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1.
Mol Divers ; 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38253844

RESUMO

Thiazolidinedione has been used successfully by medicinal chemists all over the world in the development of potent antidiabetic derivatives. The few compounds with excellent antidiabetic potency that we have identified in this review could be used as a lead for further research into additional antidiabetic mechanisms. The information provided in this review regarding the design, biological activity, structure-activity relationships, and docking studies may be useful for scientists who wish to further explore this scaffold in order to fully utilize its biological potential and develop antidiabetic agents that would overcome the limitations of currently available medications for the treatment of diabetes. This review outlines the antidiabetic potential of Thiazolidinedione-based derivatives that have been published in the year 2021- till date.

2.
Skeletal Radiol ; 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38949678

RESUMO

There are numerous cases reported of the accessory muscles of the hand and wrist in surgical, cadaveric, and imaging-based studies. Anatomical muscle variations in the flexor compartment of the wrist and forearm can present as a pseudo mass or space-occupying lesion causing external compression on the traversing nerves. Guyon's canal is a compact space with a high potential for nerve entrapment. Common etiologies include ganglion cysts, osteophytes, or soft tissue masses. This rare case illustrates the combined existence of two accessory muscles, an accessory flexor carpi ulnaris, and an accessory abductor digiti minimi, causing ulnar nerve compression in Guyon's canal with imaging correlation. One can raise the suspicion of an anomalous muscle when symptoms concern a patient of a younger age group in the absence of common etiologies. Furthermore, detailed anatomical knowledge of muscles around Guyon's canal is essential in making a diagnosis and aiding treatment.

3.
Biochem Genet ; 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39060643

RESUMO

The immune system plays a bifaceted role in tumour development through modulation of inflammation. MBL binds to damage-associated molecular patterns and induces inflammation through the activation of complement pathway. Dysregulated inflammation plays a major role in breast cancer pathogenesis, thereby suggesting its contribution towards breast cancer risk. Literature asserts single-nucleotide polymorphisms (SNPs) modulating serum MBL levels. Therefore, studying MBL2 SNPs in breast cancer might provide valuable insight in the disease pathogenesis. The present case-control association study aimed to elucidate the association between MBL2 5' near gene SNPs and breast cancer risk. Breast cancer patients were recruited from Government Medical College, G.N.D. Hospital, Amritsar. The age- and gender-matched genetically unrelated healthy individuals, from adjoining regions, with no history of malignancy up to three generations were recruited as controls. The SNPs of MBL2 from the 5' near gene region with putative functional significance were selected based upon the in silico analysis and literature review. The genotypic, allelic and haplotype frequencies for the studied variants were assessed and compared in the study participants by ARMS-PCR and PCR-RFLP. No difference in allelic, genotypic and haplotype frequencies was reported for rs7096206, rs7084554 and rs11003125 in both the participant groups. rs7084554 (CC) was found to confer risk towards hormone receptor-positive breast cancer. An intermediate LD was observed between rs7084554 and rs11003125. The study reports association between MBL2 variant (rs7084554) and hormone receptor-positive breast cancer risk. Further research in this direction might validate the findings.

4.
Biochem Genet ; 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38605207

RESUMO

Esophageal cancer is the eighth most common cancer worldwide and fourth most common in developing countries. Altered glycosylation pattern of cell membrane molecules along with inflammation is a characteristic attribute of oncogenesis. Galectin-4, a tandem repeat galectin, has shown effect on cancer progression/metastasis in digestive system cancers. This role of galectin-4 can be attributed to variations in LGALS4, gene encoding galectin-4. The present case-control study was designed to analyze four intronic SNPs in LGALS4 with susceptibility toward esophageal cancer.Esophageal cancer cases and age- and gender-matched apparently healthy individuals were recruited for the present study. Genotyping of rs8113319, rs4802886, rs4802887, and rs12610990 was carried out using Sanger sequencing and PCR-RFLP. MedCalc software, SNPStats and SHEsis online platform were used for statistical analysis.Genotypic analyses revealed an overall increased heterozygosity of rs12610990, rs4802886, and rs4802887, and AA genotype of rs8113319 in the study participants. Haplotypic analyses also revealed a predominance of AAAT haplotype in the cases. Moreover, combined presence of wild alleles of rs4802886 and rs4802887 could influence protection toward disease, and combined presence of wild alleles of rs12610990 and rs8113319 could influence disease susceptibility. Furthermore, a strong linkage disequilibrium was also observed between the SNPs. Further studies are underway to validate galectin-4 and its genetic variants as blood-based biomarkers in early disease diagnosis, improving treatment outcome.

5.
Eur J Clin Invest ; 53(7): e13987, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36932875

RESUMO

BACKGROUND: Galectins are ß-galactoside-binding proteins. Galectin-4 has shown an effect on cancer progression/metastasis, especially in cancers of the digestive system. This can be attributed to altered glycosylation pattern of cell membrane molecules, which is a characteristic attribute of oncogenesis. The aim of this paper is to systematically review galectin-4 in different cancers and its role in disease progression. METHODS: The study was designed on the basis of Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. PubMed, Scopus, Web of Science, and Science Direct were used to search relevant literature with keywords "galectin-4 AND cancer", "galectin-4", "LGALS4", and "LGALS4 AND cancer". Inclusion criteria for study selection were availability of full-text articles, articles in English language and articles relevant to current topic, that is, galectin-4 and cancer. Exclusion criteria were studies that investigated other disease conditions, interventions unrelated to cancer or galectin-4 and bias outcome. RESULTS: A total of 73 articles were retrieved after removing duplication from databases, out of which 40 studies were included in the review that followed the inclusion criteria, including low to moderate bias. These included 23 studies in digestive system, 5 in reproductive system, 4 in respiratory system, and 2 in brain and urothelial cancers. CONCLUSIONS: A differential expression of galectin-4 was observed in different cancer stages/ and types. Furthermore, galectin-4 was found to modulate disease progression. A meta-analysis and comprehensive mechanistic studies, pertaining to different aspects of galectin-4 biology, could give statistically driven correlations, elucidating multifaceted role of galectin-4 in cancer.


Assuntos
Galectina 4 , Neoplasias , Humanos , Galectinas/metabolismo , Viés , Progressão da Doença
6.
J Org Chem ; 88(14): 10287-10297, 2023 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-37390469

RESUMO

Microwave irradiation of O-phenyloximes triggers N-O homolysis and 1,5-hydrogen atom transfer (HAT), resulting in formal γ-C-H functionalization of ketones after trapping of the radical intermediate and in situ imine hydrolysis. The Lewis acid InCl3·H2O facilitated HAT, enabling functionalization of benzylic and nonbenzylic secondary carbon atoms. Functionalization of primary carbons was feasible but afforded low yields, requiring ClCH2CO2H instead of InCl3·H2O as an additive. C-O and C-C bond formation could both be accomplished by this method.

7.
Mol Biol Rep ; 50(10): 8145-8161, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37558798

RESUMO

BACKGROUND: The physiological interactions of MBL suggest its contribution towards the pathogenesis of COPD. OBJECTIVE: The present case-control study was undertaken to elucidate the role of MBL with COPD risk and clinical outcomes in north Indian cohort. METHODS: Patients were enrolled as per GOLD criteria. MBL2 variants were selected based on the literature and their putative functional significance. Genotyping of six single nucleotide polymorphisms of MBL2 comprising of two coding (rs1800450, rs1800451) and four non-coding variants (rs11003125, rs7096206, rs11003123 and rs7095891) was done by using PCR-RFLP and ARMS-PCR. Serum MBL levels were analysed by sandwich ELISA. RESULTS: Overall findings of the molecular genetic analysis of MBL2 indicated significant difference in frequency of three of the six studied variants, between patients and controls or among different disease severity stages. Heterozygous genotype of rs7095891 showed significant protective association towards severity of disease. Linkage disequilibrium (LD) analysis indicated a strong LD between rs1800450 and rs7095891 while intermediate LD was observed for rs11003123/rs11003125 and rs7096206/rs11003125. Haplotype analysis revealed 17.14-fold risk of developing exacerbations conferred by GGGTGG haplotype. Significantly low serum MBL levels observed in COPD patients as compared to controls. Significant difference in MBL deficiency levels were also observed for homozygous wild and variant genotypes of rs11003125 and rs7096206 respectively, as well as for all genotypes of rs11003123 than respective controls. CONCLUSION: The present study reinforces the role played by MBL in the susceptibility, protection and clinical outcomes of COPD. Therefore, including the reported associations at diagnostic, prognostic and therapeutic interventions may prove helpful.


Assuntos
Lectina de Ligação a Manose , Doença Pulmonar Obstrutiva Crônica , Humanos , Genótipo , Polimorfismo de Nucleotídeo Único/genética , Haplótipos/genética , Doença Pulmonar Obstrutiva Crônica/genética , Lectina de Ligação a Manose/genética , Estudos de Casos e Controles , Predisposição Genética para Doença
8.
Int J Mol Sci ; 24(10)2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37240368

RESUMO

This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution.


Assuntos
Síndrome de Rett , Humanos , Síndrome de Rett/terapia , Síndrome de Rett/tratamento farmacológico , Edição de Genes , Distribuição Tecidual , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Encéfalo/metabolismo , Terapia Genética
9.
J Org Chem ; 87(24): 16250-16262, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36472924

RESUMO

A detailed study of iminyl radical cyclizations of O-aryloximes tethered to alkenes is reported. The reactions can be triggered by either microwave irradiation or conventional heating in an oil bath. A variety of radical traps can be employed, enabling C-C, C-N, C-O, C-S, or C-X bond formation and producing a diverse array of functionalized pyrrolines. Substrates containing an allylic sulfide furnish terminal alkenes by a tandem cyclization-thiyl radical ß-elimination pathway. Cyclizations of hydroxylated substrates exhibit moderate diastereoselectivity that in some cases can partially be attributed to intramolecular hydrogen bonding. Computational studies suggested a possible role for thermodynamics in controlling the stereochemistry of cyclizations. The reaction temperature can be lowered from 120 to 100 °C by employing O-(p-tert-butylphenyl)oximes instead of O-phenyloximes as substrates, and these second-generation iminyl radical precursors can be used in a one-pot oxime ether formation-cyclization that is promoted by conventional heating. The functionalized pyrrolines obtained from these reactions can be conveniently transformed in several different ways.


Assuntos
Micro-Ondas , Oximas , Ciclização , Oximas/química , Alcenos/química , Ligação de Hidrogênio
10.
Inorg Chem ; 61(41): 16493-16500, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36194387

RESUMO

N-nitration of 2,6-diamino-3,5-dinitropyrazine (ANPZ) leads to a sensitive energetic compound N,N'-(3,5-dinitropyrazine-2,6-diyl)dinitramide. This nitro(nitroamino) compound was stabilized by synthesizing energetic salts, dipotassium (3,5-dinitropyrazine-2,6-diyl)bis(nitroamide) (3) and diammonium (3,5-dinitropyrazine-2,6-diyl)bis(nitroamide) (4). Compounds 3 and 4 are fully characterized by single-crystal X-ray diffraction. Compound 3 exhibits a three-dimensional energetic metal-organic framework (3D EMOF) structure and an outstanding overall performance by combining high experimental density (2.10 g cm-3), good thermal stability (Td(onset) = 220 °C), and good calculated performance of detonation (D = 8300 m s-1, P = 29.9 GPa). Compound 4 has acceptable thermal stability (155 °C), moderate experimental density (1.73 g cm-3), and good calculated performance of detonation (D = 8624 m s-1, P = 30.8 GPa). The sensitivities of compounds 3 and 4 toward impact and friction were determined following standard methods (BAM). The energetic character of compounds 3 and 4 was determined using red-hot needle and heated plate tests. The results highlight a 3D EMOF (3) based on a six-membered heterocycle as a potential energetic material.

11.
Bioorg Chem ; 118: 105479, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34801945

RESUMO

Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 µM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC50 0.4 µM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program.


Assuntos
Acetilcolinesterase/metabolismo , Antineoplásicos/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Glicoconjugados/farmacologia , Tacrina/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicoconjugados/química , Células Hep G2 , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tacrina/química , Triazóis/química
12.
Biochem Genet ; 60(6): 2120-2136, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35260951

RESUMO

Nitric oxide (NO) a potent vasodilator synthesized by endothelial cells has anti-atherosclerotic properties and maintains vascular tone. It has been documented that its reduced bioavailability in vascular endothelium plays an important role in the development and progression of coronary artery disease (CAD). Therefore, we aimed to investigate the association of - 786 T > C and 894 G > T polymorphisms of eNOS with CAD. This study included 211 CAD patients and 260 controls of North Indian Punjabi population. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Logistic regression analysis revealed that the TC and CC genotypes of - 786 T > C were significantly associated with the higher risk of CAD (OR: 2.00, p = 0.001: OR: 4.63, p = 0.001, respectively). Similarly, the GT and TT genotypes of 894 G > T were found to be significantly associated with the higher risk of CAD (OR: 1.96, p = 0.001; OR: 4.54, p = 0.005, respectively). Moreover, the recessive model in  - 786 T > C (OR: 3.58, p = 0.002) and 894 G > T (OR: 3.62, p = 0.009) polymorphisms provided 3.6-fold increased risk for CAD. Furthermore, the CG, TT, and CT haplotypes were also associated with the increased risk of CAD (OR: 2.1, p = 0.001; OR: 2, p = 0.002; OR: 3.1, p = 0.001, respectively). In addition, the CC genotype of - 786 T > C and GT genotype of 894 G > T were significantly associated with higher levels of triglycerides (TG) and very low-density lipoproteins cholesterol (VLDL-C). The present study reported the association of - 786 T > C and 894 G > T polymorphisms of eNOS with CAD and abnormal lipid levels in North Indian Punjabi population.


Assuntos
Doença da Artéria Coronariana , Óxido Nítrico Sintase Tipo III , Humanos , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/epidemiologia , Células Endoteliais , Predisposição Genética para Doença , Genótipo , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , Índia
13.
Arch Pharm (Weinheim) ; 355(6): e2200033, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35315115

RESUMO

A novel series of triazole-linked isatin-indole-3-carboxaldehyde hybrids based on the febuxostat skeleton and its binding site interactions were rationally designed and synthesized as potential xanthine oxidase inhibitors. Among the synthesized hybrids, A19 showed the most potent xanthine oxidase inhibition (IC50 = 0.37 µM) with the mixed-type inhibitory scenario. Structure-activity relationship studies revealed that methoxy (OCH3 ) substitution on position 5 of the isatin nucleus and a two-carbon distance between isatin and the triazole moiety is most tolerable for the inhibitory potential. Various binding interactions of A19 with the binding site of xanthine oxidase are also streamlined by molecular docking studies, which showcase the favorable binding pattern for xanthine oxidase inhibition by the hybrid. Furthermore, molecular dynamic studies were performed that suggest the stability of the enzyme-hybrid complex. Overall, the study suggests that hybrid A19 can act as an effective hit lead for further development of potent xanthine oxidase inhibitors.


Assuntos
Isatina , Xantina Oxidase , Inibidores Enzimáticos/química , Indóis , Isatina/química , Isatina/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/farmacologia
14.
Trop Med Int Health ; 26(4): 421-427, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33406316

RESUMO

OBJECTIVES: In this retrospective study, we evaluated the diagnostic accuracy of molecular tests (MT) for the detection of DR-TB, compared to the gold standard liquid-based drug susceptibility testing (DST) in Karakalpakstan. METHODS: A total of 6670 specimens received in the Republican TB No 1 Hospital Laboratory of Karakalpakstan between January and July 2017 from new and retreatment patients were analysed. Samples were tested using Xpert MTB/RIF and line probe assays (LPA) for the detection of mutations associated with resistance. The sensitivity and specificity of MTs were calculated relative to results based on DST. RESULTS: The accuracy of MT for detection of rifampicin resistance was high, with sensitivity and specificity over 98%. However, we observed reduced sensitivity of LPA for detection of resistance; 86% for isoniazid (95% CI 82-90%), 86% for fluoroquinolones (95% CI 68-96%), 70% for capreomycin (95% CI 46-88%) and 23% for kanamycin (95% CI 13-35%). CONCLUSIONS: We show that MTs are a useful tool for rapid and safe diagnosis of DR-TB; however, clinicians should be aware of their limitations. Although detection of rifampicin resistance was highly accurate, our data suggest that resistance mutations circulating in the Republic of Karakalpakstan for other drugs were not detected by the methods used here. This merits further investigation.


Assuntos
Antibióticos Antituberculose/uso terapêutico , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose/tratamento farmacológico , Capreomicina/uso terapêutico , Fluoroquinolonas/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Canamicina/uso terapêutico , Mutação , Mycobacterium tuberculosis/genética , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Estudos Retrospectivos , Rifampina/uso terapêutico , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Uzbequistão
15.
Chem Rec ; 21(3): 574-593, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33496384

RESUMO

The design of molecules with non-trivial topologies is an essential step in the development of methods to mimic biological transformation in artificial systems. However, the generation of supramolecular topologies of increasing complexity, such as [n]catenanes, rotaxanes, knots and links, is relatively rare and challenging. Primarily, selective and quantitative synthesis of supramolecular topologies is a formidable challenge. Template-free, non-covalent interaction-directed coordination-driven self-assembly provides an alternative approach for constructing non-trivial topologies in selective and quantitative manner. This review briefly summarizes and provides a comprehensive insight into non-trivial topologies obtained via template-free, coordination and non-covalent interaction-driven self-assembly.

16.
Inorg Chem ; 60(11): 8339-8345, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34014642

RESUMO

An axisymmetric polynitro-pyrazole molecule, 3,5-di(3,5-dinitropyrazol-4-yl)]-4-nitro-1H-pyrazole (5), and its salts (6-12) were prepared and fully characterized. These compounds not only show promising energetic properties but also show a unique tautomeric switch via combining different cations with the axisymmetric compound (5). Its salts (6-9) remain axisymmetric when the cations are potassium, ammonium, or amino-1,2,4-triazolium. However, when the cations are guanidiums, the salts (10-12) dramatically become asymmetric owing to the fixed proton. The introduction of guanidium cations breaks the tautomeric equilibrium by blocking the prototropic transformations and results in the switch-off effect to tautomerism. The structural constraints of 1H NMR and 13C NMR spectra provide strong evidence for the unusual structural constraint phenomenon. These stabilized asymmetric tautomers are very important from the point of molecular recognition, and this research may promote further developments in synthetic and isolation methodologies for novel bioactive pyrazole-based compounds.

17.
Mol Divers ; 25(1): 551-601, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32170466

RESUMO

GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer's disease, Huntington's chorea, migraine, Parkinson's disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure-activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.


Assuntos
Desenho de Fármacos , Moduladores GABAérgicos/síntese química , Moduladores GABAérgicos/farmacologia , Animais , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Receptores de GABA/química , Receptores de GABA/metabolismo
18.
Mol Divers ; 25(1): 603-624, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32886304

RESUMO

Breast cancer is the most prominent, frequently diagnosed and leading cause of death among women. Estrogen is an agonist of estrogen receptor alpha (ER-α), expressed in mammary glands and is responsible for initiating many signalling pathways that lead to differentiation and development of breast tissue. Any mutations in these signalling pathways result in irregular growth of mammary tissue, leading to the development of tumour or cancer. All these observations attract the attention of researchers to antagonize ER-α receptor either by developing selective estrogen receptor modulators or by selective estrogen receptor degraders. Therefore, this article provides a brief overview of various factors that are responsible for provoking breast cancer in women and design strategies recently used by the various research groups across the world for antagonizing or demodulating ER-α.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Terapia de Alvo Molecular , Receptor alfa de Estrogênio/antagonistas & inibidores , Feminino , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Modelos Moleculares
19.
Psychiatry Clin Neurosci ; 75(12): 369-393, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34472659

RESUMO

AIM: This systematic review identified and thematically appraised clinical evidence of movement disorders in patients with Rett syndrome (RTT). METHOD: Using PRISMA criteria, six electronic databases were searched from inception to April 2021. A thematic analysis was then undertaken on the extracted data to identify potential themes. RESULTS: Following the thematic analysis, six themes emerged: (i) clinical features of abnormal movement behaviors; (ii) mutational profile and its impact on movement disorders; (iii) symptoms and stressors that impact on movement disorders; (iv) possible underlying neurobiological mechanisms; (v) quality of life and movement disorders; and (vi) treatment of movement disorders. Current guidelines for managing movement disorders in general were then reviewed to provide possible treatment recommendations for RTT. CONCLUSION: Our study offers an enriched data set for clinical investigations and treatment of fine and gross motor issues in RTT. A detailed understanding of genotype-phenotype relationships of movement disorders allows for more robust genetic counseling for families but can also assist healthcare professionals in terms of monitoring disease progression in RTT. The synthesis also showed that environmental enrichment would be beneficial for improving some aspects of movement disorders. The cerebellum, basal ganglia, alongside dysregulation of the cortico-basal ganglia-thalamo-cortical loop, are likely anatomical targets. A review of treatments for movement disorders also helped to provide recommendations for treating and managing movement disorders in patients with RTT.


Assuntos
Transtornos dos Movimentos , Síndrome de Rett , Animais , Humanos , Transtornos dos Movimentos/complicações , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/terapia , Mutação , Qualidade de Vida , Síndrome de Rett/complicações , Síndrome de Rett/genética
20.
Drug Chem Toxicol ; 44(6): 620-630, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31368375

RESUMO

The screening of aqueous extract of Clerodendrum serratum revealed its broad-spectrum antimicrobial potential against Gram positive, Gram negative bacteria, and yeast. Optimizing the extraction strategies, revealed 15% concentration of aqueous extract prepared at 40 °C by extracting for 40 min, as optimum parameters and its statistical optimization by Box-Behnken design led to 1.16-1.35 folds enhancement in activity. Organic solvent extraction further improved the activity where methanol proved to be the best organic extractant which was effective against all the 13 pathogens tested with inhibition zone ranging from 14 to 32 mm. Minimum Inhibitory Concentration (MIC) study endorsed the methanolic extract to be the best organic extractant, as it showed the lowest MIC (0.5-10 mg/ml) in comparison to aqueous extract (1-10 mg/ml) as well as Partially Purified Phytoconstituents i.e., flavonoids (1-5 mg/ml), diterpenes (5-10 mg/ml) and cardiac glycosides (5-10 mg/ml). All these were found to be biosafe in both In-vitro (Ames and MTT assay) and In-vivo toxicity studies. Acute oral toxicity testing of flavonoids (2000 mg/ml) on Wistar rats did not reveal any significant change in relative organ weight, biochemical, hematological parameters and organs' architecture in comparison to control. Antiproliferative potential of flavonoids against human cancerous cell lines i.e., HeLa, HCT-15, and U87-MG, further increase the importance of this plant as a promising candidate for drug development. The overall study justified the medicinal importance of this plant.


Assuntos
Anti-Infecciosos , Clerodendrum , Extratos Vegetais , Animais , Anti-Infecciosos/uso terapêutico , Anti-Infecciosos/toxicidade , Contenção de Riscos Biológicos , Testes de Sensibilidade Microbiana , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Ratos , Ratos Wistar
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