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We substantiated the effect of AM251, a cannabinoid receptor-1 (CB1R) antagonist, against ß-receptor stimulated myocardial infarction (MI) in streptozotocin (STZ)-induced diabetic mice via modulation- of the NF-kB signaling pathway. The different parameters were assessed such as ECG, hemodynamic, cardiac injury markers, oxidative stress parameters, pro-inflammatory cytokines, and histopathological abnormalities. Mice were fed a high-fat diet for 30 days. On day 7, to trigger diabetes, 150 mg/kg of STZ was injected intraperitoneally. On day 10, to determine whether diabetes developed, the blood level of glucose was monitored. From days 11-30, diabetic mice were injected with either CB1R agonist oleamide or antagonist AM251 or both, with concurrent administrations of ß-agonist isoproterenol on days 28 and 29 to induce MI. In comparison to normal, the myocardial infarcted diabetic animals demonstrated alterations in ECG, hemodynamic profiles, and diminished enzymatic activities (CK-MB, LDH, SOD, GSH, catalase), with concurrently increased MDA levels, which indicated increased oxidative stress in the myocardium. Additionally, higher concentrations of cytokines that signal myocardial inflammation, such as IL-1ß, IL-6, and TNF-α, were also noted. Furthermore, elevated myonecrosis, edema, and cell infiltration which is confirmed by histopathology of heart tissue. Treatment with AM251 significantly ameliorated myocardial redox status, reduced cytokines, and repaired enzymatic activities leading to subsequent recovery in cardiac function. AM251 effectively suppressed myonecrosis and edema. This study also showed that AM251 protects against myocardial inflammation and oxidative stress triggered by isoproterenol by blocking NF-kB signalling pathway. However, upregulation of the CB1R through oleamide showed significant cardiac toxicity. Conversely, the concurrent administration of oleamide and AM251 failed to induce cardiotoxic effects in isoproterenol-induced MI in diabetic mice which indicates downregulation of the CB1R might be associated with the cardioprotective effect.
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The 5-HT3 receptor and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme play a crucial role in the pathogenesis of depression as their activation reduces serotonin contents in the brain. Since molecular docking analysis revealed lycopene as a potent 5-HT3 receptor antagonist and IDO1 inhibitor, we hypothesized that lycopene might disrupt the interplay between the 5-HT3 receptor and IDO1 to mitigate depression. In mice, the depression-like phenotypes were induced by inoculating Bacillus Calmette-Guerin (BCG). Lycopene (intraperitoneal; i.p.) was administered alone or in combination with 5-HT3 receptor antagonist ondansetron (i.p.) or IDO1 inhibitor minocycline (i.p.), and the behavioral screening was performed by the sucrose preference test, open field test, tail suspension test, and splash test which are based on the different principles. Further, the brains were subjected to the biochemical analysis of serotonin and its precursor tryptophan by the HPLC. The results showed depression-like behavior in BCG-inoculated mice, which was reversed by lycopene administration. Moreover, prior treatment with ondansetron or minocycline potentiated the antidepressant action of lycopene. Minocycline pretreatment also enhanced the antidepressant effect of ondansetron indicating the regulation of IDO1 activity by 5-HT3 receptor-triggered signaling. Biochemical analysis of brain samples revealed a drastic reduction in the levels of tryptophan and serotonin in depressed animals, which were restored following treatment with lycopene and its combination with ondansetron or minocycline. Taken together, the data from molecular docking, behavioral experiments, and biochemical estimation suggest that lycopene might block the 5-HT3 receptor and consequently inhibit the activity of IDO1 to ameliorate BCG-induced depression in mice.
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Encéfalo , Depresión , Indolamina-Pirrol 2,3,-Dioxigenasa , Licopeno , Receptores de Serotonina 5-HT3 , Animales , Licopeno/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Ratones , Depresión/tratamiento farmacológico , Depresión/metabolismo , Masculino , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Fenotipo , Simulación del Acoplamiento Molecular , Serotonina/metabolismo , Vacuna BCG/farmacología , Ondansetrón/farmacología , Conducta Animal/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Antidepresivos/farmacología , Minociclina/farmacologíaRESUMEN
Acetylcholine (ACh) is ubiquitously present in the nervous system and has been involved in the regulation of various brain functions. By modulating synaptic transmission and promoting synaptic plasticity, particularly in the hippocampus and cortex, ACh plays a pivotal role in the regulation of learning and memory. These procognitive actions of ACh are mediated by the neuronal muscarinic and nicotinic cholinergic receptors. The impairment of cholinergic transmission leads to cognitive decline associated with aging and dementia. Therefore, the cholinergic system has been of prime focus when concerned with Alzheimer's disease (AD), the most common cause of dementia. In AD, the extensive destruction of cholinergic neurons occurs by amyloid-ß plaques and tau protein-rich neurofibrillary tangles. Amyloid-ß also blocks cholinergic receptors and obstructs neuronal signaling. This makes the central cholinergic system an important target for the development of drugs for AD. In fact, centrally acting cholinesterase inhibitors like donepezil and rivastigmine are approved for the treatment of AD, although the outcome is not satisfactory. Therefore, identification of specific subtypes of cholinergic receptors involved in the pathogenesis of AD is essential to develop future drugs. Also, the identification of endogenous rescue mechanisms to the cholinergic system can pave the way for new drug development. In this article, we discussed the neuroanatomy of the central cholinergic system. Further, various subtypes of muscarinic and nicotinic receptors involved in the cognition and pathophysiology of AD are described in detail. The article also reviewed primary neurotransmitters that regulate cognitive processes by modulating basal forebrain cholinergic projection neurons.
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Enfermedad de Alzheimer , Receptores Colinérgicos , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Receptores Colinérgicos/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1ß. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-ß/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.
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Cannabinoides , Infarto del Miocardio , Receptor Cannabinoide CB1 , Humanos , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Cannabinoides/metabolismo , Endocannabinoides/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Receptores de Cannabinoides/metabolismo , Dronabinol/farmacologíaRESUMEN
Neuropeptide S (NPS) is a 20 amino acids-containing neuroactive molecule discovered by the reverse pharmacology method. NPS is detected in specific brain regions like the brainstem, amygdala, and hypothalamus, while its receptor (NPSR) is ubiquitously expressed in the central nervous system (CNS). Besides CNS, NPS and NPSR are also expressed in the peripheral nervous system. NPSR is a G-protein coupled receptor that primarily uses Gq and Gs signaling pathways to mediate the actions of NPS. In animal models of Parkinsonism and Alzheimer's disease, NPS exerts neuroprotective effects. NPS suppresses oxidative stress, anxiety, food intake, and pain, and promotes arousal. NPSR facilitates reward, reinforcement, and addiction-related behaviors. Genetic variation and single nucleotide polymorphism in NPSR are associated with depression, schizophrenia, rheumatoid arthritis, and asthma. NPS interacts with several neurotransmitters including glutamate, noradrenaline, serotonin, corticotropin-releasing factor, and gamma-aminobutyric acid. It also modulates the immune system via augmenting pro-inflammatory cytokines and plays an important role in the pathogenesis of rheumatoid arthritis and asthma. In the present review, we discussed the distribution profile of NPS and NPSR, signaling pathways, and their importance in the pathophysiology of various neurological disorders. We have also proposed the areas where further investigations on the NPS system are warranted.
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Artritis Reumatoide , Asma , Enfermedades del Sistema Nervioso , Neuropéptidos , Animales , Ansiedad , Asma/metabolismo , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/genética , Neuropéptidos/metabolismo , Receptores de Neuropéptido/metabolismo , HumanosRESUMEN
Neuroinflammation is a complex biological process that typically originates as a protective response in the brain. This inflammatory process is triggered by the release of pro-inflammatory substances like cytokines, prostaglandins, and reactive oxygen and nitrogen species from stimulated endothelial and glial cells, including those with pro-inflammatory functions, in the outer regions. While neuronal inflammation is common in various central nervous system disorders, the specific inflammatory pathways linked with different immune-mediated cell types and the various factors influencing the blood-brain barrier significantly contribute to disease-specific characteristics. The endocannabinoid system consists of cannabinoid receptors, endogenous cannabinoids, and enzymes responsible for synthesizing and metabolizing endocannabinoids. The primary cannabinoid receptor is CB1, predominantly found in specific brain regions such as the brainstem, cerebellum, hippocampus, and cortex. The presence of CB2 receptors in certain brain components, like cultured cerebellar granular cells, Purkinje fibers, and microglia, as well as in the areas like the cerebral cortex, hippocampus, and cerebellum is also evidenced by immunoblotting assays, radioligand binding, and autoradiography studies. Both CB1 and CB2 cannabinoid receptors exhibit noteworthy physiological responses and possess diverse neuromodulatory capabilities. This review primarily aims to outline the distribution of CB1 and CB2 receptors across different brain regions and explore their potential roles in regulating neuroinflammatory processes.
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Although the development of resistance by microorganisms to antimicrobial drugs has been recognized as a global public health concern, the contribution of various non-antibiotic antimicrobial agents to the development of antimicrobial resistance (AMR) remains largely neglected. The present review discusses various chemical substances and factors other than typical antibiotics, such as preservatives, disinfectants, biocides, heavy metals and improper chemical sterilization that contribute to the development of AMR. Furthermore, it encompasses the mechanisms like co-resistance and co-selection, horizontal gene transfer, changes in the composition and permeability of cell membrane, efflux pumps, transposons, biofilm formation and enzymatic degradation of antimicrobial chemicals which underlie the development of resistance to various non-antibiotic antimicrobial agents. In addition, the review addresses the resistance-associated changes that develops in microorganisms due to these agents, which ultimately contribute to the development of resistance to antibiotics. In order to prevent the indiscriminate use of chemical substances and create novel therapeutic agents to halt resistance development, a more holistic scientific approach might provide diversified views on crucial factors contributing to the persistence and spread of AMR. The review illustrates the common and less explored mechanisms contributing directly or indirectly to the development of AMR by non-antimicrobial agents that are commonly used.
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Antiinfecciosos , Desinfectantes , Antibacterianos/farmacología , Bacterias , Antiinfecciosos/farmacología , Desinfectantes/farmacología , Farmacorresistencia Bacteriana/genéticaRESUMEN
Most cancer patients rarely benefit from monodrug therapy because of both cancer complexity and tumor environment. One of the main reasons for this failure is insufficient accumulation of the optimal dose at the tumorous site. Our investigation implies a promising strategy to engineer prodrug nanoparticles (NPs) of bortezomib (BTZ) and selenium (Se) using sialic acid (SAL) as a ligand to improve breast cancer therapy. BTZ was conjugated with SAL and HPMA (N-2-hydroxypropyl methacrylamide) to prepare a prodrug conjugate; BTZ-SAL-HPMA (BSAL-HP) and then fabricated into prodrug NPs with Se (Se_BSAL-HP prodrug NPs). The self-assembly of prodrug NPs functionalized with Se showed size (204.13 ± 0.02 nm) and zeta potential (-31.0 ± 0.11 mV) in dynamic light scattering (DLS) experiments and spherical shape in TEM and SEM analysis. Good stability and low pH drug release profile were characterized by Se_BSAL-HP prodrug NPs. The tumor-selective boronate-ester-based prodrug NPs of BTZ in combination with Se endowed a synergistic effect against cancer cells. Compared to prodrug conjugate, Se_BSAL-HP prodrug NPs exhibited higher cell cytotoxicity and enhanced cellular internalization with significant changes in mitochondria membrane potential (MMP). Elevated apoptosis was observed in the (G2/M) phase of the cell cycle for Se_BSAL-HP prodrug NPs (2.7-fold) higher than BTZ. In vivo studies were performed on Sprague-Dawley rats and resulted in positive trends. The increased therapeutic activity of Se_BSAL-HP prodrug NPs inhibited primary tumor growth and showed 43.05 fold decrease in tumor volume than the control in 4T1 tumor bearing mice. The surprising and remarkable outcomes for Se_BSAL-HP prodrug NPs were probably due to the ROS triggering effect of boronate ester and selenium given together.
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Neoplasias , Profármacos , Selenio , Ratas , Animales , Ratones , Ratas Sprague-Dawley , Profármacos/uso terapéutico , Ácido N-Acetilneuramínico , Bortezomib/farmacología , Bortezomib/uso terapéutico , ÉsteresRESUMEN
Natural polysaccharides have been widely exploited in drug delivery and tissue engineering research. They exhibit excellent biocompatibility and fewer adverse effects; however, it is challenging to assess their bioactivities to that of manufactured synthetics because of their intrinsic physicochemical characteristics. Studies showed that the carboxymethylation of polysaccharides considerably increases the aqueous solubility and bioactivities of inherent polysaccharides and offers structural diversity, but it also has some limitations that can be resolved by derivatization or the grafting of carboxymethylated gums. The swelling ratio, flocculation capacity, viscosity, partition coefficient, metal absorption properties, and thermosensitivity of natural polysaccharides have been improved as a result of these changes. In order to create better and functionally enhanced polysaccharides, researchers have modified the structures and properties of carboxymethylated gums. This review summarizes the various ways of modifying carboxymethylated gums, explores the impact that molecular modifications have on their physicochemical characteristics and bioactivities, and sheds light on various applications for the derivatives of carboxymethylated polysaccharides.
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In the present study, the larvicidal efficacy of the juices of the weeds Lantana camara Linn (L. camara) and Ocimum gratissimum Linn (O. gratissimum) was evaluated against the larvae of the malaria vectors Aedes aegypti, Anopheles subpictus and Culex quinquefasciatus. The freshly prepared juices of leaves were prepared by grinding them and diluting them at concentrations of 25, 50, 75, and 100 ppm. Twenty larvae of each species were introduced in different sterile Petri dishes in aqueous media under a controlled environment for the assessment of biological activity. The larvicidal activity of both juices was evaluated at 6, 12 and 24 h post-exposure time points by observing the movement of each larva. The obtained data were subjected to probit analysis to determine the lethal concentrations that kill 50% and 90% (LC50 and LC90) of the treated larvae. The results revealed a noticeable larvicidal activity following 24 h of exposure. The juice of L. camara leaves exhibited an LC50 range of 47.47-52.06 ppm and an LC90 range of 104.33-106.70 ppm. Moreover, for the juice of O. gratissimum leaves, the LC50 range was 42.94-44.91 ppm and the LC90 range was 105.11-108.66 ppm. Taken together, the results indicate that the juices of L. camara and O. gratissimum leaves may be useful as effective, economical and eco-friendly larvicidal agents. However, additional studies are needed to explore the bioactive components of the weeds that exhibit larvicidal activity along with their mode of action.
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Aedes , Culex , Insecticidas , Lantana , Ocimum , Animales , Mosquitos Vectores , Extractos Vegetales/farmacología , Insecticidas/farmacología , Larva , Hojas de la PlantaRESUMEN
Although paclitaxel is a front-line chemotherapeutic agent for the treatment of metastatic breast cancer, its intravenous therapy produces deleterious adverse effects. In an attempt to address the issue, the present study aimed to develop a paclitaxel loaded thermosensitive/thermoresponsive hydrogel (PTXNp-TGel) for loco-regional administration to breast tumors to provide dose-dense chemotherapy. Poloxamer and xanthan gum were used to prepare TGel by the cold method. In vitro and in vivo performance of PTXNp-TGel was compared with TGel, pure drug loaded TGel (PTX-TGel) and marketed formulation, Taxol®. The formulated PTXNp-TGel showed acceptable gelation temperature and time (37 °C and 57 s), lower viscosity at room temperature and higher viscosity at body temperature to support sol-gel transition with increasing temperature, and sustained drug release up to 21 days. Additionally, PTXNp-TGel showed negligible hemolytic toxicity as compared to PTX-TGel and Taxol®. Intratumoral administration of PTXNp-TGel produced significantly higher antitumor activity as indicated by lowest relative tumor volume (1.50) and relative antitumor proliferation rate (27.71 %) in comparison with PTX-TGel, Taxol®, and PTXNp (p < 0.05). Finally, insignificant body weight loss during the experimental period, lack of hematotoxicity, nephrotoxicity, and hepatotoxicity imply improved therapeutic performance of the locally administrated dose-dense therapy of PTXNp-TGel as compared to Taxol®.
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Antineoplásicos Fitogénicos , Neoplasias de la Mama , Humanos , Femenino , Paclitaxel/farmacología , Hidrogeles , Poloxámero , Portadores de Fármacos , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL (N-2-hydroxypropylmethacrylamide-polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA-HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ-HP-PCL PMCs, while CFA-HP-PCL PMCs significantly (p < 0.001) scavenged the ROS generated in 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ-HP-PCL PMCs (p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ-HP-PCL PMCs than BTZ+CFA-HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs (p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.
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Antineoplásicos , Inhibidores de Proteasoma , Femenino , Ratones , Animales , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Micelas , Especies Reactivas de Oxígeno , Distribución Tisular , Quimioterapia Combinada , Leprostáticos/uso terapéutico , Bortezomib/farmacología , Bortezomib/química , Polímeros/química , Línea Celular Tumoral , Antineoplásicos/químicaRESUMEN
OBJECTIVES: In the era of globalization, a sedentary lifestyle is highly linked with obesity and neurobehavioral complications such as depression. While depression is associated with dopamine dysfunction in the ventral tegmental area (VTA), ghrelin enhances the dopaminergic activity in the VTA. Therefore, the present study aimed to assess the effect of ghrelin on depression-like behaviour in rats subjected to a high-fat diet (HFD) and disturbed diurnal rhythm (DDR) for 45 days. METHODS: The neurobehavioral deficits resulting from HFD and DDR in rats, and the behaviour modulation by intra-VTA administration of ghrelin, alone or in combination with ghrelin receptor antagonist were confirmed by evaluation of behavioural parameters in the elevated plus-maze, forced swim test, open field test, and rotarod assessment. Further, the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6, oxidative stress marker malondialdehyde (MDA), and antioxidants enzymes like superoxide dismutase (SOD), reduced glutathione (GSH), and catalase (CAT) were measured. RESULTS: The levels of TNF-α, IL-1ß, IL-6, and MDA were increased in the brain of HFD and DDR exposed rats, while that of SOD, GSH, and CAT were reduced. Intra-VTA ghrelin administration from day 41-45 to the HFD and DDR exposed rats improved cognitive behaviour and physical activity confirming the antidepressant effect. Moreover, ghrelin restored the levels of SOD, GSH and CAT efficiently, and reduced that of MDA, TNF-α, IL-1ß and IL-6, which signifies its protective effect. CONCLUSION: Overall, this study confirmed the ameliorative effect of ghrelin in HFD- and DDR-induced depression-like behaviour.
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Phloretin is a flavonoid of the dihydrogen chalcone class, present abundantly in apples and strawberries. The beneficial effects of phloretin are mainly associated with its potent antioxidant properties. Phloretin modulates several signaling pathways and molecular mechanisms to exhibit therapeutic benefits against various diseases including cancers, diabetes, liver injury, kidney injury, encephalomyelitis, ulcerative colitis, asthma, arthritis, and cognitive impairment. It ameliorates the complications associated with diabetes such as cardiomyopathy, hypertension, depression, memory impairment, delayed wound healing, and peripheral neuropathy. It is effective against various microbial infections including Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Escherichia coli, Candida albicans and methicillin-resistant Staphylococcus aureus. Considering the therapeutic benefits, it generated interest for the pharmaceutical development. However, poor oral bioavailability is the major drawback. Therefore, efforts have been undertaken to enhance its bioavailability by modifying physicochemical properties and molecular structure, and developing nanoformulations. In the present review, we discussed the pharmacological actions, underlying mechanisms and molecular targets of phloretin. Moreover, the review provides insights into physicochemical and pharmacokinetic characteristics, and approaches to promote the pharmaceutical development of phloretin for its therapeutic applications in the future. Although convincing experimental data are reported, human studies are not available. In order to ascertain its safety, further preclinical studies are needed to encourage its pharmaceutical and clinical development.
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Diabetes Mellitus , Staphylococcus aureus Resistente a Meticilina , Diabetes Mellitus/tratamiento farmacológico , Desarrollo de Medicamentos , Flavonoides , Humanos , Staphylococcus aureus Resistente a Meticilina/metabolismo , Floretina/química , Floretina/farmacología , Floretina/uso terapéuticoRESUMEN
Earlier studies reported that long-term treatment with thymoquinone (TQ) at a high dose (20 mg/kg) exerts a cardioprotective effect against isoproterenol (ISO)-triggered myocardial infarction (MI) in rats. In the present study, we tested the hypothesis that TQ, as a potent molecule, can exhibit cardioprotective effects at the lower dose for a short-term regimen. The rats were administered with TQ (5 mg/kg, intraperitoneal) at the 4 h interval for 2 days. ISO (100 mg/kg/day, subcutaneous) was given for 2 days to produce MI. ISO challenge results in deformation in ECG wave front, elevated left ventricular (LV) end-diastolic pressure, and reduced LVdP/dtmax and LVdP/dtmin. The levels of the cardiac biomarker in serum, such as creatine kinase MB, alanine aminotransferase, and aspartate aminotransferase, were increased. In the myocardium, a rise in malonaldehyde and decreased superoxide dismutase, glutathione, and catalase contents were observed. Furthermore, increased levels of tumor necrotic factor-α, interleukin-6, and interleukin-1ß were observed in the myocardium. TQ pretreatment significantly normalized alterations in hemodynamic parameters, strengthened the antioxidant defense system, and decreased the contents of pro-inflammatory cytokines and hepatic enzymes as compared to the ISO group. Based on the results, TQ appears to be cardioprotective at low doses, and effective even administered for a shorter duration.
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Corazón , Infarto del Miocardio , Animales , Benzoquinonas , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Inflamación/metabolismo , Isoproterenol/metabolismo , Isoproterenol/farmacología , Isoproterenol/uso terapéutico , Peroxidación de Lípido , Miocardio/metabolismo , Estrés Oxidativo , Ratas , Ratas WistarRESUMEN
Ghrelin is a peptide released by the endocrine cells of the stomach and the neurons in the arcuate nucleus of the hypothalamus. It modulates both peripheral and central functions. Although ghrelin has emerged as a potent stimulator of growth hormone release and as an orexigenic neuropeptide, the wealth of literature suggests its involvement in the pathophysiology of affective disorders including depression. Ghrelin exhibits a dual role through the advancement and reduction of depressive behavior with nervousness in the experimental animals. It modulates depression-related signals by forming neuronal networks with various neuropeptides and classical neurotransmitter systems. The present review emphasizes the integration and signaling of ghrelin with other neuromodulatory systems concerning depressive disorders. The role of ghrelin in the regulation of neurosynaptic transmission and depressive illnesses implies that the ghrelin system modulation can yield promising antidepressive therapies.
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Diverse properties of natural gums have made them quite useful for various pharmaceutical applications. However, they suffer from various problems, including unregulated hydration rates, microbial degradation, and decline in viscosity during warehousing. Among various chemical procedures for modification of gums, carboxymethylation has been widely studied due to its simplicity and efficiency. Despite the availability of numerous research articles on natural gums and their uses, a comprehensive review on carboxymethylation of natural gums and their applications in the pharmaceutical and other biomedical fields is not published until now. This review outlines the classification of gums and their derivatization methods. Further, we have discussed various techniques of carboxymethylation, process of determination of degree of substitution, and functionalization pattern of substituted gums. Detailed information about the application of carboxymethyl gums as drug delivery carriers has been described. The article also gives a brief account on tissue engineering and cell delivery potential of carboxymethylated gums.
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Portadores de Fármacos , Excipientes , Fenómenos Químicos , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Excipientes/química , Gomas de Plantas/química , ViscosidadRESUMEN
Molecular docking revealed curcumin as a potent CB2 cannabinoid receptor (CB2R) agonist. Since CB2R is involved in cardioprotective functions, we explored its role in ameliorative actions of curcumin against myocardial damage triggered by isoproterenol in diabetic animals. Mice were kept on a high-fat diet (HFD) throughout the experiment (30 days). Following 7 days of HFD feeding, streptozotocin was administered (150 mg/kg, intraperitoneal) to induce diabetes. From day 11 to 30, diabetic mice received either curcumin (100 or 200 mg/kg/day, oral), CB2R antagonist AM630 (1 mg/kg/day, intraperitoneal) or both, with concurrent isoproterenol (150 mg/kg, subcutaneous) administration on day 28 and 29. Diabetic mice with myocardial infarction showed an altered hemodynamic pattern and lipid profile, reduced injury markers, antioxidants with increased lipid peroxidation in the myocardium, and elevated glucose and liver enzymes in the blood. Moreover, an increased pro-inflammatory markers, histological severity, myonecrosis, and edema were observed. Curcumin compensated for hemodynamic fluctuations, restored biochemical markers, preserved antioxidant capacity, decreased cytokines levels, and restored cardiac functionality. However, the AM630 pre-treatment attenuated the effects of curcumin. The data suggest the involvement of CB2R in the actions of curcumin such as in the prevention of myocardial stress and in the improvement of the normal status of the myocardial membrane associated with diabetes.
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Targeted delivery of therapeutics forestalls the dreadful delocalized effects, drug toxicities and needless immunosuppression. Cancer cells are bounteous with sialic acid and the differential expression of glycosyl transferase, glycosidase and monosaccharide transporter compared to healthy tissues. The current study entails the development and characterisation of sialic acid (SA)-labelled chitosan nanoparticles encapsulating gemcitabine (GEM). Chitosan (CS) was conjugated with SA using coupling reaction and characterised spectroscopically. Furthermore, different concentrations of chitosan and tripolyphosphate (TPP) were optimised to fabricate surface modified chitosan nanoparticles. SA conjugated chitosan nanoparticles encapsulating GEM (SA-CS_GEM NPs) of 232 ± 9.69 nm with narrow distribution (PDI < 0.5) and zeta potential of - 19 ± 0.97 mV was fabricated. GEM was successfully loaded in the SA-CS NPs, depicting prolonged and biphasic drug release pattern more elated at low pH. Pronounced cellular uptake (FITC tagged) and cytotoxicity (IC50 487.4 nM) was observed in SA-CS_GEM NPs against A549 cells. IC50 for SA-CS_GEM NPs plunged with an increase in the time points from 24 to 72 h. Concentration-dependent haemolytic study confirmed significant haemocompatibility of SA-CS_GEM NPs. Pharmacokinetic study was performed on Sprague-Dawley rats and the kinetic parameters were calculated using PKSolver 2.0. Results demonstrated a consequential refinement of 2.98 times in modified SA-CS_GEM NPs with a significant increase in retention time, bioavailability and elimination half-life, and decrease in elimination rate constant and volume of distribution in comparison to CS_GEM NPs. Therefore, SA-CS shell core nanoparticles could be a beneficial approach to target and treat NSCLC (non-small cell lung cancer) and direct for research possibilities to target the other tumour cells.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Quitosano , Neoplasias Pulmonares , Nanopartículas , Animales , Portadores de Fármacos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Ácido N-Acetilneuramínico/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
Diabetes associated oxidative stress and impaired cholinergic neurotransmission causes cognitive deficits. Although phloridzin shows antioxidant- and insulin sensitizing-activities, its ameliorative potential in diabetes-induced memory dysfunction remains unexplored. In the present study, type 2 diabetes (T2D) was induced by streptozotocin (35 mg/kg, intraperitoneal) in rats on ad libitum high-fat diet. Diabetic animals were treated orally with phloridzin (10 and 20 mg/kg) for four weeks. Memory functions were evaluated by passive avoidance test (PAT) and novel object recognition (NOR) test. Brains of rats were subjected to biochemical analysis of glutathione (GSH), brain-derived neurotrophic factor (BDNF), malonaldehyde (MDA) and acetylcholinesterase (AChE). Role of cholinergic system in the effects of phloridzin was evaluated by scopolamine pre-treatment in behavioral studies. While diabetic rats showed a significant decrease in step through latency in PAT, and exploration time and discrimination index in NOR test; a substantial increase in all parameters was observed following phloridzin treatment. Phloridzin reversed abnormal levels of GSH, BDNF, MDA and AChE in the brain of diabetic animals. Moreover, in silico molecular docking study revealed that phloridzin acts as a potent agonist at M1 receptor as compared to acetylcholine. Viewed collectively, reversal of T2D-induced memory impairment by phloridzin might be attributed to upregulation of neurotrophic factors, reduced oxidative stress and increased cholinergic signaling in the brain. Therefore, phloridzin may be a promising molecule in the management of cognitive impairment comorbid with T2D.