Papers by Ranjana Bhandari
Frontiers in Endocrinology
Diabetic neuropathy is the most entrenched complication of diabetes. Usually, it affects the dist... more Diabetic neuropathy is the most entrenched complication of diabetes. Usually, it affects the distal foot and toes, which then gradually approaches the lower part of the legs. Diabetic foot ulcer (DFU) could be one of the worst complications of diabetes mellitus. Long-term diabetes leads to hyperglycemia, which is the utmost contributor to neuropathic pain. Hyperglycemia causing an upregulation of voltage-gated sodium channels in the dorsal root ganglion (DRG) was often observed in models of neuropathic pain. DRG opening frequency increases intracellular sodium ion levels, which further causes increased calcium channel opening and stimulates other pathways leading to diabetic peripheral neuropathy (DPN). Currently, pain due to diabetic neuropathy is managed via antidepressants, opioids, gamma-aminobutyric acid (GABA) analogs, and topical agents such as capsaicin. Despite the availability of various treatment strategies, the percentage of patients achieving adequate pain relief remain...
Section S1 Preparation of Naringenin loaded PLGA nanoparticles. Section S2 Single dose Pharmacoki... more Section S1 Preparation of Naringenin loaded PLGA nanoparticles. Section S2 Single dose Pharmacokinetic Studies and brain-uptake study. Table S1 Brain-to-plasma ratios of NGN-Suspension & NGN-PLGA-NPs. Figure S1 Chromatograms of A) blank brain tissue spiked with naringenin B) blank brain tissue C) blank plasma spiked with naringenin D) blank plasma (DOCX 568 kb)
Expert Opinion on Therapeutic Targets, 2021
Introduction: All psychiatric disorders exhibit excitotoxicity, mitochondrial dysfunction, inflam... more Introduction: All psychiatric disorders exhibit excitotoxicity, mitochondrial dysfunction, inflammation, oxidative stress, and neural damage as their common characteristic. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is implicated in the defense mechanism against oxidative stress and has a significant role in psychiatric disorders. Areas covered: We explore the role of Nrf2 pathway and its modulators in psychiatric disorders. The literature was searched utilizing various databases such as Embase, Medline, Web of Science, Pub-Med, and Google Scholar from 2010 to 2020. The search included research articles, clinical reports, systematic reviews, and meta-analyses. Expert opinion: Environmental factors and genetic predisposition can be a trigger for the development of psychiatric disorders. Nrf2 downregulates certain inflammatory pathways and upregulates various antioxidant enzymes to maintain a balance. However, its intricate balance with NF-Kβ (...
Neurotoxicology, 2021
Parkinson's disease (PD), a common neurodegenerative motor disorder characterized by striatal... more Parkinson's disease (PD), a common neurodegenerative motor disorder characterized by striatal dopaminergic neuronal loss and localized neuroinflammation in the midbrain region. Activation of microglia is associated with various inflammatory mediators and Kynurenine pathway (KP) being one of the major regulator of immune response, is involved in the neuroinflammatory and neurotoxic cascade in PD. In the current study, 1-Methyltryptophan (1-MT), an Indolamine-2,3-dioxygenase-1 (IDO-1) inhibitor was tested at different doses (2.5 mg/kg, 5 mg/kg and 10 mg/kg) for its effect on behavioral parameters, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, neurotransmitter levels, biochemical and behavioral alterations in unilateral 6-OHDA (3 µg/µL) murine model of PD. The results showed improved locomotion in open field test and motor coordination in rota-rod, reduced oxidative stress, neuroinflammatory markers (TNF-α, IFN-γ, IL-6), mitochondrial dysfunction and ne...
Medical hypotheses, 2021
Zika virus was declared a national emergency by WHO (World Health Organization) in 2016 when its ... more Zika virus was declared a national emergency by WHO (World Health Organization) in 2016 when its widespread outbreaks and life-threatening complications were reported, especially in newborns and adults. Numerous studies reported that neuroinflammation is one of the significant root-causes behind its major neurological complications like microcephaly and Guillain-Barré syndrome (GBS). In this hypothesis, we propose Transient Receptor Potential Vanilloid 1 channel (TRPV1) as a major culprit in triggering positive inflammatory loop, ultimately leading to sustained neuroinflammation, one of the key clinical findings in Zika induced microcephalic and GBS patients. Opening of TRPV1 channel also leads to calcium influx and oxidative stress that ultimately results in cellular apoptosis (like Schwann cell in GBS and developing fetal nerve cells in microcephaly), ultimately leading to these complications. Currently, no specific cure exists for these complications. Most of the antiviral candid...
Cancer was the leading cause of an estimated 9.6 million deaths in 2018 which accounts for about ... more Cancer was the leading cause of an estimated 9.6 million deaths in 2018 which accounts for about 1 in 6 deaths. Around one-third of deaths from cancer are due to the behavioral and dietary risks which include high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use. For therapy, surgery is preferred in case of solid tumors. Antitumor drugs along with radiation are also the treatment of choice in various instances. However, these cause serious drug toxicity in healthy tissues and are rarely able to target the tumor selectively. Antioxidants play a principal role in the maintenance of the homeostasis of the cell and the immune system. It has been evaluated by various studies that functional foods constituting these antioxidants can play a major role in cancer prophylaxis as they act as scavengers of free radicals that lie at the root of genetic alteration leading to carcinoma. In this chapter, we elaborate the pathogenesis of cancer...
Planta Medica International Open, 2019
The pharmacokinetic and pharmacodynamic (PK-PD) model was developed to describe the relationship ... more The pharmacokinetic and pharmacodynamic (PK-PD) model was developed to describe the relationship between plasma/brain concentration of naringenin and its nanocarriers with behavioral and biochemical alterations in a rat model of autism spectrum disorders (ASD). Behavioral parameters like sensorimotor dysfunction, hyperlocomotion, anxiety-like behavior, social interaction, and repetitive behavior were investigated by rotarod, actophotometer, open-field, reciprocal social interaction, and repetitive self-grooming test respectively. Naringenin was administered in doses (25, 50, and 100 mg/kg) and in the form of its uncoated and glutathione as well as tween 80–coated PLGA nanocarriers (25 mg/kg) thrice daily (8 hourly). Sigmoid Emax model was applied to study the relationship between the concentration of naringenin in plasma/brain and behavioral effects (in terms of sensorimotor dysfunction, locomotor activity, anxiety-like behavior, social interaction ability, repetitive behavior) as w...
Psychopharmacology
AIM The present research work aims at deciphering the involvement of nitric oxide pathway and its... more AIM The present research work aims at deciphering the involvement of nitric oxide pathway and its modulation by ( ±)catechin hydrate in experimental paradigm of autism spectrum disorders (ASD). METHOD An intracerebroventricular infusion of 4 μl of 1 M propanoic acid was given in the anterior region of the lateral ventricle to induce autism-like phenotype in male rats. Oral administration of ( ±)catechin hydrate (25, 50, and 100 mg/kg) was initiated from the 3rd day lasting till the 28th day. L-NAME (50 mg/kg) and L-arginine (800 mg/kg) were also given individually as well as in combination to explore the ability of ( ±)catechin hydrate to act via nitric oxide pathway. Behavior test for sociability, stereotypy, anxiety, depression, and novelty, repetitive, and perseverative behavior was carried out between the 14th and 28th day. On the 29th day, animals were sacrificed, and levels of mitochondrial complexes and oxidative stress parameters were evaluated. We also estimated the levels of neuroinflammatory and apoptotic markers such as TNF-α, IL-6, NF-κB, IFN-γ, HSP-70, and caspase-3. To evaluate the involvement of nitric oxide pathway, the levels of iNOS and homocysteine were estimated. RESULTS Treatment with ( ±)catechin hydrate significantly ameliorated behavioral, biochemical, neurological, and molecular deficits. Hence, ( ±)catechin hydrate has potential to be used as neurotherapeutic agent in ASD targeting nitric oxide pathway-mediated oxidative and nitrosative stress responsible for behavioral, biochemical, and molecular alterations via modulating nitric oxide pathway. CONCLUSION The evaluation of the levels of iNOS and homocysteine conclusively establishes the role of nitric oxide pathway in causing behavioral, biochemical, and molecular deficits and the beneficial effect of ( ±)catechin hydrate in restoring these alterations.
European Journal of Pharmacology
La miiasis se considera una infestación por dermatozoonosis causada por la infestación de larvas ... more La miiasis se considera una infestación por dermatozoonosis causada por la infestación de larvas dipteranas en tejidos u órganos, que ponen sus óvulos en humanos o animales, que durante un cierto período se alimentan de tejidos vivos o muertos del huésped la aparición de miiasis en la cavidad oral puede considerarse algo raro. Este tipo de enfermedad afecta con mayor frecuencia a personas de bajo nivel socioeconómico, inmunocomprometidos, ancianos postrados en cama y con trastornos psiquiátricos. Debido a su gran potencial destructivo, una prevención y tratamiento oportuno e importante adecuado, también hay poco conocimiento del profesional dental para el diagnóstico y tratamiento de dicha patología, por esta razón, el presente estudio informa de un caso clínico de miiasis oral en una persona de edad avanzada postrada en cama con antecedentes de lesión de neoplasia laríngea/glotal maligna, presentando debilidad física y mental y falta inadecuada de
Metabolic Brain Disease
The present study investigates the neuro-protective ability of nordihydroguaretic acid (NDGA) in ... more The present study investigates the neuro-protective ability of nordihydroguaretic acid (NDGA) in the experimental paradigm of autism spectrum disorders (ASD) and further decipher the nitric oxide pathway's role in its proposed action. An intracerebroventricular infusion of 4 μl of 1 M PPA was given in the lateral ventricle's anterior region to induce autism-like phenotype in male rats. Oral administration of NDGA (5, 10 & 15 mg/kg) was initiated from the 3rd day lasting till the 28th day. L-NAME (50 mg/kg) and L-Arginine (800 mg/kg) were also given individually and combined to explore NDGA's ability to act via the nitric oxide pathway. Behavior tests for sociability, stereotypy, anxiety, depression, novelty, repetitive and perseverative behavior were carried out between the 14th and 28th day. On the 29th day, animals were sacrificed, and mitochondrial complexes and oxidative stress parameters were evaluated. We also estimated the levels of neuroinflammatory and apoptotic markers such as TNF-α, IL-6, NF-κB, IFN-γ, HSP-70, and caspase-3. To assess the involvement of the nitric oxide pathway, levels of iNOS and homocysteine were estimated. Treatment with NDGA significantly restored behavioral, biochemical, neurological, and molecular deficits. Hence, NDGA can be used as a neurotherapeutic agent in ASD. Targeting nitric oxide pathway mediated oxidative & nitrosative stress responsible for behavioral, biochemical, and molecular alterations via modulating nitric oxide pathway. The evaluation of iNOS and homocysteine levels conclusively establishes the nitric oxide pathway's role in causing behavioral, biochemical & molecular deficits and NDGA's beneficial effect in restoring these alterations.
Advances in Neurobiology
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with symptoms ranging fro... more Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with symptoms ranging from lack of social interaction and communication deficits to rigid, repetitive, and stereotypic behavior. It has also been associated with comorbidities such as anxiety, aggression, epilepsy, deficit in sensory processing, as well as ADHD (attention deficit hyperactivity disorder). Apart from several behavioral and cognitive complications arising as a result of central nervous system dysfunction, there are various physiological comorbidities such as immune system deregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and gastrointestinal complications which can worsen existing behavioral complications. There are no available treatments for these physiological comorbidities. The prevalence of gastrointestinal complications in ASD ranges from 9% to 70% and it correlates with behaviors consistent with the autistic endophenotype indicating that these are one of the major comorbidities associated with ASD. A strong connection of gut-brain cross talk occurs as a result of gut dysbiosis responsible for excessive production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut flora in ASD patients. This worsens behavioral, neurochemical, and mitochondrial dysfunction occurring in ASD. These physiological comorbidities are responsible for the generation of free radical species that cause immune system dysfunction leading to synthesis of various pro-inflammatory cytokines and chemokines. This in turn causes activation of microglia. Dietary phytochemicals are thought to be safer and useful as an alternative neurotherapeutic moiety. These compounds provide neuroprotection by modulating signaling pathways such as Nrf2, NF-κB, MAPK pathway or Sirtuin-FoxO pathway. There has been recent evidence in scientific literature regarding the modulation of gut-brain cross talk responsible for behavioral, biochemical, and mitochondrial dysfunction as well as cellular and behavioral sensory alterations by dietary phytochemicals such as curcumin, resveratrol, naringenin, and sulforaphane. These dietary phytochemicals can be formulated in novel brain-targeted delivery systems which overcome their limitation of low oral bioavailability and short half-life leading to prolonged action. Till date, not much work has been done on the development of brain-targeted neurotherapeutics for ASD. In this chapter we discuss plausible mechanisms and evidence from our own and other scientific research for the utilization of curcumin, resveratrol, naringenin, and sulforaphane as neurotherapeutics for ASD.
Advances in Neurobiology
Autism spectrum disorder (ASD) is a complex heterogeneous consortium of pervasive development dis... more Autism spectrum disorder (ASD) is a complex heterogeneous consortium of pervasive development disorders (PDD) which ranges from atypical autism, autism, and Asperger syndrome affecting brain in the developmental stage. This debilitating neurodevelopmental disorder results in both core as well as associated symptoms. Core symptoms observed in autistic patients are lack of social interaction, pervasive, stereotyped, and restricted behavior while the associated symptoms include irritability, anxiety, aggression, and several comorbid disorders.ASD is a polygenic disorder and is multifactorial in origin. Copy number variations (CNVs) of several genes that regulate the synaptogenesis and signaling pathways are one of the major factors responsible for the pathogenesis of autism. The complex integration of various CNVs cause mutations in the genes which code for molecules involved in cell adhesion, voltage-gated ion-channels, scaffolding proteins as well as signaling pathways (PTEN and mTOR pathways). These mutated genes are responsible for affecting synaptic transmission by causing plasticity dysfunction responsible, in turn, for the expression of ASD.Epigenetic modifications affecting DNA transcription and various pre-natal and post-natal exposure to a variety of environmental factors are also precipitating factors for the occurrence of ASD. All of these together cause dysregulation of glutamatergic signaling as well as imbalance in excitatory: inhibitory pathways resulting in glial cell activation and release of inflammatory mediators responsible for the aberrant social behavior which is observed in autistic patients.In this chapter we review and provide insight into the intricate integration of various genetic, epigenetic, and environmental factors which play a major role in the pathogenesis of this disorder and the mechanistic approach behind this integration.
Molecular Neurobiology
The severity of COVID-19 infection is surging day by day. With the cases increasing daily, it is ... more The severity of COVID-19 infection is surging day by day. With the cases increasing daily, it is becoming more and more essential to understand the pathogenic mechanisms underlying the severity of the disease. It is now well known that the infection manifests itself primarily as respiratory, but the involvement of the other organ systems has now been documented in many studies. SARS-CoV-2 can invade the nervous system by a multitude of proposed mechanisms that have been discussed in this review. NF-κB and Nrf2 are transcription factors that regulate genes responsible for inflammatory and anti-oxidant response respectively. Specific focus in this review has been given to NF-κB and Nrf2 pathways that are involved in the cytokine storm and oxidative stress that are the hallmarks of COVID-19. As the immune injury is an important mechanism of neuro-invasion and neuroinflammation, there is the possible involvement of these two pathways in the neurological complications. The crosstalk mechanisms of these signaling pathways have also been discussed. Immuno-modulators both synthetic and natural are promising candidates in catering to the pathologies targeted in the aforementioned pathways.
Expert Opinion on Therapeutic Targets
Journal of Analytical Science and Technology
Background: Naringenin is a flavanone having strong antioxidant potential. It is an anti-hyperlip... more Background: Naringenin is a flavanone having strong antioxidant potential. It is an anti-hyperlipidemic, antidepressant, anti-cancer, and neuroprotective agent. However, its major limitation is its low oral bioavailability. Objective: In order to overcome this limitation and to explore its antioxidant potential in autism spectrum disorders, we developed brain targeting PLGA nanocarriers of naringenin. Current study involves development of a sensitive and robust RP-HPLC method for detection and quantification (in vitro and in vivo) of naringenin in nanoparticles. Methods: An isocratic RP-HPLC method was developed using C 18 reversed-phase column (250 × 4.6 mm internal diameter and 5 μm particle size). Flow rate of mobile phase was 1 ml/min and temperature of column was 30°C. Methanol and 0.5% ortho-phosphoric acid in MilliQ water (pH 2) (70:30) was used as mobile phase. The ultraviolet detection wavelength for quantification was at 289 nm. Results: Calibration curve showed linearity within the concentration range from 0.5 to 40 μg/ml (R 2 = 1) for the analytical method and for plasma (6.3-200 ng/ml (R 2 = 0.9975)) and brain tissue samples (31.25-12,500 ng/ ml (R 2 = 1)). Limit of detection (LOD) and limit of quantification (LOQ) were 0.15 μg/ml and 0.44 μg/ml for the analytical method. For bio-analytical method, LOD and LOQ were 9.71 ng/ml and 29.44 ng/ml for plasma and 9.06 ng/ml and 27.44 ng/ml for brain sample. Both the method was precise, accurate, and robust. Bioanalytical method showed good recovery from plasma and brain samples (> 95%). Conclusion: This analytical and bio-analytical method was applied to detect entrapment efficiency, in-vitro release, and pharmacokinetic parameters of naringenin nanoparticles.
Journal of Functional Foods
Abstract The aim of the study was to investigate pharmacotherapeutic potential of Naringenin and ... more Abstract The aim of the study was to investigate pharmacotherapeutic potential of Naringenin and its brain targeted nanoformulations in Autism Spectrum Disorders (ASD). ASD like phenotype was induced by infusion of 1 M Propanoic acid into anterior portion of lateral ventricle in rats. Naringenin (25, 50 and 100 mg/kg), uncoated and coated (glutathione & tween 80) naringenin loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (25 mg/kg) and minocycline (50 mg/kg) were administered orally for 29 days. Neurobehavioural, biochemical, blood-brain barrier permeability, TNF-α, MMP-9, HSP-70 and P-glycoprotein tests were performed. Naringenin and its nanoparticles significantly restored behavioural and biochemical deficits in ASD phenotype. Glutathione and tween 80 coated nanoparticles enhanced brain delivery of NGN by inhibition of P-glycoprotein. Naringenin (100 mg/kg) and its nanocarriers (25 mg/kg) demonstrated pharmacological efficacy comparable to minocycline (50 mg/kg). Naringenin and its coated nanocarriers have strong clinical potential as an adjunct neurotherapeutic moiety in attenuating neuropsychopathology associated with ASD.
Chemical Engineering Journal
Abstract The bio-engineering of nanoparticles for the transportation of various therapeutic agent... more Abstract The bio-engineering of nanoparticles for the transportation of various therapeutic agents specifically to brain has sparked a rapidly growing interest in the field of material chemistry. In this study, L-pGlu-(1-benzyl)–L-His–L-ProNH2 (NP-355) and L-pGlu-(2-propyl)–L-His–L-ProNH2 (NP-647) were synthesized and encapsulated in biodegradable poly-lactide-co-glycolide (PLGA) nanoparticles which were further decorated with mucoadhesive surface coating of chitosan. NP-355 and NP-647 which are analogues of thyrotropin releasing hormone, have been reported to demonstrate potential antiepileptic properties against various animal models of seizures. However, their applicability is limited by their short lives due to rapid metabolism and blood brain barrier. The treatment of disorders associated with central nervous system such as epilepsy has been a major challenge for several decades due to difficulty in delivery of drug molecules and imaging agents to brain. To overcome these issues, development of sustained release delivery system for these neuropeptides is proposed which can be administered directly from nose to brain utilizing olfactory nerve channels. The synthesized nanoparticles were evaluated for their physicochemical properties, sustained release properties, toxicity and antiepileptic potential following intranasal administration. The ability of these nanoparticles to reach the brain was evaluated by utilizing quantum dots as fluorescent probes. Our results proved that the polymeric nanoparticles can be used for successful delivery of neurological drugs to the brain.
Neurochemistry International
International Journal of Neuropsychopharmacology
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Papers by Ranjana Bhandari