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1.
Biomedicines ; 12(3)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38540165

RESUMO

Diabetic retinopathy (DR) is a debilitating diabetic disorder of the retinal microvasculature and the main cause of avoidable blindness in old people. Hesperetin is a plant flavanone largely abundant in citrus species with neuroprotective properties in animal models. This study aimed to explore the neuroprotective and autophagy-enhancing effect of hesperetin in rats with DR. Twenty-four male rats were utilized and allocated to groups: (i) the vehicle group, (ii) DR group and (iii-iv) the DR + hesperetin (50 and 100 mg/kg) groups. Treatment with hesperetin continued for 6 weeks. After the rats were euthanized, their eyes were dissected to detect the biochemical and histological changes in the retinas. Quantification of autophagy markers, beclin 1/LC3/p62, and inflammation markers was performed. Histopathologic changes were investigated after staining with hematoxylin and eosin and periodic acid-Schiff (PAS). Results demonstrated that hesperetin decreased the PAS staining in diabetic rats and attenuated histopathological changes and restored retinal organization and thickness of layers in hematoxylin and eosin staining. Moreover, hesperetin reduced the level of mRNA expression for TNF-α (4.9-fold), IL-1ß (4.15-fold), IL-6 (4.6-fold) and NFκB (5.2-fold), as well as the protein level. This was accompanied by induction of autophagy proteins, beclin 1 and LC3-II. Our results afford evidence that hesperetin is effective in alleviating the pathology of DR via suppressing the inflammatory burden and induction of autophagy. After extensive clinical examinations, hesperetin may prove to be a useful option for treatment of DR.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38470172

RESUMO

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Each year, roughly 5,000 residents conduct research on clinical and practice-based topics to meet the requirements of the ASHP residency standards related to research and project management. Several investigators have evaluated residency research project publication rates, but redundancy among projects has not been evaluated. The primary objective of this study was to determine the rate of redundancy among pharmacy residency research projects. METHODS: This was a retrospective cohort analysis of abstracts accepted to various regional pharmacy residency conferences from 2017 through 2020. Each abstract was placed in a pharmacy domain by therapeutic area. The categorized data for each year were then further evaluated to identify clinical categories for the year. Topics were labeled as redundant if at least 10 projects fell into the same focus area within a clinical category. Descriptive statistics were used to quantify the incidence of redundancy each year. RESULTS: A total of 4,027 abstracts were included. The most common pharmacy domains were infectious disease, internal medicine, and benefit of pharmacy services. Overall, 8.2% projects (332 of 4,027) were categorized as redundant. The most common focus areas were rapid diagnostics, opioid reduction protocols, and vancomycin area-under-the-curve vs trough monitoring. CONCLUSION: Pharmacy residency research projects encompassed topics across a wide range of pharmacotherapy areas. Approximately 1 in 12 projects was redundant. This is likely because the project addressed a "hot topic" in practice and may represent an opportunity for institutions to collaborate to optimize project efficiency and impact.

3.
Cells ; 13(4)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38391931

RESUMO

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Most GABAergic neurons synthesize GABA from glutamate and release it in the synaptic cleft in the CNS. However, astrocytes can also synthesize and release GABA, activating GABA receptors in the neighboring neurons in physiological and pathological conditions. As the primary homeostatic glial cells in the brain, astrocytes play a crucial role in regulating GABA homeostasis and synaptic neurotransmission. Accumulating evidence demonstrates that astrocytic GABA dysregulation is implicated in psychiatric disorders, including alcohol use disorder (AUD) and major depressive disorder (MDD), the most prevalent co-occurring psychiatric disorders. Several current medications and emerging pharmacological agents targeting GABA levels are in clinical trials for treating AUD and MDD. This review offers a concise summary of the role of astrocytic GABA regulation in AUD and MDD. We also provide an overview of the current understanding and areas of debate regarding the mechanisms by which astrocytes regulate GABA in the CNS and their potential significance in the molecular basis of AUD and MDD, paving the way toward future research directions and potential therapeutic target areas within this field.


Assuntos
Transtorno Depressivo Maior , Humanos , Astrócitos/fisiologia , Ácido gama-Aminobutírico , Receptores de GABA , Neurônios GABAérgicos
4.
Surg Infect (Larchmt) ; 25(3): 192-198, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38407831

RESUMO

Background: Appropriate antimicrobial therapy for the management of intra-abdominal infection (IAI) continues to evolve based on available literature. The Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial provided evidence to support four days of antibiotic agents in IAI post-source control but excluded patients with a planned re-laparotomy. This study aimed to determine the short- and long-term recurrent infection risk in this population. Patients and Methods: This is a single-center, retrospective, observational study of adult patients admitted to a quaternary medical center between January 1, 2016, and August 1, 2022, with IAI requiring planned laparotomy. Patients were designated as receiving five or less days of antibiotic agents (short course) or more than five days (long course) after source control. The primary outcome was IAI recurrence within 30 days. Results: Of the 104 patients who met inclusion criteria, 78 were included in analysis. Average age was 57 ± 13.3 years, 56% were male, 94% Caucasian, with a mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 17 ± 7.09. All other baseline characteristics and clinical severity markers were similar between the two groups. Regarding the primary outcome of IAI recurrence, there was no difference when comparing those who received short course versus those who received long course therapy (41.2% vs. 44.4%; p = 0.781). No differences were found between groups with respect to secondary outcomes. Conclusions: In patients admitted with IAI managed with planned re-laparotomy those who received short course antimicrobial therapy were not found to have an increase in IAI recurrence compared to those with longer courses of therapy.


Assuntos
Anti-Infecciosos , Infecções Intra-Abdominais , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Antibacterianos/uso terapêutico , Laparotomia , Estudos Retrospectivos , Infecções Intra-Abdominais/tratamento farmacológico , Infecções Intra-Abdominais/cirurgia
5.
Environ Sci Pollut Res Int ; 31(1): 458-480, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38015391

RESUMO

Nonmedical use of modafinil (MOD) led to increased rates of overdose toxicity, road accidents, addiction, withdrawal, suicide, and mental illnesses. The current study aims to determine the probable MOD brain toxicity and elucidate the possible role of selenium (Se) in ameliorating the neurotoxicity in rat models. Fifty-four male Albino rats were randomly assigned into nine groups. The groups were G1 (control negative), G2 (Se0.1), G3 (Se0.2), G4 (MOD300), G5 (MOD600), G6 (Se0.1 + MOD300), G7 (Se0.2 + MOD300), G8 (Se0.1 + MOD600), and G9 (Se0.2 + MOD600). After finishing the experiment, blood and brain tissue were harvested for biochemical and histological investigation. Neurobehavior parameters were assessed. Tissue neurotransmitter levels and oxidative stress markers were assessed. Gene expression of PI3K/Akt/mTOR-GSK3B, orexin, and orexin receptor2 was measured by qRT-PCR. Histological and immunohistochemistry assessments, as well as molecular docking, were carried out. MOD-induced neurobehavioral toxicity exhibited by behavioral and cognitive function impairments, which are associated with decreased antioxidant activities, increased MDA levels, and decreases in neurotransmitter levels. Brain levels of mRNA expression of PI3K, Akt, and mTOR were decreased, while GS3K, orexin, and orexin receptors were significantly elevated. These disturbances were confirmed by histopathological brain changes with increased silver and Bax immunostaining and decreased crystal violet levels. MOD induced neurotoxic effects in a dose-dependent manner. Compared with the MOD groups, SE coadministration significantly attenuates MOD-induced toxic changes. Docking study shows the protective role of Se as an apoptosis inhibitor and inflammation inhibitor. In conclusion, Se could be used as a biologically effective antioxidant compound to protect from MOD neurobehavioral toxicity in Wistar rats by reversing behavioral alterations, inflammation, apoptosis, and oxidative injury.


Assuntos
Glicogênio Sintase Quinase 3 beta , Selênio , Humanos , Ratos , Masculino , Animais , Selênio/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antioxidantes/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Modafinila/farmacologia , Orexinas/metabolismo , Orexinas/farmacologia , Simulação de Acoplamento Molecular , Ratos Wistar , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Estresse Oxidativo , Inflamação , Apoptose , Neurotransmissores
6.
Toxicol In Vitro ; 95: 105744, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38040128

RESUMO

Flavonoids have a pivotal cytotoxic effect against hepatocellular carcinoma (HCC). The current study aimed to investigate which flavonoid isolated from Physalis pubescens L. leaves has the most cytotoxic effect against Hep-G2 liver cancer cells and if it could ameliorate epirubicin efficacy and safety. Baicalein trimethyl ether (BTME), rutin, quercitrin and myricitrin were isolated from Physalis Pubescens L. leaves. Hep-G2 cells were treated with the isolated flavonoids as well as a combination of BTME and epirubicin. Cell viability and the chromosomal DNA fragmentation in Hep-G2 cells were assessed. BTME showed the best cytotoxic effect against Hep-G2 cells. Combination of epirubicin with (200 µg/mL) BTME significantly decreased the IC50 of epirubicin from 2.79 ± 0.626 µg/mL to 0.76 ± 0.258 µg/mL. Moreover, the same combination significantly increased the IC50 of BTME against WI-38 normal cells. DNA fragmentation as well as the concentration of beclin 1 and Bax were significantly increased in Hep-G2 cells treated with BTME and BTME+epirubicin compared to untreated cells. Besides, BTME and BTME+epirubicin significantly decreased the gene expression of TGFß1 whereas increased ATG-7 gene expression. Conclusions: BTME (200µg/mL) significantly enhanced epirubicin's cytotoxicity against Hep-G2 cells and ameliorated its safety profile. BTME could exert anti-hepatocarcinoma effect by enhancing apoptosis and autophagy.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Flavanonas , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Epirubicina , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Células Hep G2 , Flavonoides/farmacologia , Autofagia
7.
Pathol Res Pract ; 253: 154968, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38008003

RESUMO

Locally advanced gastric cancer (LAGC) still poses a clinical challenge despite multimodality treatment due to multidrug resistance (MDR). Recently, research suggested that autophagy and metabolic regulation may be potential anticancer targets due to their crucial roles in MDR. Let-7a participates in glycolytic and autophagic regulations which are both essential for tumor progression and resistance to therapy. This study used IHC stains; GLUT4 and LC3B to evaluate glycolysis and autophagy respectively. Moreover, mRNA Let-7a was detected by quantitative reverse transcription PCR (q-PCR) in 53 cases of LAGC. Elevated glycolysis and autophagy in LAGC tissue specimens as indicated by high GLUT4 and LC3B expression were significantly associated with adverse prognostic factors such as high pathological grade, positive nodal metastasis, and advanced T stage. Lower Let-7a levels were significantly associated with high tumor grade and advanced T stage. A significant positive correlation between GLUT4 and LC3B expression was detected. Significant inverse correlations between let7a level and IHC expression of both GLUT4 and LC3B were found. Elevated glycolysis and autophagy were significantly associated with poor overall survival (OS). Furthermore, low levels of let-7a were significantly associated with poor OS compared to high levels. Glycolysis and autophagy in LAGC were significantly associated with poor FLOT chemotherapy response. Let7a mRNA relative expression was significantly decreased in cases showing post therapy partial response and sustained disease. Multivariate analysis showed that histologic tumor type, high GLUT4 and high LC3B expression were independent factors associated with poor OS. Poor survival and post FLOT chemotherapy resistance in LAGC cases were significantly related to elevated glycolysis, elevated autophagy, and reduced Let-7a expression. Accordingly, combined therapeutic targeting of these pathways could enhance chemosensitivity in LAGC.


Assuntos
MicroRNAs , Neoplasias Gástricas , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Prognóstico , RNA Mensageiro , Autofagia
8.
Int Immunopharmacol ; 120: 110304, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37224649

RESUMO

Epilepsy is one of the most serious worldwide neurological disorders that lead to the cognitive-psychosocial insults in recurrent seizures. About one third of the patients are drug-resistant, so innovative drugs are needed to manage seizures to improve the quality of life. Ceftriaxone is a cephalosporin antibiotic that increases the expression of glutamate transporters-1 and improves the neurobehavioral effects caused by increased glutamate level in the CNS. Selenium is well known antioxidant. The present study aimed to investigate ceftriaxone and selenium therapeutic effects against epilepsy in rats. Epilepsy was induced by PTZ given at a dose (50 mg/kg I.P) on alternative days for 13 days. Eighty rats were randomly divided into 8 groups: Group1-2; normal and vehicle control, Group 3; PTZ group, Group 4-8; kindled rats received selenium, ceftriaxone100, ceftriaxone200, selenium + ceftriaxone100 and selenium + ceftriaxone200 mg/kg/day respectively for a week. At the end of the study, behavioral tests were performed. Oxidative stress, inflammatory markers, neurotransmitters and GLT-1 were measured in brain tissue homogenate. Brain histopathological investigation was also done. PTZ-kindled rats exhibited increased Racine score, besides behavioral tests and histopathological changes, significant elevation in oxidative stress and inflammatory markers, with decrease in serotonin, dopamine, GABA levels and GLT-1 expressions. Selenium and Ceftriaxone alone or combined treatment decreased Racine score with remarkable improvement in behavioral and histopathological changes. The antioxidant enzymes, neurotransmitters and GLT-1 expressions were increased, along with reduced TNF-α, IL-1 levels. Current study showed that selenium + ceftriaxone100 group represents a possible approach to improve epilepsy particularly through inhibiting oxidative stress and inflammation.


Assuntos
Epilepsia , Selênio , Ratos , Animais , Pentilenotetrazol , Selênio/uso terapêutico , Selênio/farmacologia , Ceftriaxona/uso terapêutico , Antioxidantes/farmacologia , Qualidade de Vida , Anticonvulsivantes/efeitos adversos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Epilepsia/induzido quimicamente , Estresse Oxidativo , Neurotransmissores/farmacologia , Glutamatos/uso terapêutico
9.
Virchows Arch ; 482(5): 823-837, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36939902

RESUMO

Autophagy is a cellular response to diverse stresses within tumor microenvironment (TME) such as hypoxia. It enhances cell survival and triggers resistance to therapy. This study investigated the prognostic importance of HIF-1α and miR-210 in triple negative breast cancer (TNBC). Also, we studied the relation between beclin-1 and Bcl-2 and their prognostic relevance in triple negative breast cancer. Furthermore, the involvement of hypoxia-related markers, beclin-1 and Bcl-2 in mediating resistance to neoadjuvant chemotherapy (NACT) in TNBC was evaluated. Immunohistochemistry was performed to evaluate HIF-1α, beclin-1 and Bcl-2 expression whereas, miR-210 mRNA was detected by quantitative reverse transcription PCR (q-PCR) in 60 TNBC patients. High HIF-1α expression was related to larger tumors, grade III cases, positive lymphovascular invasion, advanced stage, high Ki-67 and poor overall survival (OS). High miR-210 and negative Bcl-2 expression were related to nodal metastasis, advanced stage and poor OS. High beclin-1 was associated with grade III, nodal metastasis, advanced stage and poor OS. Also, high beclin-1 and negative Bcl-2 were significantly associated with high HIF-1α and high miR-210. High HIF- 1α, miR-210 and beclin-1 as well as negative Bcl-2 were inversely related to pathologic complete response following NACT. High beclin-1 and lack of Bcl-2 are significantly related to hypoxic TME in TNBC. High HIF-1α, miR-210, and beclin-1 expression together with lack of Bcl-2 are significantly associated with poor prognosis as well as poor response to NACT. HIF-1α and miR-210 could accurately predict response to NACT in TNBC.


Assuntos
MicroRNAs , Neoplasias de Mama Triplo Negativas , Humanos , Proteína Beclina-1 , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Prognóstico , Terapia Neoadjuvante , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Hipóxia , Autofagia , MicroRNAs/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia , Microambiente Tumoral
10.
Diagn Pathol ; 18(1): 11, 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36737799

RESUMO

Muscle-invasive bladder cancers (MIBCs) is a group of molecularly heterogonous diseases that could be stratified into subtypes with distinct clinical courses and sensitivities to chemotherapy. Clinical application of molecular subtypes could help in prediction of neoadjuvant chemotherapy (NAC) responders. Immunohistochemical (IHC) markers such as GATA3, cytokeratin (CK) 5/6, and p53 are associated with these subtypes and are widely available. Human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) are mutated in multiple cancers including MIBC and are potential therapeutic targets. HER2/EGFR status of MIBC subtypes has not been investigated. Tissue microarrays (TMAs) were constructed from transurethral resection of the bladder tumor (TURB) specimens and stained with GATA3,CK5/6,p53 and HER2 in addition to Quantitative Reverse Transcription PCR for detection of EGFR gene. Of the total cases, 45% were luminal, 36.7% basal and 18.3% p53 wild subtype (p53-WT). Univariate analysis showed that overall survival (OS) and disease-free progression survival (DFS) were significantly longer for luminal subtype. In multivariate analysis, molecular subtype, HER2 status and LV invasion were independent prognostic factors for DFS and OS. Basal subtype showed a significantly better response to NAC. HER2 expression was significantly higher in luminal while EGFR expression was significantly higher in basal subtype. Kaplan-Meier survival curves revealed a significant longer OS and DFS for HER2 negative than positive cases. MIBC can be stratified using a simple IHC panel [GATA3,CK5/6,P53] into clinically relevant prognostic molecular subtypes. Basal tumors are aggressive and respond well to NAC while luminal have better OS. P53-WT tumors are chemoresistant and require further treatments. HER2 and EGFR are potential therapeutic targets for molecular subtypes of MIBC where luminal tumors are more likely to benefit from HER2 and basal from EGFR directed therapies.


Assuntos
Neoplasias da Mama , Neoplasias da Bexiga Urinária , Feminino , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Genes erbB-1 , Músculos/metabolismo , Músculos/patologia , Terapia Neoadjuvante , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
11.
Int J Mol Sci ; 24(3)2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36769034

RESUMO

A mechanistic understanding of the dynamic interactions between the mitochondria and the gut microbiome is thought to offer innovative explanations for many diseases and thus provide innovative management approaches, especially in GIT-related autoimmune diseases, such as ulcerative colitis (UC). ß-Glucans, important components of many nutritious diets, including oats and mushrooms, have been shown to exhibit a variety of biological anti-inflammatory and immune-modulating actions. Our research study sought to provide insight into the function of ß-glucan and/or fidarestat in modifying the microbiome/mitochondrial gut axis in the treatment of UC. A total of 50 Wistar albino male rats were grouped into five groups: control, UC, ß-Glucan, Fidarestat, and combined treatment groups. All the groups were tested for the presence of free fatty acid receptors 2 and 3 (FFAR-2 and -3) and mitochondrial transcription factor A (TFAM) mRNA gene expressions. The reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP content were found. The trimethylamine N-oxide (TMAO) and short-chain fatty acid (SCFA) levels were also examined. Nuclear factor kappa ß (NF-kß), nuclear factor (erythroid-2)-related factor 2 (Nrf2) DNA binding activity, and peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1) were identified using the ELISA method. We observed a substantial increase FFAR-2, -3, and TFAM mRNA expression after the therapy. Similar increases were seen in the ATP levels, MMP, SCFA, PGC-1, and Nrf2 DNA binding activity. The levels of ROS, TMAO, and NF-kß, on the other hand, significantly decreased. Using ß-glucan and fidarestat together had unique therapeutic benefits in treating UC by focusing on the microbiota/mitochondrial axis, opening up a new avenue for a potential treatment for such a complex, multidimensional illness.


Assuntos
Colite Ulcerativa , Microbioma Gastrointestinal , beta-Glucanas , Ratos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Oxazolona , Aldeído Redutase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , beta-Glucanas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Wistar , Mitocôndrias/metabolismo , Ácidos Graxos Voláteis/metabolismo , Trifosfato de Adenosina/metabolismo , DNA/metabolismo
12.
Pathol Res Pract ; 241: 154293, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36586309

RESUMO

BACKGROUND: Despite advances in treatment of non-small cell lung cancer (NSCLC), its prognosis remains dismal. Development of drug resistance is a major obstacle against success of targeted epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKI) therapy. This study aimed to assess the prognostic role of annexin A2 (ANXA2) expression, within both tumor cells and stroma, as well as cancer associated fibroblasts (CAFs) in NSCLC and to investigate their potential role in induction of epithelial mesenchymal transition (EMT) and resistance to gefitinib. METHOD: Immunohistochemistry was performed to evaluate tumoral and stromal ANXA2 expression and α-SMA-stained CAFs in 110 advanced NSCLC patients. Furthermore, STAT3 and E-cadherin mRNA expression was studied by quantitative reverse transcription PCR (qRT-PCR). RESULTS: Both tumoral and stromal ANXA2 as well as CAFs were significantly related to clinical stage IV and malignant pleural effusion, while tumoral ANXA2 was significantly related to poor tumor differentiation. EGFR mutation and high tumoral ANXA2 were independent factors for poor overall survival, whereas high stromal and tumoral ANXA2 and high CAFs were independent predictors for poor progression-free survival. Moreover, high ANXA2 and CAFs were significantly associated with high STAT3 and low E-cadherin mRNA expression. Focusing on EGFR mutated cases, gefitinib resistance was significantly associated with high tumoral and stromal ANXA2, high CAFs, high STAT3 and low E-cadherin. CONCLUSION: CAFs and ANXA2 could be considered as poor prognostic parameters in advanced NSCLC and are potential factors for gefitinib therapy resistance through EMT induction.


Assuntos
Anexina A2 , Antineoplásicos , Fibroblastos Associados a Câncer , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Gefitinibe/uso terapêutico , Gefitinibe/farmacologia , Fibroblastos Associados a Câncer/metabolismo , Transição Epitelial-Mesenquimal/genética , Prognóstico , Neoplasias Pulmonares/patologia , Receptores ErbB/genética , Caderinas/metabolismo , RNA Mensageiro , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
13.
Drug Metab Pharmacokinet ; 47: 100479, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36375226

RESUMO

Dabigatran etexilate (DABE), an oral anticoagulant prodrug, is nearly completely metabolized to the dabigatran (DAB) active metabolite by carboxylesterase-1 (CES1) and carboxylesterase-2 (CES2). The high interpatient variation in DAB plasma concentrations, coupled with its low therapeutic index, emphasizes the need to understand how CES1 and CES2 impact active metabolite formation. Previous work focused on CES1 enzyme activity but the contributions of CES2 remain unclear. The purpose of this study was to determine how CES2 activity influences DAB active metabolite formation. We compared the efficiency of DAB formation from DABE when exposed sequentially to human intestinal and then human hepatic microsomes (mimicking the normal metabolic sequence) with the reverse metabolic sequence in which DABE is exposed to hepatic and then intestinal microsomes. The poor efficiency of DAB formation with reverse sequential hydrolysis indicates that CES2 activity is crucial for active metabolite formation. Thus, the decrease in DAB formation with normal sequential hydrolysis was more sensitive to CES2 inhibition by verapamil (CES2 IC50 = 3.4 µM) than CES1 inhibition by diltiazem (CES2 IC50 = 9.1 µM). These results show CES2 activity plays a crucial role in DAB formation and that variability in its activity is an important determinant of therapeutic response.


Assuntos
Dabigatrana , Pró-Fármacos , Humanos , Dabigatrana/farmacologia , Dabigatrana/metabolismo , Microssomos Hepáticos/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Carboxilesterase/metabolismo , Anticoagulantes/farmacologia , Pró-Fármacos/farmacologia , Pró-Fármacos/metabolismo
14.
Front Med (Lausanne) ; 9: 814970, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35814784

RESUMO

Background: Chronic kidney disease has emerged as a significant independent risk factor for cardiovascular disease. Cardiovascular calcification is an active process involving a complex interaction of inducers and inhibitors. High sensitivity cardiac troponin T assay detects troponin T with higher sensitivity and precision at an earlier point of time than the conventional assays, and is associated with poor outcomes. Serum osteoprotegerin is classed as an inhibitory factor for cardiovascular calcification. It is involved in the pathological processes of vascular damage and linked to the excess cardiovascular morbidity. The aim of the present study was to evaluate the extent of cardiovascular calcification and serum high sensitivity cardiac troponin T level, and their association with serum osteoprotegerin level in patients with chronic kidney disease stages 3-5. Methods: 90 chronic kidney disease patients were enrolled in this study, and they were divided into two groups: group (1) included 45 non-dialysis-dependent chronic kidney disease patients (stages 3-5) and group (2) included 45 chronic hemodialysis patients. Each group further subdivided according to the presence of cardiovascular calcification into subgroup A and B. Vascular calcifications were assessed by lateral lumbar, pelvis and hands X-ray radiographs. Valvular calcification was assessed by echocardiography. Serum cardiac troponin T was measured by high sensitivity assay and serum osteoprotegerin was measured by ELISA. Results: Cardiovascular calcification distribution was 22.2% in group (1) and 33.3% in group (2). Serum osteoprotegerin and troponin T in calcification groups (1A and 2A) were significantly higher than non-calcification groups (1B and 2B; P < 0.001). Osteoprotegerin correlated positively with high sensitivity cardiac troponin T (rs = 0.72, P < 0.001). cardiovascular calcification correlated positively with osteoprotegerin, troponin T, and phosphorus. osteoprotegerin and phosphorus were significant independent predictors of cardiovascular calcification at cut-off values ≥4.6 ng/L and ≥6.95 mg/dl, respectively (P < 0.001). Serum phosphorus and creatinine were independent predictors of osteoprotegerin (P < 0.001 and 0.048, respectively). Conclusion: Osteoprotegerin is strongly associated with cardiovascular calcification and high sensitivity cardiac troponin T. In addition, there is a positive association between calcification and troponin T. This suggests a role for osteoprotegerin in the pathogenesis and risk stratification of cardiovascular calcification and myocardial injury in chronic kidney disease patients with a potential role as a therapeutic target.

15.
Diagnostics (Basel) ; 12(7)2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35885466

RESUMO

Background: Methotrexate (MTX) is one of the most common medications used for rheumatoid arthritis (RA) treatment. Single-nucleotide polymorphisms (SNPs) could potentially predict variability in therapeutic outcomes. Aim: This study aims to assess the impact of SNPs in genes encoding for the MTX pathway for predicting clinical and therapeutic responses to MTX in a cohort of Egyptian patients with RA. Subjects and Methods: Data from 107 Egyptian RA patients (aged 44.4 ± 11.4 years) treated with MTX monotherapy, for a duration of 3.7 ± 3.3 years, were collected. Genotypes of 10 SNPs from four different genes were analyzed using the allelic discrimination PCR technique. Results: The ATIC rs3821353 G/T (p = 0.034) and the C/T and C/C of SLC19A1 rs7279445 (p = 0.0018) were associated with a non-response to MTX, while DHFR rs10072026 C/T and C/C were associated with a good response (p < 0.001). Carriers of the ATIC rs382135 3 G (p = 0.001) and ATIC rs4673990 G (p < 0.001) alleles were more likely to develop RA, while the SLC19A1 rs11702425 T (p < 0.001) and GGH rs12681874 T (p = 0.003) allele carriers were more likely to be protected against RA. Carriers of the ATIC rs4673990 A/G genotype (p < 0.001) were at risk of developing RA, while carriers of the following genotypes were mostly protected against RA: ATIC rs3821353 T/T (p < 0.001), ATIC rs3821353 G/G (p = 0.004), SLC19A1 rs11702425 T/T (p = 0.001), SLC19A1 rs11702425 C/T (p = 0.003), GGH rs12681874 C/T (p = 0.004) and GGH rs12681874 T/T (0.002). Conclusion: The genotyping of genes involved in the MTX pathway may be helpful to predict which RA patients will/will not benefit from MTX, and thus, may help to apply a personalized medicine approach in RA.

16.
Hum Exp Toxicol ; 41: 9603271221089919, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35465754

RESUMO

Bisphenol-A (BPA) is a chemical substance that is widely used in industry for manufacturing of plastic bottles and resins. Recent reports found that BPA may mimic the effects of estrogen to a great manner that might disrupt the normal hormonal balance in the human body. Fluvastatin is an agent used for treatment of hypercholesterolemia that was proven to possess promising antioxidant ant anti-inflammatory properties. Taxifolin is a polyphenolic compound with potential antioxidant and antiestrogenic effects. The present study investigated the prospect of fluvastatin with or without taxifolin to mitigate testicular dysfunction elicited by BPA in rats. In a model of BPA-induced testicular toxicity, the hormonal profile was assessed and the testicular tissues were examined by biochemical analysis, histopathology, and immunohistochemistry. Fluvastatin with or without taxifolin improved the body weight gain, hormonal profile, testicular weight and functions, sperm characteristics, the antioxidant status, and the anti-inflammatory mechanisms together with enhancement of autophagy and suppression of the proapoptotic events induced by BPA in the testicular tissues. In addition, fluvastatin with or without taxifolin significantly mitigated the histopathological and the immunohistochemical changes induced by BPA in the testicular tissues. These desirable effects were more pronounced with fluvastatin/taxifolin combination relative to the use of each of these agents alone. In tandem, fluvastatin/taxifolin combination might counteract the pathogenic events induced by BPA in the testicular tissues which may be considered as a novel strategy for amelioration of these disorders.


Assuntos
Antioxidantes , Proteínas Proto-Oncogênicas c-akt , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose , Compostos Benzidrílicos/toxicidade , Fluvastatina , Inflamassomos , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/análogos & derivados , Ratos , Serina-Treonina Quinases TOR/metabolismo , Testículo
17.
Biomed Pharmacother ; 150: 112960, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35447549

RESUMO

Autism spectrum disorder (ASD) is characterized by pervasive impairments in social communication along with repetitive or stereotyped behaviors. Although its distinctive etiology isn`t completely understood, genetic and environmental risk factors were incriminated. Being a flavonoid of high biomedical value, baicalin was recently verified as an emerging medicinal herb with numerous pharmacological activities. The objective of this study was to investigate the feasible effects of baicalin on valproic acid (VPA)-induced autism regarding its potential mitochondrial modulatory, antioxidant, and antiapoptotic effects. The present study was performed using a rodent model of autism by exposing rat fetuses to VPA on the 12.5th day of gestation. Ten male Wistar rats that were born from control pregnant females were considered as group I (control group). Twenty male Wistar rats that were born from prenatal VPA- treated females were further divided into two groups: Group II (VPA- induced ASD) and group III (VPA + Baicalin). Postnatal baicalin promoted postnatal growth and maturation. In addition, it improved motor development and ameliorated repetitive behavior as well as social deficits in prenatally exposed VPA rats. Moreover, baicalin enhanced neuronal mitochondrial functions as evidenced by elevation of mitochondrial adenosine triphosphate (ATP) level and promotion of mitofusin-2 expression. Furthermore, baicalin elevated sirtuin-1 (SIRT1) level in VPA rats' brain tissues and restored the antioxidant defense mechanisms. Besides, it abrogated the neuronal histopathological changes in the brain tissues. Based on the data herein, baicalin may provide a promising pre-clinical therapeutic line in ASD as a mitochondrial function modulator, antioxidant and anti-apoptotic agent.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Efeitos Tardios da Exposição Pré-Natal , Animais , Antioxidantes , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/patologia , Comportamento Animal , Modelos Animais de Doenças , Feminino , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Wistar , Roedores , Sirtuína 1 , Ácido Valproico
18.
Surg Infect (Larchmt) ; 23(4): 357-363, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35262418

RESUMO

Background: Necrotizing soft tissue infection (NSTI) is known to be a medical emergency with high morbidity and mortality. Guidelines do not specify the optimal duration of antibiotic agents after completion of surgical debridements of NSTI, which has created variable practice. It was hypothesized that patients with NSTI who receive 48 hours or less of post-operative antibiotic agents after final debridement have similar rates of subsequent intervention or infection recurrence, suggesting that a shorter duration of antibiotic agents may treat NSTI adequately after final surgical debridement. Patients and Methods: This was a retrospective study including adults with NSTI identified through International Classification of Diseases, Ninth Revision (ICD-9), International Classification of Diseases, Tenth Revision (ICD-10), and Current Procedural Terminology (CPT) codes admitted to one academic institution between January 1, 2010 and July 31, 2020. Demographics, surgical practices, antibiotic practices, and clinical outcomes including inpatient mortality, hospital length of stay (LOS), intensive care unit (ICU) LOS, total antibiotic days, necrotizing infection clinical composite end point (NICCE) success, and infection recurrence were compared based on the duration of antibiotic agents after final debridement. Results: Three hundred twenty-two patients with NSTI were included and baseline characteristics and clinical severity markers were well balanced between the two groups. In 71 patients (22%) who received less than 48 hours of antibiotic agents after final debridement there was no difference in recurrence (1.4% vs. 3.6%; p = 0.697), mortality (1.4% vs. 4.4%; p = 0.476), or ICU LOS (1 vs. 2 days; p = 0.300], but they did have a shorter hospital LOS (7 vs. 10 days; p = 0.011). Conclusions: Shorter duration of antibiotic therapy after final surgical debridement of NSTI may be appropriate in patients without another indication for antibiotic agents.


Assuntos
Fasciite Necrosante , Infecções dos Tecidos Moles , Adulto , Antibacterianos/uso terapêutico , Desbridamento , Humanos , Tempo de Internação , Estudos Retrospectivos , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/cirurgia
19.
Antioxidants (Basel) ; 11(2)2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-35204074

RESUMO

Peroxisome proliferator-activated receptor gamma (PPAR-γ) is ubiquitously expressed in testicular tissue and plays a crucial role in regulating various physiological processes. Pioglitazone (PIO) is one of the PPAR-γ agonists, having anti-oxidant and anti-inflammatory effects. Patients on gentamycin treatment may undergo serious side effects such as testicular damage. To the best of our knowledge, this was the first study to investigate the possible protective anti-inflammatory and anti-apoptotic effects of PIO on gentamycin-induced testicular damage. Fifty adult male Wistar albino rats included in the study as the control group (CTL) received normal saline; a gentamycin-induced testicular damage group (GM) received gentamycin (100 mg/kg); PIO5, PIO10, PIO20 groups received PIO at a dose of 5, 10, and 20 mg/ kg, respectively, for 21 days, and gentamycin was started at day 15 of the experiment for 6 days. The parameters of spermatozoa and histopathological alterations in the testes were significantly improved in the PIO20 group. Moreover, MDA levels, inflammatory mediators, and apoptotic Bax expression were decreased. The activity of glutathione peroxidase, catalase, total antioxidant capacity, and anti-apoptotic Bcl-2 genes expression were increased. It was concluded that PIO20 could protect against gentamycin-induced testicular damage in Wistar rats through its anti-oxidant, anti-inflammatory, and antiapoptotic effects.

20.
Redox Rep ; 27(1): 21-31, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35094663

RESUMO

OBJECTIVES: Necroptosis is a tightly adjusted inflammatory necrotizing cell death signaling pathway that participates in pathogenesis of discrete diseases as rheumatoid arthritis (RA). Irisin is a myokine with immuno-modulatory effect. Evaluation of irisin efficiency as a novel therapeutic agent in experimentally induced RA via modulating immuno-inflammatory, necroptotic molecular and biochemical signaling pathways. METHODS: RA was induced in 30 female Wister albino rats by a single subcutaneous injection of collagen-II with incomplete Freund's adjuvant (CII-IFA) followed by booster immunization dose 10 days later. After 14 days of the injection, arthritis chronic phase was precipitated. 15 rats were treated by S.C irisin injection daily for 4 weeks. Joint tissue homogenate RIPK-3, MLKL, HMGB1, MCP1, IL-6, CHIT1, MDA, and PN levels were assessed calorimetrically. However, TNF-α mRNA expression level was evaluated by the qrt-PCR technique. RESULTS: The results showed that irisin significantly decreases the level of all assessed biochemical parameters, except MDA, which was significantly increased in comparison with the correspondent values in the arthritic group with no treatment (ttt). CONCLUSIONS: Irisin exhibits therapeutic anti-inflammatory and antioxidant effects via modulating immuno-inflammatory, necroptotic molecular, and biochemical signaling pathways in experimentally induced RA in rats. ABBREVIATIONS: RA: rheumatoid arthritis; RIPK3: receptor-interacting protein kinase 1; MLKL: mixed lineage kinase domain-like protein; HMGB1: High-mobility group protein box 1; MCP1: Monocyte chemoattractant protein 1; IL-6: Interleukin 6; CHIT1: Chitotriosidase; MDA: Malondialdehyde; PN: Peroxynitrite; TNF-α: Tumor Necrosis Factor; qrt-PCR: quantitative real-time reverse transcription PCR; CII-IFA: collagen-II with incomplete Freund's adjuvant; ttt: treatmentNote: TNF-α gene (NCBI GenBank Nucleotide accession # NM_012675.3); The housekeeping gene GAPDH (NCBI GenBank Nucleotide accession # NM_017008.4).


Assuntos
Artrite Reumatoide , Proteína HMGB1 , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Quimiocina CCL2 , Feminino , Proteína HMGB1/genética , Hexosaminidases , Necroptose , Ratos , Ratos Wistar
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