Important Protein Research Articles

Generic model to unravel the deeper insights of viral infections: an empirical application of evolutionary graph coloring in computational network biology

PurposeGraph coloring approach has emerged as a valuable problem-solving tool for both theoretical and practical aspects across various scientific disciplines, including biology. In this study, we demonstrate the graph coloring’s effectiveness in computational network biology, more precisely in analyzing protein–protein interaction (PPI) networks to gain insights about the viral infections and its consequences on human health. Accordingly, we propose a generic model that can highlight important hub proteins of virus-associated disease manifestations, changes in disease-associated biological pathways, potential drug targets and respective drugs. We test our model on SARS-CoV-2 infection, a highly transmissible virus responsible for the COVID-19 pandemic. The pandemic took significant human lives, causing severe respiratory illnesses and exhibiting various symptoms ranging from fever and cough to gastrointestinal, cardiac, renal, neurological, and other manifestations.MethodsTo investigate the underlying mechanisms of SARS-CoV-2 infection-induced dysregulation of human pathobiology, we construct a two-level PPI network and employed a differential evolution-based graph coloring (DEGCP) algorithm to identify critical hub proteins that might serve as potential targets for resolving the associated issues. Initially, we concentrate on the direct human interactors of SARS-CoV-2 proteins to construct the first-level PPI network and subsequently applied the DEGCP algorithm to identify essential hub proteins within this network. We then build a second-level PPI network by incorporating the next-level human interactors of the first-level hub proteins and use the DEGCP algorithm to predict the second level of hub proteins.ResultsWe first identify the potential crucial hub proteins associated with SARS-CoV-2 infection at different levels. Through comprehensive analysis, we then investigate the cellular localization, interactions with other viral families, involvement in biological pathways and processes, functional attributes, gene regulation capabilities as transcription factors, and their associations with disease-associated symptoms of these identified hub proteins. Our findings highlight the significance of these hub proteins and their intricate connections with disease pathophysiology. Furthermore, we predict potential drug targets among the hub proteins and identify specific drugs that hold promise in preventing or treating SARS-CoV-2 infection and its consequences.ConclusionOur generic model demonstrates the effectiveness of DEGCP algorithm in analyzing biological PPI networks, provides valuable insights into disease biology, and offers a basis for developing novel therapeutic strategies for other viral infections that may cause future pandemic.

PHARMACOINFORMATICS ANALYSIS OF MORUS MACROURA FOR DRUG DISCOVERY AND DEVELOPMENT

Objective: Pharmacoinformatics is an innovative approach rapidly evolving in pharmaceutical research and drug development. This study focuses on analysing Morus macroura, a plant species with untapped pharmacological potential. This investigation aims to leverage pharmacoinformatics techniques to unveil the hidden potential of Morus macroura in drug discovery and development.
 Methods: The study includes analyses of protein-protein interactions, deep learning docking, adsorption tests, distribution, metabolism, excretion, molecular dynamics simulations and free energy calculation using Molecular Mechanics Generalized Born Surface Area (MMGBSA).
 Results: Nine active compounds were identified in Morus macroura, namely Andalasin A, Guangsangon K, Guangsangon L, Guangsangon M, Guangsangon N, Macrourone C, Mulberrofuran G, Mulberrofuran K, and Mulberroside C. These compounds exhibit protein-protein interaction activities against a cytochrome P450 monooxygenase that catalyses the conversion of C19 androgens. These plant compounds influence aromatase excess syndrome, deficiency, and ovarian dysgenesis. Regarding drug-likeness, Mulberroside C and Macrourone C demonstrated good absorption potential by adhering to Lipinski's rule of five. Deep learning docking simulations yielded affinity results of-9.62 kcal/mol for Guangsangon M,-10.44 kcal/mol for Macrourone C, and-10.99 kcal/mol for Guangsangon L. Subsequent molecular dynamics simulations indicated that Guangsangon L and Macrourone C remained stable during a 100 ns simulation.
 Conclusion: Morus macroura interacts with important proteins, particularly CYP19A1, which might influence health conditions like aromatase excess syndrome and ovarian dysgenesis. These findings provide potential paths for addressing specific health issues and advancing drug development. Molecular dynamics simulations indicated that Guangsangon L and Macrourone C remained stable during simulation.

African swine fever virus pH240R enhances viral replication via inhibition of the type I IFN signaling pathway.

African swine fever (ASF) is an acute, hemorrhagic, and severe infectious disease caused by ASF virus (ASFV) infection. At present, there are still no safe and effective drugs and vaccines to prevent ASF. Mining the important proteins encoded by ASFV that affect the virulence and replication of ASFV is the key to developing effective vaccines and drugs. In this study, ASFV pH240R, a capsid protein of ASFV, was found to inhibit the type I interferon (IFN) signaling pathway. Mechanistically, pH240R interacted with IFNAR1 and IFNAR2 to disrupt the interaction of IFNAR1-TYK2 and IFNAR2-JAK1. Additionally, pH240R inhibited the phosphorylation of IFNAR1, TYK2, and JAK1 induced by IFN-α, resulting in the suppression of the nuclear import of STAT1 and STAT2 and the expression of IFN-stimulated genes (ISGs). Consistent with these results, H240R-deficient ASFV (ASFV-∆H240R) infection induced more ISGs in porcine alveolar macrophages compared with its parental ASFV HLJ/18. We also found that pH240R enhanced viral replication via inhibition of ISGs expression. Taken together, our results clarify that pH240R enhances ASFV replication by inhibiting the JAK-STAT signaling pathway, which highlights the possibility of pH240R as a potential drug target.IMPORTANCEThe innate immune response is the host's first line of defense against pathogen infection, which has been reported to affect the replication and virulence of African swine fever virus (ASFV) isolates. Identification of ASFV-encoded proteins that affect the virulence and replication of ASFV is the key step in developing more effective vaccines and drugs. In this study, we found that pH240R interacted with IFNAR1 and IFNAR2 by disrupting the interaction of IFNAR1-TYK2 and IFNAR2-JAK1, resulting in the suppression of the expression of interferon (IFN)-stimulated genes (ISGs). Consistent with these results, H240R-deficient ASFV (ASFV-∆H240R) infection induces more ISGs' expression compared with its parental ASFV HLJ/18. We also found that pH240R enhanced viral replication via inhibition of ISGs' expression. Taken together, our findings showed that pH240R enhances ASFV replication by inhibiting the IFN-JAK-STAT axis, which highlights the possibility of pH240R as a potential drug target.

Comprehensive Analysis of the SUMO-related Signature: Implication for Diagnosis, Prognosis, and Immune Therapeutic Approaches in Cervical Cancer.

SUMOylation, an important post-translational protein modification, plays a critical role in cancer development and immune processes. This study aimed to construct diagnostic and prognostic models for cervical cancer (CC) using SUMOylation-related genes (SRGs) and explore their implications for novel clinical therapies. We analyzed the expression profiles of SRGs in CC patients and identified 15 SRGs associated with CC occurrence. After the subsequent qPCR verification of 20 cases of cancer and adjacent tissues, 13 of the 15 SRGs were differentially expressed in cancer tissues. Additionally, we identified molecular markers associated with the prognosis and recurrence of CC patients, based on SRGs. Next, a SUMOScore, based on SRG expression patterns, was generated to stratify patients into different subgroups. The SUMOScore showed significant associations with the tumor microenvironment, immune function features, immune checkpoint expression, and immune evasion score in CC patients, highlighting the strong connection between SUMOylation factors and immune processes. In terms of immune therapy, our analysis identified specific chemotherapy drugs with higher sensitivity in the subgroups characterized by high and low SUMOScore, indicating potential treatment options. Furthermore, we conducted drug sensitivity analysis to evaluate the response of different patient subgroups to conventional chemotherapy drugs. Our findings revealed enrichment of immune-related pathways in the low-risk subgroup identified by the prognostic model. In conclusion, this study presents diagnostic and prognostic models based on SRGs, accompanied by a comprehensive index derived from SRGs expression patterns. These findings offer valuable insights for CC diagnosis, prognosis, treatment, and immune-related analysis.

Two Main Cancer Biomarkers as Molecular Targets of Binase Antitumor Activity.

Cancer is frequently coupled with the disturbance of key signaling pathways. Aberrant activation of the mitogen-activated protein kinase (MAPK) signaling cascade, occurring in over 85% of cancers, is mainly caused by the genetic alterations of its main components-oncogenes EGFR and RAS, and plays a crucial role in cell fate. The importance of EGFR and RAS proteins in a variety of tumors suggests that they would be good therapeutic targets, but at present, no effective targeted therapy against these two oncogenes has been proven. Here, we show that ribonuclease from Bacillus pumilus (binase) inhibits MAPK signaling through direct interaction with EGFR and RAS proteins. This effect contributes to the antitumor potential of binase along with its enzymatic activity. Multitargeticity of binase prevents the development of drug resistance, which is considered a major obstacle to effective anticancer treatment.

Plasma proteomic profiles predict future dementia in healthy adults.

The advent of proteomics offers an unprecedented opportunity to predict dementia onset. We examined this in data from 52,645 adults without dementia in the UK Biobank, with 1,417 incident cases and a follow-up time of 14.1 years. Of 1,463 plasma proteins, GFAP, NEFL, GDF15 and LTBP2 consistently associated most with incident all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VaD), and ranked high in protein importance ordering. Combining GFAP (or GDF15) with demographics produced desirable predictions for ACD (area under the curve (AUC) = 0.891) and AD (AUC = 0.872) (or VaD (AUC = 0.912)). This was also true when predicting over 10-year ACD, AD and VaD. Individuals with higher GFAP levels were 2.32 times more likely to develop dementia. Notably, GFAP and LTBP2 were highly specific for dementia prediction. GFAP and NEFL began to change at least 10 years before dementia diagnosis. Our findings strongly highlight GFAP as an optimal biomarker for dementia prediction, even more than 10 years before the diagnosis, with implications for screening people at high risk for dementia and for early intervention.

Peroxin MoPex22 Regulates the Import of Peroxisomal Matrix Proteins and Appressorium-Mediated Plant Infection in Magnaporthe oryzae.

Magnaporthe oryzae, the pathogen responsible for rice blast disease, utilizes specialized infection structures known as appressoria to breach the leaf cuticle and establish intracellular, infectious hyphae. Our study demonstrates that the peroxin MoPex22 is crucial for appressorium function, specifically for the development of primary penetration hyphae. The ∆Mopex22 mutant exhibited slow growth, reduced aerial hyphae, and almost complete loss of virulence. Specifically, despite the mutant's capability to form appressoria, it showed abnormalities during appressorium development, including reduced turgor, increased permeability of the appressorium wall, failure to form septin rings, and significantly decreased ability to penetrate host cells. Additionally, there was a delay in the degradation of lipid droplets during conidial germination and appressorium development. Consistent with these findings, the ΔMopex22 mutant showed an inefficient utilization of long-chain fatty acids and defects in cell wall integrity. Moreover, our findings indicate that MoPex22 acts as an anchor for MoPex4, facilitating the localization of MoPex4 to peroxisomes. Together with MoPex4, it affects the function of MoPex5, thus regulating the import of peroxisomal matrix proteins. Overall, these results highlight the essential role of MoPex22 in regulating the transport of peroxisomal matrix proteins, which affect fatty acid metabolism, glycerol accumulation, cell wall integrity, growth, appressorium development, and the pathogenicity of M. oryzae. This study provides valuable insights into the significance of peroxin functions in fungal biology and appressorium-mediated plant infection.

Novel homozygous CARD11 variants in two patients with combined immunodeficiency and atopic skin disease

BackgroundCaspase recruitment domain family, member 11 (CARD11) is an important protein which plays a fundamental role in the activation of NF-κβ pathway in lymphocytes. CARD11 deficiency can be inherited in either autosomal dominant or autosomal recessive forms and present with different phenotypes including combined immunodeficiency, atopic dermatitis, and other variable manifestations. The present report describes clinical phenotypes and immunological defects of two unrelated patients with missense homozygous variants in CARD11 presenting with combined immunodeficiency (CID) and atopic skin disease resembling that reported in dominant negative CARD11 deficiency. The patients underwent next generation sequencing, immunophenotyping of T and B subsets by flow cytometry, T cell stimulation, and evaluation of CARD11 expression.ResultsBoth patients had features suggesting CID including repeated pneumoniae with ICU admissions, chronic diarrhea, and itchy atopic skin disease. Patient-1 has homozygous missense variant in the C terminal domain (c.2839G > A, p.Glu947Lys), and patient-2 has homozygous variant in the inhibitory domain (c.1073C > G, p.Pro568Arg). Both have profound defects in Tregs with normal recent thymic emigrants, memory, and naïve CD4+ T cells. However, in response to stimulation, T cells failed to upregulate the expression of CD25. CARD11 expression by flow cytometry was decreased rather than abolished as previously described in patients with autosomal recessive CARD11 deficiency. B cells showed marked deficiency of switched memory and increase in transitional B cells.ConclusionMissense variants causing CARD11 deficiency may affect the protein function rather than the expression and can result in a phenotype combining the atopic skin disease and the features of CID.

Sequestosome 1 (p62) mitigates hypoxia-induced cardiac dysfunction by stabilizing hypoxia-inducible factor 1α and nuclear factor erythroid 2-related factor 2.

Heart failure due to ischaemic heart disease (IHD) is a leading cause of mortality worldwide. A major contributing factor to IHD-induced cardiac damage is hypoxia. Sequestosome 1 (p62) is a multi-functional adaptor protein with pleiotropic roles in autophagy, proteostasis, inflammation, and cancer. Despite abundant expression in cardiomyocytes, the role of p62 in cardiac physiology is not well understood. We hypothesized that cardiomyocyte-specific p62 deletion evokes hypoxia-induced cardiac pathology by impairing hypoxia-inducible factor 1α (Hif-1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) signalling. Adult mice with germline deletion of cardiomyocyte p62 exhibited mild cardiac dysfunction under normoxic conditions. Transcriptomic analyses revealed a selective impairment in Nrf2 target genes in the hearts from these mice. Demonstrating the functional importance of this adaptor protein, adult mice with inducible depletion of cardiomyocyte p62 displayed hypoxia-induced contractile dysfunction, oxidative stress, and cell death. Mechanistically, p62-depleted hearts exhibit impaired Hif-1α and Nrf2 transcriptional activity. Because findings from these two murine models suggested a cardioprotective role for p62, mechanisms were evaluated using H9c2 cardiomyoblasts. Loss of p62 in H9c2 cells exposed to hypoxia reduced Hif-1α and Nrf2 protein levels. Further, the lack of p62 decreased Nrf2 protein expression, nuclear translocation, and transcriptional activity. Repressed Nrf2 activity associated with heightened Nrf2-Keap1 co-localization in p62-deficient cells, which was concurrent with increased Nrf2 ubiquitination facilitated by the E3 ligase Cullin 3, followed by proteasomal-mediated degradation. Substantiating our results, a gain of p62 in H9c2 cells stabilized Nrf2 and increased the transcriptional activity of Nrf2 downstream targets. Cardiac p62 mitigates hypoxia-induced cardiac dysfunction by stabilizing Hif-1α and Nrf2.

Identification and Molecular Characterization of the CAMTA Gene Family in Solanaceae with a Focus on the Expression Analysis of Eggplant Genes under Cold Stress.

Calmodulin-binding transcription activator (CAMTA) is an important calmodulin-binding protein with a conserved structure in eukaryotes which is widely involved in plant stress response, growth and development, hormone signal transduction, and other biological processes. Although CAMTA genes have been identified and characterized in many plant species, a systematic and comprehensive analysis of CAMTA genes in the Solanaceae genome is performed for the first time in this study. A total of 28 CAMTA genes were identified using bioinformatics tools, and the biochemical/physicochemical properties of these proteins were investigated. CAMTA genes were categorized into three major groups according to phylogenetic analysis. Tissue-expression profiles indicated divergent spatiotemporal expression patterns of SmCAMTAs. Furthermore, transcriptome analysis of SmCAMTA genes showed that exposure to cold induced differential expression of many eggplant CAMTA genes. Yeast two-hybrid and bimolecular fluorescent complementary assays suggested an interaction between SmCAMTA2 and SmERF1, promoting the transcription of the cold key factor SmCBF2, which may be an important mechanism for plant cold resistance. In summary, our results provide essential information for further functional research on Solanaceae family genes, and possibly other plant families, in the determination of the development of plants.

Molecular Docking and Absorption, Distribution, Metabolism, and Excretion (ADME) Analysis: Examining the Binding Modes and Affinities of Myricetin With Insulin Receptor, Glycogen Synthase Kinase, and Glucokinase.

Aim By using molecular docking analysis (MDA) to examine its interactions with important regulatory proteins linked to diabetes, such as glycogen synthase kinase 3 beta (GSK3β), insulin receptor (IR), and glucose kinase (GCK), this study seeks to explore the therapeutic potential of myricetin, a naturally occurring flavonoid. Objective The main goal is to determine potential effects on insulin signalling, GSK3β activity, and glucose metabolism by evaluating the binding affinities of myricetin with GCK, IR, and GSK3β through MDA. In order to assess the drug affinity of myricetin, the study also intends to perform absorption, distribution, metabolism, and excretion (ADME) studies. Materials and methods To model the interaction between myricetin and the target proteins (GCK, IR, and GSK3β), we used molecular docking analysis with computational tools. ADME studies were also included in the study to evaluate drug affinity. Identification of binding sites, essential residues, and interaction stability were all part of the structural analysis. Results As evidence of possible interactions with these regulatory proteins, myricetin showed positive binding affinities with GCK, IR, and GSK3β. Strong interactions with important ligand recognition residues were seen in the docking into IR, indicating a potential impact on insulin signalling. Moreover, a strong binding affinity for GCK indicated potential effects on the metabolism of glucose. Studies using ADME confirmed the high drug affinity of myricetin. Conclusion This work sheds light on the multi-target potential of myricetin in the regulation of diabetes. It appears that it has the ability to influence glucose metabolism, suppress GSK3β activity, and regulate insulin signalling based on its interactions with IR, GSK3β, and GCK. Although these computational results show promise, more experimental work is necessary to confirm and fully understand the precise mechanisms that underlie myricetin's effects on the regulation of diabetes.

DEAD-box RNA helicase 21 interacts with porcine circovirus type 2 Cap protein and facilitates viral replication.

Porcine circovirus type 2 (PCV2) is the etiological agent of PCV2-associated diseases that pose a serious threat to the swine industry. PCV2 capsid (Cap) protein has been shown to interact with DEAD-box RNA helicase 21 (DDX21), an important protein that regulates RNA virus replication. However, whether the interaction between DDX21 and the PCV2 Cap regulates PCV2 replication remains unclear. Herein, by using western blotting, interaction assays, and knockdown analysis, we found that PCV2 infection induced the cytoplasmic relocation of DDX21 from the nucleolus in cultured PK-15 cells. Moreover, the nuclear localization signal (NLS) of PCV2 Cap interacted directly with DDX21. The NLS of PCV2 Cap and 763GSRSNRFQNK772 residues at the C-terminal domain (CTD) of DDX21 were essential for the dual interaction. Upon shRNA-mediated DDX21 depletion in PK-15 cells, we observed impaired PCV2 replication via a lentivirus-delivered system, as evidenced by decreased levels of viral protein expression and virus production. In contrast, the replication of PCV2 increased in transiently DDX21-overexpressing cells. Our results indicate that DDX21 interacts with PCV2 Cap and plays a crucial role in virus replication. These results provide a reference for developing novel potential targets for prevention and control of PCV2 infection.

Key candidate genes for male sterility in peppers unveiled via transcriptomic and proteomic analyses.

This study aimed to enhance the use of male sterility in pepper to select superior hybrid generations. Transcriptomic and proteomic analyses of fertile line 1933A and nucleic male sterility line 1933B of Capsicum annuum L. were performed to identify male sterility-related proteins and genes. The phylogenetic tree, physical and chemical characteristics, gene structure characteristics, collinearity and expression characteristics of candidate genes were analyzed. The study identified 2,357 differentially expressed genes, of which 1,145 and 229 were enriched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases, respectively. A total of 7,628 quantifiable proteins were identified and 29 important proteins and genes were identified. It is worth noting that the existence of CaPRX genes has been found in both proteomics and transcriptomics, and 3 CaPRX genes have been identified through association analysis. A total of 66 CaPRX genes have been identified at the genome level, which are divided into 13 subfamilies, all containing typical CaPRX gene conformal domains. It is unevenly distributed across 12 chromosomes (including the virtual chromosome Chr00). Salt stress and co-expression analysis show that male sterility genes are expressed to varying degrees, and multiple transcription factors are co-expressed with CaPRXs, suggesting that they are involved in the induction of pepper salt stress. The study findings provide a theoretical foundation for genetic breeding by identifying genes, metabolic pathways, and molecular mechanisms involved in male sterility in pepper.

Role of Viral Envelope Proteins in Determining Susceptibility of Viruses to IFITM Proteins.

Interferon-induced transmembrane proteins (IFITMs) are a family of proteins which inhibit infections of various enveloped viruses. While their general mechanism of inhibition seems to be non-specific, involving the tightening of membrane structures to prevent fusion between the viral envelope and cell membrane, numerous studies have underscored the importance of viral envelope proteins in determining the susceptibility of viruses to IFITMs. Mutations in envelope proteins may lead to viral escape from direct interaction with IFITM proteins or result in indirect resistance by modifying the viral entry pathway, allowing the virus to modulate its exposure to IFITMs. In a broader context, the nature of viral envelope proteins and their interaction with IFITMs can play a crucial role in the context of adaptive immunity, leading to viral envelope proteins that are more susceptible to antibody neutralization. The precise mechanisms underlying these observations remain unclear, and further studies in this field could contribute to a better understanding of how IFITMs control viral infections.

Diterpenoid Tanshinones Can Inhibit Lung Cancer Progression by Improving the Tumor Microenvironment and Downregulation of NF-κB Expression.

Diterpenoid tanshinones (DTs) are a bioactive fraction extracted from Salvia miltiorrhiza. High-performance liquid chromatography analysis revealed the presence of four compounds, namely, tanshinone IIA, tanshinone I, cryptotanshinone, and dihydrotanshinone. In this study, we aimed to propose a possible mechanism for the anti-lung cancer effect of DT. To do so, we utilized a lung cancer nude mice model and a lung cancer cell line (PC9) to investigate the effect of DT on lung cancer. We employed immunohistochemistry, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, and immunofluorescence to analyze the pharmacological role of DT in the inhibition of lung cancer growth. The results showed that DT inhibited tumor growth, induced apoptosis in the nude mice model, and reduced inflammatory cell infiltration. Additionally, DT inhibited PC9 lung cancer cells, growth, proliferation, and migration. The mechanism of action of DT involves not only directly inhibiting cell proliferation and migration but also improving the tumor microenvironment. DT significantly increased the expression of important intestinal gap junction proteins, such as zonula occludens 1 (ZO-1) and occludin I. This upregulation contributes to the reinforcement of the intestinal mucosal barrier, thereby reducing the paracellular transport of lipopolysaccharides (LPS) through the intestine. Consequently, the decreased LPS levels lead to the inhibition of NF-κB expression and downregulation of macrophage polarization, as indicated by the decreased expression of CD68. In conclusion, this study has confirmed that DT has anti-lung cancer properties by improving the inflammatory tumor microenvironment via regulating macrophage polarization and inhibiting LPS-associated immune response. These results provide new insights into the mechanism of DT action against lung cancer.

TFPIα anticoagulant function is highly dependent on protein S in vivo.

Tissue factor pathway inhibitor α (TFPIα) is the major physiological regulator of the initiation of blood coagulation. In vitro, TFPIα anticoagulant function is enhanced by its cofactor, protein S. To define the role of protein S enhancement in TFPIα anticoagulant function in vivo, we blocked endogenous TFPI in mice using a monoclonal antibody (14D1). This caused a profound increase in fibrin deposition using the laser injury thrombosis model. To explore the role of plasma TFPIα in regulating thrombus formation, increasing concentrations of human TFPIα were coinjected with 14D1, which dose-dependently reduced fibrin deposition. Inhibition of protein S cofactor function using recombinant C4b-binding protein β chain significantly reduced the anticoagulant function of human TFPIα in controlling fibrin deposition. We report an in vivo model that is sensitive to the anticoagulant properties of the TFPIα-protein S pathway and show the importance of protein S as a cofactor in the anticoagulant function of TFPIα in vivo.

Bile Acid Application in Cell-Targeting for Molecular Receptors in Relation to Hearing: A Comprehensive Review.

Bile acids play important roles in the human body, and changes in their pool can be used as markers for various liver pathologies. In addition to their functional effects in modulating inflammatory responses and cellular survivability, the unconjugated or conjugated, secondary, or primary nature of bile acids accounts for their various ligand effects. The common hydrophilic bile acids have been used successfully as local treatment to resolve drug-induced cell damage or to ameliorate hearing loss. From various literature references, bile acids show concentration and tissue-dependent effects. Some hydrophobic bile acids act as ligands modulating vitamin D receptors, muscarinic receptors, and calcium-activated potassium channels, important proteins in the inner ear system. Currently, there are limited resources investigating the therapeutic effects of bile acid on hearing loss and little to no information on detecting bile acids in the remote ear system, let alone baseline bile acid levels and their prevalence in healthy and disease conditions. This review presents both hydrophilic and hydrophobic human bile acids and their tissue-specific effects in modulating cellular integrity, thus considering the possible effects and extended therapeutic applicability of bile acids to the inner ear tissue.

Hepatitis B Virus X Protein Induces Expression Changes of miR-21, miR-22, miR-122, miR-132, and miR-222 in Huh-7 Cell Line.

Hepatitis B virus (HBV) X protein (HBx) plays a key role in hepatocellular carcinoma (HCC). HBx may alter the expression of multiple microRNAs (miRs), which are important in hepatocarcinogenesis. This study aimed to investigate the importance of HBx protein in the expression of miR-21, miR-22, miR-122, miR-132, and miR-222. A recombinant vector expressing HBx was developed. The Huh-7 cell line was transfected with the HBx-pcDNA3.1+ recombinant plasmid. A Real-Time Polymerase Chain Reaction was used to evaluate the expression of miR-21, miR-22, miR-122, miR-132, and miR-222 in the cell line. It was found that the expression of miR-21 and miR-222 was upregulated at all points of time after HBx transfection. The expression of miR-21 was 4.24-fold 72 h after transfection. The miR-22 had a 7.69-fold downregulation after 24 h, and the miR-122 had a significant downregulation after 48 h (10-fold). The miR-132 expression reached its lowest rate 12 h after HBx transfection (8.33-fold), and the miR-222 expression was upregulated in transfected cells but was not significantly different (1.18- to 2.45-fold). Thesignificant downregulation of miR-22, miR-122, and miR-132 implicates their inhibitory roles in the progression of HBV-associated HCC. The expression of these microRNAs could be used as a prognostic marker for the progression of HBV-associated liver disease.

Disrupted nuclear import of cell cycle proteins in Huntington's/PolyQ disease causes neurodevelopment defects in cellular and Drosophila model

Huntington's disease is caused by an expansion of CAG repeats in exon 1 of the huntingtin gene encoding an extended PolyQ tract within the Huntingtin protein (mHtt). This expansion results in selective degeneration of striatal medium spiny projection neurons in the basal ganglia. The mutation causes abnormalities during neurodevelopment in human and mouse models. Here, we report that mHtt/PolyQ aggregates inhibit the cell cycle in the Drosophila brain during development. PolyQ aggregates disrupt the nuclear pore complexes of the cells preventing the translocation of cell cycle proteins such as Cyclin E, E2F and PCNA from cytoplasm to the nucleus, thus affecting cell cycle progression. PolyQ aggregates also disrupt the nuclear pore complex and nuclear import in mHtt expressing mammalian CAD neurons. PolyQ toxicity and cell cycle defects can be restored by enhancing RanGAP-mediated nuclear import, suggesting a potential therapeutic approach for this disease.

Charge cluster occurrence in land plants’ mitochondrial proteomes with functional and structural insights

The Charge Clusters (CCs) are involved in key functions and are distributed according to the organism, the protein’s type, and the charge of amino acids. In the present study, we have explored the occurrence, position, and annotation as a first large-scale study of the CCs in land plants mitochondrial proteomes. A new python script was used for data curation. The Finding Clusters Charge in Protein Sequences Program was performed after adjusting the reading window size. A 44316 protein sequences belonging to 52 species of land plants were analysed. The occurrence of Negative Charge Clusters (NCCs) (1.2%) is two times more frequent than the Positive Charge Clusters (PCCs) (0.64%). Moreover, 39 and 30 NCCs were conserved in 88 and 41 proteins in intra and in inter proteomes respectively, while 14 and 21 PCCs were conserved in 53 and 85 protein sequences in intra and inter proteomes consecutively. Sequences carrying mixed CCs are rare (0.12%). Despite this low abundance, CCs play a crucial role in protein function. The CCs tend to be located mainly in the terminal regions of proteins which guarantees specific protein targeting and import into the mitochondria. In addition, the functional annotation of CCs according to Gene Ontology shows that CCs are involved in binding functions of either proteins or macromolecules which are deployed in different metabolic and cellular processes such as RNA editing and transcription. This study may provide valuable information while considering the CCs in understanding the environmental adaptation of plants. Communicated by Ramaswamy H. Sarma