Influence of single nucleotide polymorphisms (SNPs) in genetic susceptibility towards periprosthetic osteolysis

Supriya Jagga,SHARMA ASHISH RANJAN,Manojit Bhattacharya,Chiranjib Chakraborty,이상수 한국유전학회 2019 Genes & Genomics Vol.41 No.10

Wear debris-induced inflammatory osteolysis remains a significant limiting factor for implant replacement surgeries. Hence, a comprehensive understanding of the complex network of cellular and molecular signals leading to these inflammatory responses is required. Both macrophages and monocytes have a critical role in the instigation of the inflammatory reaction to wear debris but differ in the extent to which they induce cytokine expression in patients. Lately, single nucleotide polymorphisms (SNPs) have been associated with genetic susceptibility among individual patients with implant failure. Studies have shown that SNPs in key pro-inflammatory cytokines and their receptors are associated with osteolytic susceptibility. Likewise, SNPs within several genes involved in the regulation of bone turnover have also been found to be associated with wear debris induced osteolysis. It is presumed that SNP variance might play a decisive role in the activation and signaling of macrophages, osteoblasts, chondrocytes, fibroblasts and other cells involved in inflammatory bone loss. Understanding the extent to which SNPs exist among genes that are responsible for inflammatory bone loss may provide potential targets for developing future therapeutic interventions. Herein, we attempt to summarize the various susceptible genes with possible SNP variance that could contribute to the severity of periprosthetic osteolysis in patients with implants.

Anti-inflammatory effects of traditional mixed extract of medicinal herbs (MEMH) on monosodium urate crystal-induced gouty arthritis

Nam, J.S.,Jagga, S.,Sharma, A.R.,Lee, J.H.,Park, J.B.,Jung, J.S.,Lee, S.S. Elsevier 2017 Chinese journal of natural medicines Vol.15 No.8

<P>Korean oriental medicine prescription is widely used for the treatment of gouty diseases. In the present study, we investigated anti-inflammatory effects of modified Korean herbal formulation, mixed extract of medicinal herbs (MEMH), and its modulatory effects on inflammatory mediators associated with gouty arthritis. Both in vitro and in vivo studies were carried out to assess the anti-inflammatory efficacy of MEMH on monosodium urate (MSU) crystals-induced gouty inflammation. MSU crystals stimulated human chondrosarcoma cell line, SW1353, and human primary chondrocytes were treated with MEMH in vitro. The expression levels of pro-inflammatory mediators and metalloproteases were analyzed. The effect of MEMH on NF kappa B signaling pathway in SW1353 cells was examined. Effect of MEMH on the mRNA expression level of pro-inflammatory mediators and chemotactic factor from human monocytic cell line, THP-1, was also analyzed. The probable role of MEMH in the differentiation process of osteoblast like cells, SaOS-2, after MSU treatment was also observed. To investigate the effects of MEMH in vivo, MSU crystals-induced ankle arthritic model was established. Histopathological changes in affected joints and plasma levels of pro-inflammatory mediators (IL-1 beta and TNF alpha) were recorded. MEMH inhibited NF kappa B signaling pathway and COX-2 protein expression in chondrocytes. MSU-induced mRNA expressions of pro-inflammatory mediators and chemotactic cytokines were suppressed by MEMH. In MSU crystals-induced ankle arthritic mouse model, administration of MEMH relieved inflammatory symptoms and decreased the plasma levels of IL-1 beta and TNF alpha. The results indicated that MEMH can effectively inhibit the expression of inflammatory mediators in gouty arthritis, demonstrating its potential for treating gouty arthritis.</P>

Interplay between Cartilage and Subchondral Bone Contributing to Pathogenesis of Osteoarthritis

Sharma, Ashish R.,Jagga, Supriya,Lee, Sang-Soo,Nam, Ju-Suk Molecular Diversity Preservation International (MD 2013 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.14 No.10

<P>Osteoarthritis (OA) is a common debilitating joint disorder, affecting large sections of the population with significant disability and impaired quality of life. During OA, functional units of joints comprising cartilage and subchondral bone undergo uncontrolled catabolic and anabolic remodeling processes to adapt to local biochemical and biological signals. Changes in cartilage and subchondral bone are not merely secondary manifestations of OA but are active components of the disease, contributing to its severity. Increased vascularization and formation of microcracks in joints during OA have suggested the facilitation of molecules from cartilage to bone and <I>vice versa</I>. Observations from recent studies support the view that both cartilage and subchondral bone can communicate with each other through regulation of signaling pathways for joint homeostasis under pathological conditions. In this review we have tried to summarize the current knowledge on the major signaling pathways that could control the cartilage-bone biochemical unit in joints and participate in intercellular communication between cartilage and subchondral bone during the process of OA. An understanding of molecular communication that regulates the functional behavior of chondrocytes and osteoblasts in both physiological and pathological conditions may lead to development of more effective strategies for treating OA patients.</P>

Micro-Environmental Signature of The Interactions between Druggable Target Protein, Dipeptidyl Peptidase-IV, and Anti-Diabetic Drugs

Chakraborty, Chiranjib,Mallick, Bidyut,Sharma, Ashish Ranjan,Sharma, Garima,Jagga, Supriya,Doss, C George Priya,Nam, Ju-Suk,Lee, Sang-Soo Royan Institute 2017 Cell journal (Yakhteh) Vol.19 No.1

<P><B>Objective</B></P><P> Druggability of a target protein depends on the interacting micro-environment between the target protein and drugs. Therefore, a precise knowledge of the interacting micro-environment between the target protein and drugs is requisite for drug discovery process. To understand such micro-environment, we performed in silico interaction analysis between a human target protein, Dipeptidyl Peptidase-IV (DPP-4), and three anti-diabetic drugs (saxagliptin, linagliptin and vildagliptin). </P><P><B>Materials and Methods</B></P><P> During the theoretical and bioinformatics analysis of micro-environmental properties, we performed drug-likeness study, protein active site predictions, docking analysis and residual interactions with the protein-drug interface. Micro-environmental landscape properties were evaluated through various parameters such as binding energy, intermolecular energy, electrostatic energy, van der Waals’+H-bond+desolvo energy (E<SUB>VHD</SUB>) and ligand efficiency (LE) using different in silico methods. For this study, we have used several servers and software, such as Molsoft prediction server, CASTp server, AutoDock software and LIGPLOT server. </P><P><B>Results</B></P><P> Through micro-environmental study, highest log P value was observed for linagliptin (1.07). Lowest binding energy was also observed for linagliptin with DPP-4 in the binding plot. We also identified the number of H-bonds and residues involved in the hydrophobic interactions between the DPP-4 and the anti-diabetic drugs. During interaction, two H-bonds and nine residues, two H-bonds and eleven residues as well as four H-bonds and nine residues were found between the saxagliptin, linagliptin as well as vildagliptin cases and DPP-4, respectively. </P><P><B>Conclusion</B></P><P>Our in silico data obtained for drug-target interactions and micro-environmental signature demonstrates linagliptin as the most stable interacting drug among the tested anti-diabetic medicines.</P>

Quercetin induces apoptosis and cell cycle arrest in triple-negative breast cancer cells through modulation of Foxo3a activity

Nguyen, Lich Thi,Lee, Yeon-Hee,Sharma, Ashish Ranjan,Park, Jong-Bong,Jagga, Supriya,Sharma, Garima,Lee, Sang-Soo,Nam, Ju-Suk The Korean Society of Pharmacology 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.2

Quercetin, a plant-derived flavonoid found in fruits, vegetables and tea, has been known to possess bioactive properties such as anti-oxidant, anti-inflammatory and anti-cancer. In this study, anti-cancer effect of quercetin and its underlying mechanisms in triple-negative breast cancer cells was investigated. MTT assay showed that quercetin reduced breast cancer cell viability in a time and dose dependent manner. For this, quercetin not only increased cell apoptosis but also inhibited cell cycle progression. Moreover, quercetin increased FasL mRNA expression and p51, p21 and GADD45 signaling activities. We also observed that quercetin induced protein level, transcriptional activity and nuclear translocation of Foxo3a. Knockdown of Foxo3a caused significant reduction in the effect of quercetin on cell apoptosis and cell cycle arrest. In addition, treatment of JNK inhibitor (SP 600125) abolished quercetin-stimulated Foxo3a activity, suggesting JNK as a possible upstream signaling in regulation of Foxo3a activity. Knockdown of Foxo3a and inhibition of JNK activity reduced the signaling activities of p53, p21 and GADD45, triggered by quercetin. Taken together, our study suggests that quercetin induces apoptosis and cell cycle arrest via modification of Foxo3a signaling in triple-negative breast cancer cells.

Lysophosphatidic acid enhances breast cancer cells-mediated osteoclastogenesis

Ju-Suk Nam,Ashish Ranjan Sharma,Lich Thi Nguyen,Supriya Jagga,Yeon-Hee Lee,Garima Sharma,Sang-Soo Lee 대한생리학회-대한약리학회 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.5

Lysophosphatidic acid (LPA) is known to play a critical role in breast cancer metastasis to bone. In this study, we tried to investigate any role of LPA in the regulation of osteoclastogenic cytokines from breast cancer cells and the possibility of these secretory factors in affecting osteoclastogenesis. Effect of secreted cytokines on osteoclastogenesis was analyzed by treating conditioned media from LPA-stimulated breast cancer cells to differentiating osteoclasts. Result demonstrated that IL-8 and IL-11 expression were upregulated in LPA-treated MDA-MB-231 cells. IL-8 was induced in both MDA-MB-231 and MDA-MB-468, however, IL-11 was induced only in MDA-MB-231, suggesting differential LPARs participation in the expression of these cytokines. Expression of IL-8 but not IL-11 was suppressed by inhibitors of PI3K, NFkB, ROCK and PKC pathways. In the case of PKC activation, it was observed that PKCd and PKCμ might regulate LPA-induced expression of IL-11 and IL-8, respectively, by using specific PKC subtype inhibitors. Finally, conditioned Medium from LPA-stimulated breast cancer cells induced osteoclastogenesis. In conclusion, LPA induced the expression of osteolytic cytokines (IL-8 and IL-11) in breast cancer cells by involving different LPA receptors. Enhanced expression of IL-8 by LPA may be via ROCK, PKCu, PI3K, and NFkB signaling pathways, while enhanced expression of IL-11 might involve PKCd signaling pathway. LPA has the ability to enhance breast cancer cells-mediated osteoclastogenesis by inducing the secretion of cytokines such as IL-8 and IL-11.

Lysophosphatidic acid enhances breast cancer cells-mediated osteoclastogenesis

Nam, Ju-Suk,Sharma, Ashish Ranjan,Nguyen, Lich Thi,Jagga, Supriya,Lee, Yeon-Hee,Sharma, Garima,Lee, Sang-Soo The Korean Society of Pharmacology 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.5

Lysophosphatidic acid (LPA) is known to play a critical role in breast cancer metastasis to bone. In this study, we tried to investigate any role of LPA in the regulation of osteoclastogenic cytokines from breast cancer cells and the possibility of these secretory factors in affecting osteoclastogenesis. Effect of secreted cytokines on osteoclastogenesis was analyzed by treating conditioned media from LPA-stimulated breast cancer cells to differentiating osteoclasts. Result demonstrated that IL-8 and IL-11 expression were upregulated in LPA-treated MDA-MB-231 cells. IL-8 was induced in both MDA-MB-231 and MDA-MB-468, however, IL-11 was induced only in MDA-MB-231, suggesting differential LPARs participation in the expression of these cytokines. Expression of IL-8 but not IL-11 was suppressed by inhibitors of PI3K, NF-kB, ROCK and PKC pathways. In the case of PKC activation, it was observed that $PKC{\delta}$ and $PKC{\mu}$ might regulate LPA-induced expression of IL-11 and IL-8, respectively, by using specific PKC subtype inhibitors. Finally, conditioned Medium from LPA-stimulated breast cancer cells induced osteoclastogenesis. In conclusion, LPA induced the expression of osteolytic cytokines (IL-8 and IL-11) in breast cancer cells by involving different LPA receptors. Enhanced expression of IL-8 by LPA may be via ROCK, PKCu, PI3K, and NFkB signaling pathways, while enhanced expression of IL-11 might involve $PKC{\delta}$ signaling pathway. LPA has the ability to enhance breast cancer cells-mediated osteoclastogenesis by inducing the secretion of cytokines such as IL-8 and IL-11.