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Pyridone heterocycles, such as furo[2,3-b]pyridines, have emerged as prominent scaffolds in medicinal chemistry due to their versatile pharmacological properties, including significant anticancer activity. In this study, we successfully synthesized new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives from chalcones bearing 4-(benzyloxy)phenyl and dichlorothiophenyl subunits to explore their therapeutic potential against breast cancer. By employing a synthetic strategy involving Claisen-Schmidt condensation followed by sequential cyclizations and functional modifications, we synthesized and characterized four compounds (MI-S0, MI-S1, MI-S2, and MI-S3) using various spectroscopic methods, including FT-IR, 1H-NMR, 13C-NMR, DEPT, H,H- and C,H-COSY, and HRMS. The in vitro cytotoxic activity of these compounds was evaluated against two breast cancer cell lines, MCF-7 and MDA-MB-231, and compared with a noncancerous breast cell line, MCF-10A. All compounds exhibited potent cytotoxic activities with minimal selectivity toward normal cells. Molecular docking studies targeting the serine/threonine kinase AKT1, estrogen receptor alpha (ERα), and human epidermal growth factor receptor 2 (HER2) revealed strong binding affinities, suggesting a mechanism involving the disruption of key cellular signaling pathways. These findings underscore the potential of furo[2,3-b]pyridine derivatives as promising candidates for further development into anticancer agents, laying the groundwork for future investigations into their selective therapeutic efficacy and molecular mechanisms of action.
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The synaptic tagging and capture (STC) hypothesis lays the framework on the synapse-specific mechanism of protein synthesis-dependent long-term plasticity upon synaptic induction. Activated synapses will display a transient tag that will capture plasticity-related products (PRPs). These two events, tag setting and PRP synthesis, can be teased apart and have been studied extensively-from their electrophysiological and pharmacological properties to the molecular events involved. Consequently, the hypothesis also permits interactions of synaptic populations that encode different memories within the same neuronal population-hence, it gives rise to the associativity of plasticity. In this review, the recent advances and progress since the experimental debut of the STC hypothesis will be shared. This includes the role of neuromodulation in PRP synthesis and tag integrity, behavioural correlates of the hypothesis and modelling in silico. STC, as a more sensitive assay for synaptic health, can also assess neuronal aberrations. We will also expound how synaptic plasticity and associativity are altered in ageing-related decline and pathological conditions such as juvenile stress, cancer, sleep deprivation and Alzheimer's disease. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
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Encéfalo , Memória , Plasticidade Neuronal , Sinapses , Sinapses/fisiologia , Humanos , Plasticidade Neuronal/fisiologia , Encéfalo/fisiologia , Memória/fisiologia , Animais , Modelos NeurológicosRESUMO
Necrotizi ng fasciit is [NF] i s a m ultifaceted disease of the muscle fascia and body tissues which demands the earliest intervention. Past reviews have documented ver y few cases of Aeromonas Hydroph ila [AH] induced N F fol lo wing abdominal surgery. AH can cause fatal NF as seen in a 72 year old female patient reported at Liaquat National Hospital &Medical College; a ter tiary care center in Karachi, Pakistan on 2nd April, 2022. She had a k nown comorbidity of hypertension and presented with the chief complaint of symptomatic gallstones for which she unde rwent Laparoscopic Cholecystectomy (LAPCHOL). She developed NF of the lower ab domen post- oper atively. Following uneventful Laparoscopic Cholecystectomy our pati ent presented to the ER two days later with severe lower abdo minal pain and overlyi ng celluliti s. Fasc io to my revealed extensive myonecrosis with necrotizing soft tissue in fe ction. Despite u ndergoing extensive surgical debr idement and broad spectr um antibi ot ic administration; the patient died in the ICU on the fifth postoperat ive day followi ng septic complications. Histopathologica l an alysis, confirmed i nflammat ion and necrosis. Culture sensitivity of the debrided tissue revealed AH. Approach should lie towards analyzing the behaviour of such microbes in high risk patients through collective case studies. This is the first clinical case showcasing such parameters e ncountered in the General Surger y Department.
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Colecistectomia Laparoscópica , Fasciite Necrosante , Cálculos Biliares , Feminino , Humanos , Idoso , Fasciite Necrosante/etiologia , Aeromonas hydrophila , Colecistectomia Laparoscópica/efeitos adversos , Comorbidade , Cálculos Biliares/cirurgia , Cálculos Biliares/complicaçõesRESUMO
Introduction and importance: Cystic partially differentiated nephroblastoma (CPDN) is a rare cystic tumor that affects the kidney. It has a low potential for malignancy. It usually presents as an abdominal mass. It may be difficult to confirm the diagnosis of CPDN without a histopathological study. Case presentation: The authors report a case of an 18-month-old girl with abdominal distention, which was noticed by her parents. An abdominal computed tomography scan showed a large multilocular cystic mass arising from the lower pole of the left kidney. A left total nephrectomy was performed. Immature blastemal elements without evidence of malignant cells were observed on histological analysis. Conclusion: The authors report a case of an 18-month-old girl with CPDN managed by total nephrectomy. CPDN should be considered in the differential diagnosis of patients with cystic renal lesions. The authors would also like to affirm that partial or total nephrectomy should be done in all cases of CPDN and other cystic renal tumors.
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BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by John Cunningham polyoma virus (JCV) infection. Idiopathic CD4+ T-cell lymphocytopenia (ICL) is a very rare cause of PML. METHODS: We present an individual with PML secondary to ICL treated with 3 doses of pembrolizumab, a Programmed-Death-1 Immune Checkpoint Inhibitor following with complete resolution of symptoms and conduct a review of the literature. CONCLUSION: This report illustrates the objective clinical and radiological improvement in a patient with PML due to ICL and suggests further study of immune checkpoint inhibitors as potential treatment for patients with PML.
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Vírus JC , Leucoencefalopatia Multifocal Progressiva , T-Linfocitopenia Idiopática CD4-Positiva , Humanos , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Leucoencefalopatia Multifocal Progressiva/etiologia , T-Linfocitopenia Idiopática CD4-Positiva/complicações , T-Linfocitopenia Idiopática CD4-Positiva/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
INTRODUCTION: Diabetic-related foot condition is one of the most debilitating complications with a higher rate of failure in limb correction, reconstruction, or salvage surgery. Amputation is the final option after other surgical treatments have failed. Major amputation increases energy consumption, resulting in high dependency, decreased mobility, and poor prognosis. Consequently, minor amputation is preferred to resolve these problems but elevated wound complications leading to inadequate prosthesis fit, became a detriment to minor amputation. Strict selection of patients is crucial to ensure success and good functional outcomes as demonstrated in this retrospective study of this case series. Methods: This case series included six patients who underwent Pirogoff amputation with the modification described by Nather and reported the procedure's outcome. The inclusion criteria for subjects were the presence of palpable posterior tibial artery (PTA) or at least biphasic Doppler signal and ankle-brachial systolic index (ABSI) more than 0.70. Other demographic data as well as hematological, inflammatory, and biochemical parameters that may affect wound healing such as Hb, HbA1c, ESR, CRP, WBC, and albumin were recorded as well. The rate and time for wound healing and bone union, presence of complications, and final ambulatory status of patients were determined as the outcome of this study. RESULTS: All of the patients had diabetic foot infections involving only the forefoot region with the presence of either palpable PTA or biphasic Doppler signal. Although the majority of the cases had deranged blood parameters, soft tissue and bone healing were achieved at variable times. Four had good outcomes as they were able to ambulate. One case was complicated with chronic wound dehiscence and another one had Pirogoff stump infection and required transtibial amputation. CONCLUSION: With strict selection criteria, Pirogoff amputation may provide a good functional outcome with a lesser degree of complications compared to major amputation.
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Currently, numerous ongoing studies are investigating the interaction of free radicals with biological systems, such as lipids, DNA and protein. In the present work, synthesis, characterization, antioxidant, DNA binding and molecular docking studies of Schiff base ligand and its Ni(II), Co(II), Cu(II) and Zn(II) were evaluated. The metal complexes have shown significant dose-dependent antioxidant activities higher than those of the free ligand but lesser than those of the standard antioxidant, ascorbic acid. The DNA binding constants (Kb) were found in the order Zn(pimp)2 {9.118 × 105 M-1} > H-pimp {3.487 × 105 M-1} > Co(pimp)2 {3.090 × 105 M-1} > Ni(pimp)2 {1.858 × 105 M-1} > Cu(pimp)2 {1.367 × 105 M-1}. Binding constants (Kb) values calculated from the molecular docking analysis were found to be in close agreement with the experimental results. The obtained results indicate the importance of synthesis complexes as a source of synthetic antioxidants and anticancer drugs.
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Antioxidantes , Complexos de Coordenação , Antioxidantes/farmacologia , Antioxidantes/química , Simulação de Acoplamento Molecular , Iminas , Ligantes , Metais/química , DNA/química , Bases de Schiff/química , Complexos de Coordenação/químicaRESUMO
Pelizaeus-Merzbacher disease is a tremendously rare genetic disorder caused by a mutation on the X chromosome. The mutation affects a gene critical to white matter myelination and results in significant neurological issues. Here, we present one such case of a child diagnosed with Pelizaeus-Merzbacher disease. A relatively normal gestation and birth belied the underlying issue until he presented to the emergency department a month after birth with seizure-like activity and failure to thrive. After intensive evaluation and treatment, the patient was diagnosed with the illness and received surgery to place a tracheostomy and a gastrostomy tube to treat the stridor and failure to thrive caused by his illness. After approximately a month and a half of inpatient treatment, the patient was able to be discharged home in stable condition.
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Orthopedic spinal surgeries, such as laminectomies or decompressions, have the potential to significantly increase quality of life for patients suffering from a spectrum of health issues ranging from neuropathy to chronic pain. Patients suffering from neurological symptoms such as weakness or neuropathy may lose significant function and become unable to perform the activities of daily living, however these delicate surgical interventions also come with significant risks to the health and well-being of those same patients. This is especially true with patients who have predisposing health conditions. Here, we discuss the effects of surgery on a patient with severe obesity, multiple confounding pre-existing conditions, and significant polypharmacy. An initially unremarkable spinal laminectomy and decompression surgery resulted in severe intraoperative complications that necessitated direct admission to the intensive care unit for significant post-operative management before he was able to be discharged safely. Although not a case of incredible rarity, we hope it can contribute to the growing body of data about the role of predisposing health conditions and polypharmacy in calculating and understanding the risks of orthopaedic surgery.
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Machaeriols and machaeridiols are unique hexahydrodibenzopyran-type aralkyl phytocannabinoids isolated from Machaerium Pers. Earlier studies of machaeriol A (1) and B (2) did not show any affinity for cannabinoid receptor 1 (CB1 or CNR1), although they are structural analogs of psychoactive hexahydrocannabinol. This study comprehensively reports on the affinities of isolated Machaerium Pers. compounds, namely machaeriol A-D (1-4) and machaeridiol A-C (5-7), against cannabinoid (CB1 and CB2) and opioid (κ, δ and µ) receptors. Among the isolated compounds, machaeriol D (4) and machaeridiol A-C (5-7) showed some selective binding affinity for the CB2 receptor, using a radioligand binding assay, with Ki values of >1.3, >1.77, >2.18 and >1.1 µM, respectively. On the other hand, none of the compounds showed any binding to the CB1 receptor. Due to recent reports on the anticancer potential of the endocannabinoid system, compounds 1-7 were tested against a battery of luciferase reporter gene vectors that assess the activity of many cancer-related signaling pathways, including Stat3, Smad2/3, AP-1, NF-κB, E2F, Myc, Ets, Notch, FoxO, Wnt, Hedgehog and pTK in HeLa and T98G glioblastoma cells. Complete dose-response curves have been determined for each compound in both of these cell lines, which revealed that machaeridiol 6 displayed activities (IC50 in µM in HeLa and T98G cells) towards Stat3 (4.7, 1.4), Smad2/3 (1.2, 3.0), AP-1 (5.9, 4.2), NF-κB (0.5, 4.0), E2F (5.7, 0.7), Myc (5.3, 2.0), ETS (inactive, 5.9), Notch (5.3, 4.6), Wnt (4.2, inactive) and Hedgehog (inactive, 5.0). Furthermore, a combination study between machaeriol C (3) and machaeridiol B (6) displayed additive effects for E2F, ETS, Wnt and Hedgehog pathways, where these compounds individually were either minimally active or inactive. None of the compounds inhibited luciferase expression driven by the minimal thymidine kinase promoter (pTK), indicating the lack of general cytotoxicity for luciferase enzyme inhibition at the 50 µM concentration in both of these cell lines. The significance of the inhibition of these signaling pathways via machaeridiol 5-7 and their cross-talk potential has been discussed.
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Canabinoides , Fabaceae , Neoplasias , Humanos , Canabinoides/farmacologia , Receptores Opioides , Fabaceae/química , NF-kappa B/metabolismo , Fator de Transcrição AP-1/metabolismo , Proteínas Hedgehog , Transdução de Sinais , Neoplasias/tratamento farmacológico , Receptor CB2 de Canabinoide , Receptor CB1 de CanabinoideRESUMO
Copper(II) carboxylate complexes [Cu2(OOCR)4L2] (1) and [Cu2(OOCR`)4OCO(R`)CuL2]n (2), where L = 2-methyl pyridine, R = 2-chlorophenyl acetate and R` = 2-fluorophenyl acetate were synthesized and characterized by FT-IR spectroscopy and single crystal X-ray analysis. Complex 1 exhibits the typical paddlewheel array of a dinuclear copper(II) complex with carboxylate ligands. In complex 2, this scaffold is further extended into a polymeric arrangement based on alternate paddlewheel and square planar moieties with distinct coordination spheres. The complexes showed better 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities and have been found to be more potent antileishmanial agents than their corresponding free ligand acid species. UV-Vis absorption titrations revealed good DNA binding abilities {Kb = 9.8 × 104 M-1 (1) and 9.9 × 104 M-1 (2)} implying partial intercalation of the complexes into DNA base pairs along with groove binding. The complexes displayed in vitro cytotoxic activity against malignant glioma U-87 (MG U87) cell lines. Computational docking studies further support complex-DNA binding by intercalation. Molecular docking investigations revealed probable interactions of the complexes with spike protein, the nucleocapsid protein of SARS-CoV-2 and with the angiotensin converting enzyme of human cells.
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We performed a systematic review and meta-analysis of patients with suspected recurrent cholesteatoma who underwent non-echo planar imaging (non-EPI) using diffusion-weighted magnetic resonance imaging (MRI), with surgery as the reference standard. We searched Medline, Google Scholar, and the Cochrane database for diagnostic test accuracy studies. The following prespecified subgroup analyses were performed: patient age, number of radiologists interpreting MRI, study design, and risk of bias. We used a bivariate model using a generalized linear mixed model to pool accuracies. Of the 460 records identified, 32 studies were included, of which 50% (16/32) were low risk of bias. The overall pooled sensitivity was 92.2% (95% CI 87.3-95.3%), and specificity was 91.7% (85.2-95.5%). The positive likelihood ratio was 11.1 (4.5-17.8), and the negative likelihood ratio was 0.09 (0.04-0.13). The pooled diagnostic odds ratio was 130.3 (20.5-240). Heterogeneity was moderate on visual inspection of the hierarchical summary receiver operating characteristic curve. Subgroup analyses showed prospective studies reporting higher accuracies (p=0.027), which were driven by higher specificity (prospective 93.1% (88.4-96.0%) versus retrospective 81.2% (81.0-81.4%)). There was no difference in subgroups comparing patient age (p=0.693), number of radiologists interpreting MRI (p=0.503), or risk of bias (p=0.074). No publication bias was detected (p=0.98). In conclusion, non-EPI is a highly sensitive and specific diagnostic test able to identify recurrent cholesteatomas of moderate to large sizes. This test can be considered a non-invasive alternative to second-look surgery.
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The biomedical survey reports edible plant Aegle marmelos has been utilized for centuries by tribal communities in India as a dietary supplement for the management of diabetes. Herein, we have investigated cytotoxicity, cytoprotective and antidiabetic activity of characterized alkaloid-free hydroalcoholic extract of A. marmelos (AFEAM; 200 and 400 mg/kg). Identification of polyphenols and quantification of major compounds were done using UPLC-MS and HPTLC, respectively. AFEAM showed good cytocompatibility and cytoprotective potential against oxidative stress induced by hyperglycemia in HepG2 cells. The AFEAM intake had significantly ameliorated the serum blood glucose level, state of dyslipidemia, level of pro-inflammatory markers (tumor necrosis factor-α, interleukin-6, and interleukin-1ß), and antioxidant (superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde) status in diabetic mice. Histological examination of the treated groups showed amelioration of damaged pancreas, liver, and kidney tissues. Conclusively, AFEAM intake might be promising dietary supplements for prediabetics as well as an adjuvant to modern treatment in diabetics. PRACTICAL APPLICATIONS: Different reports have been published on Aegle marmelos but as per our understanding till date, no study has been reported on the amelioration of diabetes due to alkaloid free hydroalcoholic extract of A. marmelos /polyphenolic content in the animal model. The result of this study indicated that A. marmelos supplementation effectively ameliorates diabetes through the restoration of antioxidant and anti-inflammatory status. This study has collated sufficient scientific evidence for the dietary application of A. marmelos in society especially for prediabetics, however, it can also be used as an adjuvant to modern treatments in diabetics.
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Aegle , Diabetes Mellitus Experimental , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cromatografia Líquida , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Camundongos , Extratos Vegetais/farmacologia , Folhas de Planta , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Espectrometria de Massas em TandemRESUMO
Abstract Rumex vesicarius hasbeen extensively used for the management of diabetes in the traditional system of medicine. The current study was designed to investigate antidiabetic and antihyperlipidemic effects of R.vesicarius and also to explore metabolomic profiling using UPLC-QTOF-MS. The effect of extracts was observed by checking the biochemical and histopathological parameters in diabetic rats. The results had shown a significant dose- dependent inhibition potential of aqueous extract of R. vesicarius seed against α-amylase and α-glucosidase along with significant inhibition in DPPH free-radical scavenging activity. Oral administration of R. vesicarius to diabetic rats significantly ( p< 0.05) ameliorated blood glucose level. It also improved the function of the liver and kidney as well as ameliorated dyslipidemia in diabetic rats. Histopathological examination of the treatment groups reversed the damage of the pancreas, liver, and kidney tissues confirming the antidiabetic efficacy of R. vesicarius. UPLC- QTOF-MS analysis of the extract revealed a total of 42 bioactive compounds, which might contribute to the antidiabetic activity. Based on our findings, we can conclude that R. vesicarius might be a promising candidate for the management of diabetes.
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Chondrosarcomas are the second most common primary bone malignancy. Chondrosarcomas are characterized by the production of cartilaginous matrix and are generally resistant to radiation and chemotherapy and the outcomes are overall poor. Hence, there is strong interest in determining mechanisms of cancer aggressiveness and therapeutic resistance in chondrosarcomas. There are metabolic alterations in chondrosarcoma that are linked to the epigenetic state and tumor microenvironment that drive treatment resistance. This review focuses on metabolic changes in chondrosarcoma, and the relationship between signaling via isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), hedgehog, PI3K-mTOR-AKT, and SRC, as well as histone acetylation and angiogenesis. Also, potential treatment strategies targeting metabolism will be discussed including potential synergy with immunotherapies.
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Coronavirus disease 2019 (COVID-19) is primarily a respiratory illness and pulmonary manifestations are the typical presentations of the disease. However, it became evident that the COVID-19 is not limited to the respiratory system. Specifically, gastrointestinal involvement in patients with COVID-19 is very common, particularly in patients with a critical illness. We present a case of a 52-year-old man who was diagnosed as having severe COVID-19 pneumonia and underwent endotracheal intubation and mechanical ventilation. The patient remained in the intensive care unit for seven days. Following his recovery, he started to experience generalized abdominal pain. The pain did not resolve with conservative measures. A computed tomography scan of the abdomen demonstrated small bowel loops clustered with a surrounding thin membrane. Such findings conferred the diagnosis of sclerosing encapsulating peritonitis. The patient was prepared for laparoscopic surgery. Resection of the membrane was performed without any injury to the encapsulated bowel. Analysis of peritoneal fluid by reverse transcription-polymerase chain reaction (RT-PCR) was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The patient had an uneventful recovery. Sclerosing encapsulating peritonitis is a very rare condition associated with COVID-19 pneumonia. The present case is the first reported case to document the presence of the SARS-CoV-2 virus in the peritoneal fluid in a patient with sclerosing encapsulating peritonitis.
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Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.
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Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Idoso , Subpopulações de Linfócitos B/imunologia , Basófilos/imunologia , Betacoronavirus , COVID-19 , Estudos de Casos e Controles , Ciclo Celular , Quimiocina CXCL10/imunologia , Quimiocinas/imunologia , Estudos de Coortes , Infecções por Coronavirus/sangue , Progressão da Doença , Feminino , Citometria de Fluxo , Hospitalização , Humanos , Memória Imunológica , Imunofenotipagem , Interleucina-10/imunologia , Interleucina-6/imunologia , Contagem de Leucócitos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Prognóstico , SARS-CoV-2 , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Regulação para CimaRESUMO
Research performed using model organisms such as mice and the fruit fly, Drosophila melanogaster has significantly enhanced our knowledge about cancer biology and the fundamental processes of cancer. This is because the major biological properties and genes associated with cancer including signaling pathways, oncogenes, tumor suppressors, and other regulators of cell growth and proliferation are evolutionary conserved. This review provides bibliometric analysis of research productivity, and performance of authors, institutions, countries, and journals associated with personalized animal cancer models, focussing on the role of Drosophila in cancer research, thus highlighting emerging trends in the field. A total of 1469 and 2672 original articles and reviews for Drosophila cancer model and patient-derived xenograft (PDX) respectively, were retrieved from the Scopus database and the most cited papers were thoroughly analyzed. Our analysis indicates a steadily increasing productivity of the animal models and especially of mouse models in cancer research. In addition to the many different systems that address almost all aspects of tumor research in humanized animal models, a trend towards using tailored screening platforms with Drosophila models in particular will become widespread in the future. Having Drosophila models that recapitulate major genetic aspects of a given tumor will enable the development and validation of novel therapeutic strategies for specific cancers, and provide a platform for screening small molecule inhibitors and other anti-tumor compounds. The combination of Drosophila cancer models and mouse PDX models particularly is highly promising and should be one of the major research strategies the future.
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Bibliometria , Modelos Animais de Doenças , Neoplasias/terapia , Oncogenes/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Animais Geneticamente Modificados , Terapia Combinada/métodos , Drosophila , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologiaRESUMO
OBJECTIVE: The aim of this systematic review and meta-analysis of longitudinal studies was to ascertain to effects of TNF-α inhibitor therapy on body weight and BMI. METHODS: Three databases (PubMed, OVID, and EMBASE) were systematically searched from inception to August 2018. We identified prospective, retrospective, and randomized controlled studies in adults with immune-mediated inflammatory diseases treated with TNF-α inhibitors based on pre-specified inclusion criteria. A random-effects model was used to estimate standardised mean change (SMCC). RESULTS: Twenty-six longitudinal studies with a total of 1,245 participants were included in the meta-analysis. We found evidence for a small increase in body weight (SMCC = 0.24, p = .0006, 95% CI [0.10, 0.37]) and in BMI (SMCC = 0.26, p < .0001, 95% CI [0.13, 0.39]). On average, patients gained 0.90kg (SD = 5.13) under infliximab, 2.34kg (D = 5.65) under etanercept and 2.27kg (SD = 4.69) during treatment with adalimumab within the duration of the respective studies (4-104 weeks). CONCLUSION: Our results yield further support the for the view that TNF-α inhibitors increase body weight and BMI as a potential side effect. Modulating cytokine signaling could be a future therapeutic mechanism to treat disorders associated with weight changes such as anorexia nervosa.
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A series of 2-methoxypyridine-3-carbonitrile (5a-i)-bearing aryl substituents were successfully synthesized in good yields by the condensation of chalcones (4a-i) with malononitrile in basic medium. The condensation process, in most cases, offers a route to a variety of methoxypyridine derivatives (6a-g) as side products in poor yields. All new compounds were fully characterized using different spectroscopic methods. Mass ESI-HMRS measurements were also performed. Furthermore, these compounds were screened for their in vitro cytotoxicity activities against three cancer cell lines; namely, those of the liver (line HepG2), prostate (line DU145) and breast (line MBA-MB-231). The cytotoxicity assessment revealed that compounds 5d, 5g, 5h and 5i exhibit promising antiproliferative effects (IC50 1-5 µM) against those three cancer cell lines.