RESUMO
Hepatitis E virus is a primary cause of acute hepatitis worldwide. The present study attempts to assess the genetic variability and evolutionary divergence among HEV genotypes. A vaccine promising capsid-protein coding ORF-2 gene sequences of HEV was evaluated using phylogenetics, model-based population genetic methods and principal component analysis. The analyses unveiled nine distinct clusters as subpopulations for six HEV genotypes. HEV-3 genotype samples stratified into four different subgroups, while HEV-4 stratified into three additional subclusters. Rabbit-infectious HEV-3ra samples constitute a distinct cluster. Pairwise analysis identified marked genetic distinction of HEV-4c and HEV-4i subgenotypes compared to other genotypes. Numerous admixed, inter and intragenotype recombinant strains were detected. The MEME method identified several ORF-2 codon sites under positive selection. Some selection signatures lead to amino acid substitutions within ORF-2, resulting in altered physicochemical features. Moreover, a pattern of host-specific adaptive signatures was identified among HEV genotypes. The analyses conclusively depict that recombination and episodic positive selection events have shaped the observed genetic diversity among different HEV genotypes. The significant genetic diversity and stratification of HEV-3 and HEV-4 genotypes into subgroups, as identified in the current study, are noteworthy and may have implications for the efficacy of anti-HEV vaccines.
Assuntos
Proteínas do Capsídeo , Variação Genética , Genótipo , Vírus da Hepatite E , Filogenia , Seleção Genética , Vírus da Hepatite E/genética , Vírus da Hepatite E/imunologia , Vírus da Hepatite E/classificação , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Animais , Humanos , Vacinas contra Hepatite Viral/imunologia , Vacinas contra Hepatite Viral/genética , Evolução Molecular , Hepatite E/virologia , Coelhos , Análise por Conglomerados , Recombinação Genética , Proteínas ViraisRESUMO
Environmental contamination from petroleum refinery operations has increased due to the rapid population growth and modernization of society, necessitating urgent repair. Microbial remediation of petroleum wastewater by prominent bacterial cultures holds promise in circumventing the issue of petroleum-related pollution. Herein, the bacterial culture was isolated from petroleum-contaminated sludge samples for the valorization of polyaromatic hydrocarbons and biodegradation of petroleum wastewater samples. The bacterial strain was screened and identified as Bacillus subtilis IH-1. After six days of incubation, the bacteria had degraded 25.9% of phenanthrene and 20.3% of naphthalene. The treatment of wastewater samples was assessed using physico-chemical and Fourier-transform infrared spectroscopy analysis, which revealed that the level of pollutants was elevated and above the allowed limits. Following bacterial degradation, the reduction in pollution parameters viz. EC (82.7%), BOD (87.0%), COD (80.0%), total phenols (96.3%), oil and grease (79.7%), TKN (68.8%), TOC (96.3%) and TPH (52.4%) were observed. The reduction in pH and heavy metals were also observed after bacterial treatment. V. mungo was used in the phytotoxicity test, which revealed at 50% wastewater concentration the reduction in biomass (30.3%), root length (87.7%), shoot length (93.9%), and seed germination (30.0%) was observed in comparison to control. When A. cepa root tips immersed in varying concentrations of wastewater samples, the mitotic index significantly decreased, suggesting the induction of cytotoxicity. However, following the bacterial treatment, there was a noticeable decrease in phytotoxicity and cytotoxicity. The bacterial culture produces lignin peroxidase enzyme and has the potential to degrade the toxic pollutants of petroleum wastewater. Therefore the bacterium may be immobilised or directly used at reactor scale or pilot scale study to benefit the industry and environmental safety.
Assuntos
Bacillus subtilis , Biodegradação Ambiental , Petróleo , Águas Residuárias , Bacillus subtilis/metabolismo , Bacillus subtilis/crescimento & desenvolvimento , Águas Residuárias/microbiologia , Águas Residuárias/química , Petróleo/metabolismo , Petróleo/toxicidade , Fenantrenos/metabolismo , Fenantrenos/análise , Fenantrenos/toxicidade , Naftalenos/metabolismo , Naftalenos/toxicidade , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise , Esgotos/microbiologia , Metais Pesados/metabolismo , Metais Pesados/toxicidade , Metais Pesados/análiseRESUMO
This critique evaluates a retrospective study comparing surgical outcomes for thoracic dumbbell tumors utilizing different approaches. The study provides comprehensive insights into the management of this complex condition, highlighting the strengths and weaknesses of its methodology and findings. While the study offers valuable information for guiding clinical practice, its retrospective design and inherent limitations warrant careful interpretation of the results. Addressing these limitations through prospective studies with randomized designs and larger patient populations could further enhance our understanding of the optimal surgical approach for thoracic dumbbell tumors.
Assuntos
Neoplasias , Cirurgia Torácica Vídeoassistida , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The "Letter to the Editor" titled "Scalp incision technique for decompressive hemicraniectomy: comparative systematic review and meta-analysis of the reverse question mark versus alternative retroauricular and Kempe incision techniques of published cases" provides a detailed analysis of different scalp incision techniques in decompressive hemicraniectomy procedures. While commendable for its systematic approach and valuable insights, the letter has several limitations, including a lack of transparency in the search strategy, failure to address potential sources of bias, and a narrow focus on technical aspects without considering broader outcome domains and practical considerations. Despite these limitations, the letter underscores the importance of evidence-based decision-making in neurosurgical practice and calls for further research to address these gaps.
Assuntos
Craniectomia Descompressiva , Couro Cabeludo , Humanos , Couro Cabeludo/cirurgia , Resultado do Tratamento , Revisões Sistemáticas como Assunto , Metanálise como AssuntoRESUMO
This critique provides a critical analysis of the outcomes following occipito-cervical fusion in patients with Ehlers-Danlos syndromes (EDS) and craniocervical instability. The study examines the efficacy of the surgical intervention and evaluates its impact on patient outcomes. While the article offers valuable insights into the management of EDS-related craniocervical instability, several limitations and areas for improvement are identified, including sample size constraints, the absence of a control group, and the need for long-term follow-up data. Future research efforts should focus on addressing these concerns to optimize treatment outcomes for individuals with EDS.
Assuntos
Publicações , Fusão Vertebral , Humanos , Tamanho da AmostraRESUMO
This letter offers a nuanced evaluation of the recent study on single-cell transcriptome analysis of ECM-remodeling meningioma cells. While acknowledging the positive aspects, such as enhanced understanding of tumor heterogeneity and identification of potential therapeutic targets, it also highlights potential limitations, including challenges in data interpretation and validation.The focus on ECM-remodeling may inadvertently overshadow other critical aspects of tumor biology, necessitating a more holistic approach. The abstract concludes by emphasizing the importance of considering the broader context of tumor heterogeneity and microenvironmental influences in future research endeavors to improve clinical outcomes for patients with meningioma and other malignancies.
Assuntos
Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/genética , Meningioma/patologia , Análise da Expressão Gênica de Célula Única , Matriz Extracelular/patologia , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologiaRESUMO
The recent publication titled "Optimizing Surgical Approaches for Anterior Communicating Artery Aneurysms: Development and Internal Validation of a Novel Surgical Scoring System" presents a groundbreaking study in neurosurgery. This critique examines both the positive and negative impacts of the research. Positive aspects include the potential to improve patient outcomes through personalized surgical approaches guided by a standardized scoring system. Internal validation enhances the credibility of the scoring system. However, challenges such as the need for external validation and additional surgeon training are acknowledged. Overall, while the study offers promising advancements, further research and validation are essential for widespread implementation in clinical practice.
Assuntos
Aneurisma Intracraniano , Neurocirurgia , Cirurgiões , Humanos , Aneurisma Intracraniano/cirurgia , Procedimentos NeurocirúrgicosRESUMO
This retrospective cohort study aimed to investigate the impact of low fibrinogen levels on in-hospital mortality and 6-month functional outcomes in patients with traumatic brain injury (TBI) within a single center,focusing on the strengths, weaknesses, and suggestions for future research. Patients were followed up to assess in-hospital mortality and functional outcomes at six months post-injury using standardized scales. Statistical analyses, including multivariable regression models, were employed to evaluate the association between low fibrinogen levels and outcomes, adjusting for potential confounders, and revealed a significant association between low fibrinogen levels and increased in-hospital mortality rates among patients with TBI (p < 0.05). Additionally, patients with low fibrinogen levels exhibited poorer functional outcomes at the 6-month follow-up, as evidenced by lower scores on functional assessment scales than those with normal fibrinogen levels, suggesting that low fibrinogen levels upon admission may serve as a prognostic indicator for adverse outcomes in patients with TBI, including higher in-hospital mortality rates and impaired functional recovery at 6 months post-injury. Furthermore, this study explored conservative and surgical management approaches, offering valuable insights into treatment decision-making and outcomes. Future research should prioritize prospective, multicenter studies with standardized protocols, collaborative efforts among institutions, and innovative techniques to advance our understanding and management.
Assuntos
Lesões Encefálicas Traumáticas , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Mortalidade Hospitalar , Lesões Encefálicas Traumáticas/cirurgia , FibrinogênioRESUMO
This letter provides feedback on the article titled "Volumetric Segmentation in the Context of Posterior Fossa-Related Pathologies: A Systematic Review." It highlights the positive impacts of the review, such as its comprehensive examination of existing literature and its potential to enhance diagnostic accuracy and treatment planning. However, it also addresses limitations and challenges associated with volumetric segmentation, including variability in image quality and accessibility issues.
Assuntos
Fossa Craniana Posterior , Humanos , Fossa Craniana Posterior/diagnóstico por imagem , Imageamento por Ressonância Magnética , Processamento de Imagem Assistida por ComputadorRESUMO
This critique evaluates the systematic review and meta-analysis titled "Local anesthesia with sedation and general anesthesia for the treatment of chronic subdural hematoma." The study provides valuable insights into anesthesia techniques' effectiveness in managing this condition but has limitations, including selection bias, heterogeneity among cases, lack of standardized protocols, and retrospective design. Despite these limitations, the review contributes to understanding chronic subdural hematoma management but underscores the need for future research to address these shortcomings.
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Anestesia Geral , Anestesia Local , Hematoma Subdural Crônico , Humanos , Anestesia Geral/métodos , Anestesia Local/métodos , Sedação Consciente/métodos , Hematoma Subdural Crônico/cirurgia , Revisões Sistemáticas como Assunto , Metanálise como AssuntoRESUMO
Previous studies have shown that among Bangladeshi adults, one-fifth have hypertension. The National Heart Foundation of Bangladesh participated in May Measurement Month (MMM) campaigns in 2017, 2018, 2019, as well as in 2021 as a part of a global initiative aimed at raising awareness of high blood pressure (BP) and to act as a temporary solution to the lack of nationwide screening programmes. This opportunistic screening of voluntary participants aged ≥18 years was carried out from May to July 2021. Data were collected from more than 150 screening sites in all 64 districts in Bangladesh. Blood pressure measurement, the definition of hypertension, and statistical analysis followed the MMM protocol. Data on 28 355 individuals were finally analysed. Among the participants, 17 941 (63.3%) were female. After multiple imputation, 11 194 (39.5%) had hypertension. Among the 11 194 participants with hypertension, 78.8% were aware of having hypertension and 65.6% were on antihypertensive medication. Among 11 194 participants with hypertension, 7340 participants (65.6%) were on antihypertensive medication and 43.8% had controlled BP (<140/90â mmHg). Of those on antihypertensive medication, 66.8% had controlled BP. A voluntary BP screening programme can identify significant numbers of people with raised BP and thus contributes importantly to the prevention of cardiovascular diseases.
RESUMO
Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson's disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro, Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway.
Assuntos
Sistema y+ de Transporte de Aminoácidos , Encéfalo , Ferroptose , Subunidade alfa do Fator 1 Induzível por Hipóxia , Manganês , Camundongos Endogâmicos ICR , Proteína Supressora de Tumor p53 , Animais , Ferroptose/efeitos dos fármacos , Células PC12 , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Manganês/toxicidade , Encéfalo/efeitos dos fármacos , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Ratos , Masculino , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Cicloexilaminas/farmacologia , Fenilenodiaminas/toxicidade , Fenilenodiaminas/farmacologia , Desferroxamina/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Aminoácidos DicarboxílicosRESUMO
Arbutin, a naturally soluble glycosylated phenol has antioxidant, antimicrobial, antitumor and anti-inflammatory properties. The current exploration appraises the treatment of arthritis by use of Arbutin (25, 50 and 100 mg/kg) orally in CFA-induced rat arthritis model. Body weight changes, paw size, and joint diameter were recorded till the 28th day in the arthritic-induced rats. Hematological, biochemical, oxidative and inflammatory biomarkers were measured through the blood samples of anesthetized rats. Arbutin markedly decreased paw volume, PGE-2, anti-CCP and 5-LOX levels, however, maintained metabolic and hematological balance and prevented weight loss. Radiology and histology changes improved significantly in the ankle joints of rats. Moreover, Arbutin increased gene pointers such as IL-10 and IL-4 while significantly reducing the levels of CRP and WBCs, whereas Hb, platelets and RBCs count markedly raised in post-treatments. Antioxidant levels of SOD, CAT and GSH were improved and MDA level was reduced in treated groups. Rt-PCR investigation showed a significant reduction of the interleukin-1ß, TNF-α, interleukin-6, cyclooxygenase-2, NF-κB and IL-17 and increased expression of gene pointers like IL-4, and IL-10 in treated groups. Assessment of molecular docking revealed a strong binding interaction of Arbutin against 5-LOX, IL-17, TNF-alpha and interleukin-6, cyclooxygenase-2, nuclear factor-κB, IL-4 and iNOS providing a strong association between experimental and theoretical results. As a result, Arbutin has significantly reduced CFA-induced arthritis by modulation of anti-inflammatory cytokines, i.e., IL-10 and IL-4, the pro-inflammatory cytokines panel such as NF-κB, TNF-alpha, IL-1ß, IL-6, PGE-2, 5-LOX and COX-2 and oxidative biomarkers.
Assuntos
Araquidonato 5-Lipoxigenase , Arbutina , Artrite Experimental , Dinoprostona , Interleucina-17 , NF-kappa B , Fator de Necrose Tumoral alfa , Animais , Ratos , NF-kappa B/metabolismo , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Arbutina/farmacologia , Arbutina/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo , Masculino , Araquidonato 5-Lipoxigenase/metabolismo , Dinoprostona/metabolismo , Interleucina-17/metabolismo , Ratos Wistar , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia , Simulação de Acoplamento Molecular/métodosRESUMO
An immunologic system attacking the body's own tissues is a hallmark of autoimmune disorders, which encompass a wide range of unique conditions. Numerous essential biologic functions, including the regulation of the immune system, inflammation, cell division, and tissue repair, are carried out by cytokines. Natural compounds are an effective treatment for autoimmune illnesses by modulation of inflammatory cytokines and infiltration of leukocytes into the inflamed tissue. Here, anti-arthritic study was carried out using oral administration of Azelaic acid (AzA) for 28 days with doses (20, 40, and 80 mg/kg) in Complete Freund's Adjuvant (CFA) induced arthritis model. AzA ameliorated the adjuvant-induced arthritis by decreasing arthritic score, paw volume, improved body-weight alterations and serum levels of PGE2, 5-LOX and anti-ccp. AzA showed significant down regulation of NF-κB, COX-II, TNF-α, IL-17, IL-1ß, IL-6, and up regulation of IL4 and IL10. Hemoglobin and RBCs count remarkably increased and ESR, CRP, platelets, WBCs levels markedly reduced in post treatment. In addition, the weakened SOD (superoxide dismutase), Catalase (CAT), Glutathione (GSH) activity and the increased levels of malondialdehyde (MDA) were all reversed by AzA treatment. And showed improved radiographical and histologic alterations in the structure of the joints. Molecular docking studies targeting COX-II, iNOS, TNF-α, 5-LOX, IL4, IL10, IL-6, and IL-17 establish a correlation between theoretical and experimental results. Results showed that AzA inhibit pro-inflammatory cytokines (COX-II, TNF-α, 5-LOX, IL-17, NF-κB, IL-1ß, and IL-6) and increase anti-inflammatory cytokines, which supported the anti-arthritic and immunomodulatory potential of AzA.
Assuntos
Anti-Inflamatórios , Artrite Experimental , Citocinas , Ácidos Dicarboxílicos , Adjuvante de Freund , Animais , Ratos , Citocinas/metabolismo , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Anti-Inflamatórios/farmacologia , Masculino , Ácidos Dicarboxílicos/farmacologia , Ratos Wistar , Simulação de Acoplamento Molecular/métodos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Relação Dose-Resposta a DrogaRESUMO
The monoterpene oxide, Eucalyptol (1,8-Cineole), a primary component of eucalyptus oil, has been evaluated pharmacologically for anti-inflammatory and analgesic activity. Current research aimed to evaluate Eucalyptol's anti-arthritic potential in a Complete Freund's adjuvant induced arthritis that resembles human rheumatoid arthritis. Polyarthritis developed after 0.1 mL CFA injection into the left hind footpad in rats. Oral administration of Eucalyptol at various doses (100, 200 and 400 mg/kg) significantly reduced paw edema, body weight loss, 5-LOX, PGE2 and Anti-CCP levels. Real-time PCR investigation showed significant downregulation of COX-2, TNF-α, NF-κB, IL-17, IL-6, IL-1ß and upregulation of IL-4 and IL-10 in Eucalyptol treated groups. Hemoglobin and RBCs counts significantly increased post-treatment with Eucalyptol while ESR, CRP, WBCs and platelets count significantly decreased. Eucalyptol significantly increased Superoxide Dismutase, Catalase and Glutathione levels compared to CFA-induced arthritic control however, MDA significantly decreased post-treatment. Further, radiographic and histopathological examination of the ankle joints of rodents administered Eucalyptol revealed an improvement in the structure of the joints. Piroxicam was taken as standard. Furthermore, molecular docking findings supported the anti-arthritic efficacy of Eucalyptol exhibited high binding interaction against IL-17, TNF-α, IL-4, IL-10, iNOS NF-κB, 5-LOX, and COX-2. Eucalyptol has reduced the severity of CFA induced arthritis by promoting anti-inflammatory cytokines for example IL-4, IL-10 and by inhibiting pro-inflammatory cytokines such as 5-LOX, COX-2, IL-17, NF-κB, TNF-α, IL-6 and IL-1ß. Therefore, Eucalyptol might be as a potential therapeutic agent because of its pronounced anti-oxidant and anti-arthritic activity.
Assuntos
Anti-Inflamatórios , Artrite Experimental , Ciclo-Oxigenase 2 , Eucaliptol , Interleucina-10 , Interleucina-17 , NF-kappa B , Ratos Wistar , Eucaliptol/farmacologia , Animais , NF-kappa B/metabolismo , Ratos , Ciclo-Oxigenase 2/metabolismo , Interleucina-17/metabolismo , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Masculino , Anti-Inflamatórios/farmacologia , Interleucina-10/metabolismo , Araquidonato 5-Lipoxigenase/metabolismo , Simulação de Acoplamento Molecular , Edema/tratamento farmacológico , Adjuvante de Freund , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismoRESUMO
In part I, we reported Hansen solubility parameters (HSP, HSPiP program), experimental solubility at varied temperatures for TOTA delivery. Here, we studied dose volume selection, stability, pH, osmolality, dispersion, clarity, and viscosity of the explored combinations (I-VI). Ex vivo permeation and deposition studies were performed to observe relative diffusion rate from the injected site in rat skin. Confocal laser scanning microscopy (CLSM) study was conducted to support ex vivo findings. Moreover, GastroPlus predicted in vivo parameters in humans and the impact of various critical factors on pharmacokinetic parameters (PK). Immediate release product (IR) contained 60% of PEG400 whereas controlled release formulation (CR) contained PEG400 (60%), water (10%) and d-limonene (30%) to deliver 2 mg of TOTA. GastroPlus predicted the plasma drug concentration of weakly basic TOTA as function of pH (from pH 2.0 to 9). The cumulative drug permeation and drug deposition were found to be in the order as B-VIË C-VIËA-VI across rat skin. This finding was further supported with CLSM. Moreover, IR and CR were predicted to achieve Cmax of 0.0038 µg/ mL and 0.00023 µg/mL, respectively, after sub-Q delivery. Added limonene in CR extended the plasma drug concentration over period of 12 h as predicted in GastroPlus. Parameters sensitivity analysis (PSA) assessment predicted that sub-Q blood flow rate is the only factor affecting PK parameters in IR formulation whereas this was insignificant for CR. Thus, sub-Q delivery CR would be promising alternative with ease of delivery to children and aged patient.
Assuntos
Absorção Cutânea , Solubilidade , Tartarato de Tolterodina , Animais , Ratos , Humanos , Absorção Cutânea/efeitos dos fármacos , Absorção Cutânea/fisiologia , Tartarato de Tolterodina/administração & dosagem , Tartarato de Tolterodina/farmacocinética , Termodinâmica , Solventes/química , Pele/metabolismo , Concentração de Íons de Hidrogênio , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Terpenos/química , Terpenos/administração & dosagem , Terpenos/farmacocinética , Administração Cutânea , Limoneno/administração & dosagem , Limoneno/farmacocinética , Limoneno/química , Masculino , Polietilenoglicóis/química , Sistemas de Liberação de Medicamentos/métodos , Química Farmacêutica/métodos , Cicloexenos/química , Cicloexenos/farmacocinética , Cicloexenos/administração & dosagem , Ratos Sprague-DawleyRESUMO
Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral delivery. Hansen solubility parameters (HSP, HSPiP program), experimental solubility (T = 298.2 to 318.2 K and p = 0.1 MPa), computational (van't Hoff and Apelblat models), and thermodynamic models were used to the select solvent(s). HSPiP predicted PEG400 as the most suitable co-solvent based on HSP values (δd = 17.88, δp = 4.0, and δh = 8.8 of PEG400) and comparable to the drug (δd = 17.6, δp = 2.4, and δh = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (xe = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δp and δh interacting forces. The activity coefficient (Ïi) was found to be increased with temperature. The higher values of r2 (linear regression coefficient) and low RMSD (root mean square deviation) indicated a good correlation between the generated "xe" data for crystalline TOTA and the explored models (modified Apelblat and van't Hoff models). TOTA solubility in "PEG400 + water mixture" was endothermic and entropy-driven. IR (immediate release product) formulation can be tailored using 60% PEG400 in buffer solution for 2 mg of TOTA in 0.25 mL (dosing volume). The isotonic binary solution was associated with a pH of 7.2 suitable for sub-Q delivery. The approach would be a promising alternative with ease of delivery to children and aged patients.
Assuntos
Solubilidade , Solventes , Termodinâmica , Tartarato de Tolterodina , Humanos , Tartarato de Tolterodina/administração & dosagem , Tartarato de Tolterodina/química , Tartarato de Tolterodina/farmacocinética , Solventes/química , Polietilenoglicóis/química , Disponibilidade Biológica , Química Farmacêutica/métodos , Injeções Subcutâneas , Sistemas de Liberação de Medicamentos/métodosRESUMO
Oxidative stress (OS) is a cytopathic outcome of excessively generated reactive oxygen species (ROS), down regulated antioxidant defense signaling pathways, and the imbalance between the produced radicals and their clearance. It plays a role in the genesis of several illnesses, especially hyperglycemia and its effects. Diabetic retinal illness, a micro vascular side effect of the condition, is the prime reason of diabetic related blindness. The OS (directly or indirectly) is associated with diabetic retinopathy (DR) and related consequences. The OS is responsible to induce and interfere the metabolic signaling pathways to enhance influx of the polyol cascades and hexosamine pathways, stimulate Protein Kinase-C (PKC) variants, and accumulate advanced glycation end products (AGEs). Additionally, the inequity between the scavenging and generation of ROS is caused by the epigenetic alteration caused by hyperglycemia that suppresses the antioxidant defense system. Induced by an excessive buildup of ROS, retinal changes in structure and function include mitochondrial damage, cellular death, inflammation, and lipid peroxidation. Therefore, it is crucial to comprehend and clarify the mechanisms connected to oxidative stress that underlie the development of DR.
Assuntos
Diabetes Mellitus , Retinopatia Diabética , Hiperglicemia , Humanos , Retinopatia Diabética/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Estresse Oxidativo , Hiperglicemia/metabolismo , Produtos Finais de Glicação Avançada/metabolismoRESUMO
Armatenols A-C (1-3), new isoflavan-4-ols, have been isolated from the CHCl3-soluble sub-fraction of Colutea armata Hemsl. & Lace, along with two known compounds namely 8-methoxyvestitol (4) and colutequinone (5), reported for the first time from this species. Their structures have been elucidated through spectroscopic techniques including MS, IR, UV, CD, 1 D and 2 D NMR. Compounds 1-2 invariably showed significant antioxidant activity using the methods of 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity (DPPH), Fe3+ reducing antioxidant power (FRAP) assay and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) radical scavenging activity (ABTS).
Assuntos
Antioxidantes , Fabaceae , Antioxidantes/farmacologia , Antioxidantes/química , Fabaceae/química , Espectroscopia de Ressonância MagnéticaRESUMO
MiRNAs regulate both physiological and pathological heart functions. Altered expression of miRNAs is associated with cardiovascular diseases (CVDs), making miRNAs attractive therapeutic strategies for the diagnosis and treatment of heart diseases. A recent publication defined, for the first time, the term theranoMiRNA, meaning the miRNAs that may be used both for diagnosis and treatment. The use of in silico tools may be considered fundamental for these purposes, clarifying several molecular aspects, suggesting future directions for in vivo studies. This study aims to explore different bioinformatic tools in order to clarify miRNA interactions with candidate genes, demonstrating the need to use a computational approach when establishing the most probable associations between miRNAs and target genes. This study focused on the functions of miR-133a-3p, miR-21-5p, miR-499a-5p, miR-1-3p, and miR-126-3p, providing an up-to-date overview, and suggests future lines of research in the identification of theranoMiRNAs related to CVDs. Based on the results of the present study, we elucidated the molecular mechanisms that could be linked between miRNAs and CVDs, confirming that these miRNAs play an active role in the genesis and development of heart damage. Given that CVDs are the leading cause of death in the world, the identification of theranoMiRNAs is crucial, hence the need for a definition of in vivo studies in order to obtain further evidence in this challenging field of research.