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1.
Life Sci ; 286: 120017, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34619169

RESUMO

Tumour cells exhibit numerous defence mechanisms against various therapeutic strategies and help in developing drug resistance. These defence strategies help cancer cells prevent their elimination from an organism and prosper at a specific location. In recent times it's been observed that there is a significant contribution of secreted extracellular vesicles (EVs) from such tumorigenic sites in the development and prognosis of cancer. Amongst the various types of EVs, exosomes behave like biological carriers, play a crucial role in transporting the content between different cells, and had such an underrated defence mode by getting induced due to the hypoxia secreted highly specialised double-membrane structures. These small structure vesicles play a critical part in regulating local microenvironment and intracellular communications, cited by many research studies. Exosomes are a potential carrier of several cargo biomolecules like proteins, lipids, miRNAs, mRNAs etc., facilitating better communication within the microenvironment of cancer cells, enhancing the metastatic rate along with cancer progression. Several studies have extensively researched elucidating exosomes mediated radiation-induced bystander effects: multidrug resistance, epithelial-mesenchymal transition, and help cancer cells escape from the immune system apart from playing a critical role in angiogenesis too. Due to its natural tendency to carry different biomolecules, it can also be used to haul chemical drugs and efficiently deliver the drug molecules to the targeted site of cancer. The current review aims to explore the vivid role of hypoxia-induced exosomes in tumour progression along with its application and challenges in cancer therapeutics.

2.
Life Sci ; 285: 119985, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34592237

RESUMO

Mitochondria play a crucial role in expediting the energy homeostasis under varying environmental conditions. As mitochondria are controllers of both energy production and apoptotic pathways, they are also distinctively involved in controlling the neuronal cell survival and/or death. Numerous factors are responsible for mitochondria to get degraded with aging and huge functional failures in mitochondria are also found to be associated with the commencement of numerous neurodegenerative conditions, including Alzheimer's disease (AD). A large number of existing literatures promote the pivotal role of mitochondrial damage and oxidative impairment in the pathogenesis of AD. Numerous mitochondria associated processes such as mitochondrial biogenesis, fission, fusion, mitophagy, transportation and bioenergetics are crucial for proper functioning of mitochondria but are reported to be defective in AD patients. Though, the knowledge on the precise and in-depth mechanisms of these actions is still in infancy. Based upon the outcome of various significant studies, mitochondria are also being considered as therapeutic targets for AD. Here, we review the current status of mitochondrial defects in AD and also summarize the possible role of these defects in the pathogenesis of AD. The various approaches for developing the mitochondria-targeted therapies are also discussed here in detail. Consequently, it is suggested that improving mitochondrial activity via pharmacological and/or non-pharmacological interventions could postpone the onset and slow the development of AD. Further research and consequences of ongoing clinical trials should extend our understanding and help to validate conclusions regarding the causation of AD.

3.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443598

RESUMO

Apocynin (APO) is a known multi-enzymatic complexed compound, employed as a viable NADPH oxidase (NOX) inhibitor, extensively used in both traditional and modern-day therapeutic strategies to combat neuronal disorders. However, its therapeutic efficacy is limited by lower solubility and lesser bioavailability; thus, a suitable nanocarrier system to overcome such limitations is needed. The present study is designed to fabricate APO-loaded polymeric nanoparticles (APO-NPs) to enhance its therapeutic efficacy and sustainability in the biological system. The optimized APO NPs in the study exhibited 103.6 ± 6.8 nm and -13.7 ± 0.43 mV of particle size and zeta potential, respectively, along with further confirmation by TEM. In addition, the antioxidant (AO) abilities quantified by DPPH and nitric oxide scavenging assays exhibited comparatively higher AO potential of APO-NPs than APO alone. An in-vitro release profile displayed a linear diffusion pattern of zero order kinetics for APO from the NPs, followed by its cytotoxicity evaluation on the PC12 cell line, which revealed minimal toxicity with higher cell viability, even after treatment with a stress inducer (H2O2). The stability of APO-NPs after six months showed minimal AO decline in comparison to APO only, indicating that the designed nano-formulation enhanced therapeutic efficacy for modulating NOX-mediated ROS generation.


Assuntos
Acetofenonas/química , Acetofenonas/farmacologia , Peróxido de Hidrogênio/farmacologia , NADPH Oxidases/metabolismo , Nanopartículas/química , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos
4.
Front Pharmacol ; 12: 629607, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912046

RESUMO

Aims: Scientific biological evaluation of standardized extracts is becoming one of the central needs for the globalization of customary medication in current times. And to validate the presence of active constituents in crude medicinal extracts, analytical techniques like HPLC and HPTLC are the most suitable authentication systems. In the current study we aimed to standardize and evaluate Clerodendrum serratum (L.) Moon (Verbenaceae). For its unique anti-inflammatory and anti-arthritic properties. Evaluation and analysis of the plant, therefore, offers a new platform for the development of the herbal drug and could prove to be a safe and cost effective treatment for arthritis management. Methods: The aqueous extract of C. serratum, a common plant in the Southeastern Asian region, was used for phytochemical investigation and standardization by HPTLC and HPLC. The standardized HPLC method was further validated by using ICH guidelines. The standardized extract was investigated for anti-inflammatory and anti-arthritic activity. Complete Freund's adjuvant (CFA) model was performed to evaluate the activity. Paw diameter, joint diameter, arthritic score, and body weight was accepted as a parameter for the evaluation of biological activity. Results: HPTLC method revealed the presence of ursolic acid with an Rf value of 0.38 and the amount quantified was 0.03% w/w. The presence of the bioactive phytochemical was further analyzed and confirmed by HPLC for which the validation was done successfully in accordance with ICH guidelines. The assay content for ursolic acid was found to be 0.059% with relative standard deviation (RSD) <2.5% for specificity and precision with spike recovery between 95-110%. The anti-arthritic activity of aqueous extract exhibited COX-2 and TNF-α inhibition as observed in various parameters like paw edema, arthritic index, and joint diameter. Plant extract showed reclamation of arthritis in regard to body weight, arthritic score, paw edema, and joint diameter. The extract showed significant results for TNF-α and COX-2(p < 0.0001). The plant extract also exhibited in-vitro anti-inflammatory activity. Conclusion: The current study established the scientific basis of ethnomedicinal use of the plant for anti-inflammatory purposes and the management of arthritis and can also be used for quality control purposes.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33583387

RESUMO

BACKGROUND: Gabapentin (GBP) is an FDA approved drug for the treatment of partial and secondary generalized seizures, apart from being used for diabetic neuropathic pain. GBP displays highly intricate mechanism of action and its inhibitory response in elevated antagonism of NMDA (N-methyl-D-aspartate receptor) receptor and thus, can be repurposed for controlling neuropathic pain. OBJECTIVE: Therefore, in the present study, we have selected hBCATc (human Pyridoxal 5'-phosphate dependent branched-chain aminotransferase cytosolic) gene that is highly expressed in neuropathic stressed conditions. Thereafter, have analyzed the GBP as its competitive inhibitor by homology modeling, molecular docking, also predicting its structural alerts and pharmacokinetic suitability through ADMET. However, GBP was found to be a potential drug in controlling neuropathic pain, still it has certain critical pharmacokinetics limitations therefore, the need for its targeted delivery was required and the same was attained by designing a GBP loaded trandermal patch (TDP). METHODS: A suitable and equally efficacious GBP - TDP was developed by solvent evaporation method using PVP and HPMC in ratio of 2:1 as a polymer base for reservoir type of TDP. Also, PEG 400 was used as a plasticizer and PVA (4%) was taken for backing membrane preparation and then the optimized GBP-TDP was subjected for physical characterization, optimization and ex vivo release kinetics. RESULTS AND CONCLUSION: The results showed desired specifications with uneven and flaky surface appearance giving an avenue for controlled release of the drugs with 92.34 ± 1.43% of drug release in 10 h, further suggesting that GBP-TDP can be used as an effective tool against diabetic neuropathy pain.

6.
Curr Gene Ther ; 21(1): 23-42, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32811395

RESUMO

The technique of gene therapy, ever since its advent nearly fifty years ago, has been utilized by scientists as a potential treatment option for various disorders. This review discusses some of the major neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's Disease (PD), Motor neuron diseases (MND), Spinal Muscular Atrophy (SMA), Huntington's Disease (HD), Multiple Sclerosis (MS), etc. and their underlying genetic mechanisms along with the role that gene therapy can play in combating them. The pathogenesis and the molecular mechanisms specifying the altered gene expression of each of these NDDs have also been discussed in elaboration. The use of gene therapy vectors can prove to be an effective tool in the field of curative modern medicine for the generations to come. Therefore, consistent efforts and progressive research towards its implementation can provide us with powerful treatment options for disease conditions that have so far been considered as incurable.

7.
Curr Gene Ther ; 20(3): 195-206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32787759

RESUMO

In recent times, several approaches for targeted gene therapy (GT) had been studied. However, the emergence of extracellular vesicles (EVs) as a shuttle carrying genetic information between cells has gained a lot of interest in scientific communities. Owing to their higher capabilities in dealing with short sequences of nucleic acid (mRNA, miRNA), proteins, recombinant proteins, exosomes, the most popular form of EVs are viewed as reliable biological therapeutic conveyers. They have natural access through every biological membrane and can be employed for site-specific and efficient drug delivery without eliciting any immune responses hence, qualifying as an ideal delivery vehicle. Also, there are many research studies conducted in the last few decades on using exosome-mediated gene therapy into developing an effective therapy with the concept of a higher degree of precision in gene isolation, purification and delivery mechanism loading, delivery and targeting protocols. This review discusses several facets that contribute towards developing an efficient therapeutic regime for gene therapy, highlighting limitations and drawbacks associated with current GT and suggested therapeutic regimes.

8.
Curr Protein Pept Sci ; 21(10): 965-977, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32538723

RESUMO

Locating remedies for Alzheimer's disease (AD) has been majorly restricted by the inefficiency to establish a definitive detection model for early-stage diagnosis of pathological events. This current lapse in AD diagnosis also limits the therapeutic efficiency of the drugs, which might have been effective if given at the earlier stages of the disease. The indicated situation directs towards the burgeoned need for an effective biomarker technique that will help in early detection of AD and would be imminently useful to facilitate improved diagnosis and stimulate therapeutic trials. Till date, the major biomarkers, specifically associated with AD detection, may help in determining the early-stage AD diagnosis and identifying alterations in the cellular proteome, offering deeper insight into disease etiology. Currently existing multidisciplinary clinical diagnosis of AD is a very tedious, expensive procedure and requires highly trained and skilled professionals who are rarely available outside the specialty clinics. Mutations in amyloid precursor protein (APP) or Presenilin 1 and 2 (PSEN1 and PSEN2) are some biomarkers acting as critical checkpoints for AD diagnosis. However, the presence of some associated biomarkers in cerebrospinal fluid (CSF) such as total-Tau (tTau), phosphorylated- Tau (pTau) 181 and Amyloid-ß (Aß) 1-42 using structural or functional imaging techniques is considered for confirmatory diagnosis of AD. Furthermore, the molecular diagnosis of AD incorporates various sophisticated techniques including immuno-sensing, machine learning, nano conjugation-based detections, etc. In the current review description, we have summarized the various diagnostic approaches and their relevance in mitigating the long-standing urgency of targeted diagnostic tools for detection of AD.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Demência/genética , Testes Diagnósticos de Rotina , Proteômica/métodos , Proteínas tau/genética , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Biomarcadores/metabolismo , Demência/diagnóstico , Demência/metabolismo , Demência/patologia , Regulação da Expressão Gênica , Humanos , Imunoensaio , Neurogranina/genética , Neurogranina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Presenilina-1/genética , Presenilina-1/metabolismo , Presenilina-2/genética , Presenilina-2/metabolismo , Transdução de Sinais , Proteínas tau/metabolismo
9.
ACS Nano ; 14(6): 7398-7411, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32383856

RESUMO

Release of cargo molecules from cell-like nanocarriers can be achieved by chemical perturbations, including changes to pH and redox state and via optical modulation of membrane properties. However, little is known about the kinetics or products of vesicle breakdown due to limitations in real-time imaging at nanometer length scales. Using a library of 12 single-single type photocleavable amphiphilic Janus dendrimers, we developed a self-assembling light-responsive dendrimersome vesicle platform. A photocleavable ortho-nitrobenzyl inserted between the hydrophobic and hydrophilic dendrons of amphiphilic Janus dendrimers allowed for photocleavage and disassembly of their supramolecular assemblies. Distinct methods used to self-assemble amphiphilic Janus dendrimers produced either nanometer size small unilamellar vesicles or micron size giant multilamellar and onion-like dendrimersomes. In situ observation of giant photosensitive dendrimersomes via confocal microscopy elucidated rapid morphological transitions that accompany vesicle breakdown upon 405 nm laser illumination. Giant dendrimersomes displayed light-induced cleavage, disassembling and reassembling into much smaller vesicles at millisecond time scales. Additionally, photocleavable vesicles demonstrated rapid release of molecular and macromolecular cargos. These results guided our design of multilamellar particles to photorelease surface-attached proteins, photoinduce cargo recruitment, and photoconvert vesicle morphology. Real-time characterization of the breakdown and reassembly of lamellar structures provides insights on partial cargo retention and informs the design of versatile, optically regulated carriers for applications in nanoscience and synthetic biology.

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