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1.
Artículo en Inglés | MEDLINE | ID: mdl-38676500

RESUMEN

Synthetic drugs currently prescribed for the treatment of Human African Trypanosomiasis (HAT) are non-specific, toxic, demand extended therapeutic regimes and are of varying efficacy. Along with the challenging demographic and socio-economic hurdles, the everincreasing risk of drug resistance is another major problem to be addressed. Cysteine protease, Heat shock proteins (HSP-90), Trypanothione reductase (TR), Farnesyl diphosphate synthase, Glucose-6-phosphate dehydrogenase, UP-4-galactose epimerase, and Cytidine triphosphate synthetase are potential enzymatic targets for the development of novel inhibitors against HAT which are the main focus of this review. The potential enzymatic targets of Trypanosoma brucei, especially small molecules like cysteine proteases and heat shock proteins are identified as major candidates for the sustenance of the parasite, their proliferation, infection, and spread of the disease. The development of new compounds to combat the disease by thorough ligand modification has been explored in the current review. Extracting these compounds and studying their efficacy, toxicity, and target mechanism extensively, this review has proposed a list of different compounds, including some synthetic and natural compounds along with multi-target inhibitors such as acoziborole, fexinidazole, etc. Potential inhibitors against these enzymatic targets of the T. brucei are important candidates for designing novel therapeutics against HAT. Multi-target inhibitors have also been identified as crucial molecules because of their potential advantage against the development of drug resistance.

2.
Sci Rep ; 14(1): 9483, 2024 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-38664520

RESUMEN

The present study predicts the molecular targets and druglike properties of the phyto-compound piperine (PIP) by in silico studies including molecular docking simulation, druglikeness prediction and ADME analysis for prospective therapeutic benefits against diabetic complications. PIP was encapsulated in biodegradable polymer poly-lactide-co-glycolide (PLGA) to form nanopiperine (NPIP) and their physico-chemical properties were characterized by AFM and DLS. ∼ 30 nm sized NPIP showed 86.68% encapsulation efficiency and - 6 mV zeta potential, demonstrated great interactive stability and binding with CT-DNA displaying upsurge in molar ellipticity during CD spectroscopy. NPIP lowered glucose levels in peripheral circulation by > 65 mg/dL compared to disease model and improved glucose influx in alloxan-induced in vivo and in vitro diabetes models concerted with 3-folds decrease in ROS production, ROS-induced DNA damage and 27.24% decrease in nuclear condensation. The 25% increase in % cell viability and inhibition in chromosome aberration justified the initiation of p53 and PARP DNA repairing protein expression and maintenance of Hsp90. Thus, the experimental study corroborated well with in silico predictions of modulating the p53/PARP-1/Hsp90 axis, with predicted dock score value of - 8.72, - 8.57, - 8.76 kcal/mol respectively, validated docking-based preventive approaches for unravelling the intricacies of molecular signalling and nano-drug efficacy as therapeutics for diabetics.


Asunto(s)
Alcaloides , Benzodioxoles , Proteínas HSP90 de Choque Térmico , Hiperglucemia , Simulación del Acoplamiento Molecular , Piperidinas , Poli(ADP-Ribosa) Polimerasa-1 , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Alcamidas Poliinsaturadas , Proteína p53 Supresora de Tumor , Proteína p53 Supresora de Tumor/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Animales , Piperidinas/farmacología , Piperidinas/química , Benzodioxoles/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Alcaloides/farmacología , Alcaloides/química , Alcaloides/administración & dosificación , Alcamidas Poliinsaturadas/farmacología , Alcamidas Poliinsaturadas/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Aloxano , Ratas , Humanos , Masculino , Especies Reactivas de Oxígeno/metabolismo , Ratones , Nanopartículas/química , Daño del ADN/efectos de los fármacos
3.
J Pharmacopuncture ; 27(1): 1-13, 2024 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-38560336

RESUMEN

Objectives: The Curcuma-derived diferuloylmethane compound CUR, loaded on Poly (lactide-co-glycolic) acid (PLGA) nanoparticles was utilized to combat DN-induced renal apoptosis by selectively targeting and modulating Bcl2. Methods: Upon in silico molecular docking and screening study CUR was selected as the core phytocompound for nanoparticle formulation. PLGA-nano-encapsulated-curcumin (NCUR) were synthesized following standard solvent displacement method. The NCUR were characterized for shape, size and other physico-chemical properties by Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS) and Fourier-Transform Infrared (FTIR) Spectroscopy studies. For in vivo validation of nephro-protective effects, Mus musculus were pre-treated with CUR at a dose of 50 mg/kg b.w. and NCUR at a dose of 25 mg/kg b.w. (dose 1), 12.5 mg/kg b.w (dose 2) followed by alloxan administration (100 mg/kg b.w) and serum glucose levels, histopathology and immunofluorescence study were conducted. Results: The in silico study revealed a strong affinity of CUR towards Bcl2 (dock score -10.94 Kcal/mol). The synthesized NCUR were of even shape, devoid of cracks and holes with mean size of ~80 nm having -7.53 mV zeta potential. Dose 1 efficiently improved serum glucose levels, tissue-specific expression of Bcl2 and reduced glomerular space and glomerular sclerosis in comparison to hyperglycaemic group. Conclusion: This study essentially validates the potential of NCUR to inhibit DN by reducing blood glucose level and mitigating glomerular apoptosis by selectively promoting Bcl2 protein expression in kidney tissue.

4.
Zootaxa ; 5399(3): 281-286, 2024 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-38221155

RESUMEN

A unique ant-mimicking behaviour has been observed in the rove beetle genus Naddia sp. (Coleoptera: Staphylinidae: Staphylininae: Staphylinini: Staphylinina) from the campus of the University of Kalyani, Kalyani, Nadia, West Bengal, India. The individual has been observed to undergo imperfect Batesian mimicry by mimicking ants of the genus Pseudoneoponera (Hymenoptera: Formicidae: Ponerinae: Ponerini).


Asunto(s)
Hormigas , Escarabajos , Humanos , Animales , Distribución Animal , Universidades , India
5.
Artículo en Inglés | MEDLINE | ID: mdl-37962048

RESUMEN

BACKGROUND: Dengue, a mosquito-borne viral disease spread by the dengue virus (DENV), has become one of the most alarming health issues in the global scenario in recent days. The risk of infection by DENV is mostly high in tropical and subtropical areas of the world. The mortality rate of patients affected with DENV is ever-increasing, mainly due to a lack of anti-dengue viral-specific synthetic drug components. INTRODUCTION: Repurposing synthetic drugs has been an effective tool in combating several pathogens, including DENV. However, only the Dengvaxia vaccine has been developed so far to fight against the deadly disease despite the grave situation, mainly because of the limitations of understanding the actual pathogenicity of the disease. METHODS: To address this particular issue and explore the actual disease pathobiology, several potential targets, like three structural proteins and seven non-structural (NS) proteins, along with their inhibitors of synthetic and natural origin, have been screened using docking simulation. RESULTS: Exploration of these targets, along with their inhibitors, has been extensively studied in culmination with molecular docking-based screening to potentiate the treatment. CONCLUSION: These screened inhibitors could possibly be helpful for the designing of new congeneric potential compounds to combat dengue fever and its complications.

6.
J Biomol Struct Dyn ; : 1-18, 2023 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-37587909

RESUMEN

The present study tends to evaluate the possible potential of bio-active Morroniside (MOR), against alloxan (ALX)-induced genotoxicity and hyperglycaemia. In silico prediction revealed the interaction of MOR with Poly (ADP-ribose) polymerase (PARP) protein which corroborated well with experimental in vitro L6 cell line and in vivo mice models. Data revealed the efficacy of MOR in the selective activation of PARP protein and modulating other stress proteins NF-κB, and TNF-α to initiate protective potential against ALX-induced genotoxicity and hyperglycaemia. Further, the strong interaction of MOR with CT-DNA (calf thymus DNA) analyzed through CD spectroscopy, UV-Vis study and ITC data revealed the concerted action of bio-factors involved in inhibiting chromosomal aberration and micronucleus formation associated with DNA damage. Finally, MOR does not play any role in microbial growth inhibition which often occurs due to hyperglycemic dysbiosis. Thus, from the overall findings, we may conclude that MOR could be a potential drug candidate for the therapeutic management of induced-hyperglycaemia and genotoxicity.Communicated by Ramaswamy H. Sarma.

7.
Curr Med Chem ; 2023 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-37340748

RESUMEN

BACKGROUND: Trypanosomiasis, caused by protozoan parasites of the Trypanosoma genus, remains a significant health burden in several regions of the world. Cysteine proteases play a crucial role in the pathogenesis of Trypanosoma parasites and have emerged as potential therapeutic targets for the development of novel antiparasitic drugs. INTRODUCTION: This review article aims to provide a comprehensive overview of the role of cysteine proteases in trypanosomiasis and their potential as therapeutic targets. We discuss the biological significance of cysteine proteases in Trypanosoma parasites and their involvement in essential processes, such as host immune evasion, cell invasion, and nutrient acquisition. METHODS: A comprehensive literature search was conducted to identify relevant studies and research articles on the role of cysteine proteases and their inhibitors in trypanosomiasis. The selected studies were critically analyzed to extract key findings and provide a comprehensive overview of the topic. RESULTS: Cysteine proteases, such as cruzipain, TbCatB and TbCatL, have been identified as promising therapeutic targets due to their essential roles in Trypanosoma pathogenesis. Several small molecule inhibitors and peptidomimetics have been developed to target these proteases and have shown promising activity in preclinical studies. CONCLUSION: Targeting cysteine proteases and their inhibitors holds great potential for the development of novel antiparasitic drugs against trypanosomiasis. The identification of potent and selective cysteine protease inhibitors could significantly contribute to the combat against trypanosomiasis and improve the prospects for the treatment of this neglected tropical disease.

8.
Curr Med Chem ; 2023 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-37211853

RESUMEN

BACKGROUND: This review critically addresses the putative molecular targets of Diabetic Nephropathy (DN) and screens effective phytocompounds that can be therapeutically beneficial, and highlights their mechanistic modalities of action. INTRODUCTION: DN has become one of the most prevalent complications of clinical hyperglycemia, with individual-specific variations in the disease spectrum that leads to fatal consequences. Diverse etiologies involving oxidative and nitrosative stress, activation of polyol pathway, inflammasome formation, Extracellular Matrix (ECM) modifications, fibrosis, and change in dynamics of podocyte functional and mesangial cell proliferation adds up to the clinical complexity of DN. Current synthetic therapeutics lacks target-specific approach, and is associated with the development of inevitable residual toxicity and drug resistance. Phytocompounds provides a vast diversity of novel compounds that can become an alternative therapeutic approach to combat the DN. METHOD: Relevant publications were searched and screened from research databases like GOOGLE SCHOLAR, PUBMED and SCISEARCH. Out of 4895 publications, the most relevant publications were selected and included in this article. RESULT: This study critically reviews over 60 most promising phytochemical and provides with their molecular targets, that can be of pharmacological significance in context to current treatment and concomitant research in DN. CONCLUSION: This review highlights those most promising phytocompounds that have the potential of becoming new safer naturally-sourced therapeutic candidates and demands further attention at clinical level.

9.
J Inorg Biochem ; 243: 112182, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36933342

RESUMEN

The present article describes the systematic study on design and synthesis, physicochemical properties and spectroscopic features, and potential anticancer activities of a family of novel copper(II)-based designer metal complexes [Cu2(acdp)(µ-Cl)(H2O)2] (1), [Cu2(acdp)(µ-NO3)(H2O)2] (2) and [Cu2(acdp)(µ-O2CCF3)(H2O)2] (3) of anthracene-appended polyfunctional organic assembly, H3acdp (H3acdp = N,N'-bis[anthracene-2-ylmethyl]-N,N'-bis[carboxymethyl]-1,3-diaminopropan-2-ol). Synthesis of 1-3 was accomplished under facile experimental conditions, preserving their overall integrity in solution. The incorporation of polycyclic anthracene skeleton within the backbone of organic assembly increases lipophilicity of resulting complexes, thereby dictating the degree of cellular uptake with improved biological activity. Complexes 1-3 were characterized by elemental analysis, molar conductance, FTIR, UV-Vis absorption/fluorescence emission titration spectroscopy, PXRD and TGA/DTA studies, including DFT calculations. The cellular cytotoxicity of 1-3 when studied in HepG2 cancer cell line showed substantial cytotoxic effects, whereas no such cytotoxicity was observed when exposed to normal L6 skeletal muscle cell line. Thereafter, the signaling factors involved in the process of cytotoxicity in HepG2 cancer cells were investigated. Alteration of cytochrome c and Bcl-2 protein expression levels along with modulation of mitochondrial membrane potential (MMP) in the presence of 1-3, strongly suggested the possibility of activating mitochondria-mediated apoptotic pathway involved in halting the cancer cell propagation. However, when a comparative assessment on their bio-efficacies was made, 1 showed higher cytotoxicity, nuclear condensation, DNA binding and damage, ROS generation and lower rate of cell proliferation compared to 2 and 3 in HepG2 cell line, indicating that the anticancer activity of 1 is significantly higher than that of 2 and 3.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Cobre/farmacología , Cobre/química , Citocromos c , Complejos de Coordinación/química , Antineoplásicos/química , Espectrometría de Fluorescencia , Mitocondrias/metabolismo
10.
Curr Top Med Chem ; 23(8): 649-689, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36464871

RESUMEN

BACKGROUND: Diabetes is a chronic metabolic disorder having a global prevalence of nearly doubled over the last 30 years and has become one of the major health concerns worldwide. The number of adults with diabetes increased to 537 million in 2021. INTRODUCTION: The overarching goal of diabetic research and treatment has always been to restore insulin independence and an average blood glucose level. Chemotherapeutic antidiabetic agents can manage diabetes but often show toxicity and drug resistance. Natural phytomedicines may be useful along with stem cell therapy for diabetes management. Even if the whole pancreatic organ and islet transplantation, are becoming benchmark techniques for diabetes management and control, a considerable scarcity of eligible donors of pancreatic tissues and organs severely limits their use. Stem cell treatment provides a bunch of possibilities for treating people with diabetes. METHODS: For this purpose, comprehensive article searching was conducted, with relevant material obtained using search engines such as Scopus, PubMed, MEDLINE, Google, and others, using appropriate keywords. RESULTS: Stem cell therapies, including induced pluripotent stem cells and mesenchymal stem cells, are now becoming a popular area of investigation. Recent advancements in stem cell therapy might provide a feasible treatment option. Furthermore, in recent years, some novel bioactive compounds derived from plants have demonstrated antidiabetic action with higher potency than oral hypoglycaemic medications. Recent regenerative medicine and stem cell treatment advancements might subsequently provide a feasible diabetic management option. On the other hand, medicinal herbs have been considered a better choice for the extensive treatment of diabetes. CONCLUSION: If proper attention is not given to control diabetes by antidiabetic chemotherapeutic agents, natural phytomedicine, and sophisticated treatment like stem cell therapy, then the lifespan of patients will be decreased, and some associated secondary problems will also arise. So, the present review attempts to discuss naturopathy as an alternative resource in combination with stem cell therapy for the progressive management of diabetes and associated disorders.


Asunto(s)
Diabetes Mellitus , Naturopatía , Humanos , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Tratamiento Basado en Trasplante de Células y Tejidos
11.
Curr Neuropharmacol ; 21(4): 808-841, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36173068

RESUMEN

Neurodegeneration is the progressive loss of structure or function of neurons, which may ultimately involve cell death. The most common neurodegenerative disorder in the brain happens with Alzheimer's disease (AD), the most common cause of dementia. It ultimately leads to neuronal death, thereby impairing the normal functionality of the central or peripheral nervous system. The onset and prevalence of AD involve heterogeneous etiology, either in terms of genetic predisposition, neurometabolomic malfunctioning, or lifestyle. The worldwide relevancies are estimated to be over 45 million people. The rapid increase in AD has led to a concomitant increase in the research work directed towards discovering a lucrative cure for AD. The neuropathology of AD comprises the deficiency in the availability of neurotransmitters and important neurotrophic factors in the brain, extracellular betaamyloid plaque depositions, and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Current pharmaceutical interventions utilizing synthetic drugs have manifested resistance and toxicity problems. This has led to the quest for new pharmacotherapeutic candidates naturally prevalent in phytochemicals. This review aims to provide an elaborative description of promising Phyto component entities having activities against various potential AD targets. Therefore, naturopathy may combine with synthetic chemotherapeutics to longer the survival of the patients.


Asunto(s)
Enfermedad de Alzheimer , Naturopatía , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Naturopatía/efectos adversos , Ovillos Neurofibrilares/metabolismo , Encéfalo/metabolismo , Neuronas/metabolismo , Péptidos beta-Amiloides/metabolismo
12.
Curr Top Med Chem ; 23(30): 2877-2972, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38164722

RESUMEN

Receptor tyrosine kinase (RTK) regulates multiple pathways, including Mitogenactivated protein kinases (MAPKs), PI3/AKT, JAK/STAT pathway, etc. which has a significant role in the progression and metastasis of tumor. As RTK activation regulates numerous essential bodily processes, including cell proliferation and division, RTK dysregulation has been identified in many types of cancers. Targeting RTK is a significant challenge in cancer due to the abnormal upregulation and downregulation of RTK receptors subfamily EGFR, FGFR, PDGFR, VEGFR, and HGFR in the progression of cancer, which is governed by multiple RTK receptor signalling pathways and impacts treatment response and disease progression. In this review, an extensive focus has been carried out on the normal and abnormal signalling pathways of EGFR, FGFR, PDGFR, VEGFR, and HGFR and their association with cancer initiation and progression. These are explored as potential therapeutic cancer targets and therefore, the inhibitors were evaluated alone and merged with additional therapies in clinical trials aimed at combating global cancer.


Asunto(s)
Neoplasias , Inhibidores de Proteínas Quinasas , Humanos , Receptores ErbB , Quinasas Janus/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras , Transducción de Señal , Factores de Transcripción STAT/metabolismo
13.
Colloids Surf B Biointerfaces ; 220: 112905, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36283184

RESUMEN

The present study describes the preparation and characterization of poly-lactide-co-glycolide encapsulated nano-curcumin (NCUR) drug, and its potential efficacy against the pesticide, such as cypermethrin-induced DNA damage and genotoxicity. Cypermethrin, the chosen pesticide, contaminates the aquatic environment after being washed off from the agricultural field to nearby water bodies leading to biomagnification-related perturbation of the ecological balance and overall environmental health by elevating adverse effects on non-target organisms producing toxic metabolites through biotransformation. The physico-chemical properties of NCUR were evaluated by employing the AFM, DLS and UV-Vis techniques. Sustainable release of NCUR, their bio-availability and ability to cross the blood-brain-barrier was assessed in the fish model. The in silico molecular docking study to identify the signalling proteins that interact with phyto-core-compound curcumin (CUR) was undertaken to predict the effectiveness of NCUR to combat pesticide-induced toxicity by modulating p53, PARP, HSP 90 and XRCC1 stress proteins, and other associated parameters in in vivo model using tilapia fish and in vitro model using L6 (mammalian skeletal muscle) cell line. Overall results revealed that negatively charged poly-lactide-co-glycolide (PLGA)-encapsulated NCUR (∼46 nm) showed hyperchromic binding with DNA and modulated the signalling cascades involved in stress and DNA repair mechanisms, corroborating well with the in silico prediction that would pave a new pathway in the arena of chemical and biological sciences to serve mankind.


Asunto(s)
Curcumina , Nanopartículas , Plaguicidas , Animales , Curcumina/farmacología , Curcumina/química , Simulación del Acoplamiento Molecular , Nanopartículas/química , Mamíferos
14.
Curr Top Med Chem ; 22(29): 2410-2434, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36281864

RESUMEN

There is a need to explore natural compounds against COVID-19 due to their multitargeted actions against various targets of nCoV. They act on multiple sites rather than single targets against several diseases. Thus, there is a possibility that natural resources can be repurposed to combat COVID-19. However, the biochemical mechanisms of these inhibitors were not known. To reveal the mode of anti-nCoV action, structure-based docking plays a major role. The present study is an attempt to explore various potential targets of SARS-CoV-2 and the structure-based screening of various potential natural inhibitors to combat the novel coronavirus.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Antivirales/farmacología , Antivirales/química , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/farmacología , Simulación de Dinámica Molecular
15.
Comb Chem High Throughput Screen ; 25(14): 2398-2412, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35293289

RESUMEN

The human has two lungs responsible for respiration and drug metabolism. Severe lung infection caused by bacteria, mycobacteria, viruses, fungi, and parasites may lead to lungs injury. Smoking and tobacco consumption may also produce lungs injury. Inflammatory and pain mediators are secreted by alveolar macrophages. The inflammatory mediators, such as cytokines, interleukin (IL)-1, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α, neutrophils, and fibroblasts are accumulated in the alveoli sac, which becomes infected. It may lead to hypoxia followed by severe pulmonary congestion and the death of the patient. There is an urgent need for the treatment of artificial respiration and ventilation. However, the situation may be the worst for patients suffering from lung cancer, pulmonary tuberculosis, and acute pneumonia caused by acute respiratory distress syndrome (ARDS). Re-urgency has been happening in the case of coronavirus disease of 2019 (COVID-19) patients. Therefore, it is needed to protect the lungs with the intake of natural phytomedicines. In the present review, several selected phyto components having the potential role in lung injury therapy have been discussed. Regular intake of natural vegetables and fruits bearing these constituents may save the lungs even in the dangerous attack of SARS-CoV-2 in lung cancer, pulmonary TB, and pneumatic patients.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Lesión Pulmonar , Neumonía , Humanos , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , SARS-CoV-2 , Pulmón/metabolismo , Pulmón/patología , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-1/metabolismo , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico
16.
Anticancer Agents Med Chem ; 22(3): 485-498, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34503422

RESUMEN

Cyclin-Dependent Kinases (CDKs) are the chief regulators in cell proliferation; the kinase activities are largely regulated by their interactions with CDK Inhibitors (CKIs) and Cyclins. The association of different CDKs with CDKIs and Cyclins at the cell-cycle checkpoints of different stages of mitotic cell cycle function act more likely as the molecular switches that regulate different transcriptional events required for progression through the cell cycle. A fine balance in response to extracellular and intracellular signals is highly maintained in the orchestrated function of CDKs along with Cyclins and CDKIs for normal cell proliferation. This fine-tuning in mitotic cell cycle progression sometimes gets lost due to dysregulation of CDKs. The aberrant functioning of the CDKIs is therefore studied for its contributions as a vital hallmark of cancers. It has attracted our focus to maneuver cancer therapy. Hence, several synthetic CDKIs and their crystallography-based drug design have been explained to understand their mode of action with CDKs. Since most of the synthetic drugs function by inhibiting the CDK4/6 kinases by competitively binding to their ATP binding cleft, these synthetic drugs are reported to attack the normal, healthy growing cells adjacent to the cancer cells leading to the decrease in the life span of the cancer patients. The quest for traditional natural medicines may have a great impact on the treatment of cancer. Therefore, in the present studies, a search for naturally sourced CDK inhibitors has been briefly focused. Additionally, some synthetic crystallography-based drug design has been explained to elucidate different avenues to develop better anticancer chemotherapeutics, converting natural scaffolds into inhibitors of the CDK mediated abnormal signal transduction with lesser side effects.


Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Quinasas Ciclina-Dependientes/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Neoplasias/patología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad
17.
Comb Chem High Throughput Screen ; 25(14): 2341-2357, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34533441

RESUMEN

BACKGROUND: Cyclooxygenase (COX) and Lipoxygenase (LOX) enzymes catalyze the production of pain mediators like Prostaglandins (PGs) and Leukotrienes (LTs), respectively from arachidonic acid. INTRODUCTION: The COX and LOX enzyme modulators are responsible for the major PGs and LTs mediated complications like asthma, osteoarthritis, rheumatoid arthritis, cancer, Alzheimer's disease, neuropathy and Cardiovascular Syndromes (CVS). Many synthetic Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) used in the treatment have serious side effects like nausea, vomiting, hyperacidity, gastrointestinal ulcers, CVS, etc. Methods: The natural inhibitors of pain mediators have great acceptance worldwide due to fewer side effects on long-term uses. The present review is an extensive study of the advantages of plantbased vs synthetic inhibitors. RESULTS: These natural COX and LOX inhibitors control inflammatory response without causing side-effect-related complicacy. CONCLUSION: Therefore, the natural COX and LOX inhibitors may be used as alternative medicines for the management of pain and inflammation due to their less toxicity and resistivity.


Asunto(s)
Inhibidores de la Ciclooxigenasa , Antagonistas de Leucotrieno , Inhibidores de la Lipooxigenasa , Humanos , Antiinflamatorios no Esteroideos/efectos adversos , Inhibidores de la Ciclooxigenasa/farmacología , Dolor , Inhibidores de la Lipooxigenasa/farmacología , Antagonistas de Leucotrieno/farmacología , Manejo del Dolor
18.
Curr Med Chem ; 29(2): 212-234, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-33655823

RESUMEN

The molecular mechanisms of mitotic cell cycle progression involve very tightly restricted types of machinery which are highly regulated by a fine balance between the positive and negative accelerators (or regulators). These regulators include several checkpoints that have proteins acting as enzymes and their activating partners. These checkpoints incessantly monitor the external as well as internal environments such as growth signals, favorable conditions for growth, cell size, DNA integrity of the cell and hence function to maintain the highly ordered cell cycle progression by sustaining cell homeostasis and promoting error-free DNA replication and cell cycle division. To progress through the mitotic cell cycle, the cell has to successfully drive past the cell cycle checkpoints. Due to the abnormal behavior of some cell cycle proteins, the cells tend to divide continuously overcoming the tight regulation of cell cycle checkpoints. Such anomalies may lead to unwanted cell division, and this deregulation of cell cycle events is considered as one of the main reasons behind tumor development, and thus, cancer progression. So the understanding of the molecular mechanisms in cancer progression might be insightful for designing several cancer treatment strategies. The deregulation in the checkpoints is caused due to the changes in the tyrosine residues of TPKs via PDGFR, EGFR, FGFR, and VEGFR-mediated signaling pathways. Therefore, the inhibitors of PDGFR, EGFR, FGFR, and VEGFR-mediated signaling pathways could be potential anticancer agents. The resistance and toxicity in the existing synthetic anticancer chemotherapeutics may decrease the life span of a patient. For long, natural products have played an essential alternative source of therapeutic agents due to having least or no side effect and toxicity. The present study is an attempt to promote natural anticancer drug development focusing on the updated structural information of PDGFR, EGFR, FGFR, and VEGFR inhibitors isolated from the plant sources. The data used in this review has been collected from internet resources, viz. GOOGLE Web, GOOGLE SCHOLAR, and PubMed Central. The citation of each report was first checked, after which the articles were selected as an authentic reference for the present study. Around 200 journal articles were initially selected, of which around 142 were finally chosen for presenting the study on the natural sourced inhibitors of EGFR, PDGFR, FGFR, and VEGFR-mediated signaling pathways which may help to enhance the potential cancer treatment.


Asunto(s)
Antineoplásicos , Productos Biológicos/farmacología , Inhibidores de Proteínas Quinasas , Transducción de Señal , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Receptores ErbB/antagonistas & inhibidores , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
19.
Curr Drug Targets ; 23(5): 513-539, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34915833

RESUMEN

BACKGROUND: With the advent of food additives centuries ago, the human race has found ways to improve and maintain the safety of utility, augment the taste, color, texture, nutritional value, and appearance of the food. Since the 19th century, when the science behind food spoilage was discerned, food additives in food preservation have been increasing worldwide and at a fast pace to get along with modern lifestyles. Although food additives are thought to be used to benefit the food market, some of them are found to be associated with several health issues at an alarming rate. Studies are still going on regarding the mechanisms by which food additives affect public health. Therefore, an attempt has been made to find out the remedies by exploiting technologies that may convey new properties of food additives that can only enhance the quality of food without having any systemic side effects. Thus, this review focuses on the applications of nanotechnology in the production of nano-food additives and evaluates its success regarding reduction in the health-related hazards by collaterally maintaining the food nutrient value. METHODOLOGY: A thorough literature study was performed using scientific databases, like PubMed, Science Direct, Scopus, and Web of Science, for determining the design of the study, and each article was checked for citation and referred to formulate the present review article. CONCLUSION: Nanotechnology can be applied in the food processing industry to control the unregulated use of food additives and intervene in the biochemical mechanisms at a cellular and physiological level for ensuring the safety of food products. The prospective of nano-additive of chemical origin could be useful to reduce risks of hazards related to human health that are caused majorly due to the invasion of food contaminants (either intentional or non-intentional) into food, though this area still needs scientific validation. Therefore, this review provides comprehensive knowledge on different facets of food contaminants and also serves as a platform of ideas for encountering health risk problems about the design of improved versions of nano-additives.


Asunto(s)
Aditivos Alimentarios , Industria de Procesamiento de Alimentos , Aditivos Alimentarios/efectos adversos , Humanos , Nanotecnología , Estudios Prospectivos
20.
Inorg Chem ; 60(23): 17608-17626, 2021 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-34761905

RESUMEN

The three discrete [Zn6] complexes [Na3Zn6(cpdp)3(µ-Bz)3(CH3OH)6][ZnCl4][ZnCl3(H2O)]·3CH3OH·1.5H2O (1), [Na3Zn6(cpdp)3(µ-p-OBz)3(CH3OH)6]·2H2O (2), and [Na3Zn6(cpdp)3(µ-p-NO2Bz)3(CH3OH)6]Cl3·2H2O (3), supported by the carboxylate-based multidentate ligand N,N'-bis[2-carboxybenzomethyl]-N,N'-bis[2-pyridylmethyl]-1,3-diaminopropan-2-ol (H3cpdp), have been successfully synthesized and fully characterized (Bz = benzoate; p-OBz = dianion of p-hydroxybenzoic acid; p-NO2Bz = p-nitrobenzoate). The complexes have been characterized by elemental analysis, FTIR, UV-vis, NMR spectroscopy, PXRD, and thermal analysis, including single-crystal X-ray crystallography of 1 and 2. The molecular architectures of 1-3 are built from the self-assembly of their corresponding [Zn2] units, which are interconnected to the central [Na3(CH3OH)6]3+ core by six endogenous benzoate groups, with each linking one Zn(II) and one Na(I) ion in a µ2:η1:η1-syn-anti bidentate fashion. The composition of the (cpdp3-)3/(Zn2+)6 complexes in 1-3 has been observed to be 1:2, on the basis of the UV-vis titration and NMR spectroscopic results, which is further supported by X-ray crystallography. Systematic biological studies performed with a mice model suggested possible antidiabetic efficacy as well as anticancer activities of the complexes. When complexes 1-3 were administered intraperitoneally in mice, 1 showed a lowering in the blood glucose level, overall maintenance of the pancreatic tissue mass, restriction of DNA damage in pancreatic cells, and retention of lipid droplet (LD) frequency, whereas 2 and 3 showed hepatic tissue mass consistency by inhibiting the DNA damage in hepatic cells, prior to the exposure to a potent diabetic inducer, alloxan (ALX). Similar trends of results were observed in inhibiting the generation of reactive oxygen species (ROS) in the pancreatic and hepatic cells, as examined by spectrofluorometric methods. Thus, 1 seems to be a better compound for overall diabetic management and control, whereas 2 and 3 seem to be promising compounds for designing chemopreventive drugs against hepatic carcinoma.


Asunto(s)
Antineoplásicos/farmacología , Ácidos Carboxílicos/farmacología , Complejos de Coordinación/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Zinc/farmacología , Aloxano , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Ácidos Carboxílicos/química , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Daño del ADN , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Ensayos de Selección de Medicamentos Antitumorales , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Ratones , Estructura Molecular , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Zinc/química
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