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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(17)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34500749

RESUMO

Imidazo[1,2-b]pyridazine compounds are a new class of promising lead molecules to which we have incorporated polar nitro and amino moieties to increase the scope of their biological activity. Two of these substituted 3-nitro-6-amino-imidazo[1,2-b]pyridazine compounds (5c and 5h) showed potent acetylcholinesterase (AChE) inhibitory activity (IC50 40-50 nM), which we have previously reported. In this study, we wanted to test the biological efficacy of these compounds. Cytotoxicity assays showed that compound 5h mediated greater cell death with over 43% of cells dead at 100 µM and activation of caspase 3-mediated apoptosis. On the other hand, compound 5c mediated a dose-dependent decrease in cell proliferation. Both compounds showed cell cycle arrest in the G0/G1 phase and reduced cellular ATP levels leading to activation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced mitochondrial oxidative stress. It has to be noted that all these effects were observed at doses beyond 10 µM, 200-fold above the IC50 for AChE inhibition. Both compounds also inhibited bacterial lipopolysaccharide-mediated cyclooxygenase-2 and nitric oxide release in primary rat microglial cells. These results suggested that the substituted imidazo (1,2-b) pyridazine compounds, which have potent AChE inhibitory activity, were also capable of antiproliferative, anti-migratory, and anti-inflammatory effects at higher doses.

4.
BMJ Open ; 11(9): e044989, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518243

RESUMO

INTRODUCTION: Mental health disorder, particularly depression, is one of the leading causes of 'disease related disability' in women that both affects the women but has adverse effect on their children. This can have an impact on mothers' capacity of child care which ultimately increases the risk of infection, malnutrition, impaired growth and behavioural problems in children that might extend to adulthood too. Diminished child growth has an irreversible effect both short and long terms, affecting physical growth, brain development, performance in education, working capacity and increased risks to non-communicable diseases. To date, the reviews conducted are only limited to few countries or maternal depression or certain age group of children. Our aim is to provide a global perspective focusing on all early childhood undernutrition (under 5 years) and to see if the association between maternal mental health and child undernutrition has yielded similar or different result. Furthermore, we intend to explore the risk factors associated with copresence of maternal mental health issues and undernutrition in children. METHODS AND ANALYSIS: MEDLINE (PubMed), PsycINFO, CINAHL, Cochrane Library, Global Health Library Relevant reports from the WHO, United Nations of Children Education Fund and organisations working in maternal and child health will also be searched. Database of systematic reviews and database of abstracts of reviews of effects will also be searched for relevant literature. Papers published from 1995 to 2020 in English will be included. Title, abstract or both will be screened independently by reviewers. For data analysis and synthesis, we will present all the outcomes mentioned in the studies and a subgroup analysis for age and sex will be conducted. This study aims to conduct a meta-analysis. ETHICS AND DISSEMINATION: Ethical approval is not required to conduct this review. PROSPERO REGISTRATION NUMBER: CRD42020189315.

5.
ACS Biomater Sci Eng ; 7(9): 4463-4473, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34387486

RESUMO

Bone fractures are in need of rapid fixation methods, but the current strategies are limited to metal pins and screws, which necessitate secondary surgeries upon removal. New techniques are sought to avoid surgical revisions, while maintaining or improving the fixation speed. Herein, a method of bone fixation is proposed with transparent biopolymers anchored in place via light-activated biocomposites based on expanding CaproGlu bioadhesives. The transparent biopolymers serve as a UV light guide for the activation of CaproGlu biocomposites, which results in evolution of molecular nitrogen (from diazirine photolysis), simultaneously expanding the covalently cross-linked matrix. Osseointegration additives of hydroxyapatite or Bioglass 45S5 yield a biocomposite matrix with increased stiffness and pullout strength. The structure-property relationships of UV joules dose, pin diameter, and biocomposite additives are assessed with respect to the apparent viscosity, shear modulus, spatiotemporal pin curing, and lap-shear adhesion. Finally, a model system is proposed based on ex vivo investigation with bone tissue for the exploration and optimization of UV-active transparent biopolymer fixation.


Assuntos
Pinos Ortopédicos , Fraturas Ósseas , Diazometano , Durapatita , Fraturas Ósseas/cirurgia , Humanos
6.
J Pharm Bioallied Sci ; 13(Suppl 1): S398-S401, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34447119

RESUMO

Background: The present study was conducted to assess risk factors and prevalence of potentially malignant disorders (PMDs) among Indian population. Materials and Methods: 1280 Indian population of both genders were enrolled. Habits such as smoking bidi, cigarette, consumption of tobacco such as in the form of zarda, chaini khaini, pan masala, arecanut, and alcohol were recorded. Risk factors and prevalence rate of disorders were recorded. Results: There were 750 (58.6%) males and 530 (41.4%) females. Speckled leukoplakia was seen among 470 (36.7%), oral lichen planus (OLP) in 246 (19.2%), oral submucous fibrosis (OSMF) in 274 (21.4%), erythroplakia in 120 (9.3%), and oral squamous cell carcinoma (OSCC) in 107 (8.3%) participants. Maximum cases of speckled leukoplakia (162) was seen in the age group of 31-40 years, OLP (99) in 41-50 years, OSMF (95) in 31-40 years, erythroplakia (48) in 21-30 years, OSCC (44) in 41-50 years. Conclusion: Risks factors associated with PMDs were found to be tobacco and arecanut. There was higher prevalence of leukoplakia. Age group of 31-40 years had higher cases and most common site was buccal mucosa and vestibule.

7.
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
8.
Pediatr Blood Cancer ; 68(10): e29219, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34291860

RESUMO

BACKGROUND: Hodgkin lymphoma (HL) in childhood is an eminently curable disease. Excellent outcomes can be achieved even in resource-limited settings and increasingly, the focus is on limiting long-term toxicity. Contemporary treatment incorporates a risk-stratified, response-adapted approach using multiagent chemotherapy with or without low-dose radiotherapy (RT). Many developing countries continue to use ABVD (adriamycin, bleomycin, vinblastin, and dacarbazine)-based regimen owing to limited acute toxicity, cost, and ease of delivery. We report outcomes of children with early-stage HL using limited cycles of ABVD-based treatment in the first prospective multicentric collaborative study from India InPOG-HL-15-01. METHODS: Children <18 years with biopsy-proven HL were enrolled. Patients with stages I and IIA with or without bulky disease were classified as having early-stage disease. Patients were planned to receive four cycles of ABVD subject to satisfactory early response assessment (ERA) scheduled after two cycles of chemotherapy. RT was limited to patients with bulky disease or those with suboptimal ERA. RESULTS: Four hundred ten patients were enrolled over 30 months from 27 centers. One hundred thirty-four were classified as having early-stage disease. Fifty-three (40%) of these had bulky disease. One hundred ten (83%) of this cohort achieved complete or very good partial ERA. Fifty-four (40%) received RT. At a median of 52 months since diagnosis, 5-year event-free survival (EFS) and overall survival (OS) is 94% and 95.5%, respectively. Treatment-related mortality and abandonment were <1%. CONCLUSION: Limited cycles of ABVD with RT to selected patients is a very effective option for patients with early-stage disease in resource-limited settings.

9.
Bioorg Med Chem Lett ; 48: 128236, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34242760

RESUMO

The riboflavin biosynthetic pathway is a promising target for the development of novel antimycobacterial drugs given the lack of riboflavin transporter in M. tuberculosis. Herein, a series of riboflavin derivatives was designed, synthesized and screened for their antimycobacterial and antibacterial activity. The compounds 1a, 1b, 2a, 3a and 5a displayed noticeable antitubercular activity against M. tuberculosis with minimum inhibitory concentration (MIC99) in the range of 6.25 to 25 µM. The lead compound 5a had a selectivity index of 10.7 in the present study. The compounds 2a, 2b, 2c, 4c and 4d showed relatively low to moderate antibacterial activity (MIC = 100-200 µM) against gram-positive strains. Notably, the compounds do not show any inhibition against gram-negative strains even at 200 µM concentration. Further, molecular docking and binding experiments with representative flavin mononucleotide (FMN) riboswitch suggested that the riboflavin analogs exhibited antimycobacterial activity plausibly through FMN riboswitch-mediated repression of riboflavin biosynthesis. In addition to FMN riboswitch, flavoproteins involved in the flavin biosynthesis could also be target of riboflavin derivatives. In conclusion, the potency and low toxicity of riboflavin analogs particularly 5a (MIC99 = 6.25) make it a lead compound for the synthesis of new analogs for antimycobacterial therapy.

10.
Life Sci ; 281: 119773, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34192595

RESUMO

Treatment of cancer cells exemplifies a difficult test in the light of challenges associated with the nature of cancer cells and the severe side effects too. After making a large number of trials using both traditional and advanced therapies (immunotherapy and hormone therapy), approaches to design new therapies have reached a saturation level. However, nanotechnology-based approaches exhibit higher efficacy and great potential to bypass many of such therapeutic limitations. Because of their higher target specificity, the use of nanoparticles offers incredible potential in cancer therapeutics. Mitochondria, acting as a factory of energy production in cells, reveal an important role in the death as well as the survival of cells. Because of its significant involvement in the proliferation of cancer cells, it is being regarded as an important target for cancer therapeutics. Numerous studies reveal that nanotechnology-based approaches to directly target the mitochondria may help in improving the survival rate of cancer patients. In the current study, we have detailed the significance of mitochondria in the development of cancer phenotype, as well as indicated it as the potential targets for cancer therapy. Our study further highlights the importance of different nanoparticle-based approaches to target mitochondria of cancer cells and the associated outcomes of different studies. Though, nanotechnology-based approaches to target mitochondria of cancer cells demonstrate a potential and efficient way in cancer therapeutics. Yet, further study is needed to overcome the linked limitations.


Assuntos
Sistemas de Liberação de Medicamentos , Mitocôndrias/efeitos dos fármacos , Nanomedicina , Neoplasias/terapia , Humanos
11.
Eur J Med Chem ; 222: 113574, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34126459

RESUMO

Lysophosphatidic acid (LPA) activates six LPA receptors (LPAR1-6) and regulates various cellular activities such as cell proliferation, cytoprotection, and wound healing. Many studies elucidated the pathological outcomes of LPA are due to the alteration in signaling pathways, which include migration and invasion of cancer cells, fibrosis, atherosclerosis, and inflammation. Current pathophysiological research on LPA and its receptors provides a means that LPA receptors are new therapeutic targets for disorders associated with LPA. Various chemical modulators are developed and are under investigation to treat a wide range of pathological complications. This review summarizes the physiological and pathological roles of LPA signaling, development of various LPA modulators, their structural features, patents, and their clinical outcomes.


Assuntos
Lisofosfolipídeos/farmacologia , Receptores de Ácidos Lisofosfatídicos/agonistas , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Lisofosfolipídeos/química , Lisofosfolipídeos/metabolismo , Estrutura Molecular , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
12.
Indian J Palliat Care ; 27(1): 113-117, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34035628

RESUMO

Background: Because of some psychosocial reasons and misbelieves regarding nasogastric(NG) tube feeding, many patients refuse for NG tube insertion. Aim: Primary aim was to do survey of psychological reasons for refusal of NG tube insertion and feeding in head and neck cancer patients. Secondary aim was to assess impact of psychological counseling of patient who did not accept NG tube feeding. Method: This cross sectional study was conducted on patients referred to palliative medicine department and needed NG tube feeding but refused for the same. We prepared our own questionnaire which includes the most common cause for enteral feeding refusal which we found during our routine OPD since last five years response to those questions were recorded. Then we did psychological counseling of patients and again we assessed patient's acceptability for NG tube feeding by Likert scale and record their response. Results: Most common psychological reasons for patient's refusal were "it will disrupt my body image"(88.33%), "unable to go outside/mix with people"(80%) and "dependency on others for activities"(66.66%). Post psychological counseling out of 60 patients 47 patients were agreed while 13 patients did not agree with NG tube feeding (P value 0.000062<0.5). Conclusion: We conclude that though NG tube feeding is necessary for some head and neck cancer, there are lots of psychosocial problem regarding its acceptance for patients. For that adequate psychological assessment and counseling is necessary for patients' acceptance, compliance and good quality of life.

13.
Eur J Med Chem ; 221: 113527, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34020338

RESUMO

Dengue virus belongs to the class of RNA viruses and subclass of enveloped single-stranded positive-sense RNA virus. It causes dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS), where DHF and DSS are life-threatening. Even though dengue is an age-old disease, it is still a mystery and continues to be a global threat. Numerous attempts have been carried out in the past few decades to eradicate the virus through vaccine and antiviral drugs, but still battle continues. In this review, the possible drug targets for discovery and development of potential antiviral drugs against structural proteins of dengue virus, the current development status of the antiviral drugs against dengue around the world, and challenges that need to be addressed to overcome the shortcomings in the process of drug discovery have been discussed.


Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Dengue/tratamento farmacológico , Desenvolvimento de Medicamentos , Proteínas Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Dengue/metabolismo , Dengue/virologia , Vírus da Dengue/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteínas Estruturais Virais/metabolismo
14.
Sci Adv ; 7(14)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33811080

RESUMO

Surgical repair of lumen defects is associated with periprocedural morbidity and mortality. Endovascular repair with tissue adhesives may reduce host tissue damage, but current bioadhesive designs do not support minimally invasive deployment. Voltage-activated tissue adhesives offer a new strategy for endoluminal repair. To facilitate the clinical translation of voltage-activated adhesives, an electroceutical patch (ePATCH) paired with a minimally invasive catheter with retractable electrodes (CATRE) is challenged against the repair of in vivo and ex vivo lumen defects. The ePATCH/CATRE platform demonstrates the sealing of lumen defects up to 2 millimeters in diameter on wet tissue substrates. Water-tight seals are flexible and resilient, withstanding over 20,000 physiological relevant stress/strain cycles. No disruption to electrical signals was observed when the ePATCH was electrically activated on the beating heart. The ePATCH/CATRE platform has diverse potential applications ranging from endovascular treatment of pseudo-aneurysms/fistulas to bioelectrodes toward electrophysiological mapping.

15.
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.

16.
J Biochem Mol Toxicol ; 35(6): 1-10, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33751730

RESUMO

Tuberculosis, an airborne infectious disease, results in a high morbidity and mortality rate. The continuous emergence of TB resistance strains including MDR (multidrug-resistant tuberculosis), XDR (extensive drug-resistant tuberculosis), and especially TDR (totally drug-resistant tuberculosis) is a major public health threat and has intensified the need to develop new antitubercular agents. A natural product, curcumin, possesses diverse biological activities but suffers due to a lack of water solubility and bioavailability. To overcome these limitations, a series of 17 water-soluble monocarbonyl curcuminoids was synthesized and evaluated for antimycobacterial activity. All compounds exhibited good to moderate anti-TB activity with MIC99 in the range of 3.12-25.0 µM, out of which 7c and 7p were found the most potent compounds with MIC99 in the range of 3.12-6.25 µM. Furthermore, these compounds were observed to be nonhaemolytic, nontoxic, and stable under both physiological as well as reducing conditions. In-vitro metabolic stability data of the representative compound 7p with the human liver microsome revealed that these compounds possess a moderate metabolism with a half-life of 1.2 h and an intrinsic clearance of 1.12 ml/h/mg.


Assuntos
Antituberculosos , Diarileptanoides , Microssomos Hepáticos/metabolismo , Mycobacterium tuberculosis/crescimento & desenvolvimento , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Diarileptanoides/farmacocinética , Diarileptanoides/farmacologia , Humanos , Testes de Sensibilidade Microbiana
17.
J Immunol ; 206(8): 1966-1975, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33722878

RESUMO

Inflammation has long been associated with cancer initiation and progression; however, how inflammation causes immune suppression in the tumor microenvironment and resistance to immunotherapy is not well understood. In this study, we show that both innate proinflammatory cytokine IL-1α and immunotherapy-induced IL-1α make melanoma resistant to immunotherapy. In a mouse melanoma model, we found that tumor size was inversely correlated with response to immunotherapy. Large tumors had higher levels of IL-1α, Th2 cytokines, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and regulatory T cells but lower levels of IL-12, Th1 cytokines, and activated T cells. We found that therapy with adenovirus-encoded CD40L (rAd.CD40L) increased tumor levels of IL-1α and PMN-MDSCs. Blocking the IL-1 signaling pathway significantly decreased rAd.CD40L-induced PMN-MDSCs and their associated PD-L1 expression in the tumor microenvironment and enhanced tumor-specific immunity. Similarly, blocking the IL-1 signaling pathway improved the antimelanoma activity of anti-PD-L1 Ab therapy. Our study suggests that blocking the IL-1α signaling pathway may increase the efficacy of immunotherapies against melanoma.


Assuntos
Resistencia a Medicamentos Antineoplásicos/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Interleucina-1alfa/imunologia , Melanoma Experimental/terapia , Animais , Linhagem Celular Tumoral , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Interleucina-1alfa/metabolismo , Estimativa de Kaplan-Meier , Melanoma Experimental/imunologia , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
18.
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.

19.
Aust J Gen Pract ; 50(1-2): 55-59, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33543162
20.
Cell Death Discov ; 7(1): 13, 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33454721

RESUMO

Oxysterols play vital roles in the human body, ranging from cell cycle regulation and progression to dopaminergic neurogenesis. While naïve human mesenchymal stem cells (hMSCs) have been explored to have neurogenic effect, there is still a grey area to explore their regenerative potential after in vitro differentiation. Hence, in the current study, we have investigated the neurogenic effect of 22(R)-hydroxycholesterol (22-HC) on hMSCs obtained from bone marrow, adipose tissue and dental pulp. Morphological and morphometric analysis revealed physical differentiation of stem cells into neuronal cells. Detailed characterization of differentiated cells affirmed generation of neuronal cells in culture. The percentage of generation of non-DA cells in the culture confirmed selective neurogenic potential of 22-HC. We substantiated the efficacy of these cells in neuro-regeneration by transplanting them into Parkinson's disease Wistar rat model. MSCs from dental pulp had maximal regenerative effect (with 80.20 ± 1.5% in vitro differentiation efficiency) upon transplantation, as shown by various behavioural examinations and immunohistochemical tests. Subsequential analysis revealed that 22-HC yields a higher percentage of functional DA neurons and has differential effect on various tissue-specific primary human MSCs. 22-HC may be used for treating Parkinson's disease in future with stem cells.

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