RESUMO
Glucagon-like Peptide-1 (GLP-1) receptor agonists (GLP-1RAs) emerged as a primary treatment for type-2 diabetes mellitus (T2DM), however, their multifaceted effects on various target organs beyond glycemic control opened a new era of treatment. We conducted a comprehensive literature search using databases including Scopus, Google Scholar, PubMed, and the Cochrane Library to identify clinical, in-vivo, and in-vitro studies focusing on the diverse effects of GLP-1 receptor agonists. Eligible studies were selected based on their relevance to the varied roles of GLP-1RAs in T2DM management and their impact on other physiological functions. Numerous studies have reported the efficacy of GLP-1RAs in improving outcomes in T2DM, with demonstrated benefits including glucose-dependent insulinotropic actions, modulation of insulin signaling pathways, and reductions in glycemic excursions. Additionally, GLP-1 receptors are expressed in various tissues and organs, suggesting their widespread physiological functions beyond glycemic control potentially include neuroprotective, anti-inflammatory, cardioprotective, and metabolic benefits. However, further scientific studies are still underway to maximize the benefits of GLP-1RAs and to discover additional roles in improving health benefits. This article sought to review not only the actions of GLP1RAs in the treatment of T2DM but also explore its effects on potential targets in other disorders.
Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Humanos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Animais , Transdução de Sinais/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Agonistas do Receptor do Peptídeo 1 Semelhante ao GlucagonRESUMO
BACKGROUND: Disabled 2 (DAB2) is a multifunctional protein that has emerged as a critical component in the regulation of tumor growth. Its dysregulation is implicated in various types of cancer, underscoring its importance in understanding the molecular mechanisms underlying tumor development and progression. This review aims to unravel the intricate molecular mechanisms by which DAB2 exerts its tumor-suppressive functions within cancer signaling pathways. METHODS AND RESULTS: We conducted a comprehensive review of the literature focusing on the structure, expression, physiological functions, and tumor-suppressive roles of DAB2. We provide an overview of the structure, expression, and physiological functions of DAB2. Evidence supporting DAB2's role as a tumor suppressor is explored, highlighting its ability to inhibit cell proliferation, induce apoptosis, and modulate key signaling pathways involved in tumor suppression. The interaction between DAB2 and key oncogenes is examined, elucidating the interplay between DAB2 and oncogenic signaling pathways. We discuss the molecular mechanisms underlying DAB2-mediated tumor suppression, including its involvement in DNA damage response and repair, regulation of cell cycle progression and senescence, and modulation of epithelial-mesenchymal transition (EMT). The review explores the regulatory networks involving DAB2, covering post-translational modifications, interactions with other tumor suppressors, and integration within complex signaling networks. We also highlight the prognostic significance of DAB2 and its role in pre-clinical studies of tumor suppression. CONCLUSION: This review provides a comprehensive understanding of the molecular mechanisms by which DAB2 exerts its tumor-suppressive functions. It emphasizes the significance of DAB2 in cancer signaling pathways and its potential as a target for future therapeutic interventions.
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Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Neoplasias , Transdução de Sinais , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Animais , Transição Epitelial-Mesenquimal/genética , Progressão da Doença , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Apoptose/genéticaRESUMO
Alzheimer's disease (AD) is the primary cause of dementia and is characterized by the death of brain cells due to the accumulation of insoluble amyloid plaques, hyperphosphorylation of tau protein, and the formation of neurofibrillary tangles within the cells. AD is also associated with other pathologies such as neuroinflammation, dysfunction of synaptic connections and circuits, disorders in mitochondrial function and energy production, epigenetic changes, and abnormalities in the vascular system. Despite extensive research conducted over the last hundred years, little is established about what causes AD or how to effectively treat it. Given the severity of the disease and the increasing number of affected individuals, there is a critical need to discover effective medications for AD. The US Food and Drug Administration (FDA) has approved several new drug molecules for AD management since 2003, but these drugs only provide temporary relief of symptoms and do not address the underlying causes of the disease. Currently, available medications focus on correcting the neurotransmitter disruption observed in AD, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate (NMDA) receptor, which temporarily alleviates the signs of dementia but does not prevent or reverse the course of AD. Research towards disease-modifying AD treatments is currently underway, including gene therapy, lipid nanoparticles, and dendrimer-based therapy. These innovative approaches aim to target the underlying pathological processes of AD rather than just managing the symptoms. This review discusses the novel aspects of pathogenesis involved in the causation of AD of AD and in recent developments in the therapeutic armamentarium for the treatment of AD such as gene therapy, lipid nanoparticles, and dendrimer-based therapy, and many more.
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Doença de Alzheimer , Dendrímeros , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Dendrímeros/metabolismo , Dendrímeros/uso terapêutico , Inibidores da Colinesterase , Emaranhados Neurofibrilares/metabolismo , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismoRESUMO
SARS-CoV-2, the virus responsible for COVID-19, has caused numerous deaths worldwide and poses significant challenges. Researchers have recently studied a new antiviral drug called molnupiravir for treating COVID-19. This review examines the causes and immunopathogenesis of COVID-19, as well as the role of molnupiravir in its treatment. Molnupiravir is a prodrug of ß-D-N4-hydroxyctytidine (NHC) and has demonstrated activity against various viruses, including MERS-CoV, SARS-CoV, SARS-CoV-2, and influenza virus. The active form of molnupiravir, NHC triphosphate, acts as a nucleoside analog that disrupts viral replication by causing mutations in the viral RNA, thereby inhibiting viral growth. This review summarizes the results of multiple clinical trials that have evaluated the effectiveness of molnupiravir against SARS-CoV-2 and its variants. Animal studies have also shown that molnupiravir significantly reduces the viral load and prevents transmission to other animals. Overall, molnupiravir has demonstrated strong efficacy and reasonable safety, reducing hospitalization rates by nearly 50% among COVID-19-positive individuals at risk of complications. Patients in clinical settings have tolerated molnupiravir well and experienced positive outcomes, such as clearance of viral RNA, decreased viral load, and reduced hospitalization rates. Additionally, compared to a placebo, molnupiravir has been associated with lower mortality rates. Therefore, molnupiravir can be a beneficial drug to treat patients suffering from SARS-CoV-2, and further studies can provide more information about its safety and efficacy.
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COVID-19 , Animais , Antivirais/uso terapêutico , SARS-CoV-2 , HidroxilaminasRESUMO
Background and Purpose- Cellular Fn-EDA (fibronectin containing extra domain A) is expressed in activated endothelial cells and elevated in circulation in patients with cardiovascular diseases. Although global deficiency of Fn-EDA in mice improves stroke outcome, the specific contribution of plasma versus endothelium Fn-EDA in stroke outcome is currently unknown. We investigated the role of plasma versus endothelial Fn-EDA in stroke exacerbation in the comorbid condition of hyperlipidemia. Methods- We generated novel plasma Fn-EDA-/- ( Fn-EDA fl/fl Alb Cre) and endothelial Fn-EDA-/- ( Fn-EDA fl/fl Tie2 Cre) strains on hyperlipidemic apolipoprotein E-deficient ( ApoE-/-) background. By following the Stroke Therapy Academic Industry Roundtable guidelines, we evaluated stroke outcome in male and female mice. Susceptibility to ischemia/reperfusion injury was evaluated in 2 different models of stroke: intraluminal monofilament and embolic model on days 1, 3, and 7. Quantitative assessment of stroke outcome was evaluated by measuring infarct volume (by magnetic resonance imaging), cerebral blood flow (by laser speckle imaging), neurological and sensory-motor outcome, and postischemic thrombo-inflammation (platelet thrombi, fibrin, neutrophil, phospho-NFκB [nuclear factor κB], TNFα [tumor necrosis factor α], and IL1ß [interleukin 1ß]). Results- Stroke outcome was comparable in ApoE-/- Fn-EDA fl/fl Tie2 Cre and control ApoE-/- Fn-EDA fl/fl mice suggesting endothelial Fn-EDA does not contribute to stroke. ApoE-/- Fn-EDA fl/fl Alb Cre mice exhibited significantly smaller infarcts and improved neurological and sensory-motor outcome at days 1, 3, and 7 in monofilament and embolic models of stroke. Improved stroke outcome was concomitant with enhanced survival, and decreased postischemic thrombo-inflammatory response ( P<0.05 versus ApoE-/- Fn-EDA fl/fl). No sex-based differences were observed. Laser speckle imaging revealed significantly improved regional cerebral blood flow at 1 hour in ApoE-/- Fn-EDA fl/fl Alb Cre mice suggesting plasma Fn-EDA promotes postischemic secondary thrombosis. Coinfusion of anti-Fn-EDA antibody with r-tPA (recombinant tissue-type plasminogen activator) in ApoE-/- mice, 1 hour after embolization, improved stroke outcome with enhanced survival, and improved neurological outcome ( P<0.05 versus r-tPA). Conclusions- Genetic evidence suggests that plasma Fn-EDA exacerbates stroke outcome by promoting postischemic thrombo-inflammation. Interventions targeting plasma Fn-EDA may reduce brain damage after reperfusion.
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Células Endoteliais/metabolismo , Fibronectinas/sangue , Acidente Vascular Cerebral/sangue , Trombose/sangue , Animais , Biomarcadores/sangue , Células Endoteliais/patologia , Feminino , Inflamação/sangue , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Acidente Vascular Cerebral/patologia , Trombose/patologiaRESUMO
OBJECTIVE: VWF (von Willebrand factor) is synthesized by endothelial cells and megakaryocytes and is known to contribute to atherosclerosis. In vitro studies suggest that platelet-derived VWF (Plt-VWF) is biochemically and functionally different from endothelial cell-derived VWF (EC-VWF). We determined the role of different pools of VWF in the pathophysiology of atherosclerosis. APPROACH AND RESULTS: Using bone marrow transplantation, we generated chimeric Plt-VWF, EC-VWF, and Plt-VWF mice lacking a disintegrin and metalloprotease with thrombospondin type I repeats-13 in platelets and plasma on apolipoprotein E-deficient (Apoe-/-) background. Controls were chimeric Apoe-/- mice transplanted with bone marrow from Apoe-/- mice (wild type) and Vwf-/-Apoe-/- mice transplanted with bone marrow from Vwf-/-Apoe-/- mice (VWF-knock out). Susceptibility to atherosclerosis was evaluated in whole aortae and cross-sections of the aortic sinus in female mice fed a high-fat Western diet for 14 weeks. VWF-knock out, Plt-VWF, and Plt-VWF mice lacking a disintegrin and metalloprotease with thrombospondin type I repeats-13 exhibited reduced plaque size characterized by smaller necrotic cores, reduced neutrophil and monocytes/macrophages content, decreased MMP9 (matrix metalloproteinase), MMP2, and CX3CL1 (chemokine [C-X3-C motif] ligand 1)-positive area, and abundant interstitial collagen (P<0.05 versus wild-type or EC-VWF mice). Atherosclerotic lesion size and composition were comparable between wild-type or EC-VWF mice. Together these findings suggest that EC-VWF, but not Plt-VWF, promotes atherosclerosis exacerbation. Furthermore, intravital microscopy experiments revealed that EC-VWF, but not Plt-VWF, contributes to platelet and leukocyte adhesion under inflammatory conditions at the arterial shear rate. CONCLUSIONS: EC-VWF, but not Plt-VWF, contributes to VWF-dependent atherosclerosis by promoting platelet adhesion and vascular inflammation. Plt-VWF even in the absence of a disintegrin and metalloprotease with thrombospondin type I repeats-13, both in platelet and plasma, was not sufficient to promote atherosclerosis.
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Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Doenças de von Willebrand/metabolismo , Fator de von Willebrand/metabolismo , Proteína ADAMTS13/genética , Proteína ADAMTS13/metabolismo , Animais , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Plaquetas/metabolismo , Transplante de Medula Óssea , Adesão Celular , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Leucócitos/metabolismo , Leucócitos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica , Adesividade Plaquetária , Seio Aórtico/metabolismo , Seio Aórtico/patologia , Doenças de von Willebrand/sangue , Doenças de von Willebrand/genética , Fator de von Willebrand/genéticaRESUMO
OBJECTIVE: ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) prevents microvascular thrombosis by cleaving prothrombogenic ultralarge von Willebrand factor (VWF) multimers. Clinical studies have found association between reduced ADAMTS13-specific activity, ultralarge VWF multimers, and thrombotic angiopathy in patients with diabetic nephropathy. It remains unknown, however, whether ADAMTS13 deficiency or ultralarge VWF multimers have a causative effect in diabetic nephropathy. APPROACH AND RESULTS: The extent of renal injury was evaluated in wild-type (WT), Adamts13-/- and Adamts13-/-Vwf-/- mice after 26 weeks of streptozotocin-induced diabetic nephropathy. We found that WT diabetic mice exhibited low plasma ADAMTS13-specific activity and increased VWF levels (P<0.05 versus WT nondiabetic mice). Adamts13-/- diabetic mice exhibited deterioration of kidney function (increased albuminuria, plasma creatinine, and urea; P<0.05 versus WT diabetic mice), independent of hyperglycemia and hypertension. Deterioration of kidney function in Adamts13-/- diabetic mice was concomitant with aggravated intrarenal thrombosis (assessed by plasminogen activator inhibitor, VWF, fibrin(ogen), and CD41-positive microthrombi), increased mesangial cell expansion, and extracellular matrix deposition (P<0.05 versus WT diabetic mice). Genetic deletion of VWF in Adamts13-/- diabetic mice improved kidney function, inhibited intrarenal thrombosis, and alleviated histological changes in glomeruli, suggesting that exacerbation of diabetic nephropathy in the setting of ADAMTS13 deficiency is VWF dependent. CONCLUSIONS: ADAMTS13 retards progression of diabetic nephropathy, most likely by inhibiting VWF-dependent intrarenal thrombosis. Alteration in ADAMTS13-VWF balance may be one of the key pathophysiological mechanisms of thrombotic angiopathy in diabetes mellitus.
Assuntos
Proteína ADAMTS13/metabolismo , Nefropatias Diabéticas/prevenção & controle , Glomérulos Renais/enzimologia , Trombose/prevenção & controle , Proteína ADAMTS13/deficiência , Proteína ADAMTS13/genética , Albuminúria/enzimologia , Albuminúria/prevenção & controle , Animais , Proliferação de Células , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Progressão da Doença , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrinogênio/metabolismo , Predisposição Genética para Doença , Glomérulos Renais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Glicoproteína IIb da Membrana de Plaquetas/metabolismo , Estreptozocina , Trombose/enzimologia , Trombose/genética , Trombose/patologia , Ureia/sangue , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
Colorectal cancer (CRC) treatment strategies encompass a triad of medical interventions: surgery, radiotherapy, and chemotherapy. Among these, the use of chemotherapy, specifically 5-fluorouracil (5-FU), has become a cornerstone in CRC management. However, it is imperative to explore novel approaches that harness the synergistic potential of chemotherapy agents alongside adjunctive compounds to mitigate the severe adverse effects that often accompany treatment. In light of this pressing need, this study focuses on evaluating Kaempferol (KMP) in combination with 5-FU in a DMH-induced CRC animal model, scrutinizing its impact on haematological indices, organ health, and gastrointestinal, hepatotoxic, and nephrotoxic effects. Remarkably, KMP demonstrated haemato-protective attributes and exerted an immunomodulatory influence, effectively counteracting 5-FU-induced damage. Furthermore, organ assessments affirm the safety profile of the combined treatments while suggesting KMP's potential role in preserving the structural integrity of the intestine, and spleen. Histopathological assessments unveiled KMP's capacity to ameliorate liver injury and mitigate CRC-induced renal impairment. These multifaceted findings underscore KMP's candidacy as a promising adjunctive therapeutic option for CRC, underlining the pivotal need for personalized therapeutic strategies that concurrently optimize treatment efficacy and safeguard organ health. KMP holds tremendous promise in elevating the paradigm of CRC management.
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Antineoplásicos , Neoplasias Colorretais , Animais , Neoplasias Colorretais/patologia , Quempferóis/farmacologia , Apoptose , Fluoruracila/farmacologia , Antineoplásicos/efeitos adversosRESUMO
Theranostics refers to the combination of diagnostic biomarkers with therapeutic agents that share a specific target expressed by diseased cells and tissues. Nuclear medicine is an exciting component explored for its applicability in theranostic concepts in clinical and research investigations. Nuclear theranostics is based on the employment of radioactive compounds delivering ionizing radiation to diagnose and manage certain diseases employing binding with specifically expressed targets. In the realm of personalized medicine, nuclear theranostics stands as a beacon of potential, potentially revolutionizing disease management. Studies exploring the theranostic profile of radioactive compounds have been presented in this review along with a detailed explanation of radioactive compounds and their theranostic applicability in several diseases. It furnishes insights into their applicability across diverse diseases, elucidating the intricate interplay between these compounds and disease pathologies. Light is shed on the important milestones of nuclear theranostics beginning with radioiodine therapy in thyroid carcinomas, MIBG labelled with iodine in neuroblastoma, and several others. Our perspectives have been put forth regarding the most important theranostic agents along with emerging trends and prospects.
Assuntos
Medicina Nuclear , Medicina de Precisão , Compostos Radiofarmacêuticos , Nanomedicina Teranóstica , Humanos , Medicina Nuclear/métodos , Medicina Nuclear/tendências , Medicina de Precisão/métodos , Nanomedicina Teranóstica/métodos , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias da Glândula Tireoide/terapia , Radioisótopos do Iodo/uso terapêutico , Neoplasias/terapia , Neoplasias/diagnóstico por imagem , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/terapia , Neuroblastoma/metabolismoRESUMO
Cancer, characterized by the uncontrolled proliferation of aberrant cells, underscores the imperative for innovative therapeutic approaches. Immunotherapy has emerged as a pivotal constituent in cancer treatment, offering improved prognostic outcomes for a substantial patient cohort. Noteworthy for its precision, immunotherapy encompasses strategies such as adoptive cell therapy and checkpoint inhibitors, orchestrating the immune system to recognize and selectively target malignant cells. Exploiting the specificity of the immune response renders immunotherapy efficacious, as it selectively targets the body's immune milieu. Diverse mechanisms underlie cancer immunotherapies, leading to distinct toxicity profiles compared to conventional treatments. A remarkable clinical stride in the anticancer resources is immunotherapy. Remarkably, certain recalcitrant cancers like skin malignancies exhibit resistance to radiation or chemotherapy, yet respond favorably to immunotherapeutic interventions. Notably, combination therapies involving chemotherapy and immunotherapy have exhibited synergistic effects, enhancing overall therapeutic efficacy. Understanding the pivotal role of immunotherapy elucidates its complementary value, bolstering the therapeutic landscape. In this review, we elucidate the taxonomy of cancer immunotherapy, encompassing adoptive cell therapy and checkpoint inhibitors, while scrutinizing their distinct adverse event profiles. Furthermore, we expound on the unprecedented potential of immunogenic vaccines to bolster the anticancer immune response. This comprehensive analysis underscores the significance of immunotherapy in modern oncology, unveiling novel prospects for tailored therapeutic regimens.
Assuntos
Imunoterapia , Neoplasias Cutâneas , Humanos , Oncologia , Terapia CombinadaRESUMO
Diabetes mellitus (DM) is an intricate metabolic disorder marked by persistent hyperglycemia, arising from disruptions in glucose metabolism, with two main forms, type 1 and type 2, involving distinct etiologies affecting ß-cell destruction or insulin levels and sensitivity. The islets of Langerhans, particularly ß-cells and α-cells, play a pivotal role in glucose regulation, and both DM types lead to severe complications, including retinopathy, nephropathy, and neuropathy. Plant-derived anthocyanins, rich in anti-inflammatory and antioxidant properties, show promise in mitigating DM-related complications, providing a potential avenue for prevention and treatment. Medicinal herbs, fruits, and vegetables, abundant in bioactive compounds like phenolics, offer diverse benefits, including glucose regulation and anti-inflammatory, antioxidant, anticancer, anti-mutagenic, and neuroprotective properties. Anthocyanins, a subgroup of polyphenols, exhibit diverse isoforms and biosynthesis involving glycosylation, making them potential natural replacements for synthetic food colorants. Clinical trials demonstrate the efficacy and safety of anthocyanins in controlling glucose, reducing oxidative stress, and enhancing insulin sensitivity in diabetic patients, emphasizing their therapeutic potential. Preclinical studies revealed their multifaceted mechanisms, positioning anthocyanins as promising bioactive compounds for managing diabetes and its associated complications, including retinopathy, nephropathy, and neuropathy.
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A multifunctional scaffold protein termed Disabled-2 (Dab2) has recently gained attention in the scientific community and has emerged as a promising candidate in the realm of cancer research. Dab2 protein is involved in a variety of signaling pathways, due to which its significance in the pathogenesis of several carcinomas has drawn considerable attention. Dab2 is essential for controlling the advancement of cancer because it engages in essential signaling pathways such as the Wnt/ß-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-ß) pathways. Dab2 can also repress epithelial-mesenchymal transition (EMT) which is involved in tumor progression with metastatic expansion and adds another layer of significance to its possible impact on cancer spread. Furthermore, the role of Dab2 in processes such as cell growth, differentiation, apoptosis, invasion, and metastasis has been explored in certain investigative studies suggesting its significance. The present review examines the role of Dab2 in the pathogenesis of various cancer subtypes including breast cancer, ovarian cancer, gastric cancer, prostate cancer, and bladder urothelial carcinoma and also sheds some light on its potential to act as a therapeutic target and a prognostic marker in the treatment of various carcinomas. By deciphering this protein's diverse signaling, we hope to provide useful insights that may pave the way for novel therapeutic techniques and tailored treatment approaches in cancer management. Preclinical and clinical trial data on the impact of Dab2 regulation in cancer have also been included, allowing us to delineate role of Dab2 in tumor suppressor function, as well as its correlation with disease stage classification and potential therapy options. However, we observed that there is very scarce data in the form of studies on the evaluation of Dab2 role and treatment function in carcinomas, and further research into this matter could prove beneficial in the generation of novel therapeutic agents for patient-centric and tailored therapy, as well as early prognosis of carcinomas.
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Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Neoplasias , Transdução de Sinais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Animais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Transição Epitelial-MesenquimalRESUMO
The Disabled-2 (DAB2) protein, found in 80-90% of various tumors, including breast cancer, has been identified as a potential tumor suppressor protein. On the contrary, some hypothesis suggests that DAB2 is associated with the modulation of the Ras/MAPK pathway by endocytosing the Grb/Sos1 signaling complex, which produces oncogenes and chemoresistance to anticancer drugs, leading to increased tumor growth and metastasis. DAB2 has multiple functions in several disorders and is typically under-regulated in several cancers, making it a potential target for treatment of cancer therapy. The primary function of DAB2 is the modulation of transforming growth factor- ß (TGF-ß) mediated endocytosis, which is involved in several mechanisms of cancer development, including tumor suppression through promoting apoptosis and suppressing cell proliferation. In this review, we will discuss in detail the mechanisms through which DAB2 leads to breast cancer and various advancements in employing DAB2 in the treatment of breast cancer. Additionally, we outlined its role in other diseases. We propose that upregulating DAB2 could be a novel approach to the therapeutics of breast cancer.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Neoplasias da Mama , Transdução de Sinais , Humanos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Transdução de Sinais/efeitos dos fármacos , Feminino , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , Endocitose , Proteínas Supressoras de Tumor/metabolismoRESUMO
Biogenic metallic nanoparticles (NPs) have garnered significant attention in recent years due to their unique properties and various applications in different fields. NPs, including gold, silver, zinc oxide, copper, titanium, and magnesium oxide NPs, have attracted considerable interest. Green synthesis approaches, utilizing natural products, offer advantages such as sustainability and environmental friendliness. The theranostics applications of these NPs hold immense significance in the fields of medicine and diagnostics. The review explores intricate cellular uptake pathways, internalization dynamics, reactive oxygen species generation, and ensuing inflammatory responses, shedding light on the intricate mechanisms governing their behaviour at a molecular level. Intriguingly, biogenic metallic NPs exhibit a wide array of applications in medicine, including but not limited to anti-inflammatory, anticancer, anti-diabetic, anti-plasmodial, antiviral properties and radical scavenging efficacy. Their potential in personalized medicine stands out, with a focus on tailoring treatments to individual patients based on these NPs' unique attributes and targeted delivery capabilities. The article culminates in emphasizing the role of biogenic metallic NPs in shaping the landscape of personalized medicine. Harnessing their unique properties for tailored therapeutics, diagnostics and targeted interventions, these NPs pave the way for a paradigm shift in healthcare, promising enhanced efficacy and reduced adverse effects.
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Pulmonary diseases like asthma, chronic obstructive pulmonary disorder, lung fibrosis, and lung cancer pose a significant burden to global human health. Many of these complications arise as a result of exposure to particulate matter (PM), which has been examined in several preclinical and clinical trials for its effect on several respiratory diseases. Particulate matter of size less than 2.5 µm (PM2.5) has been known to inflict unforeseen repercussions, although data from epidemiological studies to back this are pending. Conventionally utilized two-dimensional (2D) cell culture and preclinical animal models have provided insufficient benefits in emulating the in vivo physiological and pathological pulmonary conditions. Three-dimensional (3D) structural models, including organ-on-a-chip models, have experienced a developmental upsurge in recent times. Lung-on-a-chip models have the potential to simulate the specific features of the lungs. With the advancement of technology, an emerging and advanced technique termed microfluidic organ-on-a-chip has been developed with the aim of identifying the complexity of the respiratory cellular microenvironment of the body. In the present Review, the role of lung-on-a-chip modeling in reproducing pulmonary complications has been explored, with a specific emphasis on PM2.5-induced pulmonary complications.
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ABSTRACT: Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in poststroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of poststroke DVT. Neutrophil-specific integrin α9-deficient mice (α9fl/flMrp8Cre+/-) exhibited a significant reduction in poststroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase, and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.
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Integrinas , Neutrófilos , Acidente Vascular Cerebral , Molécula 1 de Adesão de Célula Vascular , Trombose Venosa , Animais , Humanos , Masculino , Camundongos , Adesão Celular , Modelos Animais de Doenças , Integrinas/metabolismo , Camundongos Knockout , Ativação de Neutrófilo , Neutrófilos/metabolismo , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/etiologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Trombose Venosa/metabolismo , Trombose Venosa/etiologiaRESUMO
The objective of the present study was to carry out a pharmacokinetics evaluation of an oral modified release formulation [Aquarius EKX 19102 SRX-2 based osmotic pump (OP)] containing highly soluble milnacipran HCl (MH) as a model drug. It was also aimed at developing an in vitro-in vivo correlation (IVIVC) model for a developed OP. In vivo plasma concentration data were obtained from six healthy male New Zealand albino rabbits after administration of immediate-release milnacipran HCl solution (IRMHSOL) and milnacipran HCl osmotic pump (MHOP). In vitro samples were analysed using an in house developed spectrophotometry method and in vivo samples were analysed using a RP-HPLC method developed by the author. A deconvolution based Level A model was attempted through a correlation of the percent in vivo input obtained through deconvolution and the percent in vitro dissolution obtained experimentally. A good correlation between the percentages dissolved vs absorbed (R(2) = 0.978) was obtained using level A correlation. Evaluation of the internal predictability of level A correlation was calculated in terms of the percent prediction error, which was found to be below 15%. In a nutshell, the success of the present study warrants further studies in patient volunteers to assess the ability of the MHOP to provide an effective therapy for depression.
Assuntos
Inibidores da Captação Adrenérgica/farmacocinética , Ciclopropanos/farmacocinética , Modelos Biológicos , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Administração Oral , Inibidores da Captação Adrenérgica/administração & dosagem , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Ciclopropanos/administração & dosagem , Preparações de Ação Retardada , Masculino , Milnaciprano , Osmose , Coelhos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Solubilidade , EspectrofotometriaRESUMO
BACKGROUND AND OBJECTIVE: Aflibercept; a decoy receptor for vascular endothelial growth factors (VEGFs) and placental growth factor (PLGF), in combination with FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride) chemotherapy regime, was FDA approved in 2012 as second-line salvage chemotherapy for metastatic colorectal cancer (mCRC). This is the first systematic review, and meta-analysis-based evidence to determine the efficacy and safety of Aflibercept plus FOLFIRI regimen pooling randomized controlled trials and single-arm studies. METHOD: PubMed, Cochrane library, Embase, and Clinical trial.gov were systematically searched for published randomized controlled trials, single-arm studies, and national patient programs on aflibercept plus FOLFIRI chemotherapy for the treatment of mCRC till 11/10/2022. RESULT: Ten studies met the inclusion criteria comprising 1075 patients for efficacy studies and 2027 patients for safety studies. The pooled prevalences were 18% (95% CI, 5%-37%, p = 0.00) for 12 m PFS and 61% (95% CI, 53-68%, p = 0.00) for 12 m OS. The pooled prevalences were 69% (95% CI, 55-82%, p = 0.00) for any grade 3-4 toxicities, 10% (95% CI, 5-16%, p = 0.00) for grade 3-4 diarrhea, 13% (95% CI, 5-24%, p = 0.00) for grade 3-4 hypertension, 31% (95% CI, 22-40%, p = 0.00) for grade 3-4 neutropenia and 5% (95% CI, 2-7%, p = 0.00) for grade 3-4 venous thromboembolic event. CONCLUSION: Our meta-analysis shows that the aflibercept plus FOLFIRI combination shows better survival efficacies however; it is also associated with more high-grade adverse events.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Feminino , Neoplasias Colorretais/patologia , Camptotecina/efeitos adversos , Fator de Crescimento Placentário/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias do Colo/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão/efeitos adversos , Fluoruracila/efeitos adversos , Leucovorina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Colorectal cancer (CRC) is a complex disease characterized by genetic and epigenetic alterations, playing a crucial role in its development and progression. This review aims to provide insights into the emerging landscape of these alterations in CRC pathogenesis to develop effective diagnostic tools and targeted therapies. Genetic alterations in signaling pathways such as Wnt/ß-catenin, and PI3K/Akt/mTOR are pivotal in CRC development. Genetic profiling has identified distinct molecular subtypes, enabling personalized treatment strategies. Epigenetic modifications, including DNA methylation and histone modifications, also contribute to CRC pathogenesis by influencing critical cellular processes through gene silencing or activation. Non-coding RNAs have emerged as essential players in epigenetic regulation and CRC progression. Recent research highlights the interplay between genetic and epigenetic alterations in CRC. Genetic mutations can affect epigenetic modifications, leading to dysregulated gene expression and signaling cascades. Conversely, epigenetic changes can modulate genetic expression, amplifying or dampening the effects of genetic alterations. Advancements in understanding pathogenic pathways have potential clinical applications. Identifying genetic and epigenetic markers as diagnostic and prognostic biomarkers promises more accurate risk assessment and early detection. Challenges remain, including validating biomarkers and developing robust therapeutic strategies through extensive research and clinical trials. The dynamic nature of genetic and epigenetic alterations necessitates a comprehensive understanding of their temporal and spatial patterns during CRC progression. In conclusion, the genetic and epigenetic landscape of CRC is increasingly being unraveled, providing valuable insights into its pathogenesis. Integrating genetic and epigenetic knowledge holds great potential for improving diagnostics, prognostics, and personalized therapies in CRC. Continued research efforts are vital to translate these findings into clinical practice, ultimately improving patient outcomes.
Assuntos
Neoplasias Colorretais , Epigênese Genética , Humanos , Neoplasias Colorretais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Metilação de DNA , Biomarcadores/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
Pulmonary infections have been a leading etiology of morbidity and mortality worldwide. Upper and lower respiratory tract infections have multifactorial causes, which include bacterial, viral, and rarely, fungal infections. Moreover, the recent emergence of SARS-CoV-2 has created havoc and imposes a huge healthcare burden. Drug and vaccine development against these pulmonary pathogens like respiratory syncytial virus, SARS-CoV-2, Mycobacteria, etc., requires a systematic set of tools for research and investigation. Currently, in vitro 2D cell culture models are widely used to emulate the in vivo physiologic environment. Although this approach holds a reasonable promise over pre-clinical animal models, it lacks the much-needed correlation to the in vivo tissue architecture, cellular organization, cell-to-cell interactions, downstream processes, and the biomechanical milieu. In view of these inadequacies, 3D cell culture models have recently acquired interest. Mammalian embryonic and induced pluripotent stem cells may display their remarkable self-organizing abilities in 3D culture, and the resulting organoids replicate important structural and functional characteristics of organs such the kidney, lung, gut, brain, and retina. 3D models range from scaffold-free systems to scaffold-based and hybrid models as well. Upsurge in organs-on-chip models for pulmonary conditions has anticipated encouraging results. Complexity and dexterity of developing 3D culture models and the lack of standardized working procedures are a few of the setbacks, which are expected to be overcome in the coming times. Herein, we have elaborated the significance and types of 3D cell culture models for scrutinizing pulmonary infections, along with the in vitro techniques, their applications, and additional systems under investigation.