Neurodegenerative diseases (NDDs) are the primary cause of disabilities in the elderly people. Growing evidence indicates that oxidative stress, mitochondrial dysfunction, neuroinflammation and ...apoptosis are associated with aging and the basis of most neurodegenerative disorders. Quercetin is a flavonoid with significant pharmacological effects and promising therapeutic potential. It is widely distributed among plants and typically found in daily diets mainly in fruits and vegetables. It shows a number of biological properties connected to its antioxidant activity. Neuroprotection by quercetin has been reported in many in vitro as well as in in vivo studies. However, the exact mechanism of action is still mystery and similarly there are a number of hypothesis exploring the mechanism of neuroprotection. Quercetin enhances neuronal longevity and neurogenesis by modulating and inhibiting wide number of pathways. This review assesses the food sources of quercetin, its pharmacokinetic profile, structure activity relationship and its pathophysiological role in various NDDs and it also provides a synopsis of the literature exploring the relationship between quercetin and various downstream signalling pathways modulated by quercetin for neuroprotection for eg. nuclear factor erythroid 2-related factor 2 (Nrf2), Paraoxonase-2 (PON2), c-Jun N-terminal kinase (JNK), Tumour Necrosis Factor alpha (TNF-α), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α), Sirtuins, Mitogen-activated protein kinases (MAPKs) signalling cascades, CREB (Cyclic AMP response element binding protein) and Phosphoinositide 3- kinase(PI3K/Akt). Therefore, the aim of the present review was to elaborate on the cellular and molecular mechanisms of the quercetin involved in the protection against NDDs.
•Traumatic brain injury (TBI) happens due to motor vehicle accidents, the building falls, and injuries.•Neuroinflammation is caused by TBI and can aggravate the progression of tissue ...deterioration.•TBI increase the production of brain-derived neurotrophic factors.•TBI pathogenesis is associated with NOX, a class of enzymes whose sole function is to generate ROS.
TBI has been one of the top causes of death and morbidity worldwide, yet despite enormous efforts to discover neuroprotective therapeutics for this serious disease, no beneficial outcomes in human clinical trials have been reported to date. Traumatic brain injury (TBI) can occur as a result of any type of trauma, from a simple hit to the head to a penetrating injury to the brain. TBI causes delayed secondary damage events as a result of neurochemical, metabolic, and cellular alterations that account for many of the neurological impairments reported following TBI. We focus on the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration in our discussion, which is structured around the kinetics of the immune response to TBI — from immediate triggers through chronic neuroinflammation. Neuroinflammation is caused by traumatic brain injury and can aggravate the progression of tissue deterioration. Immune cells respond acutely to signals from injured cells, develop neuroinflammation, and eventually cause pathology. So neuroinflammation and the immune system could be a target for TBI treatment. However, there are various approaches to the treatment of TBI. This review will provide the literature-based modulation of receptors, ion channels, transporters, and enzymes to attenuate traumatic brain injury.
The ubiquitin-proteasome pathway (UPP) is involved in regulating several biological functions, including cell cycle control, apoptosis, DNA damage response, and apoptosis. It is widely known for its ...role in degrading abnormal protein substrates and maintaining physiological body functions via ubiquitinating enzymes (E1, E2, E3) and the proteasome. Therefore, aberrant expression in these enzymes results in an altered biological process, including transduction signaling for cell death and survival, resulting in cancer. In this review, an overview of profuse enzymes involved as a pro-oncogenic or progressive growth factor in tumors with their downstream signaling pathways has been discussed. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on modulation of ubiquitin-proteasome pathways in oncogenic signaling. Various in vitro, in vivo studies demonstrating the involvement of ubiquitin-proteasome systems in varied types of cancers and the downstream signaling pathways involved are also discussed in the current review. Several inhibitors of E1, E2, E3, deubiquitinase enzymes and proteasome have been applied for treating cancer. Some of these drugs have exhibited successful outcomes in in vivo studies on different cancer types, so clinical trials are going on for these inhibitors. This review mainly focuses on certain ubiquitin-proteasome enzymes involved in developing cancers and certain enzymes that can be targeted to treat cancer.
Cerebral ischemia is the primary cause of morbidity and mortality worldwide due to the perturbations in the blood supply to the brain. The brain triggers a cascade of complex metabolic and cellular ...defects in response to ischemic stress. However, due to the disease heterogeneity and complexity, ischemic injury's metabolic and cellular pathologies remain elusive, and the link between various pathological mechanisms is difficult to determine. Efforts to develop effective treatments for these disorders have yielded limited efficacy, with no proper cure available to date. Recent clinical and experimental research indicates that several neuronal diseases commonly coexist with metabolic dysfunction, which may aggravate neurological symptoms. As a result, it stands to a reason that metabolic hormones could be a potential therapeutic target for major NDDs. Moreover, fasting signals also influence the circadian clock, as AMPK phosphorylates and promotes the degradation of the photo-sensing receptor (cryptochrome). Here, the interplay of AMPK signaling between metabolic regulation and neuronal death and its role for pathogenesis and therapeutics has been studied. We have also highlighted a significant signaling pathway, i.e., the adenosine monophosphate-activated protein kinase (AMPK) involved in the relationship between the metabolism and ischemia, which could be used as a target for future studies therapeutics, and review some of the clinical progress in this area.
Display omitted
•Cerebral ischemia triggers a series of complex metabolic and cellular defects.•Ischemic brain is characterized by abnormal hypothalamic-pituitary-adrenal axis.•AMPK Pathway is involved in the relationship between the metabolism and ischemia.•Metabolic hormones including leptin, ghrelin, adiponectin and insulin may attenuate the cerebral injury by exerting neuroprotective effect.•Metabolic hormones play a protective role in maintaining energy homeostasis via AMPK downstream signalling target.
Statins, especially simvastatin promote bone formation by stimulating the activity of osteoblasts and suppressing osteoclast activity
the BMP-Smad signaling pathway. Statins present the liver ...first-pass metabolism. This study attempts to fabricate and evaluate simvastatin functionalized hydroxyapatite encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles (HSIM-PLGA NPs) administered subcutaneously with sustained release properties for effective management of osteoporosis.
Simvastatin functionalized hydroxyapatite (HSIM) was prepared by stirring and validated by docking studies, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Further, HSIM-loaded PLGA nanoparticles (HSIM-PLGA NPs) were developed
the solvent emulsification method. The nanoparticles were evaluated for zeta potential, particle size, entrapment efficiency, stability studies, and
drug release studies.
binding affinity of nanoparticles for hydroxyapatite was also measured. Bone morphology and its effect on bone mineral density were examined by using a glucocorticoid-induced osteoporosis rat model.
The optimized nanoparticles were found to be amorphous and showed no drug-polymer interaction. The particle size of formulated nanoparticles varied from 196.8 ± 2.27nm to 524.8 ± 5.49 nm and the entrapment efficiency of nanoparticles varied from 41.9 ± 3.44% to 70.8 ± 4.46%, respectively. The nanoparticles showed sustained release behaviour (75% in 24 hr) of the drug followed by non-fickian drug release. The nanoparticles exhibited high binding affinity to bone cell receptors, increasing bone mineral density. A significant difference in calcium and phosphorous levels was observed in disease and treatment rats. Porous bone and significant improvement in porosity were observed in osteoporotic rats and treated rats, respectively (
< 0.05).
Bone-targeting nanoparticles incorporating functionalized simvastatin can target bone. Thus, in order to distribute simvastatin subcutaneously for the treatment of osteoporosis, the developed nanoparticles may act as a promising approach.
Display omitted
•Ischemia impairs the energy balance and the generation of adenosine triphosphate (ATP).•Mitochondrial dysfunctioning is a hallmark of neuronal mortality following ...ischemia/reperfusion injury.•MiRNAs play a significant role in neuronal survival and apoptosis.•Mitochondrion-associated miRNAs are involved in various biological activities, including stress response, metabolism, and death.•Pathobiology of mitochondria dysfunctioning and Neuronal death in cerebral ischemia.
Mitochondria are double-membrane organelles that provide the majority of a cell's energy. Furthermore, mitochondria are involved in various cellular biological activities, including calcium signalling, reactive oxygen species production, apoptosis, cell development, and the cell cycle. Mitochondrial dysfunction is seen in various neurological conditions involving acute and chronic neural injury, including neurodegenerative diseases, hypoxia-induced brain injury, and ischemia. This review made a significant contribution to the explanation of the idea that mitochondria would both be critical targets of ischemia-induced processes, including intracellular calcium elevation and reactive oxygen species and essential sites for determining cell viability loss. As a result, it's not unexpected that attempts to prevent I/R damage have focused on mitochondria. Drugs such as vatiquinone, vitexin, dexprmipexole, baicalin, nobiletin, via promoting mitochondrial activities, can be used in future studies for protecting the brain from ischemia injury. This review summarizes mitochondrial pathways, i.e., Bad, Drp-1, JNK/caspase-3, MAPK-ERK, p53, Wnt/β-Catenin, that contribute to disease progression. We have précised the potential regulatory role of miRNA-mitochondrial dynamics in cerebral ischemic-reperfusion injury and associated molecular mechanisms; also provide insight into the potential therapies for cerebral injury-induced injuries.
Mitochondrial dysfunction is one of the fundamental causes of ischemia reperfusion (I/R) damage. I/R refers to the paradoxical progression of cellular dysfunction and death that occurs when blood ...flow is restored to previously ischemic tissues. I/R causes a significant rise in mitochondrial permeability resulting in the opening of mitochondrial permeability transition pores (MPTP). The MPTP are broad, nonspecific channels present in the inner mitochondrial membrane (IMM), and are known to mediate the deadly permeability alterations that trigger mitochondrial driven cell death. Protection from reperfusion injury occurs when long-term ischemia is accompanied by short-term ischemic episodes or inhibition of MPTP from opening via mitochondrial ATP dependent potassium (mitoKATP) channels. These channels located in the IMM, play an essential role in ischemia preconditioning (PC) and protect against cell death by blocking MPTP opening. This review primarily focuses on the interaction between the MPTP and mitoKATP along with their role in the I/R injury. This article also describes the molecular composition of the MPTP and mitoKATP in order to promote future knowledge and treatment of diverse I/R injuries in various organs.
Display omitted
•COVID-19 associated Acute Respiratory Distress syndrome (CARDS)•Pathophysiology of CARDS.•Prevailing pharmacological treatment.•Emerging Molecular targets for the treatment of CARDS.
...The novel Coronavirus disease 2019 (COVID-19) has caused great distress worldwide. Acute respiratory distress syndrome (ARDS) is well familiar but when it happens as part of COVID‐19 it has discrete features which are unmanageable. Numerous pharmacological treatments have been evaluated in clinical trials to control the clinical effects of CARDS, but there is no assurance of their effectiveness.
A systematic review of the literature of the Medline, Scopus, Bentham, PubMed, and EMBASE (Elsevier) databases was examined to understand the novel therapeutic approaches used in COVID-19-Associated Acute Respiratory Distress Syndrome and their outcomes.
Current therapeutic options may not be enough to manage COVID-19-associated ARDS complications in group of patients and therefore, the current review has discussed the pathophysiological mechanism of COVID-19-associated ARDS, potential pharmacological treatment and the emerging molecular drug targets.
The rationale of this review is to talk about the pathophysiology of CARDS, potential pharmacological treatment and the emerging molecular drug targets. Currently accessible treatment focuses on modulating immune responses, rendering antiviral effects, anti-thrombosis or anti-coagulant effects. It is expected that considerable number of studies conducting globally may help to discover effective therapies to decrease mortality and morbidity occurring due to CARDS. Attention should be also given on molecular drug targets that possibly will help to develop efficient cure for COVID-19-associated ARDS.
Display omitted
•Insulin resistance, results in characteristics of PD, involving motor in-coordination and deteriorated cognition.•Brain insulin resistance occurs in response to the release of ...several pro-inflammatory cytokines in the brain.•Alteration in insulin signalling pathways in dopaminergic neurons contributes to neurodegeneration and PD.•Impairment in autophagy leads to accumulation of toxic protein aggregates that are causative of Parkinson’s disease.
Parkinson’s disease (PD) is a neurodegenerative disorder linked with aging and primarily involves dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc). The deregulation of genes associated with T2D has been demonstrated by proteomic research on Parkinson's symptoms patients. Various common pathways likely to link neurodegenerative mechanisms of PD include abnormal mitochondrial function, inflammation, apoptosis/autophagy and insulin signalling/glucose metabolism in T2DM. Several pathway components including phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt), glycogen synthase kinase-3 beta (GSK-3β) and nuclear factor kappa B (NF-κB) impairment is observed in PD. Numerous novel targets are being pursued in preclinical and clinical trials that target metabolic dysfunction in PD; that elevate insulin signaling pathways in dopaminergic neurons, and show improvement in motor and cognitive measures and produce significant neuroprotective effects in PD patients.
•Cerebral I/R triggers oxidative stress, inflammation, and neurobehavioral deficit.•PCA postconditioning attenuates brain damage against I/R.•PCA pPoCo improves neurobehavioral functions via Nrf2 ...pathway.•Trigonelline negates PCA pPoCo beneficial effects by downregulating Nrf2 pathway.
Ischemia–reperfusion (I/R) injury often follows cardiovascular aberrations that predispose the patient to be neurological and cognitive abnormalities. Pharmacological postconditioning (pPoCo) aims to mitigate I/R origin cerebral infarction and neurobehavioral impairment. Protocatechuic acid (PCA) is a natural polyphenol possessing anti-oxidant and anti-inflammatory activities. This study investigated the effects of PCA pPoCo using a global I/R mice prototype. Mice were injected PCA (50 and 100 mg/kg) immediately after bilateral common carotid artery occlusion (17 min) followed by 24 h reperfusion. Trigonelline (10 mg/kg) was administered separately before I/R surgery to assess the role of the Nrf2 pathway in PCA and I/R treated mice. Results displayed neurological deficits 24 h post-reperfusion, and I/R triggered sensorimotor and memory deficits that were attenuated by PCA. PCA pPoCo increased antioxidants and Nrf2 expression in the brain against I/R injury. In I/R mice, PCA pPoCo attenuated lipid peroxidation, inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6), and myeloperoxidase activity. Histopathology revealed a decrease in total infarct area (TTC staining) and cortical neuron density by I/R surgery that was attenuated by PCA. Trigonelline antagonized beneficial effects of PCA pPoCo and attenuated Nrf2 pathway in I/R mice model. PCA pPoCo dose-dependently improves neurobehavioral functions against global I/R injury via the Nrf2 mechanism.
PDF
