NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexi... more NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 is expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 gen...
in Cysteine (SPARC), originally discovered in bone as osteonec-tin, is a mediator of collagen dep... more in Cysteine (SPARC), originally discovered in bone as osteonec-tin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. RESEARCH DESIGN AND METHODS—Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 3.7 kg). Another six lean subjects underwent fast-food– based hyperalimentation for 4 weeks (weight gain: 7.2 1.6 kg).
Chemerin, a chemoattractant protein, acts a G-protein coupled chemokine receptor, Chemokine like ... more Chemerin, a chemoattractant protein, acts a G-protein coupled chemokine receptor, Chemokine like Receptor 1/ChemR23; levels of which are elevated in pro-inflammatory states such as obesity and type 2 diabetes mellitus (T2DM). Obesity and T2DM patients are at high risk of developing cardiovascular disorders such as atherosclerosis. We have reported that chemerin induces human endothelial cell angiogenesis and since dysregulated angiogenesis and endothelial dysfunction are hallmarks of vascular disease; we sought to determine the effects of chemerin on monocyte-endothelial adhesion, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a critical pro-inflammatory transcription factor. Human endothelial cells were transfected with pNF-kappaB-Luc plasmid. Chemerin induced NF-κB activation the MAPK and PI3K/Akt pathways. Western blot analyses and monocyte-endothelial adhesion assay showed that chemerin increased endothelial cell adhesion molecule expression and secr...
Health technology assessment (Winchester, England), 2017
Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight... more Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse event...
Gestational Diabetes (GDM) is characterized by insulin resistance and a pro-inflammatory state, b... more Gestational Diabetes (GDM) is characterized by insulin resistance and a pro-inflammatory state, both factors possible related to adipokine expression. The study included 20 women with GDM, diagnosed according to the WHO criteria, and 23 matched for age and BMI women with normal glucose tolerance. Omentin and TSP-1 were measured by ELISA assays. Insulin resistance was assessed by HOMA and Insulin Resistance Index (IRI). There were no significant differences in omentin and TSP-1 levels between subjects with GDM and controls (48.0 +/- 12.0 ng/ml versus 50.2 +/- 7.9 ng/ml and 2150 +/- 1661 ng/ml versus 1569 +/- 1160 ng/ml, p = 0.64 and p = 0.29, for omentin and TSP-1 in GDM and control subjects, respectively). There was no significant correlation between either omentin or TSP-1 with HOMA or IRI, however there was a significant positive correlation between thrombospondin-1 and omentin (r = 0.49, p = 0.010). There was also a positive correlation between serum omentin and glucose levels at...
Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality... more Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality. Endothelial dysfunction is pivotal to the development of cardiovascular disease (CVD). In relation to this, adipose tissue secreted factors termed "adipokines" have been reported to modulate endothelial dysfunction. In this review, we focus on two of the most abundant circulating adipokines, that is, leptin and adiponectin, in the development of endothelial dysfunction. Leptin has been documented to influence a multitude of organ systems, that is, central nervous system (appetite regulation, satiety factor) and cardiovascular system (endothelial dysfunction leading to atherosclerosis). Adiponectin, circulating at a much higher concentration, exists in different molecular weight forms, essentially made up of the collagenous fraction and a globular domain, the latter being investigated minimally for its involvement in proinflammatory processes including activation of NF-κβ and ...
New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resist... more New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)-dependent manner and blocked the enoyl substrate-binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rat...
Obesity has reached pandemic proportions and is associated with serious cardiometabolic sequelae ... more Obesity has reached pandemic proportions and is associated with serious cardiometabolic sequelae including insulin resistance, diabetes, dyslipidemia, hypertension, and cardiovascular disease, where adipose tissue-secreted cytokines, that is, adipokines, have been implicated in these processes. Omentin is a novel adipokine preferentially produced by visceral adipose tissue with insulin-sensitizing effects, where circulating levels are decreased in insulin-resistant states, for example, obesity and diabetes. With respect to vascular biology, omentin causes vasodilatation of blood vessels and attenuates C-reactive protein-induced angiogenesis potentially via the nuclear factor B signaling pathway, a potent proinflammatory signaling pathway. Thus, omentin may have beneficial effects on the metabolic syndrome and could potentially be used as a biologic marker and/or pharmacologic agent in this respect.
The Journal of Clinical Endocrinology & Metabolism, 2011
The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in over... more The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in overweight individuals. The aim of the study was to investigate the mechanisms underlying brain nesfatin-1/NUCB-2 uptake and to determine whether reduced uptake may contribute to nesfatin-1/NUCB-2 resistance. Cerebrospinal fluid (CSF) and corresponding plasma nesfatin-1/NUCB-2 were measured by ELISA [18 men and 20 women; age, 19-80 yr; body mass index (BMI), 16.2-38.1 kg/m(2)] and correlated to body adiposity and metabolic parameters. CSF/plasma nesfatin-1/NUCB-2 ratio was significantly negatively associated with BMI, body weight, fat mass, and CSF glucose. BMI was predictive of CSF/plasma nesfatin-1/NUCB-2 ratio (β = -0.786; P = 0.045). CSF nesfatin-1/NUCB-2 was significantly positively associated with plasma nesfatin-1/NUCB-2 (R = 0.706; P < 0.01). There was a significant linear relation between CSF and plasma nesfatin-1/NUCB-2 in lean (BMI <25 kg/m(2); R = 0.744; P = 0.002) and obese (BMI ≥ 30 kg/m(2); R = 0.693; P = 0.026) subjects. Subjects in the highest plasma nesfatin-1/NUCB-2 quintile had lower CSF/plasma nesfatin-1/NUCB-2 ratio [26.5% (26.0-29.5%)] compared to the lowest plasma nesfatin-1/NUCB-2 quintile [38.5% (34.0-42.0%)] (P < 0.01), corresponding BMI [32.4 (31.0-35.0) vs. 23.3 (19.7-23.5) kg/m(2); P < 0.01], and fat mass [32.8 (29.5-40.6) vs. 30.7 (8.2-20.1) kg/m(2); P < 0.01]. Our observations have important implications with respect to the potential weight-reducing actions of nesfatin-1/NUCB-2 treatment. Future research should seek to clarify whether nesfatin-1/NUCB-2 would be beneficial in the management of obesity.
NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexi... more NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 is expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 gen...
in Cysteine (SPARC), originally discovered in bone as osteonec-tin, is a mediator of collagen dep... more in Cysteine (SPARC), originally discovered in bone as osteonec-tin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. RESEARCH DESIGN AND METHODS—Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 3.7 kg). Another six lean subjects underwent fast-food– based hyperalimentation for 4 weeks (weight gain: 7.2 1.6 kg).
Chemerin, a chemoattractant protein, acts a G-protein coupled chemokine receptor, Chemokine like ... more Chemerin, a chemoattractant protein, acts a G-protein coupled chemokine receptor, Chemokine like Receptor 1/ChemR23; levels of which are elevated in pro-inflammatory states such as obesity and type 2 diabetes mellitus (T2DM). Obesity and T2DM patients are at high risk of developing cardiovascular disorders such as atherosclerosis. We have reported that chemerin induces human endothelial cell angiogenesis and since dysregulated angiogenesis and endothelial dysfunction are hallmarks of vascular disease; we sought to determine the effects of chemerin on monocyte-endothelial adhesion, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a critical pro-inflammatory transcription factor. Human endothelial cells were transfected with pNF-kappaB-Luc plasmid. Chemerin induced NF-κB activation the MAPK and PI3K/Akt pathways. Western blot analyses and monocyte-endothelial adhesion assay showed that chemerin increased endothelial cell adhesion molecule expression and secr...
Health technology assessment (Winchester, England), 2017
Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight... more Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse event...
Gestational Diabetes (GDM) is characterized by insulin resistance and a pro-inflammatory state, b... more Gestational Diabetes (GDM) is characterized by insulin resistance and a pro-inflammatory state, both factors possible related to adipokine expression. The study included 20 women with GDM, diagnosed according to the WHO criteria, and 23 matched for age and BMI women with normal glucose tolerance. Omentin and TSP-1 were measured by ELISA assays. Insulin resistance was assessed by HOMA and Insulin Resistance Index (IRI). There were no significant differences in omentin and TSP-1 levels between subjects with GDM and controls (48.0 +/- 12.0 ng/ml versus 50.2 +/- 7.9 ng/ml and 2150 +/- 1661 ng/ml versus 1569 +/- 1160 ng/ml, p = 0.64 and p = 0.29, for omentin and TSP-1 in GDM and control subjects, respectively). There was no significant correlation between either omentin or TSP-1 with HOMA or IRI, however there was a significant positive correlation between thrombospondin-1 and omentin (r = 0.49, p = 0.010). There was also a positive correlation between serum omentin and glucose levels at...
Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality... more Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality. Endothelial dysfunction is pivotal to the development of cardiovascular disease (CVD). In relation to this, adipose tissue secreted factors termed "adipokines" have been reported to modulate endothelial dysfunction. In this review, we focus on two of the most abundant circulating adipokines, that is, leptin and adiponectin, in the development of endothelial dysfunction. Leptin has been documented to influence a multitude of organ systems, that is, central nervous system (appetite regulation, satiety factor) and cardiovascular system (endothelial dysfunction leading to atherosclerosis). Adiponectin, circulating at a much higher concentration, exists in different molecular weight forms, essentially made up of the collagenous fraction and a globular domain, the latter being investigated minimally for its involvement in proinflammatory processes including activation of NF-κβ and ...
New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resist... more New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)-dependent manner and blocked the enoyl substrate-binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rat...
Obesity has reached pandemic proportions and is associated with serious cardiometabolic sequelae ... more Obesity has reached pandemic proportions and is associated with serious cardiometabolic sequelae including insulin resistance, diabetes, dyslipidemia, hypertension, and cardiovascular disease, where adipose tissue-secreted cytokines, that is, adipokines, have been implicated in these processes. Omentin is a novel adipokine preferentially produced by visceral adipose tissue with insulin-sensitizing effects, where circulating levels are decreased in insulin-resistant states, for example, obesity and diabetes. With respect to vascular biology, omentin causes vasodilatation of blood vessels and attenuates C-reactive protein-induced angiogenesis potentially via the nuclear factor B signaling pathway, a potent proinflammatory signaling pathway. Thus, omentin may have beneficial effects on the metabolic syndrome and could potentially be used as a biologic marker and/or pharmacologic agent in this respect.
The Journal of Clinical Endocrinology & Metabolism, 2011
The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in over... more The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in overweight individuals. The aim of the study was to investigate the mechanisms underlying brain nesfatin-1/NUCB-2 uptake and to determine whether reduced uptake may contribute to nesfatin-1/NUCB-2 resistance. Cerebrospinal fluid (CSF) and corresponding plasma nesfatin-1/NUCB-2 were measured by ELISA [18 men and 20 women; age, 19-80 yr; body mass index (BMI), 16.2-38.1 kg/m(2)] and correlated to body adiposity and metabolic parameters. CSF/plasma nesfatin-1/NUCB-2 ratio was significantly negatively associated with BMI, body weight, fat mass, and CSF glucose. BMI was predictive of CSF/plasma nesfatin-1/NUCB-2 ratio (β = -0.786; P = 0.045). CSF nesfatin-1/NUCB-2 was significantly positively associated with plasma nesfatin-1/NUCB-2 (R = 0.706; P < 0.01). There was a significant linear relation between CSF and plasma nesfatin-1/NUCB-2 in lean (BMI <25 kg/m(2); R = 0.744; P = 0.002) and obese (BMI ≥ 30 kg/m(2); R = 0.693; P = 0.026) subjects. Subjects in the highest plasma nesfatin-1/NUCB-2 quintile had lower CSF/plasma nesfatin-1/NUCB-2 ratio [26.5% (26.0-29.5%)] compared to the lowest plasma nesfatin-1/NUCB-2 quintile [38.5% (34.0-42.0%)] (P < 0.01), corresponding BMI [32.4 (31.0-35.0) vs. 23.3 (19.7-23.5) kg/m(2); P < 0.01], and fat mass [32.8 (29.5-40.6) vs. 30.7 (8.2-20.1) kg/m(2); P < 0.01]. Our observations have important implications with respect to the potential weight-reducing actions of nesfatin-1/NUCB-2 treatment. Future research should seek to clarify whether nesfatin-1/NUCB-2 would be beneficial in the management of obesity.
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