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1.
Mini Rev Med Chem ; 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38629363

ABSTRACT

One of the most important organic compounds, also known as a Schiff base, imine, or azomethine, has been associated with several biological processes. The group is a component of both natural or synthetic chemicals and functions as both a precursor and an intermediary in the synthesis of therapeutically active substances. The review highlights the various non-metal Schiff bases' structure-activity relationship (SAR) studies, general model, docking, and design approach for anticonvulsant actions. Schiff bases serve as linkers in numerous synthetic compounds with a variety of activities, according to the findings of several investigations. As a result, the current review will give readers a thorough understanding of the key ideas put forth by different researchers regarding the anticonvulsant properties of Schiff bases. It will serve as a valuable information source for those planning to synthesize new anticonvulsant molecules that contain Schiff bases as pharmacophores or biologically active moieties.

2.
Chem Biodivers ; 21(5): e202301493, 2024 May.
Article in English | MEDLINE | ID: mdl-38327030

ABSTRACT

Nelumbo nucifera Gaertn is a recognised herbal plant in ancient medical sciences. Each portion of the plant leaf, flower, seed and rhizome is utilised for nutritional and medicinal purposes. The chemical compositions like phenol, alkaloids, glycoside, terpenoids and steroids have been isolated. The plant contains various nutritional values like lipids, proteins, amino acids, minerals, carbohydrates, and fatty acids. Traditional medicine confirms that the phytochemicals of plants give significant benefits to the treatment of various diseases such as leukoderma, smallpox, dysentery, haematemesis, coughing, haemorrhage, metrorrhagia, haematuria, fever, hyperlipidaemia, cholera, hepatopathy and hyperdipsia. To verify the traditional claims, researchers have conducted scientific biological in vivo and in vitro screenings, which have exhibited that the plant keeps various notable pharmacological activities such as anticancer, hepatoprotective, antioxidant, antiviral, hypolipidemic, anti-obesity, antipyretic, hypoglycaemic, antifungal, anti-inflammatory and antibacterial activities. This review, summaries the nutritional composition, chemical constituents and biological activities substantiated by the researchers done in vivo and in vitro.


Subject(s)
Nelumbo , Nelumbo/chemistry , Humans , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Extracts/isolation & purification , Animals , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/isolation & purification , Phytochemicals/pharmacology , Phytochemicals/chemistry , Phytochemicals/isolation & purification
3.
Environ Sci Pollut Res Int ; 31(3): 4910-4924, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38110678

ABSTRACT

Glaciers, in general, are sensitive to changes in the climate but Himalayan glaciers, in particular, are highly affected by climate change. Mass balance (MB) of glaciers is one of the important parameters to examine the response of glaciers to climate variability and change. The study of mass balance sensitivity (MBS) due to climate perturbations for glaciers is also important to understand future behavior of the glaciers. For Chhota Shigri Glacier, research on the estimation of long-term annual and seasonal MB and MBS as well as equilibrium-line altitude (ELA) and accumulation area ration (AAR) sensitivity analysis is not reported in detail. Accordingly, the present study carries out a detailed analysis of annual and seasonal MBS from 1953 to 2014 using annual and monthly climate perturbations as well as ELA and AAR sensitivities for the Chhota Shigri Glacier. The long-term annual and seasonal MB of Chhota Shigri Glacier from 1953 to 2014 is reconstructed using distributed temperature-index model by simulating minimal model parameters, namely melt factor, snow, and ice radiations using Monte-Carlo simulation. The mean annual MB of Chhota Shigri was -0.28 ± 0.41 m w.e./year during 1953-2014. The annual MB decreased from - 0.09 ± 0.41 m w.e./year (1953-1968) to - 0.57 ± 0.41 m w.e./year (2000-2014). The estimated MBS of Chhota Shigri Glacier is 0.57 m w.e./°C due to temperature change which is high and can be attributed to the presence of significantly less debris-covered ice in Chhota Shigri Glacier. It is analyzed that ELA and AAR of Chhota Shigri Glacier will change to + 107.7 m a.s.l. and - 15.03% respectively due to increase in temperature by + 1 °C. Further, ~ 38% more precipitation is required to compensate for the change in MB, ELA and AAR which will occur due to + 1 °C temperature rise. The findings of the present study will also support the estimation of future MB of Chhota Shigri Glacier using minimal simulated model parameters for distributed temperature-index model which have been found to produce good results using long term high resolution climate data.


Subject(s)
Climate Change , Ice Cover , Himalayas , Seasons , Freezing
4.
Adv Respir Med ; 91(6): 516-531, 2023 Nov 14.
Article in English | MEDLINE | ID: mdl-37987300

ABSTRACT

The potential cancer risk associated with electronic-cigarette (e-cigarette) use is ongoing and remains a subject of debate. E-Cigarettes work by heating a liquid that usually contains nicotine, flavorings, and other chemicals. When the liquid is heated, users inhale an aerosol into their lungs. While e-cigarettes are generally considered less harmful than traditional tobacco products, they still contain potentially harmful chemicals, which can damage DNA and lead to cancer. Several studies have investigated the potential cancer risk associated with e-cigarette use, while other studies have suggested that e-cigarette aerosol may contain carcinogenic chemicals that could increase the risk of lung and bladder cancer in humans. However, these studies are limited in their scope and do not provide conclusive evidence. Overall, the long-term cancer risk associated with e-cigarette use remains uncertain, more research is needed to fully understand the potential risks and benefits of e-cigarettes. However, this review will allow the investigator to get more recent updates about e-cigarettes.


Subject(s)
Electronic Nicotine Delivery Systems , Urinary Bladder Neoplasms , Vaping , Humans , Nicotine/adverse effects , Vaping/adverse effects , Aerosols
5.
Sci Rep ; 13(1): 18449, 2023 10 27.
Article in English | MEDLINE | ID: mdl-37891223

ABSTRACT

Obesity is a complex disease caused by various factors, and synthetic drugs used to treat it can have side effects. Natural compounds, such as olivetol, could be a promising alternative. Olivetol is a substance found in certain lichen species and has anti-inflammatory and anti-cancer properties. In this study, researchers conducted in-silico molecular docking studies and found that olivetol had significant binding affinity with receptors involved in obesity. They also investigated the effects of olivetol on a diet-induced obese zebrafish model and found that high doses of olivetol reduced excessive fat accumulation and triglyceride and lipid accumulation. The low dose of olivetol showed a significant reduction in liver enzymes' levels. However, the high dose of olivetol resulted in a significant increase in HMG-CoA levels. These results suggest that olivetol may be a promising anti-obesity agent for the treatment of hyperlipidemia-related disorders, but further research is necessary to understand its full effects on the body.


Subject(s)
Anti-Obesity Agents , Diet, High-Fat , Animals , Diet, High-Fat/adverse effects , Zebrafish , Molecular Docking Simulation , Lipid Metabolism , Obesity/drug therapy , Obesity/etiology , Obesity/metabolism , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/therapeutic use , Anti-Obesity Agents/metabolism , Liver/metabolism
6.
ACS Omega ; 8(22): 19976-19986, 2023 Jun 06.
Article in English | MEDLINE | ID: mdl-37305294

ABSTRACT

Soluble signaling molecules and extracellular matrix (ECM) regulate cell dynamics in various biological processes. Wound healing assays are widely used to study cell dynamics in response to physiological stimuli. However, traditional scratch-based assays can damage the underlying ECM-coated substrates. Here, we use a rapid, non-destructive, label-free magnetic exclusion technique to form annular aggregates of bronchial epithelial cells on tissue-culture treated (TCT) and ECM-coated surfaces within 3 h. The cell-free areas enclosed by the annular aggregates are measured at different times to assess cell dynamics. The effects of various signaling molecules, including epidermal growth factor (EGF), oncostatin M, and interleukin 6, on cell-free area closures are investigated for each surface condition. Surface characterization techniques are used to measure the topography and wettability of the surfaces. Further, we demonstrate the formation of annular aggregates on human lung fibroblast-laden collagen hydrogel surfaces, which mimic the native tissue architecture. The cell-free area closures on hydrogels indicate that the substrate properties modulate EGF-mediated cell dynamics. The magnetic exclusion-based assay is a rapid and versatile alternative to traditional wound healing assays.

7.
Chem Biodivers ; 20(2): e202201029, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36703592

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) may vary from moderately mild non-alcohol fatty liver (NAFL) towards the malignant variant known as non-alcoholic steatohepatitis (NASH), which is marked by fatty liver inflammation and may progress to liver cirrhosis (LC), liver cancer, fibrosis, or liver failure. Flavonoids can protect the liver from toxins through their anti-inflammatory, antioxidant, anti-cancer, and antifibrogenic pharmacological activities. Furthermore, flavonoids protect against LC by regulation of hepatic stellate cells (HSCs) trans-differentiation, inhibiting growth factors like TGF-ß and platelets-derived growth factor (PDGF), vascular epithelial growth factor (VEGF), viral infections like hepatitis-B, C and D viruses (HBV, HCV & HDV), autoimmune-induced, alcohol-induced, metabolic disorder-induced, causing by apoptosis, and regulating MAPK pathways. These flavonoids may be explored in the future as a therapeutic solution for hepatic diseases.


Subject(s)
Flavonoids , Non-alcoholic Fatty Liver Disease , Humans , Flavonoids/metabolism , Liver Cirrhosis/drug therapy , Liver/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Intercellular Signaling Peptides and Proteins/metabolism
8.
J Gastrointest Cancer ; 54(1): 213-226, 2023 Mar.
Article in English | MEDLINE | ID: mdl-35023010

ABSTRACT

BACKGROUND: Cholangiocarcinoma (CCA) is a malignant disease of the epithelial cells of the intrahepatic and extrahepatic bile ducts. This review focuses on various aspects of cholangiocarcinoma such as its associated causes, treatment criteria, and more. METHODS: Although it remains a rare malignancy and is the second most common primary malignancy of the liver, the incidence is increasing, especially the incidence of intrahepatic CCA. Several studies suggested that surgery is not only solution; recently, reported targeted drugs may have the potential to become an alternative option. RESULTS: This review provides an overview of the current scenario of targeted therapies for CCA, which were tabulated with their current status and it also included its associated causes and its treatment criteria. CONCLUSION: Because of its rarity and complexity, surgery remains the preferred treatment in resectable patients. Howerver, the studies suggested that the recently reported drugs may have the potential to be an alternative option for the treatment of CCA and related complications. In addition, this review will certainly benefit the community and researcher for further investigation.


Subject(s)
Bile Duct Neoplasms , Bile Ducts, Extrahepatic , Cholangiocarcinoma , Cholangitis, Sclerosing , Humans , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/therapy , Bile Duct Neoplasms/complications , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/pathology , Cholangitis, Sclerosing/surgery , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/therapy , Cholangiocarcinoma/pathology , Bile Ducts, Extrahepatic/pathology
9.
Bioinformation ; 19(13): 1377-1382, 2023.
Article in English | MEDLINE | ID: mdl-38415031

ABSTRACT

Four surgical treatment modalities namely cryosurgery, scalpel and blade surgery, diode LASER surgery and CO2 LASER surgery in the management of oral potentially malignant disorders (OPMDs) in terms of healing outcomes post operatively and recurrence is evaluated. The study included sixty outpatients whose biopsies revealed OPMDs (oral lichen planus, homogeneous leukoplakia, non-homogenous leukoplakia and erythroplakia). There is decrease in post-operative pain and oedema in all four treatment categories at one week follow up and two week follow up. It was observed that pain was low in cryosurgery treatment category at day of surgery as well as at one week of follow up as compared to diode LASER and CO2 LASER. Observations from the study highlights that all four surgical modalities used in this study were effective for treatment of OPMDs, and the overall summation of the results of the study showed that cryotherapy seems to offer better clinically significant results than laser therapy.

10.
Toxicol Rep ; 9: 977-998, 2022.
Article in English | MEDLINE | ID: mdl-35783250

ABSTRACT

Methylmercury (MeHg+) is a known neurotoxin that causes progressive motor neuron degeneration in the central nervous system. Axonal degeneration, oligodendrocyte degeneration, and myelin basic protein (MBP) deficits are among the neuropathological abnormalities caused by MeHg+ in amyotrophic lateral sclerosis (ALS). This results in demyelination and motor neuron death in both humans and animals. Previous experimental studies have confirmed that overexpression of the extracellular signalling regulated kinase (ERK1/2) signalling contributes to glutamate excitotoxicity, inflammatory response of microglial cells, and oligodendrocyte (OL) dysfunction that promotes myelin loss. Alpha-mangostin (AMG), an active ingredient obtained from the tree "Garcinia mangostana Linn," has been used in experimental animals to treat a variety of brain disorders, including Parkinson's and Huntington's disease memory impairment, Alzheimer's disease, and schizophrenia, including Parkinson's disease and Huntington's disease memory impairment, Alzheimer's disease, and schizophrenia. AMG has traditionally been used as an antioxidant, anti-inflammatory, and neuroprotective agent.Accordingly, we investigated the therapeutic potential of AMG (100 and 200 mg/kg) in experimental rats with methylmercury (MeHg+)-induced neurotoxicity. The neuroprotective effect of AMG on behavioural, cellular, molecular, and other gross pathological changes, such as histopathological alterations in MeHg+ -treated rat brains, is presented. The neurological behaviour of experimental rats was evaluated using a Morris water maze (MWM), open field test (OFT), grip strength test (GST), and force swim test (FST). In addition, we investigate AMG's neuroprotective effect by restoring MBP levels in cerebral spinal fluid and whole rat brain homogenate. The apoptotic, pro-inflammatory, and oxidative stress markers were measured in rat blood plasma samples and brain homogenate. According to the findings of this study, AMG decreases ERK-1/2 levels and modulates neurochemical alterations in rat brains, minimising MeHg+ -induced neurotoxicity.

11.
Hum Exp Toxicol ; 41: 9603271221084276, 2022.
Article in English | MEDLINE | ID: mdl-35373622

ABSTRACT

Methylmercury (MeHg) is a neurotoxin that induces neurotoxicity and cell death in neurons. MeHg increases oligodendrocyte death, glial cell activation, and motor neuron demyelination in the motor cortex and spinal cord. As a result, MeHg plays an important role in developing neurocomplications similar to amyotrophic lateral sclerosis (ALS). Recent research has implicated c-JNK and p38MAPK overactivation in the pathogenesis of ALS. Apigenin (APG) is a flavonoid having anti-inflammatory, antioxidant, and c-JNK/p38MAPK inhibitory activities. The purpose of this study is to determine whether APG possesses neuroprotective effects in MeHg-induced neurotoxicity in adult rats associated with ALS-like neuropathological alterations. In the current study, the neurotoxin MeHg causes an ALS-like phenotype in Wistar rats after 21 days of oral administration at a dose of 5 mg/kg. Prolonged administration of APG (40 and 80 mg/kg) improved neurobehavioral parameters such as learning memory, cognition, motor coordination, and grip strength. This is mainly associated with the downregulation of c-JNK and p38MAPK signaling as well as the restoration of myelin basic protein within the brain. Furthermore, APG inhibited neuronal apoptotic markers (Bax, Bcl-2, and caspase-3), restored neurotransmitter imbalance, decreased inflammatory markers (TNF- and IL-1), and alleviated oxidative damage. As a result, the current study shows that APG has neuroprotective potential as a c-JNK and p38MAPK signaling inhibitor against MeHg-induced neurotoxicity in adult rats. Based on these promising findings, we suggested that APG could be a potential new therapeutic approach over other conventional therapeutic approaches for MeHg-induced neurotoxicity in neurobehavioral, molecular, and neurochemical abnormalities.


Subject(s)
Methylmercury Compounds , Neurotoxicity Syndromes , Animals , Apigenin/metabolism , Apigenin/pharmacology , Apigenin/therapeutic use , Methylmercury Compounds/metabolism , Methylmercury Compounds/toxicity , Neurons/metabolism , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/prevention & control , Rats , Rats, Wistar
12.
Mini Rev Med Chem ; 22(2): 248-272, 2022.
Article in English | MEDLINE | ID: mdl-34126914

ABSTRACT

The incidence of cancer is increasing worldwide, affecting a vast majority of the human population, therefore, new different anticancer agents are being developed now and their safety still needs to be evaluated. Among them, pyridine based drugs are contributing a lot, as they are one of the imperative pharmacophores occurring synthetically as well as naturally in heterocyclic compounds, having a wide-range of therapeutic applications in the area of drug discovery that offers many chances for further improvement in antitumor agents via acting onto numerous receptors of extreme prominence. Many pyridine derivatives are reported to inhibit enzymes, receptors and many other targets for controlling and curing the global health issue of cancer. Nowadays in combination with other moieties, researchers are focusing on the development of pyridine-based new derivatives for cancer treatment. Therefore, this review sheds light on the recent therapeutic expansion of pyridine together with its molecular docking, structure-activity-relationship, availability in the market, a summary of recently patented and published research works that shall jointly help the scientists to produce effective drugs with the desired pharmacological activity.


Subject(s)
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Humans , Molecular Docking Simulation , Molecular Structure , Neoplasms/drug therapy , Pyridines/pharmacology , Pyridines/therapeutic use , Structure-Activity Relationship
13.
Talanta ; 236: 122841, 2022 Jan 01.
Article in English | MEDLINE | ID: mdl-34635231

ABSTRACT

A rapid detection test for SARS-CoV-2 is urgently required to monitor virus spread and containment. Here, we describe a test that uses nanoprobes, which are gold nanoparticles functionalized with an aptamer specific to the spike membrane protein of SARS-CoV-2. An enzyme-linked immunosorbent assay confirms aptamer binding with the spike protein on gold surfaces. Protein recognition occurs by adding a coagulant, where nanoprobes with no bound protein agglomerate while those with sufficient bound protein do not. Using plasmon absorbance spectra, the nanoprobes detect 16 nM and higher concentrations of spike protein in phosphate-buffered saline. The time-varying light absorbance is examined at 540 nm to determine the critical coagulant concentration required to agglomerates the nanoprobes, which depends on the protein concentration. This approach detects 3540 genome copies/µl of inactivated SARS-CoV-2.


Subject(s)
COVID-19 , Metal Nanoparticles , Gold , Humans , Oligonucleotides , SARS-CoV-2
14.
FEMS Yeast Res ; 21(8)2021 12 15.
Article in English | MEDLINE | ID: mdl-34894216

ABSTRACT

Histone tail residues drive many biological processes by regulating genome-wide transcription. Functions of histone H3 and H4 tail residues in stress-responsive gene transcriptional programs have been extensively studied. The H2A tail residues have been shown to regulate DNA damage repair and oxidative stress response, but the involvement of N-terminal tail of H2A (H2ANtT) in proteostasis regulation is unknown. The unfolded protein response pathway (UPR) is an essential mechanism adopted by cells to prevent protein toxicity in response to ER stress. The disturbance in ER can occur by various factors such as heat stress, redox imbalance, exposure to xenobiotics and metals. Copper is utilized as a cofactor by cellular enzymes, but excessive copper affects ER homeostasis. We found that cells lacking 1-20 residues of H2ANtT are intolerant to copper stress, owing to the accumulation of misfolded proteins in the mutant cells. H2A 1-20 truncation also reduces the physiological UPR, and copper exposure further aggravates this effect. Furthermore, the expression of a spliced version of HAC1 mRNA in H2A∆(1-20) cells, encoding the downstream transcription factor of UPR signalling, rescues their growth under copper stress. Altogether these results provide evidence that H2ANtT reduces copper-induced ER stress by regulating UPR signalling.


Subject(s)
Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Basic-Leucine Zipper Transcription Factors/genetics , Copper/metabolism , Copper/toxicity , Repressor Proteins/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Unfolded Protein Response
15.
Eur J Cell Biol ; 100(7-8): 151179, 2021.
Article in English | MEDLINE | ID: mdl-34560374

ABSTRACT

Cell signal transduction pathways are essential modulators of several physiological and pathological processes in the brain. During overactivation, these signaling processes may lead to disease progression. Abnormal protein kinase activation is associated with several biological dysfunctions that facilitate neurodegeneration under different biological conditions. As a result, these signaling pathways are essential in understanding brain disorders' development or progression. Recent research findings indicate the crucial role of extracellular signal-regulated kinase-1/2 (ERK-1/2) signaling during the neuronal development process. ERK-1/2 is a key component of its mitogen-activated protein kinase (MAPK) group, controlling certain neurological activities by regulating metabolic pathways, cell proliferation, differentiation, and apoptosis. ERK-1/2 also influences neuronal elastic properties, nerve growth, and neurological and cognitive processing during brain injuries. The primary goal of this review is to elucidate the activation of ERK1/2 signaling, which is involved in the development of several ALS-related neuropathological dysfunctions. ALS is a rare neurological disorder category that mainly affects the nerve cells responsible for regulating voluntary muscle activity. ALS is progressive, which means that the symptoms are getting worse over time, and there is no cure for ALS and no effective treatment to avoid or reverse. Genetic abnormalities, oligodendrocyte degradation, glial overactivation, and immune deregulation are associated with ALS progression. Furthermore, the current review also identifies ERK-1/2 signaling inhibitors that can promote neuroprotection and neurotrophic effects against the clinical-pathological presentation of ALS. As a result, in the future, the potential ERK-1/2 signaling inhibitors could be used in the treatment of ALS and related neurocomplications.


Subject(s)
Amyotrophic Lateral Sclerosis , Amyotrophic Lateral Sclerosis/drug therapy , Apoptosis , Cell Proliferation , Humans , MAP Kinase Signaling System , Neurons , Signal Transduction
16.
Biochim Biophys Acta Gene Regul Mech ; 1864(11-12): 194748, 2021.
Article in English | MEDLINE | ID: mdl-34454103

ABSTRACT

The SWI/SNF subfamily remodelers (SWI/SNF and RSC) generally promote gene expression by displacing or evicting nucleosomes at the promoter regions. Their action creates a nucleosome-depleted region where transcription machinery accesses the DNA. Their function has been shown critical for inducing stress-responsive transcription programs. Although the role of SWI/SNF and RSC complexes in transcription regulation of heat shock responsive genes is well studied, their involvement in other pathways such as unfolded protein response (UPR) and protein quality control (PQC) is less known. This study shows that SWI/SNF occupies the promoters of UPR, HSP and PQC genes in response to unfolded protein stress, and its recruitment at UPR promoters depends on Hac1 transcription factor and other epigenetic factors like Ada2 and Ume6. Disruption of SWI/SNF's activity does not affect the remodeling of these promoters or gene expression. However, inactivation of RSC and SWI/SNF together diminishes induction of most of the UPR, HSP and PQC genes tested. Furthermore, RSC and SWI/SNF colocalize at these promoters, suggesting that these two remodelers functionally cooperate to induce stress-responsive genes under proteotoxic conditions.


Subject(s)
Basic-Leucine Zipper Transcription Factors/metabolism , DNA-Binding Proteins/metabolism , Endoplasmic Reticulum Stress/genetics , Repressor Proteins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Transcription Factors/metabolism , Adenosine Triphosphate/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Chromatin Assembly and Disassembly , DNA-Binding Proteins/genetics , Gene Expression Regulation, Fungal , Gene Knockout Techniques , Promoter Regions, Genetic , Repressor Proteins/genetics , Saccharomyces cerevisiae Proteins/genetics , Transcription Factors/genetics , Unfolded Protein Response/genetics
17.
Biochem Cell Biol ; 99(5): 636-644, 2021 10.
Article in English | MEDLINE | ID: mdl-33843274

ABSTRACT

Histone residues play an essential role in the regulation of various biological processes. In the present study, we utilized the H3/H4 histone mutant library to probe the functional aspects of histone residues in amino acid biosynthesis. We found that the histone residue H3R72 plays a crucial role in the regulation of isoleucine biosynthesis. Substitution of the arginine residue (H3R72) of histone H3 to alanine (H3R72A) renders yeast cells unable to grow in minimal medium. Histone mutant H3R72A requires external supplementation of either isoleucine, serine, or threonine for growth in minimal medium. We also observed that the H3R72 residue and leucine amino acid in synthetic complete medium might play a crucial role in determining the intake of isoleucine and threonine in yeast. Furthermore, gene deletion analysis of ILV1 and CHA1 in the H3R72A mutant confirmed that isoleucine is the sole requirement for growth in minimal medium. Altogether, we have identified that histone H3R72 residue may be crucial for yeast growth in minimal medium by regulating isoleucine biosynthesis through the Ilv1 enzyme in the budding yeast Saccharomyces cerevisiae.


Subject(s)
Alanine/metabolism , Histones/metabolism , Isoleucine/biosynthesis , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Threonine Dehydratase/metabolism , Arginine/genetics , Arginine/metabolism , Histones/genetics , Mutation
18.
Mol Cell Biol ; 41(2)2021 01 25.
Article in English | MEDLINE | ID: mdl-33257505

ABSTRACT

Copper homeostasis is crucial for various cellular processes. The balance between nutritional and toxic copper levels is maintained through the regulation of its uptake, distribution, and detoxification via antagonistic actions of two transcription factors, Ace1 and Mac1. Ace1 responds to toxic copper levels by transcriptionally regulating detoxification genes CUP1 and CRS5 Cup1 metallothionein confers protection against toxic copper levels. CUP1 gene regulation is a multifactorial event requiring Ace1, TATA-binding protein (TBP), chromatin remodeler, acetyltransferase (Spt10), and histones. However, the role of histone H3 residues has not been fully elucidated. To investigate the role of the H3 tail in CUP1 transcriptional regulation, we screened the library of histone mutants in copper stress. We identified mutations in H3 (K23Q, K27R, K36Q, Δ5-16, Δ13-16, Δ13-28, Δ25-28, Δ28-31, and Δ29-32) that reduce CUP1 expression. We detected reduced Ace1 occupancy across the CUP1 promoter in K23Q, K36Q, Δ5-16, Δ13-28, Δ25-28, and Δ28-31 mutations correlating with the reduced CUP1 transcription. The majority of these mutations affect TBP occupancy at the CUP1 promoter, augmenting the CUP1 transcription defect. Additionally, some mutants displayed cytosolic protein aggregation upon copper stress. Altogether, our data establish previously unidentified residues of the H3 N-terminal tail and their modifications in CUP1 regulation.


Subject(s)
Copper/metabolism , DNA-Binding Proteins/genetics , Gene Expression Regulation, Fungal , Histones/genetics , Metallothionein/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae/genetics , Transcription Factors/genetics , Amino Acid Sequence , Copper/pharmacology , DNA-Binding Proteins/metabolism , Histone Acetyltransferases/genetics , Histone Acetyltransferases/metabolism , Histones/metabolism , Homeostasis/genetics , Metallothionein/metabolism , Mutation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Promoter Regions, Genetic , Protein Binding , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Signal Transduction , Stress, Physiological , TATA-Box Binding Protein/genetics , TATA-Box Binding Protein/metabolism , Transcription Factors/metabolism , Transcription, Genetic
19.
Biochem Pharmacol ; 180: 114200, 2020 10.
Article in English | MEDLINE | ID: mdl-32805211

ABSTRACT

The eukaryotic genetic material is packaged in the form of chromatin by wrapping DNA around nucleosomes. Cells maintain chromatin in a dynamic state by utilising various ATP-dependent chromatin remodelling complexes which can induce structural transformations in the chromatin. All chromatin remodelers contain an ATP hydrolysing-DNA translocase motor which facilitates nucleosomal DNA translocation. By DNA translocation ISWI and CHD subfamily remodelers slide nucleosomes and arrange them in a regularly spaced array. While SWI/SNF subfamily remodelers evict or displace nucleosomes from chromatin, which promotes recruitment of transcription machinery and DNA repair factors on the DNA. Besides DNA translocation, ISWI, CHD and INO80 subfamily remodelers escort nucleosome organisation and editing. In this review; we discuss different mechanisms by which chromatin remodelers regulate chromatin accessibility, nucleosome assembly and nucleosome editing. We attempt to elucidate how their action mediates various cellular and developmental processes, and their deregulation leads to disease pathogenesis. We emphasised on their role in cancer progression and potential therapeutic implications of these complexes. We also described the drugs and strategies which are being developed to target different subunits of remodelling complexes, histone modifying enzymes and polycomb repressive complex. This includes ATPase inhibitors, EZH2 (enhancer of zeste homolog 2) inhibitors, BET (bromodomain and extra terminal) inhibitors, PROTAC (proteolysis targeting chimaera) and inhibitors of protein-protein interaction.


Subject(s)
Chromatin Assembly and Disassembly/drug effects , Chromatin/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Nervous System Diseases/drug therapy , Nervous System Diseases/metabolism , Adenosine Triphosphatases/antagonists & inhibitors , Adenosine Triphosphatases/metabolism , Animals , Chromatin Assembly and Disassembly/physiology , DNA Repair/drug effects , DNA Repair/physiology , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Enhancer of Zeste Homolog 2 Protein/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/metabolism , Protein Structure, Secondary , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Cell Surface/metabolism
20.
Research (Wash D C) ; 2020: 3970530, 2020.
Article in English | MEDLINE | ID: mdl-32776011

ABSTRACT

Fibroblasts (mouse, NIH/3T3) are combined with MDA-MB-231 cells to accelerate the formation and improve the reproducibility of 3D cellular structures printed with magnetic assistance. Fibroblasts and MDA-MB-231 cells are cocultured to produce 12.5 : 87.5, 25 : 75, and 50 : 50 total population mixtures. These mixtures are suspended in a cell medium containing a paramagnetic salt, Gd-DTPA, which increases the magnetic susceptibility of the medium with respect to the cells. A 3D monotypic MDA-MB-231 cellular structure is printed within 24 hours with magnetic assistance, whereas it takes 48 hours to form a similar structure through gravitational settling alone. The maximum projected areas and circularities, and cellular ATP levels of the printed structures are measured for 336 hours. Increasing the relative amounts of the fibroblasts mixed with the MDA-MB-231 cells decreases the time taken to form the structures and improves their reproducibility. Structures produced through gravitational settling have larger maximum projected areas and cellular ATP, but are deemed less reproducible. The distribution of individual cell lines in the cocultured 3D cellular structures shows that printing with magnetic assistance yields 3D cellular structures that resemble in vivo tumors more closely than those formed through gravitational settling. The results validate our hypothesis that (1) fibroblasts act as a "glue" that supports the formation of 3D cellular structures, and (2) the structures are produced more rapidly and with greater reproducibility with magnetically assisted printing than through gravitational settling alone. Printing of 3D cellular structures with magnetic assistance has applications relevant to drug discovery, lab-on-chip devices, and tissue engineering.

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