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1.
Bioorg Med Chem Lett ; 76: 128985, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36165914

RESUMO

The anomalous absence of cisPro stabilizing CαHαXaa···πAro interactions at Xaa-Pro-Aro exclusively when Aro is His, is understood by NMR structural analyses of model peptides, as due to i â†’ i backbone-side chain C6 H-bond that forms uniquely when Aro is His, which significantly decreases its χ1-g- population essential for CαHαXaa···πAro formation.


Assuntos
Peptídeos , Isomerismo , Peptídeos/química , Espectroscopia de Ressonância Magnética
2.
Neurosurg Rev ; 44(4): 2291-2298, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33089448

RESUMO

Despite widespread popularity of navigation and angled endoscopes in endonasal endoscopy, there are hardly few studies on their efficacy with the extent of resection or retreatment. This is probably the first study to assess the independent impact of these adjuncts among pituitary tumors. Patients with pituitary tumors undergoing endonasal endoscopy were prospectively studied for their demographics, clinico-radiological features, intraoperative use of navigation, and angled endoscopes, in relation to gross total resection (GTR), near total resection (NTR), endocrine remission, and retreatment. Pertinent statistical analyses were performed. Among a total of 139 patients, navigation and angled endoscopes could be used in 54 and 48 patients, respectively, depending upon their availability rather than chosen as per the case. There was no significant difference in baseline characteristics in relation to their use. The surgeon's perception of immediate benefit was noted among 51.9% while using navigation. The use of angled endoscopes towards the end of resection could help with additional tumor removal in 62.5% of patients. Overall, the use of navigation resulted in a significantly higher GTR (80.8% vs. 59.7%, OR 2.83, p = 0.01), a higher GTR/NTR (86.5% vs. 70.8%, OR 2.65, p = 0.04), and a lower retreatment rate (7.7% vs. 20.8%, OR 3.15, p = 0.05) than the others. In functioning tumors with cavernous sinus invasion, navigation had significantly increased remission rates (69.2% vs. 0%, p = 0.03). The use of angled endoscopes yielded a significantly higher GTR/NTR (91.7% vs. 70.6%, p = 0.04) and a lower retreatment rate (0% vs. 15.7%, p = 0.05) among only non-functioning adenomas. In multivariate analyses, the use of neuronavigation had a significant association with both GTR and retreatment rates (p values 0.005 and 0.02 respectively), independent of other confounding factors. The elective intraoperative use of navigation has a significant independent impact on the extent of resection and retreatment overall. While navigation results in better remission rates among functioning tumors with cavernous sinus invasion, angled endoscopy has a significant association with surgical outcomes in non-functioning tumors.


Assuntos
Neoplasias Hipofisárias , Endoscópios , Endoscopia , Humanos , Neoplasias Hipofisárias/cirurgia , Estudos Prospectivos , Resultado do Tratamento
3.
Acta Neurochir (Wien) ; 163(4): 1053-1060, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33475830

RESUMO

BACKGROUND: The COVID19 lockdown has altered the dynamics of living. Its collateral fallout on head injury care has not been studied in detail, especially from low- and middle-income countries, possibly overwhelmed more than developed nations. Here, we analyze the effects of COVID19 restrictions on head injury patients in a high-volume Indian referral trauma center. METHODS: From the prospective trauma registry, clinico-epidemiological and radiological parameters of patients managed during 190 days before and 190 days during COVID19 phases were studied. As an indicator of care, the inpatient mortality of patients with severe HI was also compared with appropriate statistical analyses. RESULTS: Of the total 3372 patients, there were 83 head injury admissions per week before COVID19 restrictions, which decreased to 33 every week (60% drop) during the lock phases and stabilized at 46 per week during the unlock phases. COVID19 restrictions caused a significant increase in the proportion of patients arriving directly without resuscitation at peripheral centers and later than 6 h of injury. Though the most common mechanism was vehicular, a relative increase in the proportion of assaults was noted during COVID19. There was no change in the distribution of mild, moderate, and severe injuries. Despite a decrease in the percentage of patients with systemic illnesses, severe head injury mortality was significantly more during the lock phases than before COVID19 (59% vs. 47%, p = 0.02). CONCLUSIONS: COVID19 restrictions have amplified the already delayed admission among patients of head injury from north-west India. The severe head injury mortality was significantly greater during lock phases than before COVID19, highlighting the collateral fallout of lockdown. Pandemic control measures in the future should not ignore the concerns of trauma emergency care.


Assuntos
COVID-19/epidemiologia , Traumatismos Craniocerebrais/epidemiologia , Quarentena/estatística & dados numéricos , Adulto , COVID-19/prevenção & controle , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Centros de Traumatologia/estatística & dados numéricos
4.
Dermatol Ther ; 33(6): e13826, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32543093

RESUMO

Sildenafil is one of the commonest over the counter drugs which is orally taken by the people for sexual enhancement. It is an inhibitor of phosphodiesterase type 5 (PDE5) and results in engorgement of carpora cavernosa and help in erectile dysfunction. There are fewer adverse cutaneous drug reactions reported by sildenafil perhaps due to use of the drug without medical prescription. Here we are reporting a case of sildenafil induced hypersensitivity syndrome that is possibly the first one and reviewing the medical literature on type of adverse cutaneous drug eruption due to sildenafil and other PDE5 inhibitors.


Assuntos
Síndrome de Hipersensibilidade a Medicamentos , Citrato de Sildenafila , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Humanos , Masculino , Inibidores de Fosfodiesterase , Piperazinas/efeitos adversos , Purinas/efeitos adversos , Citrato de Sildenafila/efeitos adversos , Sulfonas
5.
Physiol Mol Biol Plants ; 26(7): 1437-1461, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32647460

RESUMO

The present study investigated growth, biochemical, physiological, yield and proteomic changes in 3 wheat varieties exposed to elevated CO2 (515 ppm) in a background of high ambient ozone in field. Ethylenediurea (EDU) was used as antiozonant. Average ozone concentration was 59 ppb and was sufficient enough to exert phytotoxic effects. Elevated carbon dioxide (eCO2) and EDU application individually or in combination negated the adverse effects of ozone by modulating antioxidants and antioxidative enzymes. Differential leaf proteomics revealed that at vegetative stage major changes in protein abundance were due to EDU treatment (47, 52 and 41 proteins in PBW-343, LOK1 and HD-2967, respectively). Combined treatment of eCO2 and EDU was more responsible for changes in 37 proteins during flowering stage of PBW-343 and LOK1. Functional categorization revealed more than 60% differentially abundant protein collectively belonging to carbon metabolism, protein synthesis assembly and degradation and photosynthesis. At both the growth stages, LOK1 was more responsive to eCO2 and combined treatment (eCO2 + EDU). HD-2967 was more positively responsive to EDU and combined treatment. eCO2 in combination of EDU protected these varieties against high ambient O3.

6.
Stroke ; 49(12): 2890-2895, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30571395

RESUMO

Background and Purpose- Though reports suggest decreasing fatality rates of subarachnoid hemorrhage with time, trends in outcome are not reported much especially from developing countries. This study was to analyze changes in outcome across 2 decades and elucidate probable factors. Methods- Prospective databases during 1996 to 2015 were reviewed for neurological outcome at 3 months in relation to demographics, Hunt and Hess grade, Fisher grade, and definitive treatment; and compared between 2 decades, contrasted by establishment of intensive care unit with continuous monitoring and other advancements. Univariate and multivariate analyses were performed. Results- Of the total 2039 patients, 1035 were managed in the former and 1004 in the recent decades. Compared with the former decade, there is delayed age at presentation (46 versus 49 years, P<0.001), poorer Fisher grades (81% versus 87%, P<0.001), and more patients with Hunt and Hess grade 2 (24% versus 39%, P<0.001) in the recent decade. While all patients in databases of the former decade had undergone clipping, 6% in the recent decade underwent coiling. 11% in the recent decade could not undergo definitive treatment. Despite this, there was significantly higher overall favorable outcome (50% versus 60%; odds ratio, 1.5; P<0.001) in recent decade. Favorable outcome of surgical clipping per se improved significantly from 50% to 67% (odds ratio 2.0; P<0.001). Though the improvement was across subgroups, it was more marked among Hunt and Hess grade 3 and Fisher grades 3 and 4. In multivariate analyses, both overall outcome (adjusted odds ratio, 1.7; 95% CI, 1.4-2.1; P<0.001) and surgical outcome (adjusted odds ratio, 1.8; 95% CI, 1.5-2.2; P<0.001) were significantly better in recent decade, independent of known prognostic factors. Conclusions- This is probably the first report to show independent improvement in outcome of subarachnoid hemorrhage with betterment in neurosurgical services from developing country. Dedicated intensive care unit care and focused management protocols could be the likely causes for improvement. Resource-constrained institutions may target patients in Hunt and Hess grade 3 and Fisher grades 3 and 4 for optimal intensive care unit utilization.


Assuntos
Países em Desenvolvimento , Procedimentos Neurocirúrgicos/normas , Hemorragia Subaracnóidea/terapia , Adulto , Bases de Dados Factuais , Feminino , Hidratação/métodos , Escala de Resultado de Glasgow , Humanos , Índia , Pressão Intracraniana , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Análise Multivariada , Procedimentos Neurocirúrgicos/tendências , Nimodipina/uso terapêutico , Razão de Chances , Avaliação de Resultados em Cuidados de Saúde , Qualidade da Assistência à Saúde , Resultado do Tratamento , Vasodilatadores/uso terapêutico
7.
Neurosurg Rev ; 41(2): 513-517, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28741220

RESUMO

Homocysteine (tHcy) has been hardly studied among patients with head injury. This study was to evaluate whether there is any independent impact of tHcy levels on neurological outcome following head injury in a multivariate model. Patients admitted within 24 h of injury were included in the study, along with 20 age- and gender-matched controls. Plasma levels of tHcy were measured at admission using direct immunoassay. All the variables were analyzed with respect to tHcy levels and outcome according to Glasgow Outcome Score (GOS) at 3 months. Univariate and multivariate analyses were performed using SPSS 21. There were a total of 72 patients in the study. tHcy levels were significantly higher after head injury (mean 24.03[SD ± 16.0] µmol/L), compared to matched controls (mean 16.62 [SD ± 10.4] µmol/L) (p = 0.05). Patients with severe head injury, acute SDH, or diffuse higher radiological grades had greater levels of tHcy compared to others. There was a significant relationship between tHcy level and neurological outcome. tHcy levels were significantly higher in patients who had unfavorable GOS (mean 36.22[±25.3] µmol/L), compared to those with favorable GOS (mean 22.71[±14.3] µmol/L) (P = 0.03). In multivariate analysis, tHcy level (adj. odds ratio [OR] 1.17, P = 0.05) and Glasgow Coma Scale (adj. OR 5.17, P = 0.01) had significant association with neurological outcome at 3 months independent of age, dietary habit, radiological grading and of each other. tHcy level has significant independent impact on neurological outcome and may be useful as a prognostic marker following head injury.


Assuntos
Traumatismos Craniocerebrais/sangue , Homocisteína/sangue , Adulto , Idoso , Estudos de Casos e Controles , Traumatismos Craniocerebrais/complicações , Traumatismos Craniocerebrais/diagnóstico , Feminino , Escala de Coma de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Avaliação de Resultados em Cuidados de Saúde , Fatores de Tempo
8.
Indian J Crit Care Med ; 22(3): 162-167, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29657373

RESUMO

CONTEXT: Varicella pneumonia is a rare but a serious complication of chickenpox in adults. There is paucity of data on varicella pneumonia from India. AIMS: The aim of this study is to describe the clinical manifestations, hospital course, treatment, and outcome of adult patients with severe varicella pneumonia. SETTINGS AND DESIGN: This was a retrospective, observational study of patients with severe varicella pneumonia attending a tertiary care teaching hospital. SUBJECTS AND METHODS: The cases of varicella were identified by a computerized search of the medical record for the period between January 2010 and December 2016. During this period, 137 patients got admitted with varicella of which 22 had severe varicella pneumonia. STATISTICAL ANALYSIS: Mean and standard deviation were computed. Fisher's Z-test of proportions and analysis of variance were applied. RESULTS: There were 17 (77.3%) men and 5 (22.7%) women. The mean age of the patients was 33.4 ± 10.8 years. History of contact with an infected person followed by high-grade fever and typical rash was present in all patients. Forty-five percent (10/22) of patients were immunosuppressed. All the patients received intravenous acyclovir. Forty-five percent (10/22) of patients received invasive mechanical ventilation. The various factors associated with the need for mechanical ventilation were partial pressure of oxygen:fraction of inspired oxygen ratio <150, quick sequential (sepsis-related) organ failure assessment (qSOFA) >2, and early bacterial coinfection. The mean Intensive Care Unit and hospital stay were 7 days (range; 1-16) and 9 days (range; 4-21), respectively. The overall mortality was 22.7% and reached 50% in those requiring invasive ventilation. The mortality was higher among patients with qSOFA >3, mean arterial blood pressure <60 mmHg, and severe acute respiratory distress syndrome at presentation. CONCLUSIONS: Patients with severe varicella pneumonia are at an increased risk of respiratory failure and death.

9.
Neurol India ; 65(1): 134-151, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28084258

RESUMO

The Department of Neurosurgery started functioning at the Postgraduate Institute of Medical Education and Research, Chandigarh in 1962 with the joining of Dr. Gulati. The department provides neurosurgical services primarily to the people of Chandigarh, Punjab, Haryana, Himachal Pradesh, Jammu and Kashmir as well as the neighbouring areas of Rajasthan, Uttar Pradesh and Uttarakhand. The infrastructure and subspecialties have been developed over the last 5 decades by the dedicated and tireless efforts of the faculty and residents. We attempt to chronicle the contributions of those who have served the department in the past.


Assuntos
Academias e Institutos/história , Educação de Pós-Graduação em Medicina/história , Neurocirurgia/história , Procedimentos Neurocirúrgicos/história , Faculdades de Medicina/história , História do Século XX , História do Século XXI , Humanos , Índia
10.
Neurol India ; 64(5): 943-6, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27625234

RESUMO

BACKGROUND: The fornix is the main efferent tract from the hippocampus and is an important component of the memory pathways. Variations in the anatomy of the fornix are not commonly encountered. MATERIALS AND METHODS: The anatomy of the fornix was studied in 30 cadavers of normal adult healthy males who had died in road accidents. The full extent of the hippocampus was prosected up to the tail under the magnoscope. RESULTS: In 10 of the 30 brains, the crura and the body of fornix were bilaterally broad and flat like a sheet, rather than the usual compact bundle, forming a cobra-like hood over the roof of the third ventricle. The maximum width was approximately 16 mm on the right side (mean: 11.7 mm) and 11 mm on the left (mean: 8.5mm). CONCLUSION: Knowledge of this variation will be useful during the transcallosal approach to third ventricle tumors, especially while going subchoroidal, because an unexpected lateral span of the fornix in the surgical corridor can result in inadvertent injury to it, leading to memory defects.


Assuntos
Ventrículos Cerebrais/patologia , Fórnice/anormalidades , Hipocampo/patologia , Terceiro Ventrículo/cirurgia , Adulto , Cadáver , Ventrículos Cerebrais/cirurgia , Fórnice/cirurgia , Humanos , Masculino , Procedimentos Neurocirúrgicos , Terceiro Ventrículo/patologia
11.
Acta Neurochir (Wien) ; 157(3): 399-407, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25510646

RESUMO

BACKGROUND: Homocysteine (tHcy) has been known over the last few decades for its putative impact on vascular diseases, but has not been evaluated much in patients with subarachnoid hemorrhage (SAH). This study was carried out to assess its prognostic impact on the neurological outcome following SAH. METHODS: Admission plasma tHcy was evaluated in 90 SAH patients and prospectively studied in relation to various factors and the Glasgow Outcome Scale (GOS) at 3 months. Univariate and multivariate analyses were performed using SPSS 21. RESULTS: tHcy was significantly higher following SAH compared to matched controls [median (IQR): 25.7 (17.3-35.9) vs. 14.0 (9.8-17.6) µmol/l, p < 0.001]. It was significantly higher in younger patients. However, systemic disease, WFNS and Fisher grades did not have a significant impact on its levels. tHcy was significantly lower among patients who died [median (IQR): 16.0 (14.4-20.6) vs. 29.7 (21.8-40.2) µmol/l, p < 0.001] and those with unfavorable outcome (GOS 1-3) [median (IQR): 21.6 (14.5-28.2) vs. 30.3 (20.4-40.7) µmol/l, p = 0.004] compared to others, with a significant continuous positive correlation between tHcy and GOS (p = 0.002). The beneficial association of tHcy with outcome was homogeneous with no significant subgroup difference. Multivariate analysis using binary logistic regression adjusting for the effects of age, systemic disease, WFNS grade, Fisher grade, site of aneurysm, clipping or coiling revealed higher tHcy to have a significant independent association with both survival (p = 0.01) and favorable outcome (p = 0.04). CONCLUSIONS: Higher homocysteine levels following SAH appear to have a significant association with both survival and favorable neurological outcome, independent of other known prognostic factors, apparently exemplifying "reverse epidemiology paradox" in which a conventional risk factor seems to impart a survival advantage.


Assuntos
Homocisteína/sangue , Hemorragia Subaracnóidea/diagnóstico , Adulto , Idoso , Feminino , Escala de Resultado de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Prospectivos , Fatores de Risco , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/epidemiologia
12.
Br J Neurosurg ; 29(3): 432-4, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25547007

RESUMO

Intracranial neurenteric cysts are rare. Diagnosis can only be established on histopathology with the demonstration of mucin-secreting cells in cyst wall. We report a midline, ventral, cystic lesion at the cervico-medullary junction, with the unusual radiological finding of a "fluid-fluid" level. Intraoperatively, the cyst contained fluid along with pus-like material with white flakes and specks of calcification, suggesting a dermoid cyst. However, histopathology confirmed the diagnosis of neurenteric cyst. The patient was managed with right lateral inferior suboccipital approach and near-total excision of the lesion.


Assuntos
Imageamento por Ressonância Magnética , Defeitos do Tubo Neural/patologia , Defeitos do Tubo Neural/cirurgia , Medula Espinal/cirurgia , Adulto , Biópsia , Diagnóstico Diferencial , Feminino , Humanos , Medula Espinal/patologia , Resultado do Tratamento
13.
Neurol India ; 63(2): 197-201, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25947983

RESUMO

BACKGROUND: Traumatic cerebrospinal fluid (CSF) rhinorrhea is a serious and potentially fatal condition as it may lead to meningitis. As acetazolamide decreases CSF production and hence CSF pressure, it has been proposed that the medication may help in curing CSF rhinorrhea. There is no definitive evidence, however, that acetazolamide is actually beneficial in treating traumatic CSF rhinorrhea. The aim of this study was to determine if the administration of acetazolamide in patients of head trauma with CSF rhinorrhea was beneficial in decreasing the duration of CSF rhinorrhea. The acid-base and electrolyte changes caused by the drug were also studied. MATERIALS AND METHODS: We conducted a single center randomized prospective study. Forty-four patients of head trauma with CSF rhinorrhea were divided into two groups, the experimental group (21 patients) was given acetazolamide; and, the control group (23 patients) did not receive the medication. The median duration of CSF leak in days, and the electrolyte changes observed on administration of the medication were recorded in both the groups. RESULTS: Both the experimental and control groups were well matched in terms of age, sex, mechanism of injury, Glasgow Coma Scale (GCS) and the type of skull fracture. The median duration of CSF leak in the control group was of 4 days and in the study group, of 5 days. Acetazolamide caused significant metabolic acidosis and hypokalemia (as shown by decreased serum pH, serum bicarbonate and serum potassium levels) in the experimental group when compared to the control group. CONCLUSIONS: Acetazolamide did not influence the resolution of traumatic CSF rhinorrhea and instead lead to significant metabolic and electrolyte disturbances.

14.
Neurol India ; 63(4): 531-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26238887

RESUMO

BACKGROUND: Nutritional status and adiposity have not been studied to a significant extent in subarachnoid hemorrhage (SAH). The aim of this study was to determine the trends in anthropometric indices and assess their impact on patients with SAH. METHODS: We prospectively studied in 56 patients with SAH, the triceps skinfold thickness (TSF), mid-arm circumference (MAC), mid-arm muscle circumference (MAMC), and other factors, and their relationship to clinical vasospasm and mortality. RESULTS: The median MAC decreased significantly from 29.3 cm (interquartile range [IQR] 28-31 cm) at admission to 27 cm (IQR 26-29 cm) at 1-week (P < 0.001). The median TSF decreased significantly from 34 mm (IQR 30-40 mm) at admission to 30 mm (IQR 25-35 mm) at 1-week (P < 0.001). MAMC values did not show a significant change over a week. The patients who developed clinical vasospasm had significantly higher median admission TSF of 40 mm (IQR 35-45 mm), compared to the median admission TSF of 35 mm (IQR 30-40 mm) among those who did not develop vasospasm (P = 0.03). MAMC values did not differ significantly in relation to vasospasm. Patients who expired by 3 months had significantly greater fall in median MAMC values at 1-week (7.7% [IQR 5.2-11.5%]), compared to the fall in median MAMC values at 1-week among those who were alive at 3 months (2.6% [IQR 2.1-6.6%]) [P = 0.03]. However, the fall in TSF values did not differ significantly in relation to mortality. In multivariate analysis, only the admission TSF, Hunt and Hess and Fisher grades had a significant association with vasospasm. This association was independent of other prognostic factors and of each other. CONCLUSION: Excessive adiposity of patients, measured as an increased TSF value, is significantly associated with clinical vasospasm independent of other prognostic factors, while fall in MAMC, indicating somatic protein catabolism, has some impact on mortality.

15.
Eur J Med Chem ; 265: 116057, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38142511

RESUMO

Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones, leading to the silencing of genes. Targeting specific isoforms of HDACs has emerged as a promising approach for cancer therapy, as it can overcome drawbacks associated with pan-HDAC inhibitors. HDAC6 is a unique HDAC isoform that deacetylates non-histone proteins and is primarily located in the cytoplasm. It also has two catalytic domains and a zinc-finger ubiquitin binding domain (Zf-UBD) unlike other HDACs. HDAC6 plays a critical role in various cellular processes, including cell motility, protein degradation, cell proliferation, and transcription. Hence, the deregulation of HDAC6 is associated with various malignancies. In this study, we report the design and synthesis of a series of HDAC6 inhibitors. We evaluated the synthesized compounds by HDAC enzyme assay and identified that compound 8g exhibited an IC50 value of 21 nM and 40-fold selective activity towards HDAC6. We also assessed the effect of compound 8g on various cell lines and determined its ability to increase protein acetylation levels by Western blotting. Furthermore, the increased acetylation of α-tubulin resulted in microtubule polymerization and changes in cell morphology. Our molecular docking study supported these findings by demonstrating that compound 8g binds well to the catalytic pocket via L1 loop of HDAC6 enzyme. Altogether, compound 8g represents a preferential HDAC6 inhibitor that could serve as a lead for the development of more potent and specific inhibitors.


Assuntos
Inibidores de Histona Desacetilases , Histona Desacetilases , Desacetilase 6 de Histona , Simulação de Acoplamento Molecular , Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/química , Histonas/metabolismo , Ácidos Hidroxâmicos/química
16.
Int Immunopharmacol ; 137: 112470, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38908085

RESUMO

BACKGROUND: The surplus cytokines remaining after use in the early stages of the inflammatory response stimulate immune cells even after the response is over, causing a secondary inflammatory response and ultimately damaging the host, which is called a cytokine storm. Inhibiting heat shock protein 90 (Hsp90), which has recently been shown to play an important role in regulating inflammation in various cell types, may help control excessive inflammatory responses and cytokine storms. METHODS: We discovered an anti-inflammatory compound by measuring the inhibitory effect of CD86 expression on spleen DCs (sDCs) using the chemical compounds library of Hsp90 inhibitors. Subsequently, to select the hit compound, the production of cytokines and expression of surface molecules were measured on the bone marrow-derived DCs (BMDCs) and peritoneal macrophages. Then, we analyzed the response of antigen-specific Th1 cells. Finally, we confirmed the effect of the compound using acute lung injury (ALI) and delayed-type hypersensitivity (DTH) models. RESULTS: We identified Be01 as the hit compound, which reduced CD86 expression the most in sDCs. Treatment with Be01 decreased the production of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1ß) in BMDC and peritoneal macrophages stimulated by LPS. Under the DTH model, Be01 treatment reduced ear swelling and pro-inflammatory cytokines in the spleen. Similarly, Be01 treatment in the ALI model decreased neutrophil infiltration and lower levels of secreted cytokines (IL-6, TNF-α). CONCLUSIONS: Reduction of CD80 and CD86 expression on DCs by Be01 indicates reduced secondary inflammatory response by Th1 cells, and reduced release of pro-inflammatory cytokines by peritoneal macrophages may initially control the cytokine storm.


Assuntos
Anti-Inflamatórios , Citocinas , Células Dendríticas , Proteínas de Choque Térmico HSP90 , Macrófagos Peritoneais , Camundongos Endogâmicos C57BL , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Camundongos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Hipersensibilidade Tardia/tratamento farmacológico , Hipersensibilidade Tardia/imunologia , Antígeno B7-2/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Células Cultivadas , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Células Th1/imunologia , Células Th1/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Feminino , Modelos Animais de Doenças , Baço/imunologia , Baço/efeitos dos fármacos
17.
Acta Neurochir (Wien) ; 155(2): 237-46, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23224577

RESUMO

BACKGROUND: Elective temporary clipping (ETC) is increasingly used in surgery for aneurysms. This study was to assess whether the impact of ETC on intraoperative aneurysmal rupture (IAR) translates into neurological outcome. METHODS: Patients who underwent surgery for ruptured anterior circulation aneurysms were prospectively studied for various factors related to ETC, IAR and neurological outcome at 3 months. Univariate and multivariate analyses were performed using SPSS20. RESULTS: Of the total 273 ruptured aneurysm surgeries studied, IAR was observed in only six out of 132 aneurysms (4.5 %) who had ETC, compared with 78 out of 141 (55.3 %) without ETC (p < 0.001). Aneurysms complicated by IAR had significantly longer clipping time (8.3 min) compared with those without IAR (1.9 min) (p < 0.001). IAR had significant association with unfavorable outcome (38 % vs. 24 %) (p = 0.02). Patients with ETC had significantly shorter clipping time (2.9 min) compared with those without ETC (4.8 min) (p = 0.02). Unfavorable outcome was noted in 30 out of 132 with ETC (23 %), compared with 48 out of 141 without ETC (34 %) (p = 0.04). This beneficial effect was nonsignificantly greater in younger and good clinical grade patients. While episodes of ETC within clipping time of 20 min did not show significant difference in outcome, repeated rescue clipping (45 % unfavorable outcome, p = 0.048) and total clipping time of at least 20 min (75 % unfavorable outcome, p = 0.008) had significant impact on outcome. In multivariate analysis, the use of ETC (p = 0.027) and total temporary clipping less than 20 min (p = 0.049) were noted to result in significantly better outcome, independent of other factors. CONCLUSIONS: The use of ETC decreased the occurrence of IAR and the total clipping time, thereby leading to significantly better outcome, independent of other factors. While repeated elective clipping within total clipping time of 20 min did not influence outcome, repeated rescue clipping and total clipping time of at least 20 min had significant impact on outcome.


Assuntos
Aneurisma Roto/epidemiologia , Aneurisma Roto/prevenção & controle , Procedimentos Cirúrgicos Eletivos , Aneurisma Intracraniano/cirurgia , Complicações Intraoperatórias , Adolescente , Adulto , Idoso , Aneurisma Roto/diagnóstico , Feminino , Seguimentos , Escala de Resultado de Glasgow , Humanos , Incidência , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
19.
Arch Pharm Res ; 46(9-10): 795-807, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37777709

RESUMO

Indazole-based HDAC6 inhibitors with novel zinc-binding modifications were synthesized and evaluated to determine their potential to inhibit HDAC6. The analogs were subjected to a histone deacetylase (HDAC) enzyme assay, which led to identification of compounds 3a and 3b. Both compounds demonstrated higher potency and selectivity as HDAC6 inhibitors with IC50 values of 9.1 nM and 9.0 nM, respectively, and highlighted the importance of the hydroxamic acid moiety for binding to Zn2+ inside the catalytic pocket of HDAC enzymes. In the neuroblastoma SH-SY5Y cell line, both compounds efficiently acetylated α-tubulin but not histone H3 at a low concentration of 0.5 µM. Moreover, compounds 3a and 3b effectively reversed the deacetylation of α-tubulin caused by methamphetamine in the SH-SY5Y cell line, suggesting the potential usefulness of HDAC6 selective inhibition in restoring blood brain barrier integrity by reversing methamphetamine-induced deacetylation.


Assuntos
Inibidores de Histona Desacetilases , Neuroblastoma , Tubulina (Proteína) , Humanos , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Tubulina (Proteína)/metabolismo
20.
J Morphol ; 284(11): e21644, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37856278

RESUMO

The purpose of this study is to describe, in detail, the ultrastructure of the infundibulum of the sexually mature and active female green iguana, Iguana iguana. The infundibulum of five iguanas was remarkably distinct from the uterus, and was also clearly demarcated into cranial (expanded v-shaped) and caudal (tubular) divisions. Tissue samples obtained from five portions (three from the cranial division and two from the caudal division) of the infundibulum were processed conventionally for light and electron microscopy. The epithelial lining of the most anterior, middle, and posterior, parts of the cranial division displayed nonciliated cells predominantly, and occasionally ciliated cells. The numerous secretory granules in nonciliated type 1 cell found in the fimbrial aspect of the infundibulum were homogenous and deeply electron-dense, but those in the other two regions were variants of this cell type because they contained variably electron-dense secretory granules. Two main types of nonciliated cells (type 2 and its variant, type 3, as well as type 4) occurred in the epithelial lining of the caudal division of the infundibulum, but they, clearly, showed no dense secretory granules. Whereas the nonciliated type 2 cell and its variant (type 3 cell) contained large glycogen deposits, the type 4 cell lacked these deposits but its apical part contained large lipid-like droplets and, remarkably, blebbed into the duct lumen. The nonciliated cells lining the mucosal tubular glands contained highly electron-dense secretory granules, which were similar to those found in the nonciliated type 1 cell in the epithelial lining of the fimbrial part of the cranial division of the infundibulum.


Assuntos
Células Epiteliais , Iguanas , Feminino , Animais , Epitélio/ultraestrutura , Tubas Uterinas/ultraestrutura , Hipófise
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