Suneesh Kaimala - Academia.edu (original) (raw)

Papers by Suneesh Kaimala

Advanced science, May 5, 2024

Nucleic Acids Research, 2019

The metabolic sensor Per-Arnt-Sim (Pas) domain-containing serine/threonine kinase (PASK) is expre... more The metabolic sensor Per-Arnt-Sim (Pas) domain-containing serine/threonine kinase (PASK) is expressed predominantly in the cytoplasm of different cell types, although a small percentage is also expressed in the nucleus. Herein, we show that the nuclear PASK associates with the mammalian H3K4 MLL2 methyltransferase complex and enhances H3K4 di- and tri-methylation. We also show that PASK is a histone kinase that phosphorylates H3 at T3, T6, S10 and T11. Taken together, these results suggest that PASK regulates two different H3 tail modifications involving H3K4 methylation and H3 phosphorylation. Using muscle satellite cell differentiation and functional analysis after loss or gain of Pask expression using the CRISPR/Cas9 system, we provide evidence that some of the regulatory functions of PASK during development and differentiation may occur through the regulation of these histone modifications.

PeerJ

Background Osteoporosis is a significant co-morbidity of type 1 diabetes mellitus (DM1) leading t... more Background Osteoporosis is a significant co-morbidity of type 1 diabetes mellitus (DM1) leading to increased fracture risk. Exercise-induced hormone ‘irisin’ in low dosage has been shown to have a beneficial effect on bone metabolism by increasing osteoblast differentiation and reducing osteoclast maturation, and inhibiting apoptosis and inflammation. We investigated the role of irisin in treating diabetic osteopathy by observing its effect on trabecular bone. Methods DM1 was induced by intraperitoneal injection of streptozotocin 60 mg/kg body weight. Irisin in low dosage (5 µg twice a week for 6 weeks I/P) was injected into half of the control and 4-week diabetic male Wistar rats. Animals were sacrificed six months after induction of diabetes. The trabecular bone in the femoral head and neck was analyzed using a micro-CT technique. Bone turnover markers were measured using ELISA, Western blot, and RT-PCR techniques. Results It was found that DM1 deteriorates the trabecular bone mic...

Tumor development is associated with changes in hematopoiesis that lead to an increase in myelomo... more Tumor development is associated with changes in hematopoiesis that lead to an increase in myelomonocytic cells in systemic sites as well as within the tumor tissue. The accumulation of myeloid cells within tumors not only promotes angiogenesis and tissue remodeling required for tumor growth but also maintains the tumor milieu as an immunosuppressive environment. We have previously shown that attenuated strains of the facultative anaerobic bacteria, Salmonella enterica serovar Typhimrium, can effectively retard tumor growth in a therapeutic melanoma model. Given that Salmonella organisms utilize host macrophages as their primary niche for survival, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics and functional activation within tumor tissue of B16.F1 melanoma-bearing animals. Treatment with Salmonella led a preferential expansion, within spleen and tumor tissues, of CD11b+Gr-1+, but not CD11b+Gr-1-, myeloid cells. Using 6-color FACS analysis, CD11b+Gr-1+ cells were shown to exhibit significant up-regulation in the expression of activation markers, including MHC class II, CD80, and Sca-1/Ly6A proteins. Moreover, the functional activities of total tumor infiltrating cells or CD11b-purified cells from tumor tissue were assessed by qRT-PCR. Salmonella treatment induced a dramatic increase in iNOS and IFN-g gene expression but inhibited ARG1 and IL-4 genes. Further, while expression of TGF-b and VEGF was reduced, the level of inflammation-related S100A9 gene was increased. Our findings demonstrate that systemic administration of attenuated Salmonella leads to phenotypic and functional changes in tumor myeloid suppressor cells, with a shift from a predominantly M2 phenotype to an activated, effector macrophage phenotype. Citation Format: Basel K. Al-Ramadi, Suneesh Kaimala, Yassir A. Mohamed, Jincy M. Issac, Eyad Elkord, Salem Chouaib, Maria J. Fernandez-Cabezudo. Targeting of tumor myeloid suppressor cells by Salmonella bacteria causes a shift to M1 phenotype and leads to inhibition of tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3632. doi:10.1158/1538-7445.AM2014-3632

Nucleic Acids Research, Sep 16, 2019

The metabolic sensor Per-Arnt-Sim (Pas) domaincontaining serine/threonine kinase (PASK) is expres... more The metabolic sensor Per-Arnt-Sim (Pas) domaincontaining serine/threonine kinase (PASK) is expressed predominantly in the cytoplasm of different cell types, although a small percentage is also expressed in the nucleus. Herein, we show that the nuclear PASK associates with the mammalian H3K4 MLL2 methyltransferase complex and enhances H3K4 di-and tri-methylation. We also show that PASK is a histone kinase that phosphorylates H3 at T3, T6, S10 and T11. Taken together, these results suggest that PASK regulates two different H3 tail modifications involving H3K4 methylation and H3 phosphorylation. Using muscle satellite cell differentiation and functional analysis after loss or gain of Pask expression using the CRISPR/Cas9 system, we provide evidence that some of the regulatory functions of PASK during development and differentiation may occur through the regulation of these histone modifications.

Obesity is a metabolic disorder characterized by a state of chronic inflammation. Based on epidem... more Obesity is a metabolic disorder characterized by a state of chronic inflammation. Based on epidemiological evidence, obesity has been linked to increased risk of developing several types of cancer. However, the mechanisms underlying this phenomenon remain unknown. Successful growth of cancer cells hinges on developing mechanisms to evade host immunosurveillance, particularly within the tumor microenvironment. In the current study, we utilized a high-fat-diet (HFD)-induced obesity mouse model to gain mechanistic insight into the effect of obesity on progression of implantable syngeneic tumors. When lean or obese mice were implanted with B16.F1 melanoma or MC38 colon carcinoma, tumor growth was more robust in obese group than lean controls, suggesting that obese conditions promote tumor growth. Multi-color flow cytometric analysis and gene expression profiling were carried out on distinct subpopulations of intratumoral myeloid cells. Tumors of lean mice had higher percentages of myeloid cells compared to obese counterparts with characteristics typical of activated inflammatory macrophages. In contrast, tumors of obese mice had disproportionately higher frequency of myeloid derived suppressor cells (MDSC) with a gene signature suggestive of immunosuppressive potential. These findings highlight the role of metaflammation in tumor growth promotion via the regulation of frequency and activation status of distinct subpopulations of intratumoral myeloid cells. Citation Format: Basel K. al-Ramadi, Suneesh Kaimala, Yassir A. Mohamed, Ashraf Al-Sbiei, Ghada Bashir, Maria J. Fernandez-Cabezudo. Tumor growth enhancement under obese conditions: Role of intratumoral myeloid cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A70.

Journal of Immunology, May 1, 2017

Hamdan Medical Journal, 2021

Introduction: Obesity is a metabolic disease that accumulates an excessive level of fat. It also ... more Introduction: Obesity is a metabolic disease that accumulates an excessive level of fat. It also leads to comorbidities such as cardiovascular diseases, type 2 diabetes, high blood pressure, osteoarthritis and hormonal imbalances. Obesity has also been associated with an increased risk of developing cancers and may also enhance cancer-related mortality. The global prevalence rate of obesity and overweight, especially among children, is on the rise, and the United Arab Emirates (UAE) is no exception. Methods: A recent report suggests that the prevalence of overweight and obesity is 17% and 16%, respectively, in the UAE among children between 6 and 18 years of age. Thus, this is a serious health problem that needs urgent attention. Hence in this review we have analysed the risk factors which influence DNA Methylation in Childhood Obesity by using published literature. Results: Although genetic factors contribute to childhood obesity, epigenetic factors also play a significant role in its development. Discussion: This review article discusses the different risk factors and their contribution/s through epigenetic modification, DNA methylation and the associated changes in gene expression that eventually lead to childhood obesity. Understanding how these risk factors modulate gene expression could help to avoid or reduce the impact of exposures to such factors and thus may help to evolve a healthy future generation.

Medicinal Research Reviews, 2022

A recent International Diabetes Federation report suggests that more than 463 million people betw... more A recent International Diabetes Federation report suggests that more than 463 million people between 20 and 79 years have diabetes. Of the 20 million women affected by hyperglycemia during pregnancy, 84% have gestational diabetes. In addition, more than 1.1 million children or adolescents are affected by type 1 diabetes. Factors contributing to the increase in diabetes prevalence are complex and include contributions from genetic, environmental, and epigenetic factors. However, molecular regulatory mechanisms influencing the progression of an individual towards increased susceptibility to metabolic diseases such as diabetes are not fully understood. Recent studies suggest that the pathogenesis of diabetes involves epigenetic changes, resulting in a persistently dysregulated metabolic phenotype. This review summarizes the role of epigenetic mechanisms, mainly DNA methylation and histone modifications, in the development of the pancreas, their contribution to the development of diabetes, and the potential employment of epigenetic modulators in diabetes treatment.

Scientific Reports, 2019

Type 1 diabetes mellitus (DM1) is linked to a decrease in bone strength. Bone strength entails bo... more Type 1 diabetes mellitus (DM1) is linked to a decrease in bone strength. Bone strength entails both bone mineral density and bone quality. Limited data are available regarding diabetes-induced microdamage, which can severely influence bone quality. This study has investigated bone microdamage as a measure of bone quality in an animal model of DM1. Microdamage in the neck of the femur was labelled in vivo using multiple fluorochromes at 4, 12 and 24 weeks after the onset of DM1. Microcracks were quantified and their morphology analyzed using microscopy techniques. The mean length of microcracks at 24 weeks, and crack numerical and surface densities were significantly higher (p < 0.05) 4 weeks after the onset of DM1 when compared with control. Diffuse damage density was highest at 12 weeks after the onset of DM1. The arrangement of the collagen fibrils became progressively more irregular from 4 to 24 weeks of DM. This is the first study to analyze microdamage in vivo at different t...

Journal of Diabetes Research, 2019

T2DM is linked to an increase in the fracture rate as compared to the nondiabetic population even... more T2DM is linked to an increase in the fracture rate as compared to the nondiabetic population even with normal or raised bone mineral density (BMD). Hence, bone quality plays an important role in the pathogenesis of skeletal fragility due to T2DM. This study analyzed the changes in the trabecular bone microstructure due to T2DM at various time points in ovariectomized and nonovariectomized rats. Animals were divided into four groups: (I) control (sham), (II) diabetic (sham), (III) ovariectomized, and (IV) ovariectomized with diabetes. The trabecular microarchitecture of the femoral head was characterized using a micro-CT. The differences between the groups were analyzed at 8, 10, and 14 weeks of the onset of T2DM using a two-way analysis of variance and by post hoc multiple comparisons. The diabetic group with and without ovariectomies demonstrated a significant increase in trabecular separation and a decrease in bone volume fraction, trabecular number, and thickness. BMD decreased i...

THURSDAY, 14 JUNE 2018, 2018

and 15-metre tests were significantly worse compared with control, whereas in persons with VF at ... more and 15-metre tests were significantly worse compared with control, whereas in persons with VF at lumbar spine results of Schober index, lateral trunk lean, hand grip strength and test "stand up from the chair" were worse. In patients with combined VF most of the FT (lateral trunk lean, chest excursion, hand grip strength and 15-metre test) were significantly worse in comparison with control group. The Roland-Morris questionnaire score was significantly higher in women with 2 or more VF compared to controls, unlike the women with 1 VF. We did not found any differences in EQ-5D questionnaire score depending on the number and location of VF. Conclusions: Indices of pain assessment and physical performance in women of older age groups have own peculiarities depending on the number and location of VF, which should be taken into account while assessing of physical abilities and developing of rehabilitation programs for people with VF. Acknowledgements: We are grateful for the collaboration of the group of scientists of «Institute of Gerontology named after D. F. Chebotarev of NAMS Ukraine» (Kyiv, Ukraine) who performed clinical examination, pain assessment and physical performance.

Frontiers in Oncology, 2018

The use of attenuated bacteria as cancer therapeutic tools has garnered increasing scientific int... more The use of attenuated bacteria as cancer therapeutic tools has garnered increasing scientific interest over the past 10 years. This is largely due to the development of bacterial strains that maintain good anti-tumor efficacy, but with reduced potential to cause toxicities to the host. Because of its ability to replicate in viable as well as necrotic tissue, cancer therapy using attenuated strains of facultative anaerobic bacteria, such as Salmonella, has several advantages over standard treatment modalities, including chemotherapy and radiotherapy. Despite some findings suggesting that it may operate through a direct cytotoxic effect against cancer cells, there is accumulating evidence demonstrating that bacterial therapy acts by modulating cells of the immune system to counter the growth of the tumor. Herein, we review the experimental evidence underlying the success of bacterial immunotherapy against cancer and highlight the cellular and molecular alterations in the peripheral immune system and within the tumor microenvironment that have been reported following different forms of bacterial therapy. Our improved understanding of these mechanisms should greatly aid in the translational application of bacterial therapy to cancer patients.

Disease models & mechanisms, Mar 1, 2018

Although the existence of a close relationship between the early maternal developmental environme... more Although the existence of a close relationship between the early maternal developmental environment, fetal size at birth and the risk of developing disease in adulthood has been suggested, most studies, however, employed experimentally induced intrauterine growth restriction as a model to link this with later adult disease. Because embryonic size variation also occurs under normal growth and differentiation, elucidating the molecular mechanisms underlying these changes and their relevance to later adult disease risk becomes important. The birth weight of rat pups vary according to the uterine horn positions. Using birth weight as a marker, we compared two groups of rat pups - lower birth weight (LBW, 5th to 25th percentile) and average birth weight (ABW, 50th to 75th percentile) - using morphological, biochemical and molecular biology, and genetic techniques. Our results show that insulin metabolism, Pi3k/Akt and Pparγ signaling and the genes regulating growth and metabolism are sig...

Cancer Immunology Research, 2017

Cancer Research, 2014

Gene, 2015

In mammals, the casein locus consists of stretches of non-coding DNA, the functions of most of wh... more In mammals, the casein locus consists of stretches of non-coding DNA, the functions of most of which are unknown. These regions are believed to harbour elements responsible for spatio-temporally regulated expression of genes in this locus and so far, only a few such elements have been identified. In this study, we report a novel regulatory element in the casein locus. Comparative analysis of genomic DNA sequences of casein loci from different mammals identified a 147bp long evolutionarily conserved region (ECR) upstream of Odam, a gene in this locus. The ECR was found in close proximity of Odam gene in all the mammals examined. In-silico analysis predicted the ECR as a potential regulatory element. Functional analysis in different cell lines identified it as a unidirectional repressor element. From our findings we speculate that the ECR may be involved in the repression of the Odam expression in the mammary gland during lactation.

Cancer Immunology, Immunotherapy, 2014

the spleen, but down-regulated Il-4 and tgF-β. Within the tumor, expression of inOS, IFn-γ, and S... more the spleen, but down-regulated Il-4 and tgF-β. Within the tumor, expression of inOS, IFn-γ, and S100a9 was markedly increased, but arg1, Il-4, tgF-β, and VegF were inhibited. Functionally, splenic CD11b + cells maintained their suppressive capacity following Salmonella treatment, but intratumoral myeloid cells had significantly reduced suppressive capacity. Our findings demonstrate that administration of attenuated Salmonella leads to phenotypic and functional maturation of intratumoral myeloid cells making them less suppressive and hence enhancing the host's anti-tumor immune response. Modalities that inhibit myeloid suppressor cells may be useful adjuncts in cancer immunotherapy.

Molecular Metabolism, 2018

Background: Type 2 diabetes (T2D) is a multifactorial, polygenic disease caused by impaired insul... more Background: Type 2 diabetes (T2D) is a multifactorial, polygenic disease caused by impaired insulin secretion and insulin resistance. Genomewide association studies (GWAS) were expected to resolve a large part of the genetic component of diabetes; yet, the single nucleotide polymorphisms identified by GWAS explain less than 20% of the estimated heritability for T2D. There was subsequently a need to look elsewhere to find disease-causing factors. Mechanisms mediating the interaction between environmental factors and the genome, such as epigenetics, may be of particular importance in the pathogenesis of T2D. Scope of Review: This review summarizes knowledge of the impact of epigenetics on the pathogenesis of T2D in humans. In particular, the review will focus on alterations in DNA methylation in four human tissues of importance for the disease; pancreatic islets, skeletal muscle, adipose tissue, and the liver. Caseecontrol studies and studies examining the impact of non-genetic and genetic risk factors on DNA methylation in humans will be considered. These studies identified epigenetic changes in tissues from subjects with T2D versus non-diabetic controls. They also demonstrate that non-genetic factors associated with T2D such as age, obesity, energy rich diets, physical activity and the intrauterine environment impact the epigenome in humans. Additionally, interactions between genetics and epigenetics seem to influence the pathogenesis of T2D. Conclusions: Overall, previous studies by our group and others support a key role for epigenetics in the growing incidence of T2D.

Journal of Biosciences, 2012

Mammary gland stem cells (MaSC) have not been identified in spite of extensive research spanning ... more Mammary gland stem cells (MaSC) have not been identified in spite of extensive research spanning over several decades. This has been primarily due to the complexity of mammary gland structure and its development, cell heterogeneity in the mammary gland and the insufficient knowledge about MaSC markers. At present, Lin-CD29 hi CD49f hi CD24 +/mod Sca-1cells of the mammary gland have been reported to be enriched with MaSCs. We suggest that the inclusion of stem cell markers like Oct4, Sox2, Nanog and the mammary gland differentiation marker BRCA-1 may further narrow down the search for MaSCs. In addition, we have discussed some of the other unresolved puzzles on the mammary gland stem cells, such as their similarities and/or differences with mammary cancer stem cells, use of milk as source of mammary stem cells and the possibility of in vitro differentiation of embryonic stem (ES) cells into functional mammary gland structures in this review. Nevertheless, it is the lack of identity for a MaSC that is curtailing the advances in some of the above and other related areas.