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Introduction The human immunodeficiency virus (HIV) primarily targets clusters of differentiation 4 (CD4)+ T cells and other immune cells, leading to immune dysfunction. Cytokines such as interleukin (IL)-23 and IL-27 have complex roles in HIV-associated disease progression, affecting viral replication and immune responses. This study aimed to explore the correlation between HIV-related CD4 lymphopenia and the inflammatory cytokines IL-23 and IL-27 in treatment-naive HIV patients. Materials and methods This is a single-center, prospective, observational study conducted at the Antiretroviral Treatment (ART) Center of Jawaharlal Nehru Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India. Sixty-five treatment-naive HIV seropositive patients were recruited in this study. Quantitative estimation of inflammatory biomarkers (IL-23 and IL-27) was performed using enzyme-linked immunosorbent assay (ELISA). The fluorescent-activated cell sorter count (FACSCount) technology was used to determine the CD4+ T-cell count. Results Our study revealed that HIV-infected individuals had significantly higher levels of IL-23 (868.9±246.7 pg/mL vs 98.3±86.6 pg/mL, p < 0.01) and IL-27 (1629.5±518.5 pg/mL vs 291.3±225.2 pg/mL, p < 0.01) compared to healthy controls. Additionally, we found a strong positive correlation between CD4 count and IL-23 titers (r = 0.93, p < 0.01), as well as between CD4 count and IL-27 titers (r = 0.92, p < 0.01) in HIV-positive individuals. Conclusion The findings suggest that these cytokines respond to HIV infection and may potentially play a crucial role in restraining HIV replication and slowing down the progression of the disease.
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Depression is a prevalent mental health disorder that significantly impacts primary care settings. This editorial explores the potential of artificial intelligence (AI)-powered chatbots in managing depression within primary care environments. AI chatbots offer innovative solutions to challenges faced by healthcare providers, including limited appointment times, delayed access to specialists, and stigma associated with mental health issues. These digital tools provide continuous support, personalized interactions, and early symptom detection, potentially improving accessibility and outcomes in depression management. The integration of AI chatbots in primary care presents opportunities for round-the-clock patient support, personalized interventions, and the reduction of mental health stigma. However, challenges persist, including concerns about assessment accuracy, data privacy, and integration with existing healthcare systems. Successful implementation requires systematic approaches, stakeholder engagement, and comprehensive training for healthcare providers. Ethical considerations, such as ensuring informed consent, managing algorithmic biases, and maintaining the human element in care, are crucial for responsible deployment. As AI technology evolves, future directions may include enhanced natural language processing, multimodal integration, and AI-augmented clinical decision support. This editorial emphasizes the need for a balanced approach that leverages the potential of AI while acknowledging its limitations and the irreplaceable value of human clinical judgment in depression management within primary care settings.
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BACKGROUND: Cancer is one of the leading causes of death and a great threat to people around the world. Cancer treatment modalities include surgery, radiotherapy, chemotherapy, radiochemotherapy, hormone therapy, and immunotherapy. The best approach is to use a combination of several types. Among the treatment methods mentioned above, chemotherapy is frequently used, but its activity is hampered by the development of drug resistance and many side effects. In this regard, the use of medicinal plants has been discussed, and in recent decades, the use of isolated phytochemicals came into the focus of interest. By critically evaluating the available evidence and emphasizing the unique perspective offered by this review, we provide insights into the potential of daidzein as a promising therapeutic agent, as well as outline future research directions to optimize its efficacy in clinical settings. PURPOSE: To summarized the therapeutic potential of daidzein, an isoflavone phytoestrogen in the management of several human diseases with the focuses on the current status and future prospects as a therapeutic agent. METHODS: Several search engines, including PubMed, GoogleScholar, and ScienceDirect, were used, with the search terms "daidzein", "daidzein therapeutic potential", or individual effects. The study included all peer-reviewed articles. However, the most recent publications were given priority. RESULTS: Daidzein showed protective effects against malignant diseases such as breast cancer, prostate cancer but also non-malignant diseases such as diabetes, osteoporosis, and cardiovascular diseases. Daidzein activates multiple signaling pathways leading to cell cycle arrest and apoptosis as well as antioxidant and anti-metastatic effects in malignant cells. Moreover, the anticancer effects against different cancer cells were more prominent and discussed in detail. CONCLUSIONS: In short, daidzein represents a promising compound for drug development. The comprehensive potential anticancer activities of daidzein through various molecular mechanisms and its therapeutic/clinical status required further detail studies.
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BACKGROUND: Wound healing pivots on a finely orchestrated inflammatory cascade, critical for tissue repair. Chronic wounds, compounded by persistent inflammation and susceptibility to infection, pose formidable clinical challenges. Nanofiber dressings offer promising avenues for wound care, yet their interaction with inflammation and infection remains elusive. We aim to delineate the inflammatory cascade preceding wound closure and assess Cu@Bbc nanofibers' therapeutic efficacy in mitigating inflammation and combating infection. Their unique attributes suggest promise in modulating inflammation, fostering tissue regeneration, and preventing microbial colonization. Investigating the intricate interplay between nanofiber scaffolds, inflammation, and infection may unveil mechanisms of enhanced wound healing. Our findings could stimulate the development of tailored dressings, urgently needed for effective wound management amidst immune dysregulation, infection, and inflammation. METHODS: In this investigation, we synthesized Cu@Bbc nanofibers, incorporating curcumin and berberine chloride, for wound healing applications. We evaluated their individual and combined antibacterial, anti-biofilm, and antioxidant activities, alongside binding affinity with pro-inflammatory cytokines through molecular docking. Morphological characterization was conducted via SEM, FTIR assessed functional groups, and wettability contact angle measured hydrophobic properties. The physical properties, including tensile strength, swelling behavior, and thermal stability, were evaluated using tensile testing, saline immersion method and thermogravimetric analysis. Biodegradability of the nanofibers was assessed through a soil burial test. Biocompatibility was determined via MTT assay, while wound healing efficacy was assessed with in vitro scratch assays. Controlled drug release and antibacterial activity against MRSA were examined, with in vivo assessment in a zebrafish model elucidating inflammatory responses and tissue remodeling. RESULTS: In this study, the synergistic action of curcumin and berberine chloride exhibited potent antibacterial efficacy against MRSA, with significant anti-mature biofilm disruption. Additionally, the combination demonstrated heightened antioxidant potential. Molecular docking studies revealed strong binding affinity with pro-inflammatory cytokines, suggesting a role in expediting the inflammatory response crucial for wound healing. Morphological analysis confirmed nanofiber quality, with drug presence verified via FTIR spectroscopy. Cu@Bbc demonstrated higher tensile strength, optimal swelling behavior, and robust thermal stability as evaluated through tensile testing and thermogravimetric analysis. Additionally, the Cu@Bbc nanofiber showed enhanced biodegradability, as confirmed by the soil burial test. Biocompatibility assessments showed favorable compatibility, while in vitro studies demonstrated potent antibacterial activity. In vivo zebrafish experiments revealed accelerated wound closure, re-epithelialization, and heightened immune response, indicative of enhanced wound healing. CONCLUSION: In summary, our investigation highlights the efficacy of Cu@Bbc nanofibers, laden with curcumin and berberine chloride, in displaying robust antibacterial and antioxidant attributes while also modulating immune responses and inflammatory cascades essential for wound healing. These results signify their potential as multifaceted wound dressings for clinical implementation.
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Antibacterianos , Berberina , Curcumina , Staphylococcus aureus Resistente a Meticilina , Nanofibras , Infecciones Estafilocócicas , Cicatrización de Heridas , Pez Cebra , Animales , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Curcumina/farmacología , Curcumina/química , Curcumina/uso terapéutico , Berberina/farmacología , Berberina/química , Berberina/uso terapéutico , Cicatrización de Heridas/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/inmunología , Nanofibras/química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/química , Sinergismo Farmacológico , Simulación del Acoplamiento Molecular , Citocinas/metabolismo , Biopelículas/efectos de los fármacos , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
Blood-brain barrier (BBB) disruption is a major pathophysiological event of ischemic stroke. Brain microvascular endothelial cells are critical to maintain homeostasis between central nervous system and periphery. Resveratrol protects against ischemic stroke. 3,3',4,5'-tetramethoxy-trans-stilbene (3,3',4,5'-TMS) and 3,4',5-trimethoxy-trans-stilbene (3,4',5-TMS) are resveratrol derivatives with addition of methoxy groups, showing better pharmacokinetic performance. We aimed to explore their protective effects and underlying mechanisms. Oxygen-glucose deprivation (OGD) model was applied in bEnd.3 cell line, mouse brain microvascular endothelium to mimic ischemia. The cells were pre-treated with 3,3',4,5'-TMS or 3,4',5-TMS (1 and 5 µM, 24 h) and then subjected to 2-h OGD injury. Cell viability, levels of proinflammatory cytokines and reactive oxygen species (ROS), and protein expressions were measured by molecular assays and fluorescence staining. OGD injury triggered cell death, inflammatory responses, ROS production and nuclear factor-kappa B (NF-κB) signalling pathway. These impairments were remarkably attenuated by the two stilbenes, 3,3',4,5'-TMS and 3,4',5-TMS. They also alleviated endothelial barrier injuries through upregulating the expression of tight junction proteins. Moreover, 3,3',4,5'-TMS and 3,4',5-TMS activated 5' adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Overall, 3,3',4,5'-TMS and 3,4',5-TMS exert protective effects against OGD damage through suppressing cell death, inflammatory responses, oxidative stress, as well as BBB disruption on bEnd.3 cells.
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Encéfalo , Supervivencia Celular , Células Endoteliales , Glucosa , Oxígeno , Especies Reactivas de Oxígeno , Estilbenos , Estilbenos/farmacología , Animales , Glucosa/metabolismo , Ratones , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Oxígeno/metabolismo , Línea Celular , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Supervivencia Celular/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Estrés Oxidativo/efectos de los fármacos , Citocinas/metabolismo , Transducción de Señal/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacosRESUMEN
Motion Estimation (ME) and the two-dimensional (2D) discrete cosine transform (2D-DCT) are both computationally expensive parts of HEVC standard, therefore real-time performance of the HEVC may not be free from glitches. To address this issue, this study deploys the graphics processing units (GPUs) to perform the ME and 2D-DCT tasks. In this concern, authors probed into four levels of parallelism (i.e., frame, macroblock, search area, and sum of the absolute difference (SAD) levels) existing in ME. For comparative analysis, authors involved full search (FS), test zone search (TZS) of HEVC, and hierarchical diamond search (EHDS) ME algorithms. Similarly, two levels of parallelism (i.e., macroblock and sub-macroblock) are also explored in 2D-DCT. Notably, the least computationally complex multithreaded Loeffler DCT algorithm is utilized for computing 2D-DCT. Experimental results show that ME processing task corresponding to 25 frames, with each frame of size (3840×2160) pixels, is accomplished in 0.15 seconds on the NVIDIA GeForce GTX 1080, whereas the 2D-DCT task along with the image reconstruction and differencing corresponding to 25 frames took 0.1 seconds. Collectively, both ME and 2D-DCT tasks are processed in 0.25 seconds, which still leaves enough room for the encoder's remaining parts to be executed within one second. Due to this enhancement, the resultant encoder can safely be used in real-time applications.
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Algoritmos , Gráficos por Computador , Movimiento (Física) , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
BACKGROUND: Cadmium chloride (Cd) is a pervasive environmental heavy metal pollutant linked to mitochondrial dysfunction, memory loss, and genetic disorders, particularly in the context of neurodegenerative diseases like Alzheimer's disease (AD). METHODS: This study investigated the neurotherapeutic potential of vitamin B6 (Vit. B6) in mitigating Cd-induced oxidative stress and neuroinflammation-mediated synaptic and memory dysfunction. Adult albino mice were divided into four groups: Control (saline-treated), Cd-treated, Cd+Vit. B6- treated, and Vit. B6 alone-treated. Cd and Vit. B6 were administered intraperitoneally, and behavioral tests (Morris Water Maze, Y-Maze) were conducted. Subsequently, western blotting, antioxidant assays, blood glucose, and hyperlipidemia assessments were performed. RESULTS: Cd-treated mice exhibited impaired cognitive function, while Cd+Vit. B6-treated mice showed significant improvement. Cd-induced neurotoxic effects, including oxidative stress and neuroinflammation, were observed, along with disruptions in synaptic proteins (SYP and PSD95) and activation of p-JNK. Vit. B6 administration mitigated these effects, restoring synaptic and memory deficits. Molecular docking and MD simulation studies confirmed Vit. B6's inhibitory effect on IL-1ß, NRF2, and p-JNK proteins. CONCLUSION: These results highlight Vit. B6 as a safe therapeutic supplement to mitigate neurodegenerative disorders, emphasizing the importance of assessing nutritional interventions for combating environmental neurotoxicity in the interest of public health.
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Research suggests curcumin's safety and efficacy, prompting interest in its use for treating and preventing various human diseases. The current study aimed to predict drag ability of methyl substituted curcumin derivatives (BL1 to BL4) using SwissADME and Density Functional Theory (DFT) approaches. The curcumin derivatives investigated mostly adhere to Lipinski's rule of five, with molecular properties including MW, F. Csp3, nHBA, nHBD, and TPSA falling within acceptable limits. The compounds demonstrating high lipophilicity while poor water solubility. The pharmacokinetic evaluation revealed favorable gastrointestinal absorption and blood-brain barrier permeation while none were identified as substrates for P-glycoprotein, however, revealed inhibitory actions against various cytochrome P450 enzymes. Additionally, all derivatives exhibited a consistent bioavailability score of 0.55. Similarly, the DFT computations of the compounds of the curcumin derivatives were conducted at B3LYP/6-311â¯G** level to predict and then assess the key electronic characteristics underlying the bioactivity. Accordingly, the BL4 molecule (ΔEgap= 4.105â¯eV) would prefer to interact with the external molecular system more than the other molecules due to having the biggest energy gap. The ΔNmax (2.328â¯eV) and Δεback-donat. (-0.446â¯eV) scores implied that BL1 would have more charge transfer capability and the lowest stability via back donation among the compounds. In short, the derivative (BL1 to BL4) exhibited strong extrinsic therapeutic properties and therefore stand eligible for further in vitro and in vivo studies.
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Curcumina , Teoría Funcional de la Densidad , Curcumina/química , Curcumina/farmacología , Curcumina/análogos & derivados , Estructura Molecular , Humanos , Sistema Enzimático del Citocromo P-450/metabolismoRESUMEN
BACKGROUND: Dental pathogens play a crucial role in oral health issues, including tooth decay, gum disease, and oral infections, and recent research suggests a link between these pathogens and oral cancer initiation and progression. Innovative therapeutic approaches are needed due to antibiotic resistance concerns and treatment limitations. METHODS: We synthesized and analyzed piperine-coated zinc oxide nanoparticles (ZnO-PIP NPs) using UV spectroscopy, SEM, XRD, FTIR, and EDAX. Antioxidant and antimicrobial effectiveness were evaluated through DPPH, ABTS, and MIC assays, while the anticancer properties were assessed on KB oral squamous carcinoma cells. RESULTS: ZnO-PIP NPs exhibited significant antioxidant activity and a MIC of 50 µg/mL against dental pathogens, indicating strong antimicrobial properties. Interaction analysis revealed high binding affinity with dental pathogens. ZnO-PIP NPs showed dose-dependent anticancer activity on KB cells, upregulating apoptotic genes BCL2, BAX, and P53. CONCLUSIONS: This approach offers a multifaceted solution to combatting both oral infections and cancer, showcasing their potential for significant advancement in oral healthcare. It is essential to acknowledge potential limitations and challenges associated with the use of ZnO NPs in clinical applications. These may include concerns regarding nanoparticle toxicity, biocompatibility, and long-term safety. Further research and rigorous testing are warranted to address these issues and ensure the safe and effective translation of ZnO-PIP NPs into clinical practice.
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Alcaloides , Apoptosis , Benzodioxoles , Biopelículas , Neoplasias de la Boca , Piperidinas , Alcamidas Poliinsaturadas , Óxido de Zinc , Proteína X Asociada a bcl-2 , Humanos , Alcaloides/farmacología , Antineoplásicos/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo , Proteína X Asociada a bcl-2/efectos de los fármacos , Benzodioxoles/farmacología , Biopelículas/efectos de los fármacos , Línea Celular Tumoral , Células KB , Nanopartículas del Metal/uso terapéutico , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Rastreo , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Nanopartículas , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/efectos de los fármacos , Difracción de Rayos X , Óxido de Zinc/farmacologíaRESUMEN
As a critical cause of human dysfunctionality, hepatic failure leads to approximately two million deaths per year and is on the rise. Considering multiple inflammatory, oxidative, and apoptotic mechanisms behind hepatotoxicity, it urges the need for finding novel multi-targeting agents. Curcumin is a phenolic compound with anti-inflammatory, antioxidant, and anti-apoptotic roles. Curcumin possesses auspicious health benefits and protects against several diseases with exceptional safety and tolerability. This review focused on the hepatoprotective mechanisms of curcumin. The need to develop novel delivery systems of curcumin (e.g., nanoparticles, self-micro emulsifying, lipid-based colloids, solid lipid nanoparticles, cyclodextrin inclusion, phospholipid complexes, and nanoemulsions) is also considered.
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Curcumina , Curcumina/farmacología , Curcumina/química , Humanos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Antioxidantes/farmacología , Antioxidantes/química , Hígado/efectos de los fármacos , Hígado/patología , Sustancias Protectoras/farmacología , Sustancias Protectoras/química , Nanopartículas , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
Brain-computer interface (BCI) systems include signal acquisition, preprocessing, feature extraction, classification, and an application phase. In fNIRS-BCI systems, deep learning (DL) algorithms play a crucial role in enhancing accuracy. Unlike traditional machine learning (ML) classifiers, DL algorithms eliminate the need for manual feature extraction. DL neural networks automatically extract hidden patterns/features within a dataset to classify the data. In this study, a hand-gripping (closing and opening) two-class motor activity dataset from twenty healthy participants is acquired, and an integrated contextual gate network (ICGN) algorithm (proposed) is applied to that dataset to enhance the classification accuracy. The proposed algorithm extracts the features from the filtered data and generates the patterns based on the information from the previous cells within the network. Accordingly, classification is performed based on the similar generated patterns within the dataset. The accuracy of the proposed algorithm is compared with the long short-term memory (LSTM) and bidirectional long short-term memory (Bi-LSTM). The proposed ICGN algorithm yielded a classification accuracy of 91.23 ± 1.60%, which is significantly (p < 0.025) higher than the 84.89 ± 3.91 and 88.82 ± 1.96 achieved by LSTM and Bi-LSTM, respectively. An open access, three-class (right- and left-hand finger tapping and dominant foot tapping) dataset of 30 subjects is used to validate the proposed algorithm. The results show that ICGN can be efficiently used for the classification of two- and three-class problems in fNIRS-based BCI applications.
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Algoritmos , Interfaces Cerebro-Computador , Aprendizaje Profundo , Redes Neurales de la Computación , Espectroscopía Infrarroja Corta , Humanos , Espectroscopía Infrarroja Corta/métodos , Masculino , Adulto , Femenino , Adulto Joven , Encéfalo/fisiología , Encéfalo/diagnóstico por imagenRESUMEN
Efficient Waste management plays a crucial role to ensure clean and green environment in the smart cities. This study investigates the critical role of efficient trash classification in achieving sustainable solid waste management within smart city environments. We conduct a comparative analysis of various trash classification methods utilizing deep learning models built on convolutional neural networks (CNNs). Leveraging the PyTorch open-source framework and the TrashBox dataset, we perform experiments involving ten unique deep neural network models. Our approach aims to maximize training accuracy. Through extensive experimentation, we observe the consistent superiority of the ResNext-101 model compared to others, achieving exceptional training, validation, and test accuracies. These findings illuminate the potential of CNN-based techniques in significantly advancing trash classification for optimized solid waste management within smart city initiatives. Lastly, this study presents a distributed framework based on federated learning that can be used to optimize the performance of a combination of CNN models for trash detection.
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Diabetes Mellitus (DM) is referred to as hyperglycemia in either fasting or postprandial phases. Oxidative stress, which is defined by an excessive amount of reactive oxygen species (ROS) production, increased exposure to external stress, and an excessive amount of the cellular defense system against them, results in cellular damage. Increased DNA damage is one of the main causes of genomic instability, and genetic changes are an underlying factor in the emergence of cancer. Through covalent connections with DNA and proteins, quercetin has been demonstrated to offer protection against the creation of oxidative DNA damage. It has been found that quercetin shields DNA from possible oxidative stress-related harm by reducing the production of ROS. Therefore, Quercetin helps to lessen DNA damage and improve the ability of DNA repair mechanisms. This review mainly focuses on the role of quercetin in repairing DNA damage and compensating for drug resistance in diabetic patients. Data on the target topic was obtained from major scientific databases, including SpringerLink, Web of Science, Google Scholar, Medline Plus, PubMed, Science Direct, and Elsevier. In preclinical studies, quercetin guards against DNA deterioration by regulating the degree of lipid peroxidation and enhancing the antioxidant defense system. By reactivating antioxidant enzymes, decreasing ROS levels, and decreasing the levels of 8-hydroxydeoxyguanosine, Quercetin protects DNA from oxidative damage. In clinical studies, it was found that quercetin supplementation was related to increased antioxidant capacity and decreased risk of type 2 diabetes mellitus in the experimental group as compared to the placebo group. It is concluded that quercetin has a significant role in DNA repair in order to overcome drug resistance in diabetes.
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BACKGROUND: The interleukin-2 (IL-2) family of cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, are pivotal regulators of the immune response, impacting both innate and adaptive immunity. Understanding their molecular characteristics, receptor interactions, and signalling pathways is essential for elucidating their roles in health and disease. OBJECTIVES: This review provides a comprehensive overview of the IL-2 family of cytokines, highlighting their molecular biology, receptor interactions, and signalling mechanisms. Furthermore, it explores the involvement of IL-2 family cytokines in the pathogenesis of chronic respiratory diseases, with a specific focus on chronic obstructive pulmonary disease (COPD) and asthma. METHODS: A thorough literature review was conducted to gather insights into the molecular biology, receptor interactions, and signalling pathways of IL-2 family cytokines. Additionally, studies investigating the roles of these cytokines in chronic respiratory diseases, particularly COPD and asthma, were analysed to discern their implications in wider pathophysiology of disease. RESULTS: IL-2 family cytokines exert pleiotropic effects on immune cells, modulating cellular proliferation, differentiation, and survival. Dysregulation of IL-2 family cytokines has been implicated in the pathogenesis of chronic respiratory illnesses, including COPD and asthma. Elevated levels of IL-2 and IL-9 have been associated with disease severity in COPD, while IL-4 and IL-9 play crucial roles in asthma pathogenesis by promoting airway inflammation and remodelling. CONCLUSION: Understanding the intricate roles of IL-2 family cytokines in chronic respiratory diseases provides valuable insights into potential therapeutic targets for these conditions. Targeting specific cytokines or their receptors may offer novel treatment modalities to attenuate disease progression and improve clinical outcomes in patients with COPD and asthma.
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Asma , Interleucina-2 , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Asma/inmunología , Asma/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Interleucina-2/metabolismo , Transducción de Señal , AnimalesRESUMEN
Recently, malignant neoplasms have growingly caused human morbidity and mortality. Head and neck cancer (HNC) constitutes a substantial group of malignancies occurring in various anatomical regions of the head and neck, including lips, mouth, throat, larynx, nose, sinuses, oropharynx, hypopharynx, nasopharynx, and salivary glands. The present study addresses the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway as a possible therapeutic target in cancer therapy. Finding new multitargeting agents capable of modulating PI3K/Akt/mTOR and cross-linked mediators could be viewed as an effective strategy in combating HNC. Recent studies have introduced phytochemicals as multitargeting agents and rich sources for finding and developing new therapeutic agents. Phytochemicals have exhibited immense anticancer effects, including targeting different stages of HNC through the modulation of several signaling pathways. Moreover, phenolic/polyphenolic compounds, alkaloids, terpenes/terpenoids, and other secondary metabolites have demonstrated promising anticancer activities because of their diverse pharmacological and biological properties like antiproliferative, antineoplastic, antioxidant, and anti-inflammatory activities. The current review is mainly focused on new therapeutic strategies for HNC passing through the PI3K/Akt/mTOR pathway as new strategies in combating HNC.
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Neoplasias de Cabeza y Cuello , Fosfatidilinositol 3-Quinasas , Fitoquímicos , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Fitoquímicos/farmacología , Fitoquímicos/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Antineoplásicos Fitogénicos/farmacologíaRESUMEN
One of the key strategies in chemotherapy involves crosslinking the DNA strands of cancer cells to impede their replication, with platinum (Pt) coordination compounds being a prominent class and cisplatin being its major representative. Steroidal ligands tethered to DNA interactive Pt core act as drug carriers for targeted therapy. While crosslinking of nuclear or mitochondrial DNA strands using coordination complexes has been studied for years, there remains a lack of comprehensive reviews addressing the advancements made in steroidal-Pt derivatives. This review specifically focuses on advancements made in steroid-tethered structural derivatives of Pt(II) or prodrug Pt(IV) for targeted chemotherapy, synthesized between 2000 and 2023. This period was deliberately chosen due to the widespread use of computational techniques for more accurate structure-based drug-design in last two decades. This review discusses the strategy behind tethering steroidal ligands such as testosterone, estrogen, bile acids, and cholesterol to the central DNA interactive Pt core through specific linker groups. The steroidal ligands function as drug delivery vehicles of DNA interactive Pt core and bind with their respective target receptors or proteins that are often overexpressed in cancer cells, thus enabling targeted delivery of Pt moiety to interact with DNA. We discussed structural features such as the location of the linker group on the steroid, the mono, bi, and tridentate configuration of the chelating arm in coordination with Pt, and the rigidity and flexibility of the linker group. The comparative in vitro, in vivo activities, and relative binding affinities of the designed compounds against standard Pt drugs are also discussed. We also provided a critique of observed trends and shortcomings. Our review will provide insights into future molecular designing of targeted DNA crosslinkers and their structural optimization to achieve desired drug properties. From this analysis, we proposed further research directions leading to the future of targeted chemotherapy.
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Antineoplásicos , Esteroides , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Esteroides/química , Esteroides/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/síntesis química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Animales , Estructura Molecular , ADN/química , ADN/metabolismoRESUMEN
The COVID-19 pandemic has drawn attention to acute lung injury and respiratory distress syndrome as major causes of death, underscoring the urgent need for effective treatments. Protease enzymes possess a wide range of beneficial effects, including antioxidant, anti-inflammatory, antifibrotic, and fibrinolytic effects. This study aimed to evaluate the potential therapeutic effects of bacterial protease and chymotrypsin in rats in mitigating acute lung injury induced by lipopolysaccharide. Molecular docking was employed to investigate the inhibitory effect of bacterial protease and chymotrypsin on TLR-4, the receptor for lipopolysaccharide. Bacterial protease restored TLR-4, Nrf2, p38 MAPK, NF-kB, and IKK-ß levels to normal levels, while chymotrypsin normalized TLR-4, IKK-ß, IL-6, and IL-17 levels. The expression of TGF-ß, caspase-3, and VEGF in the bacterial protease- and chymotrypsin-treated groups was markedly reduced. Our results suggest that both therapies ameliorate LPS-induced acute lung injury and modulate the TLR4/Nrf2/NF-k signaling pathway. Each protease exhibited distinct mechanisms, with bacterial protease showing a better response to oxidative stress, edema, and fibrosis, whereas chymotrypsin provided a better response in the acute phase and innate immunity. These findings highlight the potential of each protease as a promising therapeutic option for acute lung injury and respiratory distress syndrome.
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Lesión Pulmonar Aguda , Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , FN-kappa B , Síndrome de Dificultad Respiratoria , Transducción de Señal , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Transducción de Señal/efectos de los fármacos , Ratas , FN-kappa B/metabolismo , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Quimotripsina/metabolismo , Simulación del Acoplamiento Molecular , COVID-19 , Tratamiento Farmacológico de COVID-19 , Péptido Hidrolasas/metabolismo , SARS-CoV-2RESUMEN
Alzheimer's disease (AD) has few effective treatment options and continues to be a major global health concern. AD is a neurodegenerative disease that typically affects elderly people. Alkaloids have potential sources for novel drug discovery due to their diverse chemical structures and pharmacological activities. Alkaloids, natural products with heterocyclic nitrogen-containing structures, are considered potential treatments for AD. This review explores the neuroprotective properties of alkaloids in AD, focusing on their ability to regulate pathways such as amyloid-beta aggregation, oxidative stress, synaptic dysfunction, tau hyperphosphorylation, and neuroinflammation. The FDA has approved alkaloids such as acetylcholinesterase inhibitors like galantamine and rivastigmine. This article explores AD's origins, current market medications, and clinical applications of alkaloids in AD therapy. This review explores the development of alkaloid-based drugs for AD, focusing on pharmacokinetics, blood-brain barrier penetration, and potential adverse effects. Future research should focus on the clinical evaluation of promising alkaloids, developing recently discovered alkaloids, and the ongoing search for novel alkaloids for medical treatment. A pharmaceutical option containing an alkaloid may potentially slow down the progression of AD while enhancing its symptoms. This review highlights the potential of alkaloids as valuable drug leads in treating AD, providing a comprehensive understanding of their mechanisms of action and therapeutic implications.
Asunto(s)
Alcaloides , Enfermedad de Alzheimer , Fármacos Neuroprotectores , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Alcaloides/farmacología , Alcaloides/uso terapéutico , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Estrés Oxidativo/efectos de los fármacosRESUMEN
The process of developing of new drugs is greatly hampered by their inadequate physicochemical, pharmacokinetic, and intrinsic characteristics. In this regard, the selected chloro indolinone, (Z)-6-chloro-3-(2-chlorobenzylidene)indolin-2-one (C1), and nitro indolinone, (Z)-6-chloro-3-(2-nitrobenzylidene)indolin-2-one (C2), were subjected to SwissADME and density function theory (DFT) analysis. For compounds C1 and C2, the BOILED-Egg pharmacokinetic model predicted intestinal absorption, blood-brain barrier (BBB) penetration, and p-glycoprotein interaction. According to the physicochemical analysis, C1 has exceptional drug-like characteristics suitable for oral absorption. Despite only being substrates for some of the major CYP 450 isoforms, compounds C1 and C2 were anticipated to have strong plasma protein binding and efficient distribution and block these isoforms. The DFT study using the B3LYP/6-311G(d,p) approach with implicit water effects was performed to assess the structural features, electronic properties, and global reactivity parameters (GRP) of C1 and C2. The DFT results provided further support for other studies, implying that C2 is more water-soluble than C1 and that both compounds can form hydrogen bonds and (weak) dispersion interactions with other molecules, such as solvents and biomolecules. Furthermore, the GRP study suggested that C1 should be more stable and less reactive than C2. A concentration-dependent 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity was shown by both C1 and C2. In brief, this finding has provided a strong foundation to explore further the therapeutic potential of these molecules against a variety of human disorders.
RESUMEN
BACKGROUND: Metastasis driven by epithelial-mesenchymal transition (EMT) remains a significant contributor to the poor prognosis of colorectal cancer (CRC), and requires more effective interventions. GPR81 signaling has been linked to tumor metastasis, while lacks an efficient specific inhibitor. PURPOSE: Our study aimed to investigate the effect and mechanism of Gentisic acid on colorectal cancer (CRC) metastasis. STUDY DESIGN: A lung metastasis mouse model induced by tail vein injection and a subcutaneous graft tumor model were used. Gentisic acid (GA) was administered by an intraperitoneal injection. HCT116 was treated with lactate to establish an in vitro model. METHODS: MC38 cells with mCherry fluorescent protein were injected into tail vein to investigate lung metastasis ability in vivo. GA was administered by intraperitoneal injection for 3 weeks. The therapeutic effect was evaluated by survival rates, histochemical analysis, RT-qPCR and live imaging. The mechanism was explored using small interfering RNA (siRNA), Western blotting, RT-qPCR and immunofluorescence. RESULTS: GA had a therapeutic effect on CRC metastasis and improved survival rates and pathological changes in dose-dependent manner. GA emerged as an GPR81 inhibitor, effectively suppressed EMT and mTOR signaling in CRC induced by lactate both in vivo and in vitro. Mechanistically, GA halted lactate-induce degradation of DEPDC5 through impeding the activation of Chaperone-mediated autophagy (CMA). CONCLUSION: CMA-mediated DEPDC5 degradation is crucial for lactate/GPR81-induced CRC metastasis, and GA may be a promising candidate for metastasis by inhibiting GPR81 signaling.