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1.
Neuroscience ; 551: 69-78, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38754721

RESUMO

The functioning of the brain and its impact on behavior, emotions, and cognition can be affected by both neurological and psychiatric disorders that impose a significant burden on global health. Phytochemicals are helpful in the treatment of several neurological and psychological disorders, including anxiety, depression, Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD), because they have symptomatic benefits with few adverse reactions. Changes in gut microbiota have been associated with many neurological and psychiatric conditions. This review focuses on the potential efficacy of phytochemicals such as flavonoids, terpenoids, and polyphenols in regulating gut flora and providing symptomatic relief for a range of neurological and psychological conditions. Evidence-based research has shown the medicinal potentials of these phytochemicals, but additional study is required to determine whether altering gut microbiota might slow the advancement of neurological and psychological problems.

2.
J Environ Manage ; 354: 120326, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38387349

RESUMO

Chemical-based peticides are having negative impacts on both the healths of human beings and plants as well. The World Health Organisation (WHO), reported that each year, >25 million individuals in poor nations are having acute pesticide poisoning cases along with 20,000 fatal injuries at global level. Normally, only ∼0.1% of the pesticide reaches to the intended targets, and rest amount is expected to come into the food chain/environment for a longer period of time. Therefore, it is crucial to reduce the amounts of pesticides present in the soil. Physical or chemical treatments are either expensive or incapable to do so. Hence, pesticide detoxification can be achieved through bioremediation/biotechnologies, including nano-based methodologies, integrated approaches etc. These are relatively affordable, efficient and environmentally sound methods. Therefore, alternate strategies like as advanced biotechnological tools like as CRISPR Cas system, RNAi and genetic engineering for development of insects and pest resistant plants which are directly involved in the development of disease- and pest-resistant plants and indirectly reduce the use of pesticides. Omics tools and multi omics approaches like metagenomics, genomics, transcriptomics, proteomics, and metabolomics for the efficient functional gene mining and their validation for bioremediation of pesticides also discussed from the literatures. Overall, the review focuses on the most recent advancements in bioremediation methods to lessen the effects of pesticides along with the role of microorganisms in pesticides elimination. Further, pesticide detection is also a big challenge which can be done by using HPLC, GC, SERS, and LSPR ELISA etc. which have also been described in this review.


Assuntos
Praguicidas , Humanos , Praguicidas/química , Plantas , Metabolômica
3.
Environ Res ; 236(Pt 2): 116795, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37541412

RESUMO

Uranium is considered as one of the most perilous radioactive contaminants in the aqueous environment. It has shown detrimental effects on both flora and fauna and because of its toxicities on human beings, therefore its exclusion from the aqueous environment is very essential. The utilization of metal-organic frameworks (MOFs) as an adsorbent for the removal of uranium from the aqueous environment could be a good approach. MOFs possess unique properties like high surface area, high porosity, adjustable pore size, etc. This makes them promising adsorbents for the removal of uranium from contaminated water. In this paper, sources of uranium in the water environment, human health disorders, and application of the different types of MOFs as well as the mechanisms of uranium removal have been discussed meticulously.


Assuntos
Estruturas Metalorgânicas , Urânio , Poluentes Químicos da Água , Humanos , Água , Adsorção , Poluentes Químicos da Água/análise
5.
J Biomol Struct Dyn ; : 1-13, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37318006

RESUMO

SARS-CoV-2 evolution has continued to generate variants, responsible for new pandemic waves locally and globally. Varying disease presentation and severity has been ascribed to inherent variant characteristics and vaccine immunity. This study analyzed genomic data from 305 whole genome sequences from SARS-CoV-2 patients before and through the third wave in India. Delta variant was reported in patients without comorbidity (97%), while Omicron BA.2 was reported in patients with comorbidity (77%). Tissue adaptation studies brought forth higher propensity of Omicron variants to bronchial tissue than lung, contrary to observation in Delta variants from Delhi. Study of codon usage pattern distinguished the prevalent variants, clustering them separately, Omicron BA.2 isolated in February grouped away from December strains, and all BA.2 after December acquired a new mutation S959P in ORF1b (44.3% of BA.2 in the study) indicating ongoing evolution. Loss of critical spike mutations in Omicron BA.2 and gain of immune evasion mutations including G142D, reported in Delta but absent in BA.1, and S371F instead of S371L in BA.1 could explain very brief period of BA.1 in December 2021, followed by complete replacement by BA.2. Higher propensity of Omicron variants to bronchial tissue, probably ensured increased transmission while Omicron BA.2 became the prevalent variant possibly due to evolutionary trade-off. Virus evolution continues to shape the epidemic and its culmination.Communicated by Ramaswamy H. Sarma.

8.
Indian J Hematol Blood Transfus ; 39(1): 33-39, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36699426

RESUMO

We investigated the safety and efficacy of bendamustine-rituximab (BR) in previously untreated symptomatic and advanced CLL patients, as there is no data available on BR from the Indian subcontinent.This retrospective study included 120 consecutive treatment naïve patients with CLL without del (17p), who were registered at the Department of Medical Oncology, AIIMS between January 2010 and July 2018. Bendamustine was given at a dose of 90 mg/m2 on days 1 and 2, combined with rituximab 375 mg/m2 rituximab on day 1, every 28 days for up to 6 courses. Event-free survival (EFS) was defined as the date of treatment to date of relapse, disease progression, or death due to any cause.The median age was 57 years (range: 30-75 years). As per the clinical Rai stage, 30 (25%) patients were in stage II, 42 (35%) were in stage III and 48 (40%) were in stage IV. ZAP70 was positive (> 20%) in 50%, CD 38 was positive (> 30%) in 33%, and CD49d was positive (> 30%) in 49% of cases. Beta-2 microglobulin (B2M) was elevated (≥ 3.5 mg/L) in 80% of cases. Fifty-five cases (50%, n = 110) were IGHV mutated. The mean number of cycles was 5 (1-6). The overall response rate (ORR) seen with BR was 90% and complete response was 45%. Median progression-free survival was 24 months with a median follow-up period of 29 months. Haemoglobin (< 10 g/dL), elevated B2 M, unmutated IGHV had a statistically significant adverse impact on EFS on univariate analysis but on multivariate analysis, only IGHV mutation status was found to had significance on EFS. The median EFS was 27 months in IGHV mutated versus 18 months in IGHV unmutated-CLL patients (p = 0.001). Grade 3/4 neutropenia, thrombocytopenia, anemia, and infections were observed in 30.6%, 8%, and 12% respectively. The most common non-hematological toxicity was skin rash which was grade 1/2 in 24 (20%) cases and grade 3/4 in 12 (10%) cases. This is the largest study from India to demonstrate the safety and efficacy of BR in symptomatic CLL patients. BR is an effective and safe regimen in the first-line treatment of CLL. Unmutated-CLL patients have inferior EFS than mutated-CLL patients. Skin toxicity was the most common adverse effect seen in our population which was observed in around one-third of cases.

10.
Am J Clin Pathol ; 159(1): 69-80, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36317501

RESUMO

OBJECTIVES: With a substantial number of patients with multiple myeloma (MM) experiencing disease relapse, the quest for more sensitive methods to assess deeper responses indicative of cure continues. METHODS: In this prospective analysis of 170 patients with MM at day 100 after autologous stem cell transplant, we evaluated the predictive value of conventional response, measurable residual disease (MRDTOTAL: the aberrant percentage of plasma cells [PC%] among total bone marrow cells), and neoplastic plasma cell index scores (NPCI: the aberrant PC% of total PCs). RESULTS: Significantly better progression-free survival (PFS) and overall survival (OS) were observed with deepening conventional response. Conventional response-based stratification within the MRD-positive and MRD-negative subgroups showed a significantly higher PFS (hazard ratio [HR], 3.11; P < .005) and OS (HR, 3.08; P = .01) in the conventional response-positive/MRD-positive group compared with the conventional response-negative/MRD-positive group. Using K-adaptive partitioning to find the optimum threshold for MRD, patients achieving less than 0.001% MRDTOTAL had superior PFS (MRDTOTAL 0.001% to <0.1%: HR, 6.66, P < .005; MRDTOTAL ≥0.1%: HR, 11.52, P < .005) and OS (MRDTOTAL 0.001% to <0.1%: HR, 5.3, P < .05; MRDTOTAL ≥0.1%: HR = 9.21, P < .005). The C index and Akaike information criterion metrics demonstrated the superior performance of the NPCI compared with MRDTOTAL in predicting treatment outcome. CONCLUSIONS: Progressive deepening of response, conventional as well as MRD, correlates with superior survival outcomes. The NPCI proved to be a superior determinant of survival and can be explored as a better statistic than MRD.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Plasmócitos , Citometria de Fluxo/métodos , Recidiva Local de Neoplasia , Transplante de Células-Tronco/métodos , Resultado do Tratamento , Neoplasia Residual , Transplante de Células-Tronco Hematopoéticas/métodos
11.
Leukemia ; 37(2): 339-347, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36566271

RESUMO

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.


Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Prognóstico , Fator 88 de Diferenciação Mieloide/genética , Mutação , Fenótipo
12.
Environ Sci Pollut Res Int ; 29(42): 62851-62869, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35831652

RESUMO

"Water" contamination by mercury Hg(II) has become the biggest concern due to its severe toxicities on public health. There are different conventional techniques like ion exchange, reverse osmosis, and filtration that have been used for the elimination of Hg(II) from the aqueous solutions. Although, these techniques have some drawbacks during the remediation of Hg(II) present in water. Adsorption could be a better option for the elimination of Hg(II) from the aqueous solutions. "Conventional adsorbents" like zeolite, clay, and activated carbons are inefficient for this purpose. Recently, nanomaterials have attracted attention for the elimination of Hg(II) from the aqueous solutions due to high porosity, better surface properties, and high efficiency. In this review, a thorough discussion has been carried out on the synthesis and characterization of nanomaterials along with mechanisms involved in the elimination of Hg(II) from aqueous solutions.


Assuntos
Mercúrio , Nanoestruturas , Poluentes Químicos da Água , Purificação da Água , Zeolitas , Adsorção , Argila , Concentração de Íons de Hidrogênio , Mercúrio/análise , Poluentes Químicos da Água/análise , Purificação da Água/métodos
13.
Biochim Biophys Acta Biomembr ; 1864(2): 183824, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34838874

RESUMO

Antimicrobial peptides (AMPs) are naturally occurring promising candidates which can be used as antibiotics against a wide variety of bacteria. The key component for using them as a potent antibiotic is that their mechanism of action is less prone to bacterial resistance. However, the molecular details of their mechanism of action is not yet fully understood. In this study, we try to shed light on the mode of action of AMPs, possible reason behind it, and their interaction with lipid bilayers through experimental as well as molecular dynamics (MD) simulation studies. The focal of our study was Human beta defensin 3 (hBD-3) which is a naturally occurring AMP. We chose three derivatives of hBD-3, namely CHRG01, KSR, and KLR for the detailed analysis presented in this study. These three peptides are evaluated for their antibacterial potency, secondary structure analysis and mechanism of action. The experimental results reveal that these peptides are active against gram positive as well as gram negative bacteria and kill bacteria by forming membrane pores. The MD simulation results correlate well with the antibacterial activity and shed light into the early membrane insertion dynamics. Moreover, the specific amino acids responsible for membrane disruptions are also identified from the MD simulations. Understanding the molecular level interaction of individual amino acids with the lipid bilayer will greatly help in the design of more efficient antimicrobial peptides.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Bicamadas Lipídicas/metabolismo , Simulação de Dinâmica Molecular , beta-Defensinas/farmacologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos C3H
14.
J Phys Chem B ; 125(49): 13444-13459, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34870441

RESUMO

Helices (α-helix) are the most common type of secondary structure motif present in proteins. In this study, we have investigated the structural influence of phosphorylation and O-GlcNAcylation, common intracellular post-translational modifications (PTMs), on the α-helical conformation. The simulation studies were performed on the Baldwin model α-helical peptide sequence (Ac-AKAAAAKAAAAKAA-NH2). The Baldwin sequences were chosen due to the availability of site-specific experimental post-translational data for cross-validation with the simulations. The influence of PTMs was examined across the span of the α-helix, namely, at the N-terminus, position 10 (interior region), and the C-terminus for both serine and threonine residues placed at these positions. Molecular dynamics (MD) simulations revealed that phosphorylation and O-GlcNAcylation at the N-terminus lead to the stabilization of the helical conformation. PTMs in the interior or the C-terminus were found to disrupt helicity, with the disruption being more pronounced for PTMs in the interior region, in accordance with experimental studies. It was found that phosphorylation-derived destabilization was mainly due to the formation of an intraresidue HN-PO32- electrostatic interaction and interactions between the phosphate group and the side chain of adjacent lysine residues (NH3···PO32-). Hydrophobic and steric clashes were the main causes of destabilization in the case of O-GlcNAcylation. The structural disruptions were found to be more pronounced for PTM at the threonine site when compared to the serine site. The salt-bridge-dependent stability of the α-helix was found to be highly position specific, an i → i + 4 interaction stabilizing the helix, with other placements leading to the destabilization of the helix.


Assuntos
Simulação de Dinâmica Molecular , Peptídeos , Fosforilação , Conformação Proteica em alfa-Hélice , Estrutura Secundária de Proteína
15.
Am J Cancer Res ; 11(11): 5659-5679, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34873486

RESUMO

Multiple Myeloma (MM) arises from malignant transformation and deregulated proliferation of clonal plasma cells (PCs) harbouring heterogeneous molecular anomalies. The effect of evolving mutations on clone fitness and their cellular prevalence shapes the progressing myeloma genome and impacts clinical outcomes. Although clonal heterogeneity in MM is well established, which subclonal mutations emerge/persist/perish with progression in MM and which of these can be targeted therapeutically remains an open question. In line with this, we have sequenced pairwise whole exomes of 62 MM patients collected at two time points, i.e., at diagnosis and on progression. Somatic variants were called using a novel ensemble approach where a consensus was deduced from four variant callers (Illumina's Dragen, Strelka2, SomaticSniper and SpeedSeq) and actionable/druggable gene targets were identified. A marked intraclonal heterogeneity was observed. Branching evolution was observed among 72.58% patients, of whom 64.51% had low TMBs (<10) and 61.29% had 2 or more founder clones. The hypermutator patients (with high TMB levels ≥10 to ≤100) showed a significant decrease in their TMBs from diagnosis (median TMB 77.11) to progression (median TMB 31.22). A distinct temporal fall in subclonal driver mutations was identified recurrently across diagnosis to progression e.g., in PABPC1, BRAF, KRAS, CR1, DIS3 and ATM genes in 3 or more patients suggesting such patients could be treated early with target specific drugs like Vemurafenib/Cobimetinib. An analogous rise in driver mutations was observed in KMT2C, FOXD4L1, SP140, NRAS and other genes. A few drivers such as FAT4, IGLL5 and CDKN1A retained consistent distribution patterns at two time points. These findings are clinically relevant and point at consideration of evaluating multi time point subclonal mutational landscapes for designing better risk stratification strategies and tailoring time to time risk adapted combination therapies in future.

16.
Int Immunopharmacol ; 101(Pt A): 108328, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34768236

RESUMO

AIMS: 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. MATERIALS AND METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19/complicações , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/tratamento farmacológico , Animais , COVID-19/etiologia , Síndrome da Liberação de Citocina/virologia , Humanos , Terapia de Alvo Molecular/métodos , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2/patogenicidade
17.
Chemosphere ; 280: 130654, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34162069

RESUMO

Mercury (Hg(II)) is the 16th rarest element present in the earth's crust. Due to rapid industrialization and urban expansions, the mercury concentration has been elevated in the environment. Hg(II) contamination in the aqueous environment has become a great challenge for human beings. The main source of Hg(II) in the aqueous phase is untreated effluent industries (such as the paper industry). Hg(II) is non-biodegradable in nature and even its trace amount in an aqueous environment can pose chronic threats among the humans (damage to the central nervous system, respiratory system, and cardiovascular system, mutation of DNA), animals, and aquatic creatures. Therefore, the removal of mercury from aqueous solutions is an urgent need of the modern era. The conventional techniques such as ion exchange, precipitation, membrane filtrations are costly and also generate byproducts in the environment. Bioremediation is a sustainable, environmentally sound, and cost-effective technique to remove Hg(II) from the aqueous solutions. In this process, naturally occurring microorganisms are utilized to remove the Hg(II) from the aqueous solutions. Lentinus edodes, U. lactuca, and Typha domingensis are found to have great potential to remove mercury from water ranged from ~100 mg g-1 to 337 mg g-1.


Assuntos
Mercúrio , Poluentes Químicos da Água , Purificação da Água , Animais , Biodegradação Ambiental , Humanos , Concentração de Íons de Hidrogênio , Mercúrio/análise , Soluções , Água
18.
Sci Rep ; 11(1): 10957, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34040057

RESUMO

Multiple myeloma (MM) is a plasma cell malignancy with diverse clinical phenotypes and molecular heterogeneity not completely understood. Differentially expressed genes (DEGs) and miRNAs (DEMs) in MM may influence disease pathogenesis, clinical presentation / drug sensitivities. But these signatures overlap meagrely plausibly due to complexity of myeloma genome, diversity in primary cells studied, molecular technologies/ analytical tools utilized. This warrants further investigations since DEGs/DEMs can impact clinical outcomes and guide personalized therapy. We have conducted genome-wide meta-analysis of DEGs/DEMs in MM versus Normal Plasma Cells (NPCs) and derived unified putative signatures for MM. 100 DEMs and 1,362 DEGs were found deranged between MM and NPCs. Signatures of 37 DEMs ('Union 37') and 154 DEGs ('Union 154') were deduced that shared 17 DEMs and 22 DEGs with published prognostic signatures, respectively. Two miRs (miR-16-2-3p, 30d-2-3p) correlated with survival outcomes. PPI analysis identified 5 topmost functionally connected hub genes (UBC, ITGA4, HSP90AB1, VCAM1, VCP). Transcription factor regulatory networks were determined for five seed DEGs with ≥ 4 biomarker applications (CDKN1A, CDKN2A, MMP9, IGF1, MKI67) and three topmost up/ down regulated DEMs (miR-23b, 195, let7b/ miR-20a, 155, 92a). Further studies are warranted to establish and translate prognostic potential of these signatures for MM.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs/genética , Mieloma Múltiplo/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Biologia Computacional , Mineração de Dados , Conjuntos de Dados como Assunto , Estudo de Associação Genômica Ampla , Humanos , Plasmócitos/metabolismo , Prognóstico , Mapas de Interação de Proteínas
19.
ACS Chem Neurosci ; 12(9): 1621-1631, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33877805

RESUMO

Taupathies involve the deposition of abnormal tau protein into neurofibrillary tangles (NFTs) in the human brain. The abnormally hyperphosphorylated tau dissociates from microtubules and forms insoluble aggregates known as paired helical filaments (PHFs), highlighting the importance of post-translational modifications in taupathies. The present study examines the factors responsible for the structural stability of PHFs in native as well as in phosphorylated and O-GlcNAcylated tau. We carried out molecular dynamics simulations on the R3-R4 repeat domains of the human tau protein to gain atomic insights into the key noncovalent interactions responsible for their unique dimeric C-shaped structure. The structural effects upon post-translational modification were found to be prominent for phosphorylation when compared with O-GlcNAcylation. O-GlcNAcylated tau was found to retain the "C conformation" observed in the native tau PHF, whereas upon phosphorylation, we observed a conformational transition to a more opened "H conformation". We found that this conformational transition is brought about by the loss of a key salt bridge between Lys353 and Asp358 due to the phosphorylation at Ser356 that results in the reorganization of the dimeric interface.


Assuntos
Doença de Alzheimer , Proteínas tau , Doença de Alzheimer/metabolismo , Humanos , Emaranhados Neurofibrilares/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas tau/metabolismo
20.
Mini Rev Med Chem ; 21(4): 426-470, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33100202

RESUMO

BACKGROUND: The global incidence of type 2 diabetes mellitus (T2DM) has enthused the development of new antidiabetic targets with low toxicity and long-term stability. In this respect, free fatty acid receptor 1 (FFAR1), which is also recognized as a G protein-coupled receptor 40 (GPR40), is a novel target for the treatment of T2DM. FFAR1/GPR40 has a high level of expression in ß-cells of the pancreas, and the requirement of glucose for stimulating insulin release results in immense stimulation to utilise this target in the medication of T2DM. METHODS: The data used for this review is based on the search of several scienctific databases as well as various patent databases. The main search terms used were free fatty acid receptor 1, FFAR1, FFAR1 agonists, diabetes mellitus, G protein-coupled receptor 40 (GPR40), GPR40 agonists, GPR40 ligands, type 2 diabetes mellitus and T2DM. RESULTS: The present review article gives a brief overview of FFAR1, its role in T2DM, recent developments in small molecule FFAR1 (GPR40) agonists reported till now, compounds of natural/plant origin, recent patents published in the last few years, mechanism of FFAR1 activation by the agonists, and clinical status of the FFAR1/GPR40 agonists. CONCLUSION: The agonists of FFAR1/GRP40 showed considerable potential for the therapeutic control of T2DM. Most of the small molecule FFAR1/GPR40 agonists developed were aryl alkanoic acid derivatives (such as phenylpropionic acids, phenylacetic acids, phenoxyacetic acids, and benzofuran acetic acid derivatives) and thiazolidinediones. Some natural/plant-derived compounds, including fatty acids, sesquiterpenes, phenolic compounds, anthocyanins, isoquinoline, and indole alkaloids, were also reported as potent FFAR1 agonists. The clinical investigations of the FFAR1 agonists demonstrated their probable role in the improvement of glucose control. Though, there are some problems still to be resolved in this field as some FFAR1 agonists terminated in the late phase of clinical studies due to "hepatotoxicity." Currently, PBI-4050 is under clinical investigation by Prometic. Further investigation of pharmacophore scaffolds for FFAR1 full agonists as well as multitargeted modulators and corresponding clinical investigations will be anticipated, which can open up new directions in this area.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Descoberta de Drogas , Humanos , Hipoglicemiantes/uso terapêutico , Receptores Acoplados a Proteínas G/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico
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