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1.
J Infect Dev Ctries ; 18(1): 75-81, 2024 Jan 31.
Article in English | MEDLINE | ID: mdl-38377091

ABSTRACT

INTRODUCTION: By administering inferior vena cava (IVC) directed fluid, it is possible to avoid the use of additional fluid and fluid overload in patients with septic shock (SS) and sepsis-induced hypoperfusion (SIH). METHODOLOGY: In patients with SIH and SS, we conducted prospective observational research on fluid therapy. A time-motion trace of the IVC diameter was created using M-mode imaging. The ability to predict fluid responsiveness was based on the IVC collapsibility index (cIVC) > 40%. Participants were randomised into 2 groups using a permuted block-of-four randomization list, with the investigators being blinded prior to patient allocation. They were split equally between the usual-care (UC) group, which received sepsis-guided fluid treatment, and the interventional ultrasound-guided fluid therapy (UGFT) group. RESULTS: The average age of the participants was 63.2 years (62.8 years for the UGFT group and 63.7 years for the UC group). Co-morbid health conditions were practically the same in both arms at baseline. Prior to enrolment, both groups received the same quantity of fluid as part of resuscitation (UGFT arm received 2.4 0.6 L, UC group received 2.2 0.7 L). The UGFT group outperformed the UC group with a P value of 0.02 due to a significantly lower positive fluid balance after 72 hours of ICU discharge (-1.37 L), which rendered the UGFT group superior to the UC group. Even after accounting for the fluids consumed before enrolment, there was still a sizable difference in the fluids infused. When the pre-enrolment fluids were counted at 72 hours, UGFT participants still displayed a decreased positive fluid balance. However, there was no discernible difference in the 30-day mortality rate overall (6.3% difference, UGFT: 15.7%, and UC: 22.0%). CONCLUSIONS: In contrast to the UC group, the UGFT arm of our study demonstrated a statistically significant benefit of Point of Care USG (POCUS) guided fluid therapy during resuscitation in sepsis in reducing the positive fluid balance in 72 hours, preventing fluid overload, and reducing the need for dialysis and invasive ventilation. However, there was no statistically significant variation in the 30-day mortality rate.


Subject(s)
Sepsis , Shock, Septic , Humans , Middle Aged , Shock, Septic/therapy , Vena Cava, Inferior/diagnostic imaging , Prospective Studies , Fluid Therapy/methods , Sepsis/therapy
2.
Front Immunol ; 14: 1217776, 2023.
Article in English | MEDLINE | ID: mdl-37575259

ABSTRACT

Background: ILC2s are capable of generating memory. The mechanism of memory induction and memory-driven effector function (trained immunity) in ILC2s is unknown. Objective: NFκB1 is preferentially expressed at a high level in ILC2s. We examined the role of NFkB1 in memory induction and memory-driven effector function in a mouse model of asthma. Methods: Intranasal administration of Alternaria, flexivent, ELISA, histology, real-time PCR, western blot, flow cytometry and immunofluorescence staining. Results: NFκB1 was essential for the effector phase of memory-driven asthma. NFκB1 was critical for IL33 production, ILC2 generation, and production of type-2 cytokines, which resulted in eosinophilic inflammation and other features of asthma. NFκB1 induction of type-2 cytokines in ILC2s was independent of GATA3. NFκB1 was important for allergen induction of ILC3s and FoxP3+ Tregs. NFκB1 did not affect Th2 cells or their cytokine production. In contrast to its protagonistic role in the effector phase, NFκB1 had an antagonistic role in the memory phase. NFκB1 inhibited allergen-induced upregulation of memory-associated repressor and preparedness genes in ILC2s. NFκB1 upregulated RUNX1. NFκB1 formed a heterodimer with RUNX1 in ILC2s. Conclusions: NFκB1 positively regulated the effector phase but inhibited the induction phase of memory. The foregoing pointed to an interdependent antagonism between the memory induction and the memory effector processes. The NFκB1-RUNX1 heterodimer represented a non-canonical transcriptional activator of type-2 cytokines in ILC2s.


Subject(s)
Asthma , Immunity, Innate , Animals , Mice , Allergens , Core Binding Factor Alpha 2 Subunit , Cytokines , Lymphocytes , NF-kappa B p50 Subunit/genetics , NF-kappa B p50 Subunit/metabolism
3.
J Clin Invest ; 133(4)2023 02 15.
Article in English | MEDLINE | ID: mdl-36480284

ABSTRACT

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3-7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions.


Subject(s)
Macrophages , Mitochondria , Myocardial Infarction , Animals , Mice , Electron Transport Complex I/metabolism , Inflammation/etiology , Inflammation/metabolism , Macrophages/metabolism , Macrophages/pathology , Mice, Inbred C57BL , Mitochondria/metabolism , Mitochondria/pathology , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardium/metabolism , Phagocytosis
4.
Sci Rep ; 11(1): 22018, 2021 11 10.
Article in English | MEDLINE | ID: mdl-34759299

ABSTRACT

Although microRNA-7 (miRNA-7) is known to regulate proliferation of cancer cells by targeting Epidermal growth factor receptor (EGFR/ERBB) family, less is known about its role in cardiac physiology. Transgenic (Tg) mouse with cardiomyocyte-specific overexpression of miRNA-7 was generated to determine its role in cardiac physiology and pathology. Echocardiography on the miRNA-7 Tg mice showed cardiac dilation instead of age-associated physiological cardiac hypertrophy observed in non-Tg control mice. Subjecting miRNA-7 Tg mice to transverse aortic constriction (TAC) resulted in cardiac dilation associated with increased fibrosis bypassing the adaptive cardiac hypertrophic response to TAC. miRNA-7 expression in cardiomyocytes resulted in significant loss of ERBB2 expression with no changes in ERBB1 (EGFR). Cardiac proteomics in the miRNA-7 Tg mice showed significant reduction in mitochondrial membrane structural proteins compared to NTg reflecting role of miRNA-7 beyond the regulation of EGFR/ERRB in mediating cardiac dilation. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized rounded mitochondria that was associated with mitochondrial dysfunction. These findings show that expression of miRNA-7 in the cardiomyocytes results in cardiac dilation instead of adaptive hypertrophic response during aging or to TAC providing insights on yet to be understood role of miRNA-7 in cardiac function.


Subject(s)
Cardiomegaly/diagnostic imaging , MicroRNAs/metabolism , Myocytes, Cardiac/metabolism , Ventricular Remodeling , Animals , Aorta, Thoracic/surgery , Echocardiography , ErbB Receptors/metabolism , Ligation/methods , Membrane Proteins/metabolism , Mice, Transgenic , MicroRNAs/genetics , Mitochondrial Membranes/metabolism , Receptor, ErbB-2/metabolism
5.
Blood Adv ; 3(22): 3713-3723, 2019 11 26.
Article in English | MEDLINE | ID: mdl-31765479

ABSTRACT

High-altitude (HA) hypoxia exposure is believed to induce venous thromboembolism (VTE) in otherwise healthy individuals, although this needs to be fully established. The present study aims to ascertain the role of HA exposure in aggravating any predisposition toward VTE and to explore whether the etiology of HA-induced VTE is different from that of VTE closer to sea level. We compared manifestation-matched male VTE patients from HA (HAPs) and VTE patients from the plains closer to sea level (SLPs) for 54 parameters, including coagulation-related, fibrinolytic, and thrombophilic variables, as well as markers for stress and inflammatory response and platelet and endothelial activation. Our results established an association between HA hypoxia and VTE in alterations of primarily hemostatic variables. Approximately 96% of HAPs presented with ≥10 altered parameters out of 54 studied compared with 7% of SLPs. Elevated platelet count, von Willebrand factor, and clotting factors and altered coagulation exhibited significant associations with VTE events and altitude exposure (all P < .05). Additionally, most VTEs at HA were associated with younger age groups, unlike those on the plains. A receiver operator characteristic curve analysis revealed differences between HAPs and SLPs for CD40 ligand (area under the curve [AUC], 0.90; 95% confidence interval [CI], 0.84-0.96]), P-selectin (0.79; 0.70-0.88), platelet factor-4 (0.90; 0.84-0.96), intracellular adhesion molecule-1 (0.86; 0.79-0.93), vascular cell adhesion molecule-1 (0.97; 0.95-0.99), vascular endothelial growth factor (0.87; 0.8-0.94), FLT4 (0.94; 0.89-0.99), and Toll-like receptor-2 (0.98; 0.96-1.0) (all P < .05). In conclusion, this study suggests that HA exposure perturbs the molecules associated with vascular integrity and contributes to the early onset of VTE.


Subject(s)
Altitude , Environmental Exposure/adverse effects , Venous Thromboembolism/etiology , Venous Thromboembolism/metabolism , Adult , Biomarkers , Blood Coagulation , Blood Coagulation Tests , Blood Platelets/metabolism , Endothelial Cells/metabolism , Hemostasis , Humans , Male , Middle Aged , ROC Curve , Risk Assessment , Risk Factors , Venous Thromboembolism/diagnosis
6.
Thromb Haemost ; 118(7): 1279-1295, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29864786

ABSTRACT

Venous thromboembolism (VTE), a multi-factorial disease, is the third most common cardiovascular disease. Established genetic and acquired risk factors are responsible for the onset of VTE. High altitude (HA) also poses as an additional risk factor, predisposing individuals to VTE; however, its molecular mechanism remains elusive. This study aimed to identify genes/pathways associated with the pathophysiology of deep vein thrombosis (DVT) at HA. Gene expression profiling of DVT patients, who developed the disease, either at sea level or at HA-DVT locations, resulted in differential expression of 378 and 875 genes, respectively. Gene expression profiles were subjected to bioinformatic analysis, followed by technical and biological validation of selected genes using quantitative reverse transcription-polymerase chain reaction. Both gene ontology and pathway analysis showed enrichment of genes involved in haemostasis and platelet activation in HA-DVT patients with the most relevant pathway being 'response to hypoxia'. Thus, given the environmental condition the differential expression of hypoxia-responsive genes (angiogenin, ribonuclease, RNase A family, 5; early growth response 1; lamin A; matrix metallopeptidase 14 [membrane-inserted]; neurofibromin 1; PDZ and LIM domain 1; procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase 1; solute carrier family 6 [neurotransmitter transporter, serotonin], member 4; solute carrier family 9 [sodium/hydrogen exchanger], member 1; and TEK tyrosine kinase, endothelial) in HA-DVT could be a determining factor to understand the pathophysiology of DVT at HA.


Subject(s)
Altitude , Blood Coagulation Disorders/genetics , Blood Coagulation/genetics , Gene-Environment Interaction , Hypoxia/genetics , Venous Thrombosis/genetics , Adult , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/diagnosis , Case-Control Studies , Gene Expression Profiling/methods , Gene Regulatory Networks , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Hypoxia/complications , Hypoxia/diagnosis , Male , Phenotype , Risk Assessment , Risk Factors , Transcriptome , Venous Thrombosis/blood , Venous Thrombosis/diagnosis
7.
EBioMedicine ; 26: 175-186, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29217135

ABSTRACT

Venous thromboembolism (VTE), the third leading cardiovascular complication, requires more understanding at molecular levels. Here, we have identified miR-145 as a key molecule for regulating thrombus formation in venous thrombosis (VT) employing network based bioinformatics approach and in vivo experiments. Levels of miR-145 showed an inverse correlation with thrombus load determined by coagulation variables. MiRNA target prediction tools and in vitro study identified tissue factor (TF) as a target gene for miR-145. The restoration of miR-145 levels in thrombotic animals via in vivo miR-145 mimic delivery resulted in decreased TF level and activity, accompanied by reduced thrombogenesis. MiR-145 levels were also reduced in VT patients and correlated with increased TF levels in patients, thereby, confirming our preclinical findings. Our study identifies a previously undescribed role of miRNA in VT by regulating TF expression. Therefore, restoration of miR-145 levels may serve as a promising therapeutic strategy for management of VT.


Subject(s)
MicroRNAs/genetics , Thromboplastin/genetics , Thrombosis/genetics , Venous Thrombosis/genetics , Animals , Blood Coagulation/genetics , Disease Models, Animal , Gene Expression Regulation/genetics , Humans , Rats , Thrombosis/physiopathology , Venous Thromboembolism/genetics , Venous Thromboembolism/pathology , Venous Thrombosis/physiopathology
8.
Proc Natl Acad Sci U S A ; 114(18): 4763-4768, 2017 05 02.
Article in English | MEDLINE | ID: mdl-28420787

ABSTRACT

Venous thromboembolism (VTE), caused by altered hemostasis, remains the third most common cause of mortality among all cardiovascular conditions. In addition to established genetic and acquired risk factors, low-oxygen environments also predispose otherwise healthy individuals to VTE. Although disease etiology appears to entail perturbation of hemostasis pathways, the key molecular determinants during immediate early response remain elusive. Using an established model of venous thrombosis, we here show that systemic hypoxia accelerates thromboembolic events, functionally stimulated by the activation of nucleotide binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome complex and increased IL-1ß secretion. Interestingly, we also show that the expression of NLRP3 is mediated by hypoxia-inducible factor 1-alpha (HIF-1α) during these conditions. The pharmacological inhibition of caspase-1, in vivo knockdown of NLRP3, or HIF-1α other than IL-1ß-neutralizing antibodies attenuated inflammasome activation and curtailed thrombosis under hypoxic conditions. We extend the significance of these preclinical findings by studying modulation of this pathway in patients with altitude-induced venous thrombosis. Our results demonstrate distinctive, increased expression of NLRP3, caspase-1, and IL-1ß in individuals with clinically established venous thrombosis. We therefore propose that an early proinflammatory state in the venous milieu, orchestrated by the HIF-induced NLRP3 inflammasome complex, is a key determinant of acute thrombotic events during hypoxic conditions.


Subject(s)
Hypoxia/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/biosynthesis , Venous Thrombosis/metabolism , Animals , Caspase 1/biosynthesis , Disease Models, Animal , Female , Gene Expression Regulation , Humans , Hypoxia/pathology , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Interleukin-1beta/biosynthesis , Male , Rats , Rats, Sprague-Dawley , Venous Thrombosis/pathology
9.
Clin Appl Thromb Hemost ; 23(5): 429-437, 2017 Jul.
Article in English | MEDLINE | ID: mdl-27481876

ABSTRACT

OBJECTIVES: Genes related to endothelial function are responsible for the regulation of vascular functions. AIM: The aim of this study is to investigate whether endothelial gene-associated polymorphism and their plasma levels can be used to predict the risk for venous thromboembolism (VTE). METHODS: We studied 133 patients with VTE and 164 healthy controls. Endothelin (EDN) G8002A, EDN T1370G, EDN 3A/4A, eNOSG894T, angiotensin-converting enzyme I/D, vascular endothelial growth factor C936T, and endothelial cell protein C receptor A6936G polymorphism was genotyped by restriction fragment length polymorphism. Plasma levels of endothelin 1 (EDN1), endothelial nitric oxide synthase, and angiotensin-converting enzyme were measured by enzyme-linked immunoassay kit. RESULTS: The genotype and allele frequency between control and patients with VTE were significantly altered only for EDN T1370G polymorphism. The plasma EDN1 concentration was relatively higher in patients with VTE ( P = .0017) compared to healthy controls and showed an association with the EDN1 gene polymorphism in male Indian population. Logistic regression model analysis for EDN T1370G indicated a significant association between EDN G allele and occurrence of VTE. CONCLUSION: The EDN1 gene polymorphism may play a significant role in predicting individual's susceptibility toward VTE and its clinical progression.


Subject(s)
Alleles , Endothelin-1/genetics , Polymorphism, Genetic , Venous Thromboembolism/genetics , Adult , Humans , India/epidemiology , Male , Risk Factors , Venous Thromboembolism/epidemiology
10.
Sci Rep ; 6: 37099, 2016 11 28.
Article in English | MEDLINE | ID: mdl-27892526

ABSTRACT

Thrombosis is a leading cause of morbidity and mortality in patients with myeloproliferative disorders (MPDs), particularly polycythemia vera (PV) and essential thrombocythemia (ET). Despite the attempts to establish a link between them, the shared biological mechanisms are yet to be characterized. An integrated gene expression meta-analysis of five independent publicly available microarray data of the three diseases was conducted to identify shared gene expression signatures and overlapping biological processes. Using INMEX bioinformatic tool, based on combined Effect Size (ES) approaches, we identified a total of 1,157 differentially expressed genes (DEGs) (697 overexpressed and 460 underexpressed genes) shared between the three diseases. EnrichR tool's rich library was used for comprehensive functional enrichment and pathway analysis which revealed "mRNA Splicing" and "SUMO E3 ligases SUMOylate target proteins" among the most enriched terms. Network based meta-analysis identified MYC and FN1 to be the most highly ranked hub genes. Our results reveal that the alterations in biomarkers of the coagulation cascade like F2R, PROS1, SELPLG and ITGB2 were common between the three diseases. Interestingly, the study has generated a novel database of candidate genetic markers, pathways and transcription factors shared between thrombosis and MPDs, which might aid in the development of prognostic therapeutic biomarkers.


Subject(s)
Myeloproliferative Disorders/genetics , Polycythemia Vera/genetics , Thrombocythemia, Essential/genetics , Transcriptome , Biomarkers/metabolism , Databases, Genetic , Humans , Microarray Analysis , Myeloproliferative Disorders/complications , Polycythemia Vera/complications , Thrombocythemia, Essential/complications
11.
Thrombosis ; 2014: 182762, 2014.
Article in English | MEDLINE | ID: mdl-25349733

ABSTRACT

The genetic variants linked with the susceptibility of individuals to VTE are well known; however, the studies explaining the ethnicity based difference in susceptibility to VTE are limited. Present study assesses mutations in six candidate genes contributing to the etiology of VTE in Indian subjects. The study comprised 93 VTE patients and 102 healthy controls. A PCR-RFLP based analysis was performed for nine mutations in the following genes associated with VTE: favtor V Leiden (FVL), prothrombin, tissue factor pathway inhibitor (TFPI), fibrinogen-beta, plasminogen activator inhibitor 1 (PAI-1), and methylene tetrahydrofolatereductase (MTHFR). All the subjects were found to be monomorphic for FVL 1691G/A, prothrombin 20210G/A and TFPI -536C/T mutations. The mutation in the MTHFR gene (677C/T) was observed only in patients. Contrarily, higher frequency of mutation in the PAI-1 -844G/A and the fibrinogen-ß -455G/A was observed in controls in comparison to the patients. This study suggests that the PAI-1 -844G/A and fibrinogen-ß -455G/A could be protective variants against VTE in Indians. While MTHFR 677C/T mutation was found to be associated, in contrast to other populations, the established genetic variants FVL 1691G/A, prothrombin 20210G/A, and TFPI -536C/T may not be associated with VTE in Indians thus revealing the basis of ethnicity related differences in susceptibility of Indians to VTE.

12.
Int J Oncol ; 44(6): 2009-15, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24718855

ABSTRACT

Breast cancer metastasis is one of the major reasons for the high morbidity and mortality of breast cancer patients. In spite of surgical interventions, chemotherapy, radiation therapy and targeted therapy, some patients are considering alternative therapies with herbal/natural products. In the present study, we evaluated a well-characterized extract from the medicinal mushroom Ganoderma lucidum (GLE) for its affects on tumor growth and breast-to-lung cancer metastasis. MDA-MB-231 human breast cancer cells were implanted into the mammary fat pads of nude mice. GLE (100 mg/kg/every other day) was administered to the mice by an oral gavage for 4 weeks, and tumor size was measured using microcalipers. Lung metastases were evaluated by hematoxylin and eosin (H&E) staining. Gene expression in MDA-MB-231 cells was determined by DNA microarray analysis and confirmed by quantitative PCR. Identified genes were silenced by siRNA, and cell migration was determined in Boyden chambers and by wound-healing assay. Although an oral administration of GLE only slightly suppressed the growth of large tumors, the same treatment significantly inhibited the number of breast-to-lung cancer metastases. GLE also downregulated the expression of genes associated with invasive behavior (HRAS, VIL2, S100A4, MCAM, I2PP2A and FN1) in MDA-MB-231 cells. Gene silencing of HRAS, VIL2, S100A4, I2PP2A and FN1 by siRNA suppressed migration of MDA-MB­231 cells. Our study suggests that an oral administration of GLE can inhibit breast-to-lung cancer metastases through the downregulation of genes responsible for cell invasiveness. The anti-metastatic benefits of GLE warrant further clinical studies.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/secondary , Cell Movement/drug effects , Gene Expression Regulation, Leukemic/drug effects , Lung Neoplasms/drug therapy , Plant Extracts/pharmacology , Reishi/chemistry , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Gene Expression Profiling , Humans , Lung Neoplasms/pathology , Mammary Neoplasms, Experimental , Mice , Mice, Nude , Xenograft Model Antitumor Assays
13.
Diabetes Care ; 37(3): 876-86, 2014.
Article in English | MEDLINE | ID: mdl-24558078

ABSTRACT

OBJECTIVE: We performed a systematic review to identify which genetic variants predict response to diabetes medications. RESEARCH DESIGN AND METHODS: We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance. RESULTS: Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication-gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis. CONCLUSIONS: We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition.


Subject(s)
Blood Glucose/genetics , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Hypoglycemic Agents/therapeutic use , Acarbose/therapeutic use , Biomarkers, Pharmacological/metabolism , Blood Glucose/metabolism , Carbamates/therapeutic use , Diabetes Mellitus, Type 2/metabolism , Humans , Metformin/therapeutic use , Pharmacogenetics , Pioglitazone , Piperidines/therapeutic use , Polymorphism, Genetic , Prediabetic State/drug therapy , Prediabetic State/genetics , Prediabetic State/metabolism , Rosiglitazone , Sulfonylurea Compounds/therapeutic use , Thiazolidinediones/therapeutic use
14.
Blood ; 123(8): 1250-60, 2014 Feb 20.
Article in English | MEDLINE | ID: mdl-24297866

ABSTRACT

Oxygen-compromised environments, such as high altitude, air travel, and sports, and pathological conditions, such as solid tumors, have been suggested to be prothrombotic. Despite the indispensable role of platelets in thrombus formation, the studies linking hypoxia, platelet reactivity, and thrombus formation are limited. In the present study, platelet proteome/reactivity was analyzed to elucidate the acute hypoxia-induced prothrombotic phenotype. Rats exposed to acute simulated hypoxia (282 torr/8% oxygen) demonstrated a decreased bleeding propensity and increased platelet reactivity. Proteomic analysis of hypoxic platelets revealed 27 differentially expressed proteins, including those involved in coagulation. Among these proteins, calpain small subunit 1, a 28-kDa regulatory component for calpain function, was significantly upregulated under hypoxic conditions. Moreover, intraplatelet Ca(2+) level and platelet calpain activity were also found to be in accordance with calpain small subunit 1 expression. The inhibition of calpain activity demonstrated reversal of hypoxia-induced platelet hyperreactivity. The prothrombotic role for calpain was further confirmed by an in vivo model of hypoxia-induced thrombosis. Interestingly, patients who developed thrombosis while at extreme altitude had elevated plasma calpain activities and increased soluble P-selectin level. In summary, this study suggests that augmented calpain activity is associated with increased incidence of thrombosis under hypoxic environments.


Subject(s)
Blood Platelets/metabolism , Calpain/metabolism , Hypoxia/metabolism , Thrombosis/metabolism , Adult , Altitude Sickness/metabolism , Animals , Calpain/genetics , Disease Models, Animal , Enzyme Activation/physiology , Humans , Male , Platelet Activation/physiology , Proteome/metabolism , Rats , Rats, Sprague-Dawley , Thrombophilia/metabolism
15.
Int J Oncol ; 42(6): 1869-74, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23588713

ABSTRACT

Poria cocos is a medicinal mushroom that is widely used in traditional Asian medicine. Here, we show that a characterized mixture of triterpenes extracted from P. cocos (PTE) and three purified triterpenes: pachymic acid (PA), dehydropachymic acid (DPA) and polyporenic acid C (PPAC) suppress the proliferation of the human pancreatic cancer cell lines Panc-1, MiaPaca-2, AsPc-1 and BxPc-3. Moreover, the most effective compound, PA, only slightly affects the proliferation of HPDE-6 normal pancreatic duct epithelial cells. The anti-proliferative effects of PTE on BxPc-3 cells are mediated by the cell cycle arrest at G0/G1 phase. DNA microarray analysis demonstrated that PTE significantly downregulates the expression of KRAS and matrix metalloproteinase-7 (MMP-7) in BxPc-3 cells. In addition, PTE and PA suppress the invasive behavior of BxPc-3 cells. The inhibition of invasiveness by PTE and PA was associated with the reduction of MMP-7 at the protein level and the role of MMP-7 further confirmed by the gene silencing of MMP-7 which also suppressed the invasiveness of BxPc-3 cells. In conclusion, triterpenes from P. cocos demonstrate anticancer and anti-invasive effects on human pancreatic cancer cells and can be considered as new therapeutic agents in the treatment of pancreatic cancer.


Subject(s)
Matrix Metalloproteinase 7/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Poria/chemistry , Triterpenes/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , Gene Silencing , Humans , Lanosterol/analogs & derivatives , Lanosterol/pharmacology , Matrix Metalloproteinase 7/genetics , Pancreatic Ducts/cytology , Pancreatic Ducts/pathology , Pancreatic Neoplasms/metabolism , Triterpenes/isolation & purification
16.
Oncol Rep ; 28(4): 1139-45, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22842551

ABSTRACT

We have recently demonstrated that a natural dietary supplement BreastDefend (BD), which contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin), inhibits proliferation and metastatic behavior of MDA-MB-231 invasive human breast cancer cells in vitro. In the present study, we evaluated whether BD suppresses growth and breast-to lung cancer metastasis in an orthotopic model of human breast cancer cells implanted in mice. Oral application of BD (100 mg/kg of body weight for 4 weeks) by intragastric gavage did not affect body weight or activity of liver enzymes and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. Moreover, BD significantly decreased the change in tumor volume over time compared to the control group (p=0.002). BD treatment also markedly decreased the incidence of breast-to-lung cancer metastasis from 67% (control) to 20% (BD) (p<0.05) and the number of metastases from 2.8 (0.0, 48.0) in the control group to 0.0 (0.0, 14.2) in the BD treatment group (p<0.05). Finally, anti-metastatic activity of BD in vivo was further confirmed by the downregulation of expression of PLAU (urokinase plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor-4) genes in breast tumors. In conclusion, BD may be considered as a biological therapeutic agent against invasive breast cancers.


Subject(s)
Breast Neoplasms/pathology , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Plant Extracts/pharmacology , Administration, Oral , Animals , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Dietary Supplements/adverse effects , Disease Models, Animal , Down-Regulation , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung Neoplasms/genetics , Mice , Mice, Nude , Plant Extracts/adverse effects , Plants, Medicinal/chemistry , Receptors, CXCR4/genetics , Toxicity Tests , Urokinase-Type Plasminogen Activator/genetics , Xenograft Model Antitumor Assays
17.
PLoS One ; 7(3): e34283, 2012.
Article in English | MEDLINE | ID: mdl-22479587

ABSTRACT

BACKGROUND: We have recently synthesized novel N-alkylated amino acid-derived hydroxamate, 2-[Benzyl-(2-nitro-benzenesulfonyl)-amino]-N-hydroxy-3-methyl-N-propyl-butyramide (NAHA). Here, we evaluate the anticancer activity of NAHA against highly invasive human breast cancer cells MDA-MB-231 in vitro and in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Cell growth was evaluated by MTT and soft agar assays. Protein expression was determined by DNA microarray and Western blot analysis. Metastatic potential was evaluated by cell adhesion, migration, invasion, capillary morphogenesis, and ELISA assays. The anticancer activity in vivo was evaluated in mouse xenograft model. NAHA inhibited proliferation and colony formation of MDA-MB-231 cells together with the down-regulation of expression of Cdk2 and CDC20 proteins. NAHA inhibited cell adhesion, migration, and invasion through the suppression of secretion of uPA. NAHA suppressed secretion of VEGF from MDA-MB-231 cells and inhibited capillary morphogenesis of human aortic endothelial cells (HAECs). Finally, NAHA at 50 mg/kg was not toxic and decreased tumor volume and tumor weight in vivo. This suppression of tumor growth was associated with the inhibition of mitotic figures and induction of apoptosis, and the reduction of CD31 and VEGF positive cells in tumors. CONCLUSION: NAHA could be a novel promising compound for the development of new drugs for the therapy of invasive breast cancers.


Subject(s)
Amides/chemistry , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Hydroxamic Acids/chemistry , Valine/analogs & derivatives , Animals , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Female , Humans , In Vitro Techniques , Mice , Mice, Nude , Models, Chemical , Neoplasm Invasiveness , Neoplasm Transplantation , Oligonucleotide Array Sequence Analysis , Valine/chemistry , Vascular Endothelial Growth Factor A/metabolism
18.
Biomol Concepts ; 3(4): 371-80, 2012 Aug.
Article in English | MEDLINE | ID: mdl-25436543

ABSTRACT

Abstract The scavenger receptor (SR) super family consists of integral membrane glycoproteins that are involved in recognition of polyanionic structures of either endogenous (e.g., oxidized low-density lipoprotein) or exogenous (e.g., bacterial lipopolysaccharides) origin. SRs are structurally diverse and can be classified into seven different classes (A-G) based on the multidomain structure of the individual members. SRs are present on various types of tissues, such as vascular, adipose, and steroidogenic tissues. In addition to modified lipoprotein uptake, these proteins are also known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens. Different SRs are involved in many physiological and pathological processes; more importantly, the function of SRs is highly implicated in the initiation and progression of atherosclerotic plaque. Targeting the SR gene products that mediate the response to and uptake of modified lipids holds great promise in the prevention of cardiovascular diseases. Inhibition of SR expression using a combined gene therapy and RNA interference strategy also appears to be an option for long-term therapy. The present review focuses on the involvement of SRs in atherosclerosis, thrombosis, and other cardiovascular diseases. Moreover, the role of SRs is not restricted to vascular lesions; it is also implicated in a number of different cellular functions.

19.
BMC Complement Altern Med ; 11: 74, 2011 Sep 19.
Article in English | MEDLINE | ID: mdl-21929808

ABSTRACT

BACKGROUND: Obesity is a health hazard which is closely associated with various complications including insulin resistance, hypertension, dyslipidemia, atherosclerosis, type 2 diabetes and cancer. In spite of numerous preclinical and clinical interventions, the prevalence of obesity and its related disorders are on the rise demanding an urgent need for exploring novel therapeutic agents that can regulate adipogenesis. In the present study, we evaluated whether a dietary supplement ReishiMax (RM), containing triterpenes and polysaccharides extracted from medicinal mushroom Ganoderma lucidum, affects adipocyte differentiation and glucose uptake in 3T3-L1 cells. METHODS: 3T3-L1 pre-adipocytes were differentiated into adipocytes and treated with RM (0-300 µg/ml). Adipocyte differentiation/lipid uptake was evaluated by oil red O staining and triglyceride and glycerol concentrations were determined. Gene expression was evaluated by semi-quantitative RT-PCR and Western blot analysis. Glucose uptake was determined with [³H]-glucose. RESULTS: RM inhibited adipocyte differentiation through the suppresion of expression of adipogenic transcription factors peroxisome proliferator-activated receptor-γ (PPAR-γ), sterol regulatory element binding element protein-1c (SREBP-1c) and CCAAT/enhancer binding protein-α (C/EBP-α). RM also suppressed expression of enzymes and proteins responsible for lipid synthesis, transport and storage: fatty acid synthase (FAS), acyl-CoA synthetase-1 (ACS1), fatty acid binding protein-4 (FABP4), fatty acid transport protein-1 (FATP1) and perilipin. RM induced AMP-activated protein kinase (AMPK) and increased glucose uptake by adipocytes. CONCLUSION: Our study suggests that RM can control adipocyte differentiation and glucose uptake. The health benefits of ReishiMax warrant further clinical studies.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Adipocytes/drug effects , Adipogenesis/drug effects , Biological Factors/pharmacology , Dietary Supplements/analysis , Down-Regulation/drug effects , Ganoderma/chemistry , Obesity/metabolism , 3T3-L1 Cells , AMP-Activated Protein Kinases/genetics , Adipocytes/cytology , Adipocytes/metabolism , Animals , Biological Transport , Enzyme Activation/drug effects , Glucose/metabolism , Humans , Mice , Obesity/drug therapy , Obesity/enzymology , Obesity/physiopathology
20.
Int J Oncol ; 38(3): 761-7, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21225227

ABSTRACT

Colorectal cancer is one of the most common cancers in men and women in the world. Previous molecular studies have revealed that deregulation of the ß-catenin signaling pathway plays a crucial role in the progression of colorectal cancer. Therefore, modulation of the ß-catenin pathway offers a strategy to control colorectal cancer progression. The medicinal mushroom Ganoderma lucidum (GL) is a rich source of triterpenes with anticancer properties. Here, we show that ganodermanontriol (GNDT), a purified triterpene from GL, inhibited proliferation of HCT-116 and HT-29 colon cancer cells without a significant effect on cell viability. Moreover, GNDT inhibited transcriptional activity of ß-catenin and protein expression of its target gene cyclin D1 in a dose-dependent manner. A marked inhibition effect was also seen on Cdk-4 and PCNA expression, whereas expression of Cdk-2, p21 and cyclin E was not affected by the GNDT treatment. In addition, GNDT caused a dose-dependent increase in protein expression of E-cadherin and ß-catenin in HT-29 cells. Finally, GNDT suppressed tumor growth in a xenograft model of human colon adenocarcinoma cells HT-29 implanted in nude mice without any side-effects and inhibited expression of cyclin D1 in tumors. In conclusion, our data suggest that ganodermanontriol might be a potential chemotherapeutic agent for the treatment of cancer.


Subject(s)
Adenocarcinoma/pathology , Cell Proliferation/drug effects , Colonic Neoplasms/pathology , Lanosterol/analogs & derivatives , Reishi/chemistry , beta Catenin/physiology , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Down-Regulation/drug effects , Female , HCT116 Cells , HT29 Cells , Humans , Lanosterol/chemistry , Lanosterol/pharmacology , Lanosterol/therapeutic use , Male , Mice , Mice, Nude , Signal Transduction/drug effects , Signal Transduction/physiology , Triterpenes/chemistry , Triterpenes/pharmacology , Triterpenes/therapeutic use , Xenograft Model Antitumor Assays , beta Catenin/metabolism
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