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Derailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs. 1-4). Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and is accompanied by a senescence-associated secretory phenotype (SASP), which comprises pro-inflammatory cytokines, extracellular-matrix-active factors and pro-coagulatory mediators5-7. Patients with COVID-19 displayed markers of senescence in their airway mucosa in situ and increased serum levels of SASP factors. In vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, which mirrored hallmark features of COVID-19 such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue1,8,9. Moreover, supernatant from VIS cells, including SARS-CoV-2-induced senescence, induced neutrophil extracellular trap formation and activation of platelets and the clotting cascade. Senolytics such as navitoclax and a combination of dasatinib plus quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-infected hamsters and mice. Our findings mark VIS as a pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest that senolytic targeting of virus-infected cells is a treatment option against SARS-CoV-2 and perhaps other viral infections.
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Tratamento Farmacológico da COVID-19 , COVID-19/patologia , COVID-19/virologia , Senescência Celular/efeitos dos fármacos , Terapia de Alvo Molecular , SARS-CoV-2/patogenicidade , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Animais , COVID-19/complicações , Linhagem Celular , Cricetinae , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Quercetina/farmacologia , Quercetina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Trombose/complicações , Trombose/imunologia , Trombose/metabolismoRESUMO
Primary microcephaly is a rare neurogenic and genetically heterogeneous disorder characterized by significant brain size reduction that results in numerous neurodevelopmental disorders (NDD) problems, including mild to severe intellectual disability (ID), global developmental delay (GDD), seizures and other congenital malformations. This disorder can arise from a mutation in genes involved in various biological pathways, including those within the brain. We characterized a recessive neurological disorder observed in nine young adults from five independent consanguineous Pakistani families. The disorder is characterized by microcephaly, ID, developmental delay (DD), early-onset epilepsy, recurrent infection, hearing loss, growth retardation, skeletal and limb defects. Through exome sequencing, we identified novel homozygous variants in five genes that were previously associated with brain diseases, namely CENPJ (NM_018451.5: c.1856A > G; p.Lys619Arg), STIL (NM_001048166.1: c.1235C > A; p.(Pro412Gln), CDK5RAP2 (NM_018249.6 c.3935 T > G; p.Leu1312Trp), RBBP8 (NM_203291.2 c.1843C > T; p.Gln615*) and CEP135 (NM_025009.5 c.1469A > G; p.Glu490Gly). These variants were validated by Sanger sequencing across all family members, and in silico structural analysis. Protein 3D homology modeling of wild-type and mutated proteins revealed substantial changes in the structure, suggesting a potential impact on function. Importantly, all identified genes play crucial roles in maintaining genomic integrity during cell division, with CENPJ, STIL, CDK5RAP2, and CEP135 being involved in centrosomal function. Collectively, our findings underscore the link between erroneous cell division, particularly centrosomal function, primary microcephaly and ID.
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Proteínas de Ciclo Celular , Deficiência Intelectual , Microcefalia , Linhagem , Humanos , Microcefalia/genética , Deficiência Intelectual/genética , Masculino , Feminino , Proteínas de Ciclo Celular/genética , Adulto , Proteínas Cromossômicas não Histona/genética , Proteínas do Tecido Nervoso/genética , Divisão Celular/genética , Mutação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Genômica , Adulto Jovem , Consanguinidade , Sequenciamento do Exoma , Homozigoto , Deficiências do Desenvolvimento/genética , Adolescente , Paquistão , Proteínas Associadas aos MicrotúbulosRESUMO
The current stratification of tumor nodules in colorectal cancer (CRC) staging is subjective and leads to high interobserver variability. In this study, the objective assessment of the shape of lymph node metastases (LNMs), extranodal extension (ENE), and tumor deposits (TDs) was correlated with outcomes. A test cohort and a validation cohort were included from 2 different institutions. The test cohort consisted of 190 cases of stage III CRC. Slides with LNMs and TDs were annotated and processed using a segmentation algorithm to determine their shape. The complexity ratio was calculated for every shape and correlated with outcomes. A cohort of 160 stage III CRC cases was used to validate findings. TDs showed significantly more complex shapes than LNMs with ENE, which were more complex than LNMs without ENE (P < .001). In the test cohort, patients with the highest sum of complexity ratios had significantly lower disease-free survival (P < .01). When only the nodule with the highest complexity was considered, this effect was even stronger (P < .001). This maximum complexity ratio per patient was identified as an independent prognostic factor in the multivariate analysis (hazard ratio, 2.47; P < .05). The trends in the validation cohort confirmed the results. More complex nodules in stage III CRC were correlated with significantly worse disease-free survival, even if only based on the most complex nodule. These results suggest that more complex nodules reflect more invasive tumor biology. As most of the more complex nodules were diagnosed as TDs, we suggest providing a more prominent role for TDs in the nodal stage and include an objective complexity measure in their definition.
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Neoplasias Colorretais , Humanos , Prognóstico , Estadiamento de Neoplasias , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Linfonodos/patologiaRESUMO
Intellectual disability (ID) is a large group of neurodevelopmental disorders characterized by a congenital limitation in intellectual functioning (reasoning, learning, and problem solving), adaptive behavior (conceptual, social, and practical skills), originated at birth and manifested before the age of 18. By whole exome sequencing of five consanguineous Pakistani families presenting hallmark features of ID, global developmental delay, aggressive and self-injurious behaviors, microcephaly, febrile seizures and facial dysmorphic features, we identified three novel homozygous missense variants (NM_024298.5: c.588G > T; p.Trp196Cys, c.736 T > C; p.Tyr246His and c.524A > C; p. Asp175Ala) and one rare homozygous in-frame deletion variant (c.758_778del;p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) gene previously associated with autosomal recessive neurodevelopmental disorder. The segregation of the variants was validated by Sanger sequencing in all family members. In silico homology modeling of wild-type and mutated proteins revealed substantial changes in the structure of both proteins, indicating a possible effect on function. The identification and validation of new pathogenic MBOAT7 variants in five cases of autosomal recessive ID further highlight the importance of this genes in proper brain function and development.
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Deficiência Intelectual , Malformações do Sistema Nervoso , Transtornos do Neurodesenvolvimento , Recém-Nascido , Humanos , Sequenciamento do Exoma , Linhagem , Transtornos do Neurodesenvolvimento/genética , Deficiência Intelectual/patologia , Família , Malformações do Sistema Nervoso/complicações , Aciltransferases/genética , Proteínas de Membrana/genéticaRESUMO
OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. METHODS: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. RESULTS: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants. SIGNIFICANCE: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.
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Encefalopatias , Epilepsia Generalizada , Epilepsia , Deficiência Intelectual , Humanos , Estudos Retrospectivos , Hipotonia Muscular , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Epilepsia/complicações , Encefalopatias/genética , Convulsões/complicações , Epilepsia Generalizada/complicações , Eletroencefalografia/métodos , Deficiência Intelectual/genética , Deficiência Intelectual/complicações , Proteína 4 Homóloga a Disks-Large/genéticaRESUMO
BACKGROUND: Hydrocephalus is a neurological disease with higher prevalence in the pediatric population, often managed by placing a shunt. This hollow tube drains excess cerebrospinal fluid from the brain to other body parts, resulting in several complications, including neurological and psychometric manifestations and a compromised quality-of-life (QoL). This study aimed to evaluate QoL in patients with hydrocephalus shunt placement within the pediatric population. METHODS: This prospective observational study was conducted in two major Pakistani tertiary care hospitals. A total of 100 subjects were enrolled, of which 52 were found eligible. A validated questionnaire, HOQ, was used to evaluate patients' QoL. RESULTS: This study included pediatric patients with a mean age of 6.54 and a standard deviation of ± 2.64. The male-to-female ratio was 27:25. 2% of patients had congenital or tumor-induced hydrocephalus, while cases of meningitis, encephalocele, and encephalitis accounted for 8, 4, and 2 percent respectively. Myelomeningocele had the highest prevalence at 16%. The overall health scores range from 0.39 to 0.51. Social, cognitive, and physical health scores have mean values of 0.54, 0.50, and 0.48, respectively. The minimum physical health score is 0.17, indicating the most significant impact of hydrocephalus on physical function. CONCLUSION: This study highlights variations in hydrocephalus severity among pediatric patients, impacting their overall QoL, primarily physical and behavioral functioning. Worse health outcomes were associated with frequent seizures, prolonged hospital stays for diagnosis and treatment, shunt infections, increased number of shunt catheters, and longer travel distances to medical facilities.
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Luteolin, a flavonoid, is mainly found in various vegetables and fruits, including carrots, cabbages, onions, parsley, apples, broccoli, and peppers. Extensive research in vivo and in vitro has been performed to explore its role in disease prevention and treatment. Moreover, this compound possesses the ability to combat cancer by modulating cell-signaling pathways across various types of cancer. The studies have confirmed that luteolin can inhibit cancer-cell survival and proliferation, angiogenesis, invasion, metastasis, mTOR/PI3K/Akt, STAT3, Wnt/ß-catenin, and cell-cycle arrest, and induce apoptosis. Further, scientific evidence describes that this compound plays a vital role in the up/down-regulation of microRNAs (miRNAs) in cancer therapy. This review aims to outline the anti-cancer mechanisms of this compound and its molecular targets. However, a knowledge gap remains regarding the studies on its safety and efficacy and clinical trials. Therefore, it is essential to conduct more research based on safety, efficacy, and clinical trials to explore the beneficial role of this compound in disease management, including cancer.
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Luteolina , Neoplasias , Humanos , Luteolina/farmacologia , Flavonoides/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Neoplasias/tratamento farmacológico , Inflamação/tratamento farmacológico , Apoptose , Proliferação de Células , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Objectives: To determine the response of various histological types of locally advanced rectal cancer to neoadjuvant multimodality therapy. METHODS: The non-randomised, quasi-experimental retrospective cohort study was conducted at the Combined Military Hospital, Rawalpindi, Pakistan, and comprised data of patients treated between January 1, 2020, to September 30, 2021. The data retrieved related to histologically proven and locally advanced rectal cancer patients aged 18-70 years receiving neoadjuvant chemoradiotherapy. Radiotherapy dose was 45 gray to pelvis with a boost to gross tumour of 5.4 gray in 3 fractions by using volumetric arc therapy concurrently with capecitabine 625mg/m² daily. A magnetic resonance imaging scan of pelvis with contrast was done at 5-10 weeks before surgery. Histological response to neoadjuvant treatment of various histological types was evaluated using the Rectal Cancer Regression Grade. Data was analysed using SPSS 22. RESULTS: Of the 182 patients evaluated, 108(59.34%) were included; 64(59.3%) males and 44(40.7%) females. The overall mean age was 45.4±5.2 years. Regression status was grade 1 in 24(22%) patients, grade 2 in 43(40%) and grade 3 in 41(38%) (p=0.074). There were 12(11.11%) patients with signet ring cell and 10(83.3%) showed pathological tumour regression. There were 17(15.74%) patients with mucinous variant, and 12(70.5%) had tumour regression. There were 79(73.15%) patients with adenocarcinoma, and 59(74.6%) of them showed tumour regression. . CONCLUSIONS: There was less tumour regression in mucinous and signet ring cell variants of adenocarcinoma. Modification and intensification of neoadjuvant therapy may be required in such histologies.
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Adenocarcinoma , Capecitabina , Terapia Neoadjuvante , Neoplasias Retais , Humanos , Neoplasias Retais/terapia , Neoplasias Retais/patologia , Neoplasias Retais/diagnóstico por imagem , Pessoa de Meia-Idade , Masculino , Feminino , Terapia Neoadjuvante/métodos , Adulto , Estudos Retrospectivos , Adenocarcinoma/terapia , Adenocarcinoma/patologia , Adenocarcinoma/diagnóstico por imagem , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Idoso , Paquistão , Quimiorradioterapia Adjuvante , Quimiorradioterapia/métodos , Imageamento por Ressonância Magnética , Carcinoma de Células em Anel de Sinete/terapia , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/diagnóstico por imagem , Adulto Jovem , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/diagnóstico por imagemRESUMO
Globally, retinal disorders impact thousands of individuals. Early diagnosis and treatment of these anomalies might halt their development and prevent many people from developing preventable blindness. Iris spot segmentation is critical due to acquiring iris cellular images that suffer from the off-angle iris, noise, and specular reflection. Most currently used iris segmentation techniques are based on edge data and noncellular images. The size of the pigment patches on the surface of the iris increases with eye syndrome. In addition, iris images taken in uncooperative settings frequently have negative noise, making it difficult to segment them precisely. The traditional diagnosis processes are costly and time consuming since they require highly qualified personnel and have strict environments. This paper presents an explainable deep learning model integrated with a multiclass support vector machine to analyze iris cellular images for early pigment spot segmentation and classification. Three benchmark datasets MILE, UPOL, and Eyes SUB were used in the experiments to test the proposed methodology. The experimental results are compared on standard metrics, demonstrating that the proposed model outperformed the methods reported in the literature regarding classification errors. Additionally, it is observed that the proposed parameters are highly effective in locating the micro pigment spots on the iris surfaces.
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Screening of lymph node metastases in colorectal cancer (CRC) can be a cumbersome task, but it is amenable to artificial intelligence (AI)-assisted diagnostic solution. Here, we propose a deep learning-based workflow for the evaluation of CRC lymph node metastases from digitized hematoxylin and eosin-stained sections. A segmentation model was trained on 100 whole-slide images (WSIs). It achieved a Matthews correlation coefficient of 0.86 (±0.154) and an acceptable Hausdorff distance of 135.59 µm (±72.14 µm), indicating a high congruence with the ground truth. For metastasis detection, 2 models (Xception and Vision Transformer) were independently trained first on a patch-based breast cancer lymph node data set and were then fine-tuned using the CRC data set. After fine-tuning, the ensemble model showed significant improvements in the F1 score (0.797-0.949; P <.00001) and the area under the receiver operating characteristic curve (0.959-0.978; P <.00001). Four independent cohorts (3 internal and 1 external) of CRC lymph nodes were used for validation in cascading segmentation and metastasis detection models. Our approach showed excellent performance, with high sensitivity (0.995, 1.0) and specificity (0.967, 1.0) in 2 validation cohorts of adenocarcinoma cases (n = 3836 slides) when comparing slide-level labels with the ground truth (pathologist reports). Similarly, an acceptable performance was achieved in a validation cohort (n = 172 slides) with mucinous and signet-ring cell histology (sensitivity, 0.872; specificity, 0.936). The patch-based classification confidence was aggregated to overlay the potential metastatic regions within each lymph node slide for visualization. We also applied our method to a consecutive case series of lymph nodes obtained over the past 6 months at our institution (n = 217 slides). The overlays of prediction within lymph node regions matched 100% when compared with a microscope evaluation by an expert pathologist. Our results provide the basis for a computer-assisted diagnostic tool for easy and efficient lymph node screening in patients with CRC.
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Inteligência Artificial , Neoplasias Colorretais , Humanos , Metástase Linfática/patologia , Diagnóstico por Computador , Linfonodos/patologia , Aprendizado de Máquina , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologiaRESUMO
IDDBCS is a heterogeneous genetic syndrome with diverse clinical features including Intellectual disability and epilepsy. Using WES, Sanger sequencing, we identified a novel nonsense variant in the PHF21A gene responsible for IDDBCS syndrome. The patient has diverse and overlapping clinical phenotypes. The identified variant leads to abnormal secondary and tertiary structure of the protein and, consequently, affects its function.
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Anormalidades Craniofaciais , Epilepsia , Deficiência Intelectual , Humanos , Deficiência Intelectual/genética , Epilepsia/genética , Síndrome , Fenótipo , Anormalidades Craniofaciais/genética , Histona Desacetilases/genéticaRESUMO
BACKGROUND: Patients with chronic kidney diseases (CKD) are susceptible to the toxic drug effects if given unadjusted doses. Although Pakistan harbors a high burden of CKD patients, there is limited information available on the frequency, pattern and factors associated with unadjusted drug doses among CKD patients. METHODS: This cross-sectional study conducted at Sandeman Provincial Hospital, Quetta included 303 non-dialysis ambulatory CKD patients (glomerular filtration rate < 60 ml/min/1.73m2). The patients' data were collected through a purpose designed data collection form. The appropriateness of doses was checked against the renal drug handbook-2018, Kidney Disease Improving Global Outcomes guidelines, British National Formulary-2022, and manufacturer leaflets. Data were analysed by SPSS 23 and multiple binary logistic regression analysis was used to assess the factors associated with receiving inappropriate high doses. A p-value < 0.05 was considered statistically significant. RESULTS: The patients received a total of 2265 prescription lines, with a median of eight different drugs per patient (interquartile range: 6-9 drugs). A total of 34.5% (783/2265) drugs required dose adjustment. Of these, doses were not adjusted for 56.1% (440) drugs in 162 (53.4%) patients. The most common pharmacological class of drugs requiring dose adjustment were antibiotics (79.1%), followed by antidiabetics (59.2%), diuretics (57.0%), angiotensin converting enzyme inhibitors (56.9%), beta blockers (56.9%), analgesics (56.0%), angiotensin receptor blockers (55.2%), domperidone (53.9%) and antihyperlipidmics (46.1%). Patient's age of 41-60 (OR = 5.76) and > 60 years (OR = 9.49), hypertension (OR = 2.68), diabetes mellitus (OR = 3.47) and cardiovascular diseases (OR = 2.82) had statistically significant association (p-value < 0.05) with inappropriate high doses. CONCLUSION: The high frequency of inappropriate high doses suggests an important quality gap in medication dosing for patients with ND-CKD at the study site. Special attention should be paid to the drugs and patients with identified risk factors for receiving inappropriate high doses.
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Rim , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Taxa de Filtração Glomerular , Paquistão/epidemiologia , Estudos Transversais , Pessoa de Meia-Idade , Antibacterianos/efeitos adversos , Hipoglicemiantes/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Rim/efeitos dos fármacos , Adulto , Idoso , Prescrição Inadequada , Comorbidade , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/epidemiologiaRESUMO
Cancer is one of the main causes of death in all developed and developing countries. Various factors are involved in cancer development and progression, including inflammation and alterations in cellular processes and signaling transduction pathways. Natural compounds have shown health-promoting effects through their antioxidant and anti-inflammatory potential, having an important role in the inhibition of cancer growth. In this regard, formononetin, a type of isoflavone, plays a significant role in disease management through the modulation of inflammation, angiogenesis, cell cycle, and apoptosis. Furthermore, its role in cancer management has been proven through the regulation of different signal transduction pathways, such as the signal transducer and activator of transcription 3 (STAT 3), Phosphatidyl inositol 3 kinase/protein kinase B (PI3K/Akt), and mitogen activating protein kinase (MAPK) signaling pathways. The anticancer potential of formononetin has been reported against various cancer types, such as breast, cervical, head and neck, colon, and ovarian cancers. This review focuses on the role of formononetin in different cancer types through the modulation of various cell signaling pathways. Moreover, synergistic effect with anticancer drugs and methods to improve bioavailability are explained. Thus, detailed studies based on clinical trials are required to explore the potential role of formononetin in cancer prevention and treatment.
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Antineoplásicos , Isoflavonas , Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Neoplasias/tratamento farmacológicoRESUMO
Cancer is a major public health concern worldwide and main burden of the healthcare system. Regrettably, most of the currently used cancer treatment approaches such as targeted therapy, chemotherapy, radiotherapy and surgery usually cause adverse complications including hair loss, bone density loss, vomiting, anemia and other complications. However, to overcome these limitations, there is an urgent need to search for the alternative anticancer drugs with better efficacy as well as less adverse complications. Based on the scientific evidences, it is proven that naturally occurring antioxidants present in medicinal plants or their bioactive compounds might constitute a good therapeutic approach in diseases management including cancer. In this regard, myricetin, a polyhydroxy flavonol found in a several types of plants and its role in diseases management as anti-oxidant, anti-inflammatory and hepato-protective has been documented. Moreover, its role in cancer prevention has been noticed through modulation of angiogenesis, inflammation, cell cycle arrest and induction of apoptosis. Furthermore, myricetin plays a significant role in cancer prevention through the inhibition of inflammatory markers such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2). Moreover, myricetin increases the chemotherapeutic potential of other anticancer drugs through modulation of cell signaling molecules activity. This review elaborates the information of myricetin role in cancer management through modulating of various cell-signaling molecules based on in vivo and in vitro studies. In addition, synergistic effect with currently used anticancer drugs and approaches to improve bioavailability are described. The evidences collected in this review will help different researchers to comprehend the information about its safety aspects, effective dose for different cancers and implication in clinical trials. Moreover, different challenges need to be focused on engineering different nanoformulations of myricetin to overcome the poor bioavailability, loading capacity, targeted delivery and premature release of this compound. Furthermore, some more derivatives of myricetin need to be synthesized to check their anticancer potential.
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Antineoplásicos , Neoplasias , Humanos , Transdução de Sinais , Inflamação/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Neoplasias/tratamento farmacológico , ApoptoseRESUMO
Cancer is the principal cause of death and its incidence is increasing continuously worldwide. Various treatment approaches are in practice to treat cancer, but these treatment strategies may be associated with severe side effects and also produce drug resistance. However, natural compounds have established their role in cancer management with minimal side effects. In this vista, kaempferol, a natural polyphenol, mainly found in vegetables and fruits, has been revealed to have many health-promoting effects. Besides its health-promoting potential, its anti-cancer potential has also been described in in vivo as well as in in vitro studies. The anti-cancer potential of kaempferol has been proven through modulation of cell signaling pathways in addition to the induction of apoptosis and cell cycle arrest in cancer cells. It leads to the activation of tumor suppressor genes, inhibition of angiogenesis, PI3K/AKT pathways, STAT3, transcription factor AP-1, Nrf2 and other cell signaling molecules. Poor bioavailability of this compound is one of the major limitations for its proper and effective disease management actions. Recently, some novel nanoparticle-based formulations have been used to overcome these limitations. The aim of this review is to provide a clear picture regarding the mechanism of action of kaempferol in different cancers through the modulation of cell signaling molecules. Besides this, strategies to improve the efficacy and synergistic effects of this compound have also been described. However, more studies are needed based on clinical trials to fully explore the therapeutic role of this compound, especially in cancer treatment.
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Neoplasias , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Quempferóis/farmacologia , Quempferóis/uso terapêutico , Quempferóis/metabolismo , Neoplasias/tratamento farmacológico , Transdução de Sinais , Inflamação , ApoptoseRESUMO
The blood-brain barrier (BBB) is a functional interface that provides selective permeability, protection from toxic substances, transport of nutrients, and clearance of brain metabolites. Additionally, BBB disruption has been shown to play a role in many neurodegenerative conditions and diseases. Therefore, the aim of this study was to establish a functional, convenient, and efficient in vitro co-cultured BBB model that can be used for several physiological conditions related to BBB disruption. Mouse brain-derived endothelial (bEnd.3) and astrocyte (C8-D1A) cells were co-cultured on transwell membranes to establish an intact and functional in vitro model. The co-cultured model and its effects on different neurological diseases and stress conditions, including Alzheimer's disease (AD), neuroinflammation, and obesity, have been examined by transendothelial electrical resistance (TEER), fluorescein isothiocyanate (FITC) dextran, and tight junction protein analyses. Scanning electron microscope images showed evidence of astrocyte end-feet processes passing through the membrane of the transwell. Moreover, the co-cultured model showed effective barrier properties in the TEER, FITC, and solvent persistence and leakage tests when compared to the mono-cultured model. Additionally, the immunoblot results showed that the expression of tight junction proteins such as zonula occludens-1 (ZO-1), claudin-5, and occludin-1 was enhanced in the co-culture. Lastly, under disease conditions, the BBB structural and functional integrity was decreased. The present study demonstrated that the co-cultured in vitro model mimicked the BBB's structural and functional integrity and, under disease conditions, the co-cultured model showed similar BBB damages. Therefore, the present in vitro BBB model can be used as a convenient and efficient experimental tool to investigate a wide range of BBB-related pathological and physiological studies.
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Barreira Hematoencefálica , Encéfalo , Camundongos , Animais , Barreira Hematoencefálica/metabolismo , Técnicas de Cocultura , Fluoresceína-5-Isotiocianato/metabolismo , Encéfalo/metabolismo , Astrócitos/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo , Células CultivadasRESUMO
Trolox is a potent antioxidant and a water-soluble analog of vitamin E. It has been used in scientific studies to examine oxidative stress and its impact on biological systems. Trolox has been shown to have a neuroprotective effect against ischemia and IL-1ß-mediated neurodegeneration. In this study, we investigated the potential protective mechanisms of Trolox against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. Western blotting, immunofluorescence staining, and ROS/LPO assays were performed to investigate the role of trolox against neuroinflammation, the oxidative stress mediated by MPTP in the Parkinson's disease (PD) mouse model (wild-type mice (C57BL/6N), eight weeks old, average body weight 25-30 g). Our study showed that MPTP increased the expression of α-synuclein, decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels in the striatum and substantia nigra pars compacta (SNpc), and impaired motor function. However, Trolox treatment significantly reversed these PD-like pathologies. Furthermore, Trolox treatment reduced oxidative stress by increasing the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Lastly, Trolox treatment inhibited the activated astrocytes (GFAP) and microglia (Iba-1), also reducing phosphorylated nuclear factor-κB, (p-NF-κB) and tumor necrosis factor-alpha (TNF-α) in the PD mouse brain. Overall, our study demonstrated that Trolox may exert neuroprotection on dopaminergic neurons against MPTP-induced oxidative stress, neuroinflammation, motor dysfunction, and neurodegeneration.
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Transtornos Motores , Fármacos Neuroprotetores , Doença de Parkinson , Animais , Camundongos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Doenças Neuroinflamatórias , Vitamina E/farmacologia , Transtornos Motores/metabolismo , Substância Negra/metabolismo , Camundongos Endogâmicos C57BL , Tirosina 3-Mono-Oxigenase/metabolismo , Neurônios Dopaminérgicos/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/metabolismo , Estresse Oxidativo , Modelos Animais de DoençasRESUMO
The innovative advances in transforming clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) into different variants have taken the art of genome-editing specificity to new heights. Allosteric modulation of Cas9-targeting specificity by sgRNA sequence alterations and protospacer adjacent motif (PAM) modifications have been a good lesson to learn about specificity and activity scores in different Cas9 variants. Some of the high-fidelity Cas9 variants have been ranked as Sniper-Cas9, eSpCas9 (1.1), SpCas9-HF1, HypaCas9, xCas9, and evoCas9. However, the selection of an ideal Cas9 variant for a given target sequence remains a challenging task. A safe and efficient delivery system for the CRISPR/Cas9 complex at tumor target sites faces considerable challenges, and nanotechnology-based stimuli-responsive delivery approaches have significantly contributed to cancer management. Recent innovations in nanoformulation design, such as pH, glutathione (GSH), photo, thermal, and magnetic responsive systems, have modernized the art of CRISPR/Cas9 delivery approaches. These nanoformulations possess enhanced cellular internalization, endosomal membrane disruption/bypass, and controlled release. In this review, we aim to elaborate on different CRISPR/Cas9 variants and advances in stimuli-responsive nanoformulations for the specific delivery of this endonuclease system. Furthermore, the critical constraints of this endonuclease system on clinical translations towards the management of cancer and prospects are described.
Assuntos
Sistemas CRISPR-Cas , Neoplasias , Humanos , Sistemas CRISPR-Cas/genética , Proteína 9 Associada à CRISPR/metabolismo , Edição de Genes , Neoplasias/genética , Neoplasias/terapia , TecnologiaRESUMO
Background and Objectives: Several vaccines have been approved for the prevention of the coronavirus disease, discovered on 31 December in Wuhan, China. Pakistan procured vaccines from various countries. However, the lack of knowledge and reluctance of the general population to embrace the use of the vaccines are considered to be the major determinant of the slow vaccination rate. Hence, it is necessary to evaluate the willingness of the general population about their perception of the COVID-19 vaccination. Materials and Methods: A cross sectional survey based on a self-structured questionnaire comprising 18 questions was conducted (from 21 April-21 June) on 400 Pakistani participants to evaluate their knowledge, attitude, and perception towards the COVID-19 vaccination. Chi-square independent t-test and one-way Anova including a multiple step wise linear regression were used to draw conclusions about the results. p < 0.05 was considered significant. Results: A total of 400 participants responded in the knowledge, attitude, and perception (KAP) survey of which 46.5% were female and 53.5% were male. The mean age of participants was 36.08 years. This survey showed a poor knowledge (50.5%), a fair attitude (75.1%) and a poor perception (58.1%) towards the COVID-19 vaccination. Higher mean knowledge and attitude scores were reported in the age group 21-40, females, and unmarried urban citizens. Regression analysis showed that age, education, residence, and employment status influenced the knowledge and perception score to a considerable extent. Conclusions: The findings reflect an inadequate knowledge and perception on the one hand, but a better attitude towards the COVID-19 vaccination. This knowledge attitude and perception (KAP) survey will help in better understanding the opinion of the general population towards vaccination, and will be useful for policy makers and health care authorities aiming to increase the vaccination rate.
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COVID-19 , Vacinas , Humanos , Masculino , Feminino , Adulto , Estudos Transversais , Conhecimentos, Atitudes e Prática em Saúde , Paquistão , Vacinas contra COVID-19 , Vacinação , Inquéritos e QuestionáriosRESUMO
In this article NHS England and NHS Education for Scotland describe practical ways we are tackling differences in the attainment of people training as general practitioners (GPs).Trainees from minority ethnic groups and international medical graduates are less likely than others to qualify as GPs. It is difficult to change systemic inequalities, but over the past five years we have made practical changes to GP speciality training. Educators recognise there is an issue and are trying to tackle it.For example, people who had not successfully qualified had an opportunity to return to GP training. When we provided individualised targeted support, the proportion who completed training significantly increased (76%).This was a catalyst for reviewing unconscious bias in GP training. We implemented a national programme to tackle differential attainment and system-level bias. Educators now work with all GP trainees to identify their individual needs. Supervisors are trained to recognise bias and provide targeted support. There is mental health support and regular reviews to see whether trainees are ready to sit exams. Trainee representatives are championing the learner voice in national committees. Exams are being altered to reduce unconscious bias. We are monitoring attainment over time.The key message is that differential attainment should not be in the 'too hard basket'. The narrative is changing from 'can't do' to 'must do', supported by appropriate leadership, promotion and resourcing. There is much more to do, but we are making changes, evaluating and applying our learning. We have moved from talking to taking action.