•Cytokines, and proteases expressed by macrophages play key roles in atherosclerosis.•The proteases ADAMTS-1, -4 and -5 were expressed in human atherosclerotic lesions.•The anti-atherogenic cytokine interleukin-33 (IL-33) inhibited the expression of these ADAMTS proteases in human macrophages.•This action of IL-33 required extracellular signal-regulated kinase, c-Jun N-terminal kinase and phosphoinositide 3-kinase signaling pathways.•These studies reveal novel anti-atherogenic action of IL-33 along with the underlying molecular mechanisms involved.
Atherosclerosis is an inflammatory disorder of the vasculature regulated by cytokines. Amongst the cytokines, IL-33 attenuates the development of atherosclerosis in mouse model systems via several mechanisms, including inhibition of macrophage foam cell formation and promotion of a Th1 to Th2 shift. Proteases produced by macrophages, such as matrix metalloproteinases and members of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, play potential roles in regulating atherosclerotic plaque stability. Despite such importance, the action of IL-33 on the expression of such proteases has not been analyzed. We have therefore investigated the effect of IL-33 on the expression of ADAMTS-1, -4 and -5 in human macrophages. Immunohistochemical analysis showed that these three proteases were expressed in human atherosclerotic lesions, particularly by macrophages and, to a lesser extent, by smooth muscle cells and endothelial cells. The expression of ADAMTS-1, -4 and -5 in human macrophages was specifically inhibited by IL-33. The action of IL-33 on the expression of these ADAMTS members was mediated through its receptor ST2. IL-33 activated ERK1/2, JNK1/2 and c-Jun, but not p38 MAPK or Akt, in human macrophages. RNA interference assays using a combination of adenoviral encoding small hairpin RNA and small interfering RNA showed a requirement of ERK1/2, JNK1/2, c-Jun, PI3Kγ and PI3Kδ, but not p38α, in the IL-33-inhibited expression of these ADAMTS isoforms. These studies provide novel insights into the expression of ADAMTS-1, -4 and -5 in human atherosclerotic lesions and the regulation of their expression in human macrophages by the key anti-atherogenic cytokine IL-33.
ADAMTS; Cytokine action; Cardiovascular disease; Macrophages; Signal transduction; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; apoE, apolipoprotein E; BMDM, bone marrow-derived macrophages; DAB, 3,3′-diaminobenzidine; ECM, extracellular matrix; HMDM, human monocyte-derived macrophages; IHC, immunohistochemistry; MMP, matrix metalloproteinase; RT-qPCR, real-time quantitative PCR; shRNA, small hairpin RNA; siRNA, small interfering RNA
To assess the impact of being born preterm or small for gestational age (SGA) on several adult outcomes.
We analyzed data for 4518 adult participants in 5 birth cohorts from Brazil, Guatemala, India, the Philippines, and South Africa.
In the study population, 12.8% of males and 11.9% of females were born preterm, and 26.8% of males and 22.4% of females were born term but SGA. Adults born preterm were 1.11 cm shorter (95% CI, 0.57-1.65 cm), and those born term but SGA were 2.35 cm shorter (95% CI, 1.93-2.77 cm) compared with those born at term and appropriate size for gestational age. Blood pressure and blood glucose level did not differ by birth category. Compared with those born term and at appropriate size for gestational age, schooling attainment was 0.44 years lower (95% CI, 0.17-0.71 years) in those born preterm and 0.41 years lower (95% CI, 0.20-0.62 years) in those born term but SGA.
Being born preterm or term but SGA is associated with persistent deficits in adult height and schooling, but is not related to blood pressure or blood glucose level in low- and middle-income settings. Increased postnatal growth is associated with gains in height and schooling regardless of birth status, but not with increases in blood pressure or blood glucose level.
AGA, Appropriate for gestational age; BMI, Body mass index; GA, Gestational age; IFG, Impaired fasting glucose; LGA, Large for gestational age; LMP, Last menstrual period; SGA, Small for gestational age
Signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) are transcription factors involved in cell survival, inflammation and metastasis. Constitutively activated STAT3 is found in many cancers, including melanoma. To study the crosstalk between STAT3 and NFκB signaling and its role in regulation of cancer cell survival, we used RNA interference (RNAi) to down-regulate STAT3 expression in human melanoma cells. RNAi strategies including double-stranded RNA, small interfering RNA (siRNA), short hairpin RNA (shRNA) and microRNA are widely used to knock down disease-causing genes in a targeted fashion. We found that shRNAs up-regulate non-specific NFκB activity, while siRNA directed against STAT3 specifically increase NFκB activity. The basal survival of melanoma cells is unaffected by STAT3 knockdown—likely due to activation of pro-survival NFκB signaling. Whereas, owing to off-target effects, plasmid-transcribed shRNA affects melanoma survival. Our data show that shRNA-mediated gene silencing induces non-specific or off-target effects that may influence cell functions.
Electronic supplementary material
The online version of this article (doi:10.1007/s11033-013-2817-7) contains supplementary material, which is available to authorized users.
Transcription factor STAT3; STAT3-NFκB crosstalk; Cancer cell survival; RNAi
We report a 50-year-old female patient with a stage 2 idiopathic macular hole that closed spontaneously.
The case is presented on the basis of an observational case report.
The stage 2 idiopathic macular hole closed spontaneously in 6 weeks with a lamellar defect in the outer retina due to the formation of the bridging retinal tissue, but without any evidence of the common mechanisms of spontaneous closure such as posterior vitreous detachment or epiretinal membrane formation.
Macular holes; Posterior vitreous detachment; Retina; Optical coherence tomography
Currently there is no treatment for juvenile Batten disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3Δex1-6) mouse model recapitulates several features of the human disorder. Cln3Δex1-6 mice, similarly to juvenile Batten disease patients, have a motor coordination deficit detectable as early as postnatal day 14. Previous studies demonstrated that acute attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6–7-month-old Cln3Δex1-6 mice results in improvement in motor coordination. Here we show that acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the impaired motor coordination of one-month-old Cln3Δex1-6 mice. At a later stage of the disease, in 6–7-month-old Cln3Δex1-6 mice, memantine induced a delayed but extended (8 days) improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. An age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten disease changes during disease progression. In contrast to acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3Δex1-6 mice had no beneficial effect on motor coordination. Moreover, repeated treatments did not impact microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex.
Acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten disease.
juvenile Batten disease; neuronal ceroid lipofuscinoses; Cln3; NMDA receptor; AMPA receptor; rotarod
•Macrophages can internalise LDL through scavenger receptor-independent mechanisms.•Macropinocytosis has been shown to contribute significantly to foam cell formation.•Cytokines such as TGF-β, IL-33, IFN-γ and IL-17A can modulate macropinocytosis.•TGF-β mediated inhibition of macropinocytosis is a Smad-2/-3-independent process.•Macropinocytosis is a promising target for therapeutic intervention of atherosclerosis.
A key event during the formation of lipid-rich foam cells during the progression of atherosclerosis is the uptake of modified low-density lipoproteins (LDL) by macrophages in response to atherogenic mediators in the arterial intima. In addition to scavenger receptor-dependent uptake of LDL, macropinocytosis is known to facilitate the uptake of LDL through the constitutive and passive internalization of large quantities of extracellular solute. In this study we confirm the ability of macropinocytosis to facilitate the uptake of modified LDL by human macrophages and show its modulation by TGF-β, IFN-γ, IL-17A and IL-33. Furthermore we show that the TGF-β-mediated inhibition of macropinocytosis is a Smad-2/-3-independent process.
AcLDL, acetylated LDL; Apo, apolipoprotein; BMDM, bone marrow-derived macrophage; CD-36, cluster of differentiation 36; DiI, 1,1-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyane perchlorate; THP-1, human acute monocytic leukemia cells; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HMDM, human monocyte-derived macrophages; IL, interleukin; IFN-γ, interferon-γ; LDL, low-density lipoproteins; LY, lucifer yellow; OxLDL, oxidized LDL; SR-A, scavenger receptor A; shRNA, short hairpin RNA; TGF-β, transforming growth factor-β; Macropinocytosis; Cytokine; Foam cell; Atherosclerosis; Low density lipoprotein
•Atherosclerosis is an inflammatory disorder regulated by cytokines.•ADAMTS proteases have been suggested to play an important role in this disease.•The action of key cytokines on the expression of ADAMTS proteases in macrophages is poorly understood.•The effect of IFN-γ, TGF-β, TL1A and IL-17A on the expression of ADAMTS-1, -4 and -5 was studied.•Novel differential actions and synergistic interactions were identified.
Atherosclerosis is an inflammatory disease of the vasculature regulated by cytokines. Macrophages play a crucial role at all stages of this disease, including regulation of foam cell formation, the inflammatory response and stability of atherosclerotic plaques. For example, matrix metalloproteinases produced by macrophages play an important role in modulating plaque stability. More recently, the ADAMTS proteases, which are known to play a key role in the control of cartilage degradation during arthritis, have been found to be expressed in atherosclerotic lesions and suggested to have potentially important functions in the control of plaque stability. Unfortunately, the action of cytokines on the expression of ADAMTS family in macrophages is poorly understood. We have investigated the effect of classical cytokines (IFN-γ and TGF-β) and those that have been recently identified (TL1A and IL-17) on the expression of ADAMTS-1, -4 and -5 in human macrophages. The expression of all three ADAMTS members was induced during differentiation of monocytes into macrophages. TGF-β had a differential action with induction of ADAMTS-1 and -5 expression and attenuation in the levels of ADAMTS-4. In contrast, IFN-γ suppressed the expression of ADAMTS-1 without having an effect on ADAMTS-4 and -5. Although TL-1A or IL-17A alone had little effect on the expression of all the members, they induced their expression synergistically when present together. These studies provide new insight into the regulation of key ADAMTS family members in human macrophages by major cytokines in relation to atherosclerosis.
ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; ApoB, apolipoprotein B; ApoE, apolipoprotein E; DR3, death receptor 3; ECM, extracellular matrix; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMDM, human monocyte-derived macrophages; IFN-γ, interferon-γ; IL, interleukin; LDL, low-density lipoprotein; LDLR, LDL receptor; LPL, lipoprotein lipase; MMP, matrix metalloproteinase; PMA, phorbol 12-myristate 13-acetate; RT-qPCR, real-time quantitative polymerase chain reaction; TGF-β, transforming growth factor-β; TL1A, tumour necrosis factor-like protein 1A; TNF-α, tumour necrosis factor-α; VSMC, vascular smooth muscle cells; ADAMTS proteases; Atherosclerosis; Cytokines; Macrophages; Gene expression
A case of multidrug resistance central nervous system tuberculosis is described. During the initial 6 months of therapy, intracranial embolic spread of tuberculomas from exudates around the proximal left middle cerebral artery was seen. This phenomenon was reported earlier. Further management, therapeutic considerations, particularly with secondary and tertiary line of antitubercular medication and neuroimaging are discussed.
Carotid intima-media thickness (CIMT) and carotid plaques represent preclinical markers of atherosclerosis. We sought to describe predictors of CIMT and carotid plaques, including early life growth, in a young urban Indian cohort free of clinical cardiovascular disease (CVD).
In 2006-2009, we performed B-mode carotid ultrasound on 600 participants (mean [SD] age 36 [1.1] years; 45% women) from the New Delhi Birth Cohort to evaluate CIMT and carotid plaques (> 1mm). Height and weight were recorded at birth, 2 and 11 years of age. Data on CVD risk factors, anthropometry, medical history, socio-economic position, and lifestyle habits were collected in 1998-2002.
Mean (SD) CIMT for men and women was 0.91 (0.12) and 0.86 (0.13) mm, respectively. Carotid plaque was present in 33% of men and 26% of women. Waist circumference in 1998-2002 was positively associated with CIMT (β coefficient 0.26 mm [0.17, 0.36] per SD) and carotid plaque (OR 1.27 [1.06,1.52] per SD) in 2006-2009. Higher triglycerides, PAI-1, insulin resistance, and diastolic blood pressure, metabolic syndrome, and lower HDL-cholesterol and physical activity predicted higher CIMT and/or plaque (p<0.05). Longer length at 2 years was associated with higher CIMT (p<0.05). These associations were attenuated after adjusting for adult waist circumference.
These are the first prospective data from India showing that early life growth, adult socio-demographics, and CVD risk factors predict future CIMT and /or carotid plaque. These relationships appear primarily mediated through central adiposity, highlighting the importance of maintaining a healthy weight in early adulthood to prevent CVD.
carotid intima media thickness; carotid plaque; India; cohort; birth weight; infant and childhood growth
Supracondylar fractures are the commonest elbow injury in children. Most displaced Supracondylar fractures are manipulated and held with a medial/lateral entry or two lateral Kirschner wires. It was the purpose of this study to investigate the treatment of this injury in this unique patient population.
Materials and Methods:
This study was conducted in the Department of Orthopaedic surgery in M. M. Medical College from July 2005 to July 2010. One hundred seventy patients were recruited from Emergency and outpatient department having closed displaced Supracondylar fractures of humerus in children. They were treated either with medial-lateral pin fixation (n = 85) or with 2-lateral pin fixation (n = 85). All patients were operated under general anaesthesia. All patients were followed for 6 months. Results were analysed using Flynn's criteria.
Statistical Analysis Used:
Chi Square Test. Chi Square calculator was used as a software.
All children achieved union in a mean time of 4 weeks (range: 3-6 weeks). Post-operatively, eight patients (4.70%) got ulnar nerve injury and six (3.52%) patients got pin tract infection. Comparison between two groups such as cross K-wire group (85) and lateral K-wire group (n = 85) by using the Chi Square Test showed that in case of 8 weeks with (P-values = 0.89), in 16 weeks (P = 0.91) and 24 weeks (P = 0.85) with respective excellent, good, fair and poor categories were not found statistically significant.
The lateral percutaneous pinning technique of displaced Supracondylar fractures of the humerus offers a viable alternative to the crossed pinning group as it offers the same stability without the incipient risk of iatrogenic ulnar nerve injury.
Close reduction; chi square test; humerus; percutaneous pinning; supracondylar fracture
Fractures of the humeral shaft are uncommon, representing less than 10 percent of all fractures in children. Humeral shaft fractures in children can be treated by immobilisation alone. A small number of fractures are unable to be reduced adequately or maintained in adequate alignment, and these should be treated surgically. In the present study, Kirschner wires (K-wire) were used to achieve a closed intramedullary fixation of humeral shaft fractures. The objective of this study was to evaluate the efficacy of intramedullary K-wires for the treatment of humeral shaft fracture in children.
Patients and Methods:
This prospective study was conducted in the Department of Orthopaedic surgery in M. M. Medical College from June 2005 to June 2010. Sixty-eight children with a mean age of 7.7 years (range, 2-14 years) were recruited from Emergency and out patient department having closed fracture of humerus shaft. All patients were operated under general anaesthesia. All patients were followed for 12 months.
Out of 68 patients, 64 patients underwent union in 42-70 days with a mean of 56 days. Complications found in four patients who had insignificant delayed union which were united next 3 weeks. Intramedullary K-wires were removed after an average of 5 months without any complications. The results were excellent in 94.11% and good in 5% children.
This technique is simple, quick to perform, safe and reliable and avoids prolonged hospitalization with good results and is economical.
Children; humerus shaft fractures; percutaneous Kirschner wires
A number of environmental factors (e.g. toxicants) have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germ line are those associated with primordial germ cell development and subsequent fetal germline development. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation) progeny in regards to the primordial germ cell (PGC) epigenetic reprogramming of the F3 generation (i.e. great-grandchildren). The F3 generation germline transcriptome and epigenome (DNA methylation) were altered transgenerationally. Interestingly, disruptions in DNA methylation patterns and altered transcriptomes were distinct between germ cells at the onset of gonadal sex determination at embryonic day 13 (E13) and after cord formation in the testis at embryonic day 16 (E16). A larger number of DNA methylation abnormalities (epimutations) and transcriptional alterations were observed in the E13 germ cells than in the E16 germ cells. These observations indicate that altered transgenerational epigenetic reprogramming and function of the male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided.
Thrombocytopenia in pregnancy carries a major risk of feto-maternal morbidity and mortality. We present a case of hypocellular bone marrow with severe thrombocytopenia with pregnancy induced hypertension (PIH) for emergency lower segment cesarean section (LSCS). This disease is characterized by pancytopenia and hypocellular bone marrow with impaired morphology and maturation. Causes of death due to this disease include hemorrhage and infection secondary to thrombocytopenia and neutropenia especially following surgery. We report successful management of emergency LSCS with severe thrombocytopenia with severe PIH.
Hypocellular bone marrow; pregnancy induced hypertension; thrombocytopenia
Chronic hepatitis C remains a significant medical and economic burden in Canada, affecting nearly 1% of the population. Since the last consensus conference on the management of chronic hepatitis C, major advances have warranted a review of recommended management approaches for these patients. Specifically, direct-acting antiviral agents with dramatically improved rates of virological clearance compared with standard therapy have been developed, and several single nucleotide polymorphisms associated with an increased probability of spontaneous and treatment-induced viral clearance have been identified. In light of this new evidence, a consensus development conference was held in November 2011; the present document highlights the results of the presentations and discussions surrounding these issues. It reviews the epidemiology of hepatitis C in Canada, preferred diagnostic testing approaches and recommendations for the treatment of chronically infected patients with the newly approved protease inhibitors (boceprevir and telaprevir), including those who have previously failed pegylated interferon and ribavirin therapy. In addition, recommendations are made regarding approaches to reducing the burden of hepatitis C in Canada.
Antiviral; Boceprevir; Guideline; Hepatitis C; Interferon; Peginterferon; Protease inhibitor; Ribavirin; Telaprevir; Therapy; Treatment
To study the relationship of height and body mass index (BMI) during childhood with adult bone mineral content (BMC), areal density (aBMD) and apparent density (BMAD, estimated volumetric density).
Participants were 565 men and women aged 33-39 years from the New Delhi Birth Cohort, India, whose weight and height were recorded at birth and annually during infancy (0-2 years), childhood (2-11 years) and adolescence (11 years-adult). Lumbar spine, femoral neck and forearm BMC and aBMD were measured using dual X-ray absorptiometry; lumbar spine and femoral neck BMAD were calculated.
Birth length, and height and height gain during infancy, childhood and adolescence were positively correlated with adult BMC (p≤0.01 all sites except birth length with femoral neck). Correlations increased with height from birth-6 years, then remained constant for later height measurements. There were no associations with BMAD. BMI at birth, and during childhood and adolescence was also positively correlated with BMC (p<0.01 all sites). BMI at 11 years, and BMI gain in childhood and adolescence, were correlated with aBMD and BMAD (p<0.001 for all); these correlations strengthened with increasing age of BMI measurement. The associations with height and BMI in early life became non-significant after adjustment for adult height and BMI.
Greater skeletal growth and BMI gain in utero and during infancy are associated with higher peak BMC, and greater BMI gain in childhood and adolescence is associated with higher peak aBMD and BMAD. These associations are mediated by the attainment of adult height and BMI respectively.
Birth cohort; childhood growth; height; body mass index; bone mineral content; bone mineral density
Leprosy involves peripheral nerves sooner or later in the course of the disease leading to gross deformities and disabilities. Sadly, by the time it becomes clinically apparent, the nerve damage is already quite advanced. However, if the preclinical damage is detected early in the course of disease, it can be prevented to a large extent.
Materials and Methods:
We conducted an electrophysiological pilot study on 10 patients with clinically manifest leprosy, in the Dermatology Department of Mahatma Gandhi Institute of Medical Sciences, Sewagram. This study was done to assess the nerve conduction velocity, amplitude and latency of ulnar and median nerves.
Results and Conclusion:
We found reduced conduction velocities besides changes in latency and amplitude in the affected nerves. Changes in sensory nerve conduction were more pronounced. Also, sensory latencies and amplitude changes were more severe than motor latencies and amplitude in those presenting with muscle palsies. However, further studies are going on to identify parameters to detect early nerve damage in leprosy.
Electrophysiology; leprosy; nerve conduction study
Saccharum officinarum is one of the most cultivated hybrid varieties among the sugarcane varieties. In sugarcane plant sucrose is the
major carbohydrate which can be stored and transported. Different physiological and biochemical studies on this crop report that
invertase activity and sucrose concentration some how are key limiting step in the process of sucrose accumulation. Significant
efforts have been made in relation to the sucrose cycle by altering the sucrose phosphate synthetase, sucrose synthetase and
invertase. In sugarcane two types of invertase enzymes have been reported on the basis of pH and cellular localization. Invertase
breaks the sucrose into hexoses as a source of energy and carbon. It has also been reported that this enzyme is involved in the
process of cell differentiation and plant development. Progress has been made for the understanding of invertase activity and its
role in sugarcane plant. With the help of biotechnology it is possible to target the desired gene with genetic engineering approach
to increase sucrose content by careful manipulation of invertase (enzyme) gene to increase the sucrose yield in sugarcane. Purpose
of this mini review is to high-light the role of invertase in sugarcane and how to overcome sucrose recovery in sugarcane.
Sugarcane; Invertase; Sucrose metabolism; Differentiation; Development
This study considers three questions: 1. What are the Canadian public’s prioritization preferences for new government spending on a range of public health-related goods outside the scope of the country’s national system of health insurance? 2. How homogenous or heterogeneous is the Canadian public in terms of these preferences? 3. What factors are predictive of the Canadian public’s preferences for new government spending? Data were collected in 2008 from a national random sample of Canadian adults through a telephone interview survey (n =1,005). Respondents were asked to rank five spending priorities in terms of their preference for new government spending. Bivariate and multivariable logistic regression analyses were conducted. As a first priority, Canadian adults prefer spending on child care (26.2%), followed by pharmacare (23.1%), dental care (20.8%), home care (17.2%), and vision care (12.7%). Sociodemographic characteristics predict spending preferences, based on the social position and needs of respondents. Policy leaders need to give fair consideration to public preferences in priority setting approaches in order to ensure that public health-related goods are distributed in a manner that best suits population needs.
Public preferences; Health care; Priority setting; Health services needs and demand
The anti-atherogenic cytokine, TGF-β, plays a key role during macrophage foam cell formation by modulating the expression of key genes involved in the control of cholesterol homeostasis. Unfortunately, the molecular mechanisms underlying these actions of TGF-β remain poorly understood. In this study we examine the effect of TGF-β on macrophage cholesterol homeostasis and delineate the role of Smads-2 and ‐3 during this process. Western blot analysis showed that TGF-β induces a rapid phosphorylation-dependent activation of Smad-2 and ‐3 in THP-1 and primary human monocyte-derived macrophages. Small interfering RNA-mediated knockdown of Smad-2/3 expression showed that the TGF-β-mediated regulation of key genes implicated in the uptake of modified low density lipoproteins and the efflux of cholesterol from foam cells was Smad-dependent. Additionally, through the use of virally delivered Smad-2 and/or Smad-3 short hairpin RNA, we demonstrate that TGF-β inhibits the uptake of modified LDL by macrophages through a Smad-dependent mechanism and that the TGF-β-mediated regulation of CD36, lipoprotein lipase and scavenger receptor-A gene expression was dependent on Smad-2. These studies reveal a crucial role for Smad signaling, particularly Smad-2, in the inhibition of foam cell formation by TGF-β through the regulation of expression of key genes involved in the control of macrophage cholesterol homeostasis.
► Anti-atherogenic cytokine TGF-β inhibits macrophage foam cell formation. ► The role of Smads in the control of macrophage cholesterol homeostasis was studied. ► Smads were found to play a key role in the TGF-β-mediated uptake of modified LDL. ► A dominant role of Smad2 was identified in the regulation of gene expression. ► The TGF-β-Smad axis may represent a powerful anti-foam cell therapeutic target.
AcLDL, acetylated low density lipoprotein; ABCA-1, ATP-binding cassette transporter A-1; ABCG-1, ATP-binding cassette transporter G-1; ApoE, apolipoprotein E; ApoE−/−, apolipoprotein E deficient; CD36, cluster of differentiation 36; DiI, 1,1′-dioctadecyl-3,3,3′,3′-tetramethyllindocarbocyane perchlorate; HMDM, human monocyte-derived macrophages; LDL, low density lipoprotein; LPL, lipoprotein lipase; OxLDL, oxidized low density lipoprotein; shRNA, short hairpin RNA; SR-A, scavenger receptor A; THP-1, human acute monocytic leukemia cell line; Foam cell; Atherosclerosis; Cholesterol; TGF-β; Macrophage
A major event in mammalian male sex determination is the induction of the testis determining factor Sry and its downstream gene Sox9. The current study provides one of the first genome wide analyses of the downstream gene binding targets for SRY and SOX9 to help elucidate the molecular control of Sertoli cell differentiation and testis development. A modified ChIP-Chip analysis using a comparative hybridization was used to identify 71 direct downstream binding targets for SRY and 109 binding targets for SOX9. Interestingly, only 5 gene targets overlapped between SRY and SOX9. In addition to the direct response element binding gene targets, a large number of atypical binding gene targets were identified for both SRY and SOX9. Bioinformatic analysis of the downstream binding targets identified gene networks and cellular pathways potentially involved in the induction of Sertoli cell differentiation and testis development. The specific DNA sequence binding site motifs for both SRY and SOX9 were identified. Observations provide insights into the molecular control of male gonadal sex determination.
Weight gain and growth in early life may influence adult pro-inflammatory and pro-thrombotic cardiovascular risk factors.
Follow-up of a birth cohort in New Delhi, India, whose weight and height were measured 6-monthly until age 21 years. BMI at birth, during infancy (2 years), childhood (11 years) and adulthood (26-32 years) and BMI gain between these ages were analyzed in 886 men and 640 women in relation to adult fibrinogen, high-sensitivity C-reactive protein (hsCRP) and plasminogen activator inhibitor (PAI-1) concentrations.
All the pro-inflammatory/pro-thrombotic risk factors were higher in participants with higher adiposity. In women, BMI at birth and age 2 years was inversely related to fibrinogen (p=0.002 and 0.05) and, after adjusting for adult adiposity, to hsCRP (p=0.02 and 0.009). After adjusting for adult adiposity, BMI at 2 years was inversely related to hsCRP and PAI-1 concentrations (p<0.001 and p=0.02) in men. BMI gain between 2-11 years and/or 11 years to adulthood was positively associated with fibrinogen and hsCRP in women and with hsCRP and PAI-1 in men.
Thinness at birth or during infancy, and accelerated BMI gain during childhood/adolescence are associated with a pro-inflammatory/pro-thrombotic state in adult life. An altered inflammatory state could be one link between small newborn/infant size and adult cardiovascular disease. Associations between pro-inflammatory markers and childhood/adolescent BMI gain are probably mediated through adult adiposity.
Birthweight; growth; C-reactive protein; fibrinogen; plasminogen activator inhibitor-1