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1.
Cell Mol Biol (Noisy-le-grand) ; 69(2): 162-171, 2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-37224028

RESUMO

We have previously reported that the α1 subunit of sodium-potassium adenosine triphosphatase (Na/K-ATPase), acts as a receptor and an amplifier for reactive oxygen species, in addition to its distinct pumping function. On this background, we speculated that the blockade of Na/K-ATPase-induced ROS amplification with a specific peptide, pNaKtide, might attenuate the development of steatohepatitis. To test this hypothesis, pNaKtide was administered to a murine model of NASH: the C57Bl6 mouse fed a "western" diet containing high amounts of fat and fructose. The administration of pNaKtide reduced obesity as well as hepatic steatosis, inflammation and fibrosis. Of interest, we also noted a marked improvement in mitochondrial fatty acid oxidation, insulin sensitivity, dyslipidemia and aortic streaking in this mouse model. To further elucidate the effects of pNaKtide on atherosclerosis, similar studies were performed in ApoE knockout mice also exposed to the western diet. In these mice, pNaKtide not only improved steatohepatitis, dyslipidemia, and insulin sensitivity but also ameliorated significant aortic atherosclerosis. Collectively, this study demonstrates that the Na/K-ATPase/ROS amplification loop contributes significantly to the development and progression of steatohepatitis and atherosclerosis. Furthermore, this study presents a potential treatment, the pNaKtide, for the metabolic syndrome phenotype.


Assuntos
Aterosclerose , Fígado Gorduroso , Resistência à Insulina , Animais , Camundongos , Dieta Ocidental/efeitos adversos , Espécies Reativas de Oxigênio , Aterosclerose/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Camundongos Endogâmicos C57BL , Adenosina Trifosfatases
2.
J Public Health (Oxf) ; 45(2): 338-346, 2023 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-36418235

RESUMO

BACKGROUND: Tuberculosis (TB) like many other infectious diseases has a strong relationship with climatic parameters. METHODS: The present study has been carried out on the newly diagnosed sputum smear-positive pulmonary TB cases reported to National TB Control Program across Pakistan from 2007 to 2020. In this study, spatial and temporal distribution of the disease was observed through detailed district wise mapping and clustered regions were also identified. Potential risk factors associated with this disease depending upon population and climatic variables, i.e. temperature and precipitation were also identified. RESULTS: Nationwide, the incidence rate of TB was observed to be rising from 7.03% to 11.91% in the years 2007-2018, which then started to decline. However, a declining trend was observed after 2018-2020. The most populous provinces, Punjab and Sindh, have reported maximum number of cases and showed a temporal association as the climatic temperature of these two provinces is higher with comparison to other provinces. Machine learning algorithms Maxent, Support Vector Machine (SVM), Environmental Distance (ED) and Climate Space Model (CSM) predict high risk of the disease with14.02%, 24.75%, 34.81% and 43.89% area, respectively. CONCLUSION: SVM has a higher significant probability of prediction in the diseased area with a 1.86 partial receiver-operating characteristics (ROC) value as compared with other models.


Assuntos
Tuberculose Pulmonar , Tuberculose , Humanos , Paquistão/epidemiologia , Tuberculose/epidemiologia , Tuberculose/diagnóstico , Tuberculose Pulmonar/epidemiologia , Fatores de Risco , Simulação por Computador
3.
Sensors (Basel) ; 23(4)2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36850377

RESUMO

Climate change and the COVID-19 pandemic have disrupted the food supply chain across the globe and adversely affected food security. Early estimation of staple crops can assist relevant government agencies to take timely actions for ensuring food security. Reliable crop type maps can play an essential role in monitoring crops, estimating yields, and maintaining smooth food supplies. However, these maps are not available for developing countries until crops have matured and are about to be harvested. The use of remote sensing for accurate crop-type mapping in the first few weeks of sowing remains challenging. Smallholder farming systems and diverse crop types further complicate the challenge. For this study, a ground-based survey is carried out to map fields by recording the coordinates and planted crops in respective fields. The time-series images of the mapped fields are acquired from the Sentinel-2 satellite. A deep learning-based long short-term memory network is used for the accurate mapping of crops at an early growth stage. Results show that staple crops, including rice, wheat, and sugarcane, are classified with 93.77% accuracy as early as the first four weeks of sowing. The proposed method can be applied on a large scale to effectively map crop types for smallholder farms at an early stage, allowing the authorities to plan a seamless availability of food.


Assuntos
COVID-19 , Aprendizado Profundo , Humanos , Fazendas , Pandemias , Agricultura , Produtos Agrícolas
4.
Acad Psychiatry ; 47(2): 174-180, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35761064

RESUMO

OBJECTIVE: The objectives of this study were to examine the prevalence of burnout, specify contributors to and protective factors against burnout, and gather suggestions to improve well-being in psychiatry Program Directors. METHODS: A survey regarding burnout and wellness was distributed to psychiatric Program Directors through the email listserv of the American Association of Directors of Psychiatric Residency Training (AADPRT). RESULTS: The survey response rate was 273 responses out of 880 members surveyed (31%). The majority of respondents were current residency or fellowship Program Directors or Associate Program Directors or had another current educational role (93%, 227/245). Almost half of current Program Directors or Associate Program Directors reported feeling burned out almost daily or once a week (44%, 93/210). These Program Directors reported a desire to resign (77%), experienced discrimination within the past 5 years (66%), and struggled with finding meaning in their job (44%). The most frequently endorsed contributors to burnout were increasing administrative burden and insufficient support. CONCLUSIONS: The survey findings confirm that burnout characteristics are common among respondents, associated with a desire to resign and a struggle to find meaning in the highly demanding position of Program Director or Associate Program Director. Advocacy for resources, decreased administrative overload, and increased protected time would enhance well-being in Program Directors. Most striking was the frequency of discrimination reported and its relationship to burnout. Departments may benefit from a careful review of policies, procedures, and training to decrease hostile workplaces for women, international medical graduate, and under-represented in medicine Program Directors.


Assuntos
Esgotamento Profissional , Internato e Residência , Psiquiatria , Humanos , Feminino , Estados Unidos , Liderança , Inquéritos e Questionários , Esgotamento Profissional/epidemiologia
5.
Am J Physiol Renal Physiol ; 322(6): F655-F666, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35435001

RESUMO

We have previously demonstrated that the Na-K-ATPase signaling-mediated oxidant amplification loop contributes to experimental uremic cardiomyopathy and anemia induced by 5/6th partial nephrectomy (PNx). This process can be ameliorated by systemic administration of the peptide pNaKtide, which was designed to block this oxidant amplification loop. The present study demonstrated that the PNx-induced anemia is characterized by marked decreases in red blood cell (RBC) survival as assessed by biotinylated RBC clearance and eryptosis as assessed by annexin V binding. No significant change in iron homeostasis was observed. Examination of plasma samples demonstrated that PNx induced significant increases in systemic oxidant stress as assessed by protein carbonylation, plasma erythropoietin concentration, and blood urea nitrogen. Systemic administration of pNaKtide, but not NaKtide (pNaKtide without the TAT leader sequence) and a scramble "pNaKtide" (sc-pNaKtide), led to the normalization of hematocrit, RBC survival, and plasma protein carbonylation. Administration of the three peptides had no significant effect on PNx-induced increases in plasma erythropoietin and blood urea nitrogen without notable changes in iron metabolism. These data indicate that blockage of the Na-K-ATPase signaling-mediated oxidant amplification loop ameliorates the anemia of experimental renal failure by increasing RBC survival.NEW & NOTEWORTHY The anemia of CKD is multifactorial, and the current treatment based primarily on stimulating bone marrow production of RBCs with erythropoietin or erythropoietin analogs is unsatisfactory. In a murine model of CKD that is complicated by anemia, blockade of Na-K-ATPase signaling with a specific peptide (pNaKtide) ameliorated the anemia primarily by increasing RBC survival. Should these results be confirmed in patients, this strategy may allow for novel and potentially additive strategies to treat the anemia of CKD.


Assuntos
Anemia , Eritropoetina , Insuficiência Renal Crônica , Anemia/tratamento farmacológico , Anemia/etiologia , Animais , Eritrócitos/metabolismo , Eritropoetina/metabolismo , Eritropoetina/farmacologia , Feminino , Meia-Vida , Humanos , Ferro/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nefrectomia , Oxidantes , Peptídeos/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo
6.
Monaldi Arch Chest Dis ; 92(4)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35044137

RESUMO

The COVID-19 pandemic has led to mortality and morbidity since December 2019. Many possible treatment options have been advised till date. The role of ivermectin in the treatment of COVID-19 disease remains controversial. The aim of our study was to evaluate the effect of ivermectin in hospitalized patients with non-severe and severe COVID-19 disease. We conducted a retrospective cohort study that compared outcomes in 2 groups of COVID-19 patients hospitalized at the largest tertiary care center of Pakistan. The study group was given ivermectin along with standard treatment of covid-19 disease; the comparison group was not. Data on mortality, inflammatory markers such as C-reactive protein (CRP) and ferritin, length of hospital stay and baseline characteristics were collected from Aga Khan University's database from October 2020 till February 2021. Statistical analysis was done to determine the effectiveness of ivermectin in non-severe and severe COVID-19. Comparison of effectiveness of Ivermectin in both the genders was also conducted. The cohort included 188 patients out of which 90 were treated with ivermectin. Mortality and length of hospitalization was not found to be significantly different in the study group compared with the control group (5.6% vs 5.1%; p=0.87 and 5 days vs 4 days; p=0.27). Analysis of secondary outcomes did not yield statistically significant results, apart from ferritin levels which were significantly less in patients treated with ivermectin (547.1 vs 756.7; p=0.03). The ferritin and CRP levels in affected males were higher than in females on admission and discharge. Our findings suggest ivermectin does not significantly affect all-cause mortality, length of hospitalization and CRP levels in hospitalized COVID-19 patients. Large scale randomized controlled trials (RCTs) are required to further evaluate the role of ivermectin in covid-19 disease.


Assuntos
Tratamento Farmacológico da COVID-19 , Proteína C-Reativa , Feminino , Ferritinas , Humanos , Ivermectina/uso terapêutico , Masculino , Estudos Retrospectivos , SARS-CoV-2
7.
J Pak Med Assoc ; 72(3): 448-451, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35320223

RESUMO

OBJECTIVE: To determine the frequency of sleep paralysis among university students, and to determine the association between sleep paralysis and sleep quality along with different predictive factors leading to sleep paralysis. METHODS: The descriptive cross-sectional study was conducted at the National University of Modern Languages, Islamabad, Pakistan, from June to October, 2019, and comprised adult students of either gender who had experienced at least one episode of sleep paralysis in the past. Demographic variables were obtained using Google Form, while experiences of sleep paralysis were assessed using the Waterloo Unusual Sleep Experience Questionnaire, and sleep quality was assessed with the Sleep Condition Indicator. Data was analysed using SPSS 20. RESULTS: Initially, 440 students were assessed/ Of them, 233(53%) were males, 207(47%) were females, 208(47.3%) were aged 20-23 years, and 129(29.3%) were studying in the third year of their university programme. Of the total, 130(29.5%) subjects had experienced sleep paralysis at least once in their lifetime. The most frequent sensation experienced was feeling of floating 22(16.9%). Mean age at the time of the first experience was 9.7±3.1 years, and 66(50.8%) had experienced the episodes while lying on their back, while 32(24.6%) had positive family history of sleep paralysis. Sleep paralysis had significant relationship with sleep quality (p<0.001). CONCLUSIONS: About one-third of the sample had experienced sleep paralysis once in their lifetime. The relationship between sleep paralysis and insomnia was significant.


Assuntos
Paralisia do Sono , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Paralisia do Sono/epidemiologia , Qualidade do Sono , Estudantes , Universidades , Adulto Jovem
8.
Am J Physiol Renal Physiol ; 320(2): F234-F242, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33356956

RESUMO

Chronic kidney disease (CKD) is one of the most prominent diseases affecting our population today. According to the Factsheet published by Centers for Disease Control and Prevention (CDC), it effects approximately 15% of the total population in the United States in some way, shape, or form. Within the myriad of symptomatology associated with CKD, one of the most prevalent factors in terms of affecting quality of life is anemia. Anemia of CKD cannot be completely attributed to one mechanism or cause, but rather has a multifactorial origin in the pathophysiology of CKD. While briefly summarizing well-documented risk factors, this review, as a hypothesis, aims to explore the possible role of Na-K-ATPase and its signaling function [especially recent identified reactive oxygen species (ROS) amplification function] in the interwoven mechanisms of development of the anemia of CKD.


Assuntos
Anemia/enzimologia , Anemia/etiologia , Insuficiência Renal Crônica/complicações , Transdução de Sinais/fisiologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Humanos , ATPase Trocadora de Sódio-Potássio/genética
9.
J Community Health ; 46(3): 441-449, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632645

RESUMO

An online cross-sectional study was carried out to evaluate the knowledge, attitude, and practice about coronavirus disease 2019 (COVID-19) among primary health care providers (PHPs) at three tertiary care hospital, Peshawar, Pakistan. Data was collected via email and online social media platforms. Statistical package for social science (SPSS) version 25.0 was used for data analysis. Among the total participants (n = 114), 74 (66.7%) were male and 37 (33.3%) were female. The mean scores for knowledge, attitude and practice were 12.7 ± 0.89, 8.9 ± 4.1 and 7.3 ± 1.2, respectively. Most of the participants knew the term COVID-19 and its mode of transmission (90%), signs and symptoms (84%) and risk factors (72%) associated with it. Most of the participants agreed that COVID-19 can be transmitted through coughing and sneezing (74.3%) and 84.6% were in favor that COVID-19 can be prevented by adopting preventive measures. Around 68.8% of the participants disagreed with the use of antibiotics in the prevention of COVID-19. Ninety percent of the respondents were avoiding close contact with the people having cough and flu-like symptoms. Most PHPs had good knowledge, positive attitude and reasonable practices regarding COVID-19. Moreover, focused training programs for PHPs at the Government level can further improve their understanding of risks and preventive strategies related to COVID-19, which will help them to provide appropriate care to their patients as well as to protect themselves from this infection.


Assuntos
COVID-19/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Corpo Clínico Hospitalar/psicologia , Atenção Primária à Saúde , Adulto , COVID-19/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Corpo Clínico Hospitalar/estatística & dados numéricos , Paquistão/epidemiologia , Centros de Atenção Terciária , Adulto Jovem
10.
J Am Soc Nephrol ; 31(8): 1746-1760, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32587074

RESUMO

BACKGROUND: Oxidative stress in adipocyte plays a central role in the pathogenesis of obesity as well as in the associated cardiovascular complications. The putative uremic toxin indoxyl sulfate induces oxidative stress and dramatically alters adipocyte phenotype in vitro. Mice that have undergone partial nephrectomy serve as an experimental model of uremic cardiomyopathy. This study examined the effects on adipocytes of administering a peptide that reduces oxidative stress to the mouse model. METHODS: A lentivirus vector introduced the peptide NaKtide with an adiponectin promoter into the mouse model of experimental uremic cardiomyopathy, intraperitoneally. Then adipocyte-specific expression of the peptide was assessed for mice fed a standard diet compared with mice fed a western diet enriched in fat and fructose. RESULTS: Partial nephrectomy induced cardiomyopathy and anemia in the mice, introducing oxidant stress and an altered molecular phenotype of adipocytes that increased production of systemic inflammatory cytokines instead of accumulating lipids, within 4 weeks. Consumption of a western diet significantly worsened the adipocyte oxidant stress, but expression of NaKtide in adipocytes completely prevented the worsening. The peptide-carrying lentivirus achieved comparable expression in skeletal muscle, but did not ameliorate the disease phenotype. CONCLUSIONS: Adipocyte-specific expression of NaKtide, introduced with a lentiviral vector, significantly ameliorated adipocyte dysfunction and uremic cardiomyopathy in partially nephrectomized mice. These data suggest that the redox state of adipocytes controls the development of uremic cardiomyopathy in mice subjected to partial nephrectomy. If confirmed in humans, the oxidative state of adipocytes may be a therapeutic target in chronic renal failure.


Assuntos
Adipócitos/metabolismo , Cardiomiopatias/etiologia , Fragmentos de Peptídeos/fisiologia , ATPase Trocadora de Sódio-Potássio/fisiologia , Uremia/complicações , Animais , Apoptose , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nefrectomia , Estresse Oxidativo
11.
Sensors (Basel) ; 21(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673425

RESUMO

Unmanned Aerial Vehicle (UAV) is one of the latest technologies for high spatial resolution 3D modeling of the Earth. The objectives of this study are to assess low-cost UAV data using image radiometric transformation techniques and investigate its effects on global and local accuracy of the Digital Surface Model (DSM). This research uses UAV Light Detection and Ranging (LIDAR) data from 80 meters and UAV Drone data from 300 and 500 meters flying height. RAW UAV images acquired from 500 meters flying height are radiometrically transformed in Matrix Laboratory (MATLAB). UAV images from 300 meters flying height are processed for the generation of 3D point cloud and DSM in Pix4D Mapper. UAV LIDAR data are used for the acquisition of Ground Control Points (GCP) and accuracy assessment of UAV Image data products. Accuracy of enhanced DSM with DSM generated from 300 meters flight height were analyzed for point cloud number, density and distribution. Root Mean Square Error (RMSE) value of Z is enhanced from ±2.15 meters to 0.11 meters. For local accuracy assessment of DSM, four different types of land covers are statistically compared with UAV LIDAR resulting in compatibility of enhancement technique with UAV LIDAR accuracy.

12.
Environ Res ; 183: 109191, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32062182

RESUMO

In this study, exposure to arsenic (As), lead (Pb), cadmium (Cd), copper (Cu) and zinc (Zn) was investigated in the blood, pectoral muscles and tail feathers of two terrestrial (spotted owlet; Athena brama and bank myna; Acridotheres ginginianus) and two aquatic (cattle egret; Bubulcus ibis and pond heron; Ardeola grayii) bird species inhabiting Pakistan. Food chain specimens, as well as the dietary proxies δ15N and δ13C, were also analyzed to validate potential trophic and dietary transfers of metals and As in birds. Zn was found to be the most prevalent metal in the tissues of birds followed by Pb, As, Cu, and Cd. The bioaccumulation of metals and As was higher in tail feathers reflecting the combined effect of both endogenous and exogenous contamination. Pectoral muscle and blood harbored lower levels of As and metals, indicating less recent exposure through diet. Aquatic birds feeding at higher trophic levels accumulated significantly higher concentrations of metals and As in their tissues (P < 0.05) and, therefore, may be at a greater risk of metal and As toxicity than terrestrial birds. Linear regression model depicts δ15N as a strong predictor of metals and As levels in the tissues of both aquatic and terrestrial birds, followed by the δ13C dietary proxy. All metals in aquatic species, except for Cd, as well as terrestrial species, except for Cu, exhibit bioaccumulative potential through the food chain (Trophic transfer factor: TTFs > 1) indicating potential harmful consequences for birds. Elevated concentrations of metals and As in tissues may cause harmful effects in birds potentially leading to declines in their populations.


Assuntos
Arsênio , Dieta , Metais Pesados , Animais , Aves , Bovinos , Biomarcadores Ambientais , Exposição Ambiental , Monitoramento Ambiental , Plumas , Cadeia Alimentar , Paquistão
13.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32069992

RESUMO

In recent years, Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions, including cardiac hypertrophy and uremic cardiomyopathy. Cardiotonic steroids (CTS), specific ligands of Na/K-ATPase, regulate its enzymatic activity (at higher concentrations) and signaling function (at lower concentrations without significantly affecting its enzymatic activity) and increase reactive oxygen species (ROS) generation. On the other hand, an increase in ROS alone also regulates the Na/K-ATPase enzymatic activity and signaling function. We termed this phenomenon the Na/K-ATPase-mediated oxidant-amplification loop, in which oxidative stress regulates both the Na/K-ATPase activity and signaling. Most recently, we also demonstrated that this amplification loop is involved in the development of uremic cardiomyopathy. This review aims to evaluate the redox-sensitive Na/K-ATPase-mediated oxidant amplification loop and uremic cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Estresse Oxidativo/genética , ATPase Trocadora de Sódio-Potássio/genética , Uremia/genética , Glicosídeos Cardíacos/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Humanos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Uremia/complicações , Uremia/tratamento farmacológico , Uremia/patologia
14.
Entropy (Basel) ; 22(10)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33286862

RESUMO

The complexity and high dimensionality are the inherent concerns of big data. The role of feature selection has gained prime importance to cope with the issue by reducing dimensionality of datasets. The compromise between the maximum classification accuracy and the minimum dimensions is as yet an unsolved puzzle. Recently, Monte Carlo Tree Search (MCTS)-based techniques have been invented that have attained great success in feature selection by constructing a binary feature selection tree and efficiently focusing on the most valuable features in the features space. However, one challenging problem associated with such approaches is a tradeoff between the tree search and the number of simulations. In a limited number of simulations, the tree might not meet the sufficient depth, thus inducing biasness towards randomness in feature subset selection. In this paper, a new algorithm for feature selection is proposed where multiple feature selection trees are built iteratively in a recursive fashion. The state space of every successor feature selection tree is less than its predecessor, thus increasing the impact of tree search in selecting best features, keeping the MCTS simulations fixed. In this study, experiments are performed on 16 benchmark datasets for validation purposes. We also compare the performance with state-of-the-art methods in literature both in terms of classification accuracy and the feature selection ratio.

15.
IUBMB Life ; 71(10): 1418-1427, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31169978

RESUMO

Altered enzymatic machineries are a substantial biochemical characteristic of tumor cell metabolism that switch metabolic profile from oxidative phosphorylation to amplified glycolysis as well as increased lactate production under hypoxia conditions. Reprogrammed metabolic profile is an emerging hallmark of cancer. Overexpression of several glycolytic enzymes and glucose transporters has been reported in 24 different types of cancers that represent approximately 70% of all the cancer cases around the globe. Thus, targeting glycolytic enzymes could serve as tempting avenue for drug design against cancer. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate. Recent investigations have revealed the overexpression of PGAM1 in several human cancers that is linked with tumor growth, survival, and invasion. The aim of this review is to update scientific research network with cancer-specific role of PGAM1 to elucidate its capability as bonafide therapeutic target for cancer therapy. Moreover, we have also summarized the reported genetic and pharmacological inhibitors of PGAM1. This study suggests that further investigations on PGAM1 should focus on the exploration of molecular mechanisms of PGAM1 overexpression in development of cancer, assessment of biosafety profiles of known inhibitors of PGAM1, and utilization of PGAM1 inhibitors in combinatorial therapies. These future studies will surely support the unbiased strategies for the development of novel PGAM1 inhibitors for cancer therapies.


Assuntos
Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/terapia , Fosfoglicerato Mutase/genética , Proliferação de Células/genética , Ácidos Glicéricos/metabolismo , Glicólise/genética , Humanos , Neoplasias/diagnóstico
16.
Int J Mol Sci ; 20(14)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315267

RESUMO

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.


Assuntos
Hipertensão/metabolismo , Sistema de Sinalização das MAP Quinases , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Hipertensão/etiologia , Hipertensão/genética , Rim/metabolismo , Masculino , Síndrome Metabólica/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Obesidade/genética , Carbonilação Proteica , Espécies Reativas de Oxigênio/metabolismo , Sódio/sangue , Sódio/urina , Cloreto de Sódio na Dieta/efeitos adversos , Quinases da Família src/metabolismo
17.
Medicina (Kaunas) ; 55(5)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137751

RESUMO

Background and Objectives: Lipid-based self-nanoemulsifying drug delivery systems (SNEDDS) have resurged the eminence of nanoemulsions by modest adjustments and offer many valuable opportunities in drug delivery. Chlorpromazine, an antipsychotic agent with poor aqueous solubility-with extensive first-pass metabolism-can be a suitable candidate for the development of SNEDDS. The current study was designed to develop triglyceride-based SNEDDS of chlorpromazine to achieve improved solubility, stability, and oral bioavailability. Materials and Methods: Fifteen SNEDDS formulations of each short, medium, and long chain, triglycerides were synthesized and characterized to achieve optimized formulation. The optimized formulation was characterized for several in vitro and in vivo parameters. Results: Particle size, zeta potential, and drug loading of the optimized SNEDDS (LCT14) were found to be 178 ± 16, -21.4, and 85.5%, respectively. Long chain triglyceride (LCT14) showed a 1.5-fold increased elimination half-life (p < 0.01), up to 6-fold increased oral bioavailability, and 1.7-fold decreased plasma clearance rate (p < 0.01) compared to a drug suspension. Conclusion: The findings suggest that SNEDDS based on long-chain triglycerides (LCT14) formulations seem to be a promising alternative for improving the oral bioavailability of chlorpromazine.


Assuntos
Disponibilidade Biológica , Clorpromazina/metabolismo , Emulsificantes/metabolismo , Administração Oral , Animais , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/normas , Emulsificantes/uso terapêutico , Ratos
18.
Pak J Pharm Sci ; 32(4): 1709-1714, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608894

RESUMO

Resistance pattern both in newly and previously treated-TB patients and risk factors associated in spread of tuberculosis are investigated in the current study. A total 244 Mycobacterium tuberculosis isolates were used for drug-susceptibility test against four drugs. Environmental risk factors were assessed by using self-designed history proforma. Among 244 TB-isolates, 64% were categorized as MDR-TB in drug-susceptibility test. Male proportion was 51% while 32% belonged to 15-34 years age group and 49% were from city Lahore whereas majority of people (31%) was working on daily wages. Divergent drug-resistance pattern was obtained; RIF (68%), SM (52%), EMB (51%). INH showed only (27%) resistance against first-line anti-TB drug. Drug-resistance prevalence for two drug combination was highest (50%) for (INH+SM) and (INH+EMB) followed by (RIF+SM) (49%) whereas for three drugs combination (INH+RIF+EMB) and (INH+RIF+SM) the prevalence was almost same 50% and 49% respectively while 66% patients were categorized as previously treated and 34% as new TB cases. In drug susceptibility test, 71% were identified as MDR-TB among New TB cases, while 63% were identified as MDR-TB from previously treated cases. Surprisingly DST results displayed that percentage prevalence of MDR-TB both in newly and previously treated cases was almost same.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/microbiologia , Adolescente , Adulto , Idoso , Antituberculosos/uso terapêutico , Meio Ambiente , Feminino , Humanos , Isoniazida/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Paquistão/epidemiologia , Prevalência , Rifampina/farmacologia , Fatores de Risco , Tuberculose/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto Jovem
19.
Pak J Pharm Sci ; 32(4(Supplementary)): 1767-1772, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31680071

RESUMO

A chemically preserved food has raised mental health issues. Abnormalities in liver and kidney functions have been reported from mentally imbalanced individuals. This study was focused on finding anxiety issues and biochemistry alterations in brain tumor patients and in controls. The levels of liver & kidney enzymes were compared in both groups through Mann-Whitney U test. Kendall's tau-b correlation was conducted to determine that is there any relationship between anxiety levels and biochemistry parameters in both groups. There was more occurrence of severe anxiety levels (58%) in brain tumor patients. There were more mood swings in CG (64%) as compared to BP (48%). Less sleeping pattern was found in CG (42%) as compared to BP (37%). More patients (58%) were having severe anxiety levels as compared to CG (52%). 73% patients were having low levels of alkaline phosphatase (AP). 52% individuals in CG were having low levels of AP. AP was found significantly associated with anxiety levels in brain tumor patients only. A nutrient deprived food from preservation can reduce levels of alkaline phosphatase. This can impact metabolism of necessary minerals for proper brain function. This epidemiological study reports a significant association between anxiety and reduced AP levels.


Assuntos
Antipsicóticos/efeitos adversos , Neoplasias Encefálicas/fisiopatologia , Aditivos Alimentares/efeitos adversos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Água/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/metabolismo , Ansiedade/induzido quimicamente , Neoplasias Encefálicas/metabolismo , Estudos de Casos e Controles , Criança , Estudos Epidemiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Pak J Pharm Sci ; 32(6(Supplementary)): 2859-2864, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32024625

RESUMO

Frozen food chemicals contain neurotoxins which disturb electrolyte levels. Altered electrolyte levels can induce mental illnesses. This study was focused on finding the prevalence of depression, dementia, intake of antidepressants and electrolytic alterations in brain cancer (BC) patients and in control group (CG) who were taking frozen and canned food. The levels of electrolytes were compared in both groups through Mann-Whitney U test. The Odds Ratio (OR) and Relative Risks (RR) were calculated of having a specific occurrence or condition of brain cancer patients vs. controls. Majority (41.42%) patients were from the age group 33-57 years. There were 52% male and 47% female patients. There was more occurrence of dementia (41%) and depression (6%) in patients as compared to CG. 94% patients were found with dementia. 32% patients were having low levels of sodium and 43% were having low levels of potassium. High levels of potassium (26%) were found in CG. 76% patients and 73% controls were taking canned food in moderation. 69% patients and 50% controls were taking frozen food in moderation. The potassium levels (p value: 0.00001) and sodium levels (p value: 0.01468) were found at significant difference in brain cancer patients and control group. Statistically significantly higher odds of outcome (OR>1) and increased relative risks (RR) were reported in dementia, depression and intake of anti-depressants for BC vs. CG. This epidemiological study reports hyponatremia as a significantly different parameter between brain cancer patients and controls. Food's chemicals induce hyponatremia, which can disturb mental states to develop different neurological conditions.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Demência/etiologia , Depressão/etiologia , Alimentos Congelados/efeitos adversos , Hiponatremia/induzido quimicamente , Adolescente , Adulto , Idoso , Antidepressivos/uso terapêutico , Neoplasias Encefálicas/metabolismo , Estudos de Casos e Controles , Criança , Demência/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Feminino , Humanos , Hiponatremia/metabolismo , Masculino , Pessoa de Meia-Idade , Razão de Chances , Potássio/metabolismo , Prevalência , Risco , Sódio/metabolismo , Adulto Jovem
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