single AAS nor SARM to date is completely risk free. As such, a significant portion of research efforts has been dedicated to manipulating anabolic pathways beyond the AR. Another class of PEDs, myostatin inhibitors, have shown to cause drastic muscle anabolism across multiple species by inhibiting myostatin, the primary deterrent to continuous muscle growth. The myostatin inhibitor, YK-11, blocks myostatin by upregulating its antagonist, follistatin. This effect appears to be mediated through the AR, suggesting a novel and promising gene-selective approach to engineering AR ligands that isolate benefits from risks. At any rate, the exact mechanisms by which these PEDs function is not well understood. Further pioneering regarding these topics is encouraged as it appears that the innovation of a truly tissue-selective anabolic agent is within reach.
Jeremy Park,Vera Mcllvain,Jared Rosenberg,Lorin Donovan,Priya Desai,김준영 대한스포츠의학회 2022 대한스포츠의학회지 Vol.40 No.3
A complex network of biochemical pathways carries out the process of muscle regeneration/growth followingresistance exercise. The initial inflammatory response following muscle damage is primarily mediated by the nuclearfactor κ-light-chain-enhancer of activated B cells (NF-κB), cyclooxygenase enzymes, and prostaglandins. Muscledamage also stimulates the activation, proliferation, differentiation, migration, and fusion of satellite cells ontodamaged myofibers, resulting in myofibrillar hypertrophy. The progression of the myogenic lineage is predominantlycoordinated by the wingless/integrated family of glycoproteins which engages in crosstalk with NF-κB and themitogen-activated protein kinase (MAPK)/extracellular signaling-regulated kinase network. The MAPK cascade isessential for mechanotransduction, the process of converting mechanical stimuli into biochemical responses suchas accelerated protein synthesis and satellite cell activation. Muscle protein synthesis is primarily governed by theinsulin-like growth factor 1/phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway. Several calcium-dependent pathways are also integrated into the process of myogenesis and influence skeletalmuscle plasticity. These dynamic interactions are part of the anabolic priming by resistance exercise effect, whichdefines resistance exercise as an acute catabolic event that potentiates multiple downstream anabolic pathways. Plateaus in muscle growth are attributed to deteriorating inflammatory signaling with repeated bouts of muscledamage as well as increasing thresholds for continuous adaptations, which ultimately become unreachable beyonda certain point. The physiological ceiling of skeletal muscle mass is also credited to myostatin. However, recentdiscoveries suggest the role of myostatin is not limited to preventing excessive skeletal muscle hypertrophy
Park, Sang Min,Lim, Jae Seok,Ramakrishina, Suresh,Kim, Se Hoon,Kim, Woo Kyeong,Lee, Junehawk,Kang, Hoon-Chul,Reiter, Jeremy F.,Kim, Dong Seok,Kim, Hyongbum (Henry),Lee, Jeong Ho Elsevier 2018 Neuron Vol.99 No.1
<P><B>Summary</B></P> <P>Focal malformations of cortical development (FMCDs), including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are major etiologies of pediatric intractable epilepsies exhibiting cortical dyslamination. Brain somatic mutations in <I>MTOR</I> have recently been identified as a major genetic cause of FMCDs. However, the molecular mechanism by which these mutations lead to cortical dyslamination remains poorly understood. Here, using patient tissue, genome-edited cells, and mouse models with brain somatic mutations in <I>MTOR</I>, we discovered that disruption of neuronal ciliogenesis by the mutations underlies cortical dyslamination in FMCDs. We found that abnormal accumulation of OFD1 at centriolar satellites due to perturbed autophagy was responsible for the defective neuronal ciliogenesis. Additionally, we found that disrupted neuronal ciliogenesis accounted for cortical dyslamination in FMCDs by compromising Wnt signals essential for neuronal polarization. Altogether, this study describes a molecular mechanism by which brain somatic mutations in <I>MTOR</I> contribute to the pathogenesis of cortical dyslamination in FMCDs.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Brain somatic mutations in <I>MTOR</I> result in defective neuronal ciliogenesis </LI> <LI> The aberrant accumulation of OFD1 by impaired autophagy disrupts neuronal ciliogenesis </LI> <LI> Defective ciliogenesis accounts for cortical dyslamination in FMCDs </LI> <LI> Defective ciliogenesis abrogates Wnt signaling essential for neuronal polarization </LI> </UL> </P>
Biology of Glioma Cancer Stem Cells
Deric M. Park,Jeremy N. Rich 한국분자세포생물학회 2009 Molecules and cells Vol.28 No.1
Gliomas, much like other cancers, are composed of a het-erogeneous mix of neoplastic and non-neoplastic cells that include both native and recruited cells. There is ex-tensive diversity among the tumor cells, with differing ca-pacity for in vitro and in vivo growth, a property intimately linked to the cell’s differentiation status. Those cells that are undifferentiated, self-renewing, with the capacity for developing tumors (tumorigenic) cells are designated by some as cancer stem cells, because of the stem-like prop-erties. These cells may be a critical therapeutic target. However the exact identity and cell(s) of origin of the so-called glioma cancer stem cell remain elusive. Here we review the current understanding of glioma cancer stem cell biology.
Microneedles: A versatile strategy for transdermal delivery of biological molecules
Lim, Dong-Jin,Vines, Jeremy B.,Park, Hansoo,Lee, Soo-Hong Elsevier 2018 International journal of biological macromolecules Vol.110 No.-
<P><B>Abstract</B></P> <P>Human skin is made up of multiple layers and is designed to protect the human body. The stratum corneum (SC), specifically, is a keratinized layer of skin through which molecules heavier than 500 Da cannot penetrate. Traditional methods of transdermal drug delivery through the SC, such as hypodermic needles, are less than ideal because their size and appearance can cause fear and pain, creating hesitation, limiting self-administration, and preventing their use in some patients altogether. A new technology has been developed to address these limitations, in which an array of needles, each microns in diameter and length, called microneedles, are able to pierce the skin’s SC to deliver therapeutic agents without stimulating the proprioceptive pain nerves. These needles provide a strong advantage because they are capable of being incorporated into patches that can be conveniently self-administered by patients, while also offering the same bioabsorption and bioavailability currently provided by hypodermic needles. There have been many advancements in microneedle fabrication, and there are currently many variations of microneedle technology. Therefore, the purpose of this review is to provide a broad, introductory summary of current microneedle technology.</P>