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1.
Molecules ; 28(6)2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36985680

RESUMO

Bis-acyl-thiourea derivatives, namely N,N'-(((4-nitro-1,2-phenylene)bis(azanediyl)) bis(carbonothioyl))bis(2,4-dichlorobenzamide) (UP-1), N,N'-(((4-nitro-1,2-phenylene) bis(azanediyl))bis(carbonothioyl))diheptanamide (UP-2), and N,N'-(((4-nitro-1,2-phenylene)bis(azanediyl))bis(carbonothioyl))dibutannamide (UP-3), were synthesized in two steps. The structural characterization of the derivatives was carried out by FTIR, 1H-NMR, and 13C-NMR, and then their DNA binding, anti-urease, and anticancer activities were explored. Both theoretical and experimental results, as obtained by density functional theory, molecular docking, UV-visible spectroscopy, fluorescence (Flu-)spectroscopy, cyclic voltammetry (CV), and viscometry, pointed towards compounds' interactions with DNA. However, the values of binding constant (Kb), binding site size (n), and negative Gibbs free energy change (ΔG) (as evaluated by docking, UV-vis, Flu-, and CV) indicated that all the derivatives exhibited binding interactions with the DNA in the order UP-3 > UP-2 > UP-1. The experimental findings from spectral and electrochemical analysis complemented each other and supported the theoretical analysis. The lower diffusion coefficient (Do) values, as obtained from CV responses of each compound after DNA addition at various scan rates, further confirmed the formation of a bulky compound-DNA complex that caused slow diffusion. The mixed binding mode of interaction as seen in docking was further verified by changes in DNA viscosity with varying compound concentrations. All compounds showed strong anti-urease activity, whereas UP-1 was found to have comparatively better inhibitory efficiency, with an IC50 value of 1.55 ± 0.0288 µM. The dose-dependent cytotoxicity of the synthesized derivatives against glioblastoma MG-U87 cells (a human brain cancer cell line) followed by HEK-293 cells (a normal human embryonic kidney cell line) indicated that UP-1 and UP-3 have greater cytotoxicity against both cancerous and healthy cell lines at 400 µM. However, dose-dependent responses of UP-2 showed cytotoxicity against cancerous cells, while it showed no cytotoxicity on the healthy cell line at a low concentration range of 40-120 µM.


Assuntos
Neoplasias Encefálicas , Urease , Humanos , Simulação de Acoplamento Molecular , Células HEK293 , Antibacterianos/farmacologia , DNA/química , Tioureia/química , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia
2.
Semin Cancer Biol ; 69: 178-189, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-31419527

RESUMO

Cancer is an outrageous disease with uncontrolled differentiation, growth, and migration to the other parts of the body. It is the second-most common cause of death both in the U.S. and worldwide. Current conventional therapies, though much improved and with better prognosis, have several limitations. Chemotherapeutic agents, for instance, are cytotoxic to both tumor and healthy cells, and the non-specific distribution of drugs at tumor sites limits the dose administered. Nanotechnology, which evolved from the coalescence and union of varied scientific disciplines, is a novel science that has been the focus of much research. This technology is generating more effective cancer therapies to overcome biomedical and biophysical barriers against standard interventions in the body; its unique magnetic, electrical, and structural properties make it a promising tool. This article reviews endogenous- and exogenous-based stimulus-responsive drug delivery systems designed to overcome the limitations of conventional therapies. The article also summarizes the study of nanomaterials, including polymeric, gold, silver, magnetic, and quantum dot nanoparticles. Though an array of drug delivery systems has so far been proposed, there remain many challenges and concerns that should be addressed in order to fill the gaps in the field. Prominence is given to drug delivery systems that employ external- and internal-based stimuli and that are emerging as promising tools for cancer therapeutics in clinical settings.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanomedicina , Nanopartículas/administração & dosagem , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Animais , Humanos , Nanopartículas/química , Neoplasias/patologia
3.
Semin Cancer Biol ; 69: 52-68, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32014609

RESUMO

Nanotechnology is reshaping health care strategies and is expected to exert a tremendous impact in the coming years offering better healthcare facilities. It has led to not only therapeutic drug delivery feasibility but also to diagnostics. Materials in the size of nano range (1-100 nm) used in the design, fabrication, regulation, and application of therapeutic drugs or devices are classified as medical nanotechnology and nanopharmacology. Delivery of more complex molecules to the specific site of action as well as gene therapy has pushed forward the nanoparticle-based drug delivery to its maximum. Areas that benefit from nano-based drug delivery systems are cancer, diabetes, infectious diseases, neurodegenerative diseases, blood disorders and orthopedic-related ailments. Moreover, development of nanotherapeutics with multi-functionalities has a considerable potential to fill the gaps that exist in the present therapeutic domain. In cancer treatment, nanomedicines have superiority over current therapeutic practices as they can effectively deliver the drug to the affected tissues, thus reducing drug toxicities. Along this line, polymeric conjugates of asparaginase and polymeric micelles of paclitaxel have recently been recommended for the treatment of various types of cancers. Nanotechnology-based therapeutics and diagnostics provide greater effectiveness with less or no toxicity concerns. Similarly, diagnostic imaging holds promising future applications with newer nano-level imaging elements. Advancements in nanotechnology have emerged to a newer direction which use nanorobotics for various applications in healthcare. Accordingly, this review comprehensively highlights the potentialities of various nanocarriers and nanomedicines for multifaceted applications in diagnostics and drug delivery, especially the potentialities of polymeric nanoparticle, nanoemulsion, solid-lipid nanoparticle, nanostructured lipid carrier, self-micellizing anticancer lipids, dendrimer, nanocapsule and nanosponge-based therapeutic approaches in the field of cancer. Furthermore, this article summarizes the most recent literature pertaining to the use of nano-technology in the field of medicine, particularly in treating cancer patients.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanomedicina , Nanopartículas/administração & dosagem , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Animais , Humanos , Nanopartículas/química
4.
Cancer Cell Int ; 22(1): 284, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109789

RESUMO

The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety of biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating a cellular environment conducive to it. Deregulation of such a system in terms of genetic mutations and amplification has been related to several human cancers. Consequently, mTOR has been recognized as a key target for the treatment of cancer, especially for treating cancers with elevated mTOR signaling due to genetic or metabolic disorders. In vitro and in vivo, rapamycin which is an immunosuppressant agent actively suppresses the activity of mTOR and reduces cancer cell growth. As a result, various sirolimus-derived compounds have now been established as therapies for cancer, and now these medications are being investigated in clinical studies. In this updated review, we discuss the usage of sirolimus-derived compounds and other drugs in several preclinical or clinical studies as well as explain some of the challenges involved in targeting mTOR for treating various human cancers.

5.
Cancer Cell Int ; 22(1): 246, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941592

RESUMO

MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) pathway is an important link in the transition from extracellular signals to intracellular responses. Because of genetic and epigenetic changes, signaling cascades are altered in a variety of diseases, including cancer. Extant studies on the homeostatic and pathologic behavior of MAPK signaling have been conducted; however, much remains to be explored in preclinical and clinical research in terms of regulation and action models. MAPK has implications for cancer therapy response, more specifically in response to experimental MAPK suppression, compensatory mechanisms are activated. The current study investigates MAPK as a very complex cell signaling pathway that plays roles in cancer treatment response, cellular normal conduit maintenance, and compensatory pathway activation. Most MAPK inhibitors, unfortunately, cause resistance by activating compensatory feedback loops in tumor cells and tumor microenvironment components. As a result, innovative combinatorial treatments for cancer management must be applied to limit the likelihood of alternate pathway initiation as a possibility for generating novel therapeutics based on incorporation in translational research. We summarize current knowledge about the implications of ERK (MAPK) in cancer, as well as bioactive products from plants, microbial organisms or marine organisms, as well as the correlation with their chemical structures, which modulate this pathway for the treatment of different types of cancer.

6.
J Mol Struct ; 1253: 132308, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-34980930

RESUMO

Copper(II) carboxylate complexes [Cu2(OOCR)4L2] (1) and [Cu2(OOCR`)4OCO(R`)CuL2]n (2), where L = 2-methyl pyridine, R = 2-chlorophenyl acetate and R` = 2-fluorophenyl acetate were synthesized and characterized by FT-IR spectroscopy and single crystal X-ray analysis. Complex 1 exhibits the typical paddlewheel array of a dinuclear copper(II) complex with carboxylate ligands. In complex 2, this scaffold is further extended into a polymeric arrangement based on alternate paddlewheel and square planar moieties with distinct coordination spheres. The complexes showed better 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities and have been found to be more potent antileishmanial agents than their corresponding free ligand acid species. UV-Vis absorption titrations revealed good DNA binding abilities {Kb = 9.8 × 104 M-1 (1) and 9.9 × 104 M-1 (2)} implying partial intercalation of the complexes into DNA base pairs along with groove binding. The complexes displayed in vitro cytotoxic activity against malignant glioma U-87 (MG U87) cell lines. Computational docking studies further support complex-DNA binding by intercalation. Molecular docking investigations revealed probable interactions of the complexes with spike protein, the nucleocapsid protein of SARS-CoV-2 and with the angiotensin converting enzyme of human cells.

7.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204308

RESUMO

Globally, Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disorders associated with cognitive decline and memory deficits due to beta-amyloid deposition (Aß) and tau protein hyperphosphorylation. To date, approximately 47 million people worldwide have AD. This figure will rise to an estimated 75.6 million by 2030 and 135.5 million by 2050. According to the literature, the efficacy of conventional medications for AD is statistically substantial, but clinical relevance is restricted to disease slowing rather than reversal. Withaferin A (WA) is a steroidal lactone glycowithanolides, a secondary metabolite with comprehensive biological effects. Biosynthetically, it is derived from Withania somnifera (Ashwagandha) and Acnistus breviflorus (Gallinero) through the mevalonate and non-mevalonate pathways. Mounting evidence shows that WA possesses inhibitory activities against developing a pathological marker of Alzheimer's diseases. Several cellular and animal models' particulates to AD have been conducted to assess the underlying protective effect of WA. In AD, the neuroprotective potential of WA is mediated by reduction of beta-amyloid plaque aggregation, tau protein accumulation, regulation of heat shock proteins, and inhibition of oxidative and inflammatory constituents. Despite the various preclinical studies on WA's therapeutic potentiality, less is known regarding its definite efficacy in humans for AD. Accordingly, the present study focuses on the biosynthesis of WA, the epidemiology and pathophysiology of AD, and finally the therapeutic potential of WA for the treatment and prevention of AD, highlighting the research and augmentation of new therapeutic approaches. Further clinical trials are necessary for evaluating the safety profile and confirming WA's neuroprotective potency against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Vitanolídeos/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Humanos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Placa Amiloide/tratamento farmacológico , Solanaceae/metabolismo , Withania/metabolismo , Vitanolídeos/metabolismo , Proteínas tau/metabolismo
8.
Molecules ; 26(23)2021 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-34885950

RESUMO

Berberine (BBR), a potential bioactive agent, has remarkable health benefits. A substantial amount of research has been conducted to date to establish the anticancer potential of BBR. The present review consolidates salient information concerning the promising anticancer activity of this compound. The therapeutic efficacy of BBR has been reported in several studies regarding colon, breast, pancreatic, liver, oral, bone, cutaneous, prostate, intestine, and thyroid cancers. BBR prevents cancer cell proliferation by inducing apoptosis and controlling the cell cycle as well as autophagy. BBR also hinders tumor cell invasion and metastasis by down-regulating metastasis-related proteins. Moreover, BBR is also beneficial in the early stages of cancer development by lowering epithelial-mesenchymal transition protein expression. Despite its significance as a potentially promising drug candidate, there are currently no pure berberine preparations approved to treat specific ailments. Hence, this review highlights our current comprehensive knowledge of sources, extraction methods, pharmacokinetic, and pharmacodynamic profiles of berberine, as well as the proposed mechanisms of action associated with its anticancer potential. The information presented here will help provide a baseline for researchers, scientists, and drug developers regarding the use of berberine as a promising candidate in treating different types of cancers.


Assuntos
Antineoplásicos/uso terapêutico , Berberina/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Berberina/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos
9.
Semin Cancer Biol ; 52(Pt 1): 85-102, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-28774835

RESUMO

Recent investments in research associated with the discovery of specific tumor biomarkers important for efficient diagnosis and prognosis are beginning to bear fruit. Key biomarkers could potentially outweigh traditional radiological or pathological methods by enabling specificity of early detection, when coupled with tumor molecular profiling and clinical associations. Only few biomarkers are approved by regulatory authorities for Central Nervous System Tumors (CNSTs), despite the evaluation of a large number of CNST related markers during clinical trials. Traditional CNSTs biomarkers include 1p/19q co-deletion, O6-Methylguanine-DNA Methyltransferase Methylation, and mutations in IDH1/IDH2. Recently tested CNSTs biomarkers include VEGFR-2, EGFRvIII, IL2, PDGFR, MMPs, BRAF, STAT3, PTEN, TERT, AKT, NF2, and BCL2. Additional studies have highlighted new and novel MicroRNAs, circular RNAs and long non-coding RNAs as promising biomarkers. Studies on microvesicles pinpoint exosomes as promising, less invasive biomarkers that could be isolated from the serum of cancer patients. Furthermore, Cancer Stem Cells (CSCs) related molecules, such as CD133, SOX2 and Nestin, utilized as CNST biomarkers, might enable efficient monitoring of cancer progression, and/or surveillance of emerging drug resistant cells. Approved protocols that implement novel molecular markers in diagnostics, prognostics and drug development will herald a new era of precision and personalized neuro-oncology. This review summarizes and discusses putative CNST biomarkers that are under clinical development, and are ready to move into diagnostic, prognostic and therapeutic applications. Data presented here is predicted to aid in streamlining the process of biomarker's research and development.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Sistema Nervoso Central/genética , Mutação , Células-Tronco Neoplásicas/metabolismo , Ácidos Nucleicos Livres/genética , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Exossomos/genética , Humanos , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Prognóstico , RNA Longo não Codificante/genética
10.
Phytother Res ; 33(10): 2585-2608, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31373097

RESUMO

Traditionally, sesame oil (SO) has been used as a popular food and medicine. The review aims to summarize the antioxidant and antiinflammatory effects of SO and its identified compounds as well as further fatty acid profiling and molecular docking study to correlate the interaction of its identified constituents with cyclooxygenase-2 (COX-2). For this, a literature study was made using Google Scholar, Pubmed, and SciFinder databases. Literature study demonstrated that SO has potential antioxidant and antiinflammatory effects in various test systems, including humans, animals, and cultured cells through various pathways such as inhibition of COX, nonenzymatic defense mechanism, inhibition of proinflammatory cytokines, NF-kB or mitogen-activated protein kinase signaling, and prostaglandin synthesis pathway. Fatty acid analysis of SO using gas chromatography identified known nine fatty acids. In silico study revealed that sesamin, sesaminol, sesamolin, stigmasterol, Δ5-avenasterol, and Δ7-avenasterol (-9.6 to -10.7 kcal/mol) were the most efficient ligand for interaction and binding with COX-2. The known fatty acid also showed binding efficiency with COX-2 to some extent (-6.0 to -8.4 kcal/mol). In summary, it is evident that SO may be one of promising traditional medicines that we could use in the prevention and management of diseases associated with oxidative stress and inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Simulação de Acoplamento Molecular , Óleo de Gergelim/farmacologia , Animais , Humanos , Estresse Oxidativo/efeitos dos fármacos , Óleo de Gergelim/análise , Óleo de Gergelim/química
11.
Phytother Res ; 32(10): 1885-1907, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30009484

RESUMO

Natural dietary agents have attracted considerable attention due to their role in promoting health and reducing the risk of diseases including cancer. Ginger, one of the most ancient known spices, contains bioactive compounds with several health benefits. [6]-Gingerol constitutes the most pharmacologically active among such compounds. The aim of the present work was to review the literature pertaining to the use of ginger extract and [6]-gingerol against tumorigenic and oxidative and inflammatory processes associated with cancer, along with the underlying mechanisms of action involved in signaling pathways. This will shed some light on the protective or therapeutic role of ginger derivatives in oxidative and inflammatory regulations during metabolic disturbance and on the antiproliferative and anticancer properties. Data collected from experimental (in vitro or in vivo) and clinical studies discussed in this review indicate that ginger extract and [6]-gingerol exert their action through important mediators and pathways of cell signaling, including Bax/Bcl2, p38/MAPK, Nrf2, p65/NF-κB, TNF-α, ERK1/2, SAPK/JNK, ROS/NF-κB/COX-2, caspases-3, -9, and p53. This suggests that ginger derivatives, in the form of an extract or isolated compounds, exhibit relevant antiproliferative, antitumor, invasive, and anti-inflammatory activities.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Catecóis/farmacologia , Álcoois Graxos/farmacologia , Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacologia , Zingiber officinale/química , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular Tumoral , Humanos , Inflamação/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
12.
Cancer Cell Int ; 17: 72, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28736504

RESUMO

BACKGROUND: Meningioma tumors arise in arachnoid membranes, and are the most reported central nervous system (CNS) tumors worldwide. Up to 20% of grade I meningioma tumors reoccur and currently predictive cancer stem cells (CSCs) markers for aggressive and drug resistant meningiomas are scarce. METHODS: Meningioma tissues and primary cell lines were investigated using whole transcriptome microarray analysis, immunofluorescence staining of CSCs markers (including CD133, Sox2, Nestin, and Frizzled 9), and drug treatment with cisplatin or etoposide. RESULTS: Unsupervised hierarchical clustering of six meningioma samples separated tissues into two groups. Analysis identified stem cells related pathways to be differential between the two groups and indicated the de-regulation of the stem cell associated genes Reelin (RELN), Calbindin 1 (CALB1) and Anterior Gradient 2 Homolog (AGR2). Immunofluorescence staining for four tissues confirmed stemness variation in situ. Biological characterization of fifteen meningioma primary cell lines concordantly separated cells into two functionally distinct sub-groups. Pleomorphic cell lines (NG type) grew significantly faster than monomorphic cell lines (G type), had a higher number of cells that express Ki67, and were able to migrate aggressively in vitro. In addition, NG type cell lines had a lower expression of nuclear Caspase-3, and had a significantly higher number of CSCs co-positive for CD133+ Sox2+ or AGR2+ BMI1+. Importantly, these cells were more tolerant to cisplatin and etoposide treatment, showed a lower level of nuclear Caspase-3 in treated cells and harbored drug resistant CSCs. CONCLUSION: Collectively, analyses of tissues and primary cell lines revealed stem cell associated genes as potential targets for aggressive and drug resistant meningiomas.

13.
Plant Methods ; 20(1): 111, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39054477

RESUMO

Clematis graveolens Lindl., an indigenous climbing plant found in the Himalayan areas, is used by local communities for the treatment of neck tumors. The objective of this work is to examine the comprehensive metabolomic profile, antioxidant capability, in vitro and in silico anti-glioma effects on U-87 human glioma cell lines of the crude extract and fractions from C. graveolens. Liquid chromatography coupled with mass spectroscopy (LC-MS/MS) was used to establish detailed metabolite profiling of C. graveolens. The assessment of cell cytotoxicity was conducted using MTT cell viability assay on U-87 and BHK-21. Through molecular docking studies, the mode of inhibition and binding interaction between identified compounds and target proteins were also determined to evaluate the in vitro results. The use of LC-MS/MS-based global natural products social (GNPS) molecular networking analysis resulted in the identification of 27 compounds. The crude extract, ethyl acetate fraction, and chloroform fraction exhibited significant inhibitory activity against the U-87 cell lines, with IC50 values of 112.0, 138.1, and 142.7 µg/mL, respectively. The ethyl acetate fraction exhibited significant inhibitory concentration for 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) activity, 2,2-diphenyl-1-picrylhydrazyl (DPPH) activity and the metal chelation activity with IC50 value of 39.50 µg/mL, 32.27 µg/mL, and 53.46 µg/mL, respectively. The crude extract showed maximum total phenolic, and total flavonoid concentration measuring 338.7 µg GAE/mg, and 177.04 µg QE/mg, respectively. The findings of this study indicate that C. graveolens consists of a diverse range of active phytoconstituents that possess antioxidant and anti-glioma properties.

14.
Neoplasia ; 51: 100989, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38537553

RESUMO

Gene mutations are a source of genetic instability which fuels the progression of cancer. Mutations in BRCA1 and BRCA2 are considered as major drivers in the progression of breast cancer and their detection indispensable for devising therapeutic and management approaches. The current study aims to identify novel pathogenic and recurrent mutations in BRCA1 and BRCA2 in Pakhtun population from the Khyber Pakhtunkhwa. To determine the BRCA1 and BRCA2 pathogenic mutation prevalence in Pakhtun population from KP, whole exome sequencing of 19 patients along with 6 normal FFPE embedded blocks were performed. The pathogenicity of the mutations were determined and they were further correlated with different hormonal, sociogenetic and clinicopathological features. We obtained a total of 10 mutations (5 somatic and 5 germline) in BRCA1 while 27 mutations (24 somatic and 3 germline) for BRCA2. Five and seventeen pathogenic or deleterious mutations were identified in BRCA1 and BRCA2 respectively by examining the mutational spectrum through SIFT, PolyPhen-2 and Mutation Taster. Among the SNVs, BRCA1 p.P824L, BRCA2 p. P153Q, p.I180F, p.D559Y, p.G1529R, p.L1576F, p.E2229K were identified as mutations of the interaction sites as predicted by the deep algorithm based ISPRED-SEQ prediction tool. SAAFEQ-SEQ web-based algorithm was used to calculate the changes in free energy and effect of SNVs on protein stability. All SNVs were found to have a destabilizing effect on the protein. ConSurf database was used to determine the evolutionary conservation scores and nature of the mutated residues. Gromacs 4.5 was used for the molecular simulations. Ramachandran plots were generated using procheck server. STRING and GeneMania was used for prediction of the gene interactions. The highest number of mutations (BRCA1 7/10, 70 %) were on exon 9 and (BRCA2, 11/27; 40 %) were on exon 11. 40 % and 60 % of the BRCA2 mutations were associated Grade 2 and Grade 3 tumors respectively. The present study reveals unique BRCA1 and BRCA2 mutations in Pakhtun population. We further suggest sequencing of the large cohorts for further characterizing the pathogenic mutations.


Assuntos
Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama , Feminino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Etnicidade , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Mutação , Paquistão/epidemiologia , População do Sul da Ásia/genética
15.
J Biomol Struct Dyn ; 42(4): 1826-1845, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37114651

RESUMO

Three triorganotin(IV) compounds, R3Sn(L), with R = CH3 (1), n-C4H9 (2) and C6H5 (3), and LH = 4-[(2-chloro-4-methylphenyl)carbamoyl]butanoic acid, were prepared and confirmed by various techniques. A five-coordinate, distorted trigonal-bipyramidal geometry was elucidated for tin(IV) centres both in solution and solid states. An intercalation mode was confirmed for the compound SS-DNA interaction by UV-visible, viscometric techniques and molecular docking. MD simulation revealed stable binding of LH with SS-DNA. Anti-bacterial investigation revealed 2 to be generally the most potent, especially against Sa and Ab, i.e. having the lowest MIC values (≤0.25 µg/mL) compared to the standard anti-biotics vancomycin-HCl (MIC = 1 µg/mL) and colistin-sulphate (MIC = 0.25 µg/mL). Similarly, the anti-fungal profile shows 2 exhibits 100% inhibition against Ca and Cn fungal strains and has MIC values (≤0.25 µg/mL) comparatively lower than standard drug fluconazole (0.125 and 8 µg/mL for Ca and Cn, respectively). Compound 2 has the greatest activity with CC50 ≤ 25 µg/mL and HC50 > 32 µg/mL performed against HEC239 and RBC cell lines. The anti-cancer potential was assessed against the MG-U87 cell line, using cisplatin as the standard (133 µM), indicates 2 displays the greatest activity (IC50: 5.521 µM) at a 5 µM dose. The greatest anti-leishmanial potential was observed for 2 (87.75 at 1000 µg/mL) in comparison to amphotericin B (90.67). The biological assay correlates with the observed maximum of 89% scavenging activity exhibited by 2. The Swiss-ADME data publicised the screened compounds generally follow the rule of 5 of drug-likeness and have good bioavailability potential.


Assuntos
DNA , Simulação de Acoplamento Molecular , Ácido Butírico , Linhagem Celular , DNA/química , Simulação por Computador , Testes de Sensibilidade Microbiana
16.
Pharmaceuticals (Basel) ; 17(2)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38399386

RESUMO

Significant progress has been made in the field of gene therapy, but effective treatments for brain tumors remain challenging due to their complex nature. Current treatment options have limitations, especially due to their inability to cross the blood-brain barrier (BBB) and precisely target cancer cells. Therefore options that are safer, more effective, and capable of specifically targeting cancer cells are urgently required as alternatives. This current study aimed to develop highly biocompatible natural biopolymeric chitosan nanoparticles (CNPs) as potential gene delivery vehicles that can cross the BBB and serve as gene or drug delivery vehicles for brain disease therapeutics. The efficiency of the CNPs was evaluated via in vitro transfection of Green Fluorescent Protein (GFP)-tagged plasmid in HEK293-293 and brain cancer MG-U87 cell lines, as well as within in vivo mouse models. The CNPs were prepared via a complex coacervation method, resulting in nanoparticles of approximately 260 nm in size. In vitro cytotoxicity analysis revealed that the CNPs had better cell viability (85%) in U87 cells compared to the chemical transfection reagent (CTR) (72%). Moreover, the transfection efficiency of the CNPs was also higher, as indicated by fluorescent emission microscopy (20.56% vs. 17.79%) and fluorescent-activated cell sorting (53% vs. 27%). In vivo assays using Balb/c mice revealed that the CNPs could efficiently cross the BBB, suggesting their potential as efficient gene delivery vehicles for targeted therapies against brain cancers as well as other brain diseases for which the efficient targeting of a therapeutic load to the brain cells has proven to be a real challenge.

17.
Front Genet ; 15: 1383284, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38784039

RESUMO

In this study, we report the mutational profiles, pathogenicity, and their association with different clinicopathologic and sociogenetic factors in patients with Pashtun ethnicity for the first time. A total of 19 FFPE blocks of invasive ductal carcinoma (IDC) from the Breast Cancer (BC) tissue and 6 normal FFPE blocks were analyzed by whole-exome sequencing (WES). Various somatic and germline mutations were identified in cancer-related genes, i.e., ATM, CHEK2, PALB2, and XRCC2. Among a total of 18 mutations, 14 mutations were somatic and 4 were germline. The ATM gene exhibited the maximum number of mutations (11/18), followed by CHEK2 (3/18), PALB2 (3/18), and XRCC2 (1/18). Except one frameshift deletion, all other 17 mutations were nonsynonymous single-nucleotide variants (SNVs). SIFT prediction revealed 7/18 (38.8%) mutations as deleterious. PolyPhen-2 and MutationTaster identified 5/18 (27.7%) mutations as probably damaging and 10/18 (55.5%) mutations as disease-causing, respectively. Mutations like PALB2 p.Q559R (6/19; 31.5%), XRCC2 p.R188H (5/19; 26.31%), and ATM p.D1853N (4/19; 21.05%) were recurrent mutations and proposed to have a biomarker potential. The protein network prediction was performed using GeneMANIA and STRING. ISPRED-SEQ indicated three interaction site mutations which were further used for molecular dynamic simulation. An average increase in the radius of gyration was observed in all three mutated proteins revealing their perturbed folding behavior. Obtained SNVs were further correlated with various parameters related to the clinicopathological status of the tumors. Three mutation positions (ATM p. D1853N, CHEK2 p.M314I, and PALB2 p.T1029S) were found to be highly conserved. Finally, the wild- and mutant-type proteins were screened for two drugs: elagolix (DrugBank ID: DB11979) and LTS0102038 (a triterpenoid, isolated from the anticancer medicinal plant Fagonia indica). Comparatively, a higher number of interactions were noted for normal ATM with both compounds, as compared to mutants.

19.
RSC Adv ; 14(9): 5754-5763, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38362085

RESUMO

In the current research, we produced green, cost-effective, eco-friendly silver nanoparticles using a single-step approach. Plants are considered highly desirable systems for nanoparticle synthesis because they possess a variety of secondary metabolites with significant reduction potential. In the current research, the dried leaf extract of Rubus fruticosus was utilized as a capping and reducing agent for the fabrication of silver nanoparticles, to prepare reliable biogenic silver nanoparticles and subsequently to investigate their potential against some common phytopathogens. The prepared silver nanoparticles were exploited to quantify the total flavonoid content (TFC), total phenolic content (TPC) and DPPH-based antioxidant activity. Different concentrations of aqueous extracts of plant leaves and silver nitrate (AgNO3) were reacted, and the color change of the reactant mixture confirmed the formation of Rubus fruticosus leaf-mediated silver nanoparticles (RFL-AgNPs). A series of characterization techniques such as UV-vis spectroscopy, transmission electron microscopy, energy dispersive X-ray analysis and X-ray diffraction revealed the successful synthesis of silver nanoparticles. The surface plasmon resonance peak appeared at 449 nm. XRD analysis demonstrated the crystalline nature, EDX confirmed the purity, and TEM demonstrated that the nanoparticles are mostly spherical in form. Furthermore, the biosynthesized nanoparticles were screened for in vitro antibacterial activity, antioxidant activity, and total phenolic and flavonoid content. The nanoparticles were used in different concentrations alone and in combination with plant extracts to inhibit Erwinia caratovora and Ralstonia solanacearum. In high-throughput assays used to inhibit these plant pathogens, the nanoparticles were highly toxic against bacterial pathogens. This study can be exploited for planta assays against phytopathogens utilizing the same formulations for nanoparticle synthesis and to develop potent antibacterial agents to combat plant diseases.

20.
ACS Omega ; 8(45): 43318-43331, 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-38024667

RESUMO

Herein, we report the mutational spectrum of three breast cancer candidate genes (TP53, PIK3CA, and PTEN) using WES for identifying potential biomarkers. The WES data were thoroughly analyzed using SAMtools for variant calling and identification of the mutations. Various bioinformatic tools (SIFT, PolyPhen-2, Mutation Taster, ISPRED-SEQ, SAAFEQ-SEQ, ConSurf, PROCHECK etc.) were used to determine the pathogenicity and nature of the SNVs. Selected interaction site (IS) mutations were visualized in PyMOL after building 3D structures in Swiss-Model. Ramachandran plots were generated by using the PROCHECK server. The selected IS mutations were subjected to molecular dynamic simulation (MDS) studies using Gromacs 4.5. STRING and GeneMANIA were used for the prediction of gene-gene interactions and pathways. Our results revealed that the luminal A molecular subtype of the breast cancer was most common, whereas a high percentage of was Her2 negatives. Moreover, the somatic mutations were more common as compared to the germline mutations in TP53, PIK3CA, and PTEN. 20% of the identified mutations are reported for the first time from Khyber Pakhtunkhwa. In the enrolled cohort, 23 mutations were nonsynonymous SNVs. The frequency of mutations was the highest in PIK3CA, followed by TP53 and PTEN. A total of 13 mutations were found to be highly pathogenic. Four novel mutations were identified on PIK3CA and one each on PTEN and TP53. SAAFEQ-SEQ predicted the destabilizing effect for all mutations. ISPRED-SEQ predicted 9 IS mutations (6 on TP53 and 3 on PIK3CA), whereas no IS mutation was predicted on PTEN. The TP53 IS mutations were TP53R43H, TP53Y73X, TP53K93Q, TP53K93R, TP53D149E, and TP53Q199X; whereas for PIK3CA, the IS mutations were PIK3CAL156V, PIK3CAM610K, and PIK3CAH1047R. Analysis from the ConSurf Web server revealed five SNVs with a highly conserved status (conservation score 9) across TP53 and PTEN. TP53P33R was found predominant in the grade 3 tumors, whereas PTENp.C65S was distributed on ER+, ER-, PR+, PR-, Her2+, and Her2- patients. TP53p.P33R mutation was found to be recurring in the 14/19 (73.6%) patients and, therefore, can be considered as a potential biomarker. Finally, these mutations were studied in the context of their potential association with different hormonal and social factors.

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