Potential JAK2 Inhibitors from Selected Natural Compounds: A Promising Approach for Complementary Therapy in Cancer Patients.

Background: Janus-activated kinase 2 (JAK2) plays a pivotal role in numerous essential biological processes, including proliferation, apoptosis, and metastasis in human cells. Prior studies have indicated that inhibiting JAK2 could be a promising strategy to mitigate cell proliferation and induce apoptosis in tumor cells. Objectives: This study aimed to estimate the binding affinity of 79 herbal compounds, comprising 46 flavonoids, 21 anthraquinones, and 12 cinnamic acids, to the ATP-binding cleft of JAK2 to identify potential herbal inhibitors of JAK2. Methods: The binding affinities between ligands and JAK2 were calculated utilizing AutoDock 4.0 software in conjunction with the Cygwin environment. Cross-validation was conducted using the Schrödinger tool. Molecular dynamics simulations were employed to evaluate the stability of docked poses for the most significant JAK2 inhibitors. Furthermore, the Discovery Studio Visualizer tool was utilized to elucidate interactions between the top-ranked JAK2 inhibitors and residues within the JAK2 ATP-binding site. Results: Twelve flavonoids, two anthraquinones, and three cinnamic acids demonstrated substantial binding affinities to the protein kinase domain of the receptor, with a criterion of ΔGbinding < -10 kcal/mol. Among the studied flavonoids, anthraquinones, and cinnamic acid derivatives, orientin, chlorogenic acid, and pulmatin emerged as the most potent JAK2 inhibitors, exhibiting ΔGbinding scores of -14.49, -11.87, and -10.76 kcal/mol, respectively. Furthermore, the docked poses of orientin, pulmatin, and chlorogenic acid remained stable throughout 60 ns computer simulations. The average root mean square deviation values calculated for JAK2 when complexed with orientin, chlorogenic acid, and pulmatin were 2.04 Å, 2.06 Å, and 1.95 Å, respectively. Conclusion: This study underscores the robust inhibitory potential of orientin, pulmatin, and chlorogenic acid against JAK2. The findings hold promise for the development of novel and effective drugs for cancer treatment.

Determination of HLA class II risk alleles and prediction of self/non-self-epitopes contributing Hashimoto's thyroiditis in a group of Iranian patients.

One of the probable hypotheses for the onset of autoimmunity is molecular mimicry. This study aimed to determine the HLA-II risk alleles for developing Hashimoto's thyroiditis (HT) in order to analyze the molecular homology between candidate pathogen-derived epitopes and potentially self-antigens (thyroid peroxidase, TPO) based on the presence of HLA risk alleles. HLA-DRB1/-DQB1 genotyping was performed in 100 HT patients and 330 ethnically matched healthy controls to determine the predisposing/protective alleles for HT disease. Then, in silico analysis was conducted to examine the sequence homology between epitopes derived from autoantigens and four potentially relevant pathogens and their binding capacities to HLA risk alleles based on peptide docking analysis. We identified HLA-DRB1*03:01, *04:02, *04:05, and *11:04 as predisposing alleles and DRB1*13:01 as a potentially predictive allele for HT disease. Also, DRB1*11:04 ~ DQB1*03:01 (Pc = 0.002; OR, 3.97) and DRB1*03:01 ~ DQB1*02:01 (Pc = 0.004; OR, 2.24) haplotypes conferred a predisposing role for HT. Based on logistic regression analysis, carrying risk alleles increased the risk of HT development 4.5 times in our population (P = 7.09E-10). Also, ROC curve analysis revealed a high predictive power of those risk alleles for discrimination of the susceptible from healthy individuals (AUC, 0.70; P = 6.6E-10). Analysis of peptide sequence homology between epitopes of TPO and epitopes derived from four candidate microorganisms revealed a homology between envelop glycoprotein D of herpes virus and sequence 151-199 of TPO with remarkable binding capacity to HLA-DRB1*03:01 allele. Our findings indicate the increased risk of developing HT in those individuals carrying HLA risk alleles which can also be related to herpes virus infection.

BACE1 Inhibition Utilizing Organic Compounds Holds Promise as a Potential Treatment for Alzheimer's and Parkinson's Diseases.

Background: Neurological disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) manifest through gradually deteriorating cognitive functions. An encouraging strategy for addressing these disorders involves the inhibition of precursor-cleaving enzyme 1 (BACE1). Objectives: In the current research, a virtual screening technique was employed to identify potential BACE1 inhibitors among selected herbal isolates. Methods: This study evaluated 79 flavonoids, anthraquinones (AQs), and cinnamic acid derivatives for their potential blood-brain barrier (BBB) permeability. Using the AutoDock 4.0 tool, molecular docking analysis was conducted to determine the binding affinity of BBB permeable compounds to the BACE1 active site. Molecular dynamics (MD) simulations were performed to assess the stability of the docked poses of the most potent inhibitors. The interactions between the most effective plant-based inhibitors and the residues within the BACE1 catalytic site were examined before and after MD simulations. Results: Ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine were among the highest-ranking BACE1 inhibitors, with inhibition constant values calculated in the nanomolar range. Furthermore, during 10 ns simulations, the docked poses of these ligands were observed to be stable. Conclusion: The findings propose that ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine might serve as potential choices for the treatment of AD and PD, laying the groundwork for the creation of innovative BACE1 inhibitors.

Mechanisms Involved in Therapeutic Effects of Scutellaria baicalensis Georgi in Oral Squamous Cell Carcinoma Based on Systems Biology and Structural Bioinformatics Approaches.

Objective: Oral squamous cell carcinoma (OSCC) is the most frequent oral cancer, constituting more than 90% of all oral carcinomas. The 5-year survival rate of OSCC patients is not satisfactory, and therefore, there is an urgent need for new practical therapeutic approaches besides the current therapies to overcome OSCC. Scutellaria baicalensis Georgi (SBG) is a plant of the family Lamiaceae with several pharmaceutical properties such as antioxidant, anti-inflammatory, and anticancer effects. Previous studies have demonstrated the curative effects of SBG in OSCC. Methods: A systems biology approach was conducted to identify differentially expressed miRNAs (DEMs) in OSCC patients with a dismal prognosis compared to OSCC patients with a favorable prognosis. A protein interaction map (PIM) was built based on DEMs targets, and the hub genes within the PIM were indicated. Subsequently, the prognostic role of the hubs was studied using Kaplan-Meier curves. Next, the binding affinity of SBG's main components, including baicalein, wogonin, oroxylin-A, salvigenin, and norwogonin, to the prognostic markers in OSCC was evaluated using molecular docking analysis. Results: Survival analysis showed that overexpression of CAV1, SERPINE1, ACTB, SMAD3, HMGA2, MYC, EIF2S1, HSPA4, HSPA5, and IL6 was significantly related to a poor prognosis in OSCC. Besides, molecular docking analysis demonstrated the ΔGbinding and inhibition constant values between SBG's main components and SERPINE1, ACTB, HMGA2, EIF2S1, HSPA4, and HSPA5 were as <-8.00 kcal/mol and nanomolar concentration, respectively. The most salient binding affinity was observed between wogonin and SERPINE1 with a criterion of ΔGbinding < -10.02 kcal/mol. Conclusion: The present results unraveled potential mechanisms involved in therapeutic effects of SBG in OSCC based on systems biology and structural bioinformatics analyses.

Synergistic effects of nano curcumin mediated photodynamic inactivation and nano-silver@colistin against Pseudomonas aeruginosa biofilms.

BACKGROUND: Patients with burn injuries colonized by multidrug-resistant Pseudomonas aeruginosa face increased mortality risk. The efficacy of colistin, a last-resort treatment, is declining as resistance levels rise. P. aeruginosa's robust biofilm exacerbates antibiotic resistance. Photodynamic Inactivation (PDI) shows promise in fighting biofilm. MATERIALS AND METHODS: Nano curcumin (nCur) particles were synthesized, and their chemical characteristics were determined using zeta potential (ZP), dynamic light scattering analysis (DLS), energy-dispersive X-ray (EDX) analysis, and fourier transform infrared (FTIR). We conducted an MTT assay to assess the cytotoxicity of nCur-mediated PDI in combination with nanosilver colistin. The fractional biofilm inhibitory concentration (FBIC) of two P. aeruginosa clinical isolates and P. aeruginosa ATCC 27853 during nCur-mediated PDI@AgNPs@CL was determined using a 3-dimensional (3-D) checkerboard assay. To study the effect of nCur-mediated PDI@AgNPs@CL on lasI, lasR, rhlI, rhlR, pelA, and pslA gene expression, Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was conducted at each isolate's FBIC. The impact of treatments was also investigated using scanning electron microscopy (SEM). RESULTS: The ZP and mean DLS values of the nCur were 10.3 mV and 402.6 ± 24.6 nm, respectively. The distinct functional groups of nCur corresponded with the peaks of FTIR absorption. Moreover, the EDX analysis showed the ratios of different metals in nCur. Cell viability percentages of nCur-mediated PDI@AgNPs@CL at FBIC concentrations of clinical isolates Nos. 30, 354, and P. aeruginosa ATCC 27853 were 91.36 %, 83.20 %, and 92.48 %, respectively. nCur-mediated PDI@AgNPs@CL treatment showed synergistic effects in clinical isolates and P. aeruginosa ATCC 27853 in a 3-D checkerboard assay. All six of the investigated genes showed down-regulation after nCur-mediated PDI@AgNPs@CL treatment. The most suppressed gene during nCur-mediated PDI@AgNPs@CL treatment was the rhlR gene (-11.9-fold) of P. aeruginosa ATCC 27853. The SEM micrographs further proved the connecting cement reduction and biofilm mass mitigation following nCur-mediated PDI@AgNPs@CL treatments. CONCLUSIONS: The combined effect of nCur-mediated PDI and AgNPs@CL synergistically reduce the formation of biofilm in P. aeruginosa. This may be attributable to the suppression of the genes responsible for regulating the production of biofilms.

Exploring natural anthraquinones as potential MMP2 inhibitors: A computational study.

OBJECTIVE: Matrix metalloproteinase-2 (MMP2) plays a significant role in cleaving extracellular matrix components, leading to many cancer cells' progression and invasion behavior. Therefore, MMP2 inhibition may hold promise for cancer treatment. Anthraquinones have shown antineoplastic effects, some of which have been used in clinical practice as anticancer drugs. This study used a computational drug discovery approach to assess the possible inhibitory effects of selected anthraquinones on MMP2. The results were then compared with that of Captopril, which was considered a standard drug. METHODS: This study used the AutoDock 4.0 tool to evaluate the binding affinity of 21 anthraquinones to the MMP2 catalytic domain. The most favorable scores based on the Gibbs free binding energy scores were given to the highest-ranked ligands. The Discovery Studio Visualizer tool illustrated interactions between MMP2 residues and top-ranked anthraquinones. RESULTS: A total of 12 anthraquinones were identified with ΔGbinding scores less than - 10 kcal/mol. Pulmatin (Chrysophanol-8-glucoside) was the most potent MMP2 inhibitor, with a ΔGbinding score of - 12.91 kcal/mol. This anthraquinone was able to restrict MMP2 activity within a picomolar range. CONCLUSION: MMP2 inhibition by anthraquinones, notably Pulmatin, may be a useful therapeutic approach for cancer treatment.

Using machine learning approach for screening metastatic biomarkers in colorectal cancer and predictive modeling with experimental validation.

Colorectal cancer (CRC) liver metastasis accounts for the majority of fatalities associated with CRC. Early detection of metastasis is crucial for improving patient outcomes but can be delayed due to a lack of symptoms. In this research, we aimed to investigate CRC metastasis-related biomarkers by employing a machine learning (ML) approach and experimental validation. The gene expression profile of CRC patients with liver metastasis was obtained using the GSE41568 dataset, and the differentially expressed genes between primary and metastatic samples were screened. Subsequently, we carried out feature selection to identify the most relevant DEGs using LASSO and Penalized-SVM methods. DEGs commonly selected by these methods were selected for further analysis. Finally, the experimental validation was done through qRT-PCR. 11 genes were commonly selected by LASSO and P-SVM algorithms, among which seven had prognostic value in colorectal cancer. It was found that the expression of the MMP3 gene decreases in stage IV of colorectal cancer compared to other stages (P value < 0.01). Also, the expression level of the WNT11 gene was observed to increase significantly in this stage (P value < 0.001). It was also found that the expression of WNT5a, TNFSF11, and MMP3 is significantly lower, and the expression level of WNT11 is significantly higher in liver metastasis samples compared to primary tumors. In summary, this study has identified a set of potential biomarkers for CRC metastasis using ML algorithms. The findings of this research may provide new insights into identifying biomarkers for CRC metastasis and may potentially lay the groundwork for innovative therapeutic strategies for treatment of this disease.

Herbal Metabolites as Potential Carbonic Anhydrase Inhibitors: Promising Compounds for Cancer and Metabolic Disorders.

Background: Human carbonic anhydrases (CAs) play a role in various pathological mechanisms by controlling intracellular and extracellular pH balance. Irregular expression and function of CAs have been associated with multiple human diseases, such as obesity, cancer, glaucoma, and epilepsy. In this work, we identify herbal compounds that are potential inhibitors of CA VI. Methods: We used the AutoDock tool to evaluate binding affinity between the CA VI active site and 79 metabolites derived from flavonoids, anthraquinones, or cinnamic acids. Compounds ranked at the top were chosen for molecular dynamics (MD) simulations. Interactions between the best CA VI inhibitors and residues within the CA VI active site were examined before and after MD analysis. Additionally, the effects of the most potent CA VI inhibitor on cell viability were ascertained in vitro through the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Results: Kaempferol 3-rutinoside-4-glucoside, orientin, kaempferol 3-rutinoside-7-sophoroside, cynarin, and chlorogenic acid were estimated to establish binding with the CA VI catalytic domain at the picomolar scale. The range of root mean square deviations for CA VI complexes with kaempferol 3-rutinoside-4-glucoside, aloe-emodin 8-glucoside, and cynarin was 1.37 to 2.05, 1.25 to 1.85, and 1.07 to 1.54 Å, respectively. The MTT assay results demonstrated that cynarin had a substantial effect on HCT-116 cell viability. Conclusion: This study identified several herbal compounds that could be potential drug candidates for inhibiting CA VI.

MicroRNA-Based Markers of Oral Tongue Squamous Cell Carcinoma and Buccal Squamous Cell Carcinoma: A Systems Biology Approach.

Objective: Oral tongue squamous cell carcinoma (OTSCC) and buccal squamous cell carcinoma (BSCC) are the first and second leading causes of oral cancer, respectively. OTSCC and BSCC are associated with poor prognosis in patients with oral cancer. Thus, we aimed to indicate signaling pathways, Gene Ontology terms, and prognostic markers mediating the malignant transformation of the normal oral tissue to OTSCC and BSCC. Methods: The dataset GSE168227 was downloaded and reanalyzed from the GEO database. Orthogonal partial least square (OPLS) analysis identified common differentially expressed miRNAs (DEMs) in OTSCC and BSCC compared to their adjacent normal mucosa. Next, validated targets of DEMs were identified using the TarBase web server. With the use of the STRING database, a protein interaction map (PIM) was created. Using the Cytoscape program, hub genes and clusters within the PIM were shown. Next, gene-set enrichment analysis was carried out using the g:Profiler tool. Using the GEPIA2 web tool, analyses of gene expression and survival analysis were also performed. Results: Two DEMs, including has-miR-136 and has-miR-377, were common in OTSCC and BSCC (p value <0.01; |Log2 FC| > 1). A total of 976 targets were indicated for common DEMs. PIM included 96 hubs, and the upregulation of EIF2S1, CAV1, RAN, ANXA5, CYCS, CFL1, MYC, HSP90AA1, PKM, and HSPA5 was significantly associated with a poor prognosis in the head and neck squamous cell carcinoma (HNSCC), while NTRK2, HNRNPH1, DDX17, and WDR82 overexpression was significantly linked to favorable prognosis in the patients with HNSCC. "Clathrin-mediated endocytosis" was considerably dysregulated in OTSCC and BSCC. Conclusion: The present study suggests that has-miR-136 and has-miR-377 are underexpressed in OTSCC and BSCC than in normal oral mucosa. Moreover, EIF2S1, CAV1, RAN, ANXA5, CYCS, CFL1, MYC, HSP90AA1, PKM, HSPA5, NTRK2, HNRNPH1, DDX17, and WDR82 demonstrated prognostic markers in HNSCC. These findings may benefit the prognosis and management of individuals with OTSCC/BSCC. However, additional experimental verification is required.

Cinnamic acids as promising bioactive compounds for cancer therapy by targeting MAPK3: a computational simulation study.

OBJECTIVES: Mitogen-activated protein kinase-3 (MAPK3) is the upstream regulator in the MAPK cascade and is involved in many critical signaling pathways and biological processes, such as cell proliferation, survival, and apoptosis. MAPK3 overexpression is linked to onset, development, metastasis, and drug resistance in several human cancers. Thus, identifying novel and effective MAPK3 inhibitors is highly demanded. Herein, we aimed to discover organic compounds from cinnamic acid derivatives as potential MAPK3 inhibitors. METHODS: The binding affinity of 20 cinnamic acids to the MAPK3 active site was tested using the AutoDock 4.0 software. Top-ranked cinnamic acids were ranked based on the ΔG binding values between the ligands and the receptor's active site. Interaction modes between top-ranked cinnamic acids and MAPK3 catalytic site were indicated using the Discovery Studio Visualizer tool. Molecular dynamics (MD) simulation was carried out to study the stability of the docked pose for the most potent MAPK3 inhibitor in this study. RESULTS: Cynarin, chlorogenic acid, rosmarinic acid, caffeic acid 3-glucoside, and cinnamyl caffeate exhibited a salient binding affinity to the MAPK3 active site with the criteria of ΔG binding <-10 k cal/mol. Further, the inhibition constant value for cynarin was calculated at the picomolar concentration. The docked pose of cynarin within the MAPK3 catalytic domain was stable in 100 ns simulation. CONCLUSIONS: Cynarin, chlorogenic acid, rosmarinic acid, caffeic acid 3-glucoside, and cinnamyl caffeate might be helpful in cancer therapy by inhibiting MAPK3.

Cinnamic acid derivatives as potential matrix metalloproteinase-9 inhibitors: molecular docking and dynamics simulations.

Matrix metalloproteinase-9 (MMP-9) is a zinc and calcium-dependent proteolytic enzyme involved in extracellular matrix degradation. Overexpression of MMP-9 has been confirmed in several disorders, including cancers, Alzheimer's disease, autoimmune diseases, cardiovascular diseases, and dental caries. Therefore, MMP-9 inhibition is recommended as a therapeutic strategy for combating various diseases. Cinnamic acid derivatives have shown therapeutic effects in different cancers, Alzheimer's disease, cardiovascular diseases, and dental caries. A computational drug discovery approach was performed to evaluate the binding affinity of selected cinnamic acid derivatives to the MMP-9 active site. The stability of docked poses for top-ranked compounds was also examined. Twelve herbal cinnamic acid derivatives were tested for possible MMP-9 inhibition using the AutoDock 4.0 tool. The stability of the docked poses for the most potent MMP-9 inhibitors was assessed by molecular dynamics (MD) in 10 nanosecond simulations. Interactions between the best MMP-9 inhibitors in this study and residues incorporated in the MMP-9 active site were studied before and after MD simulations. Cynarin, chlorogenic acid, and rosmarinic acid revealed a considerable binding affinity to the MMP-9 catalytic domain (ΔGbinding < -10 kcal/ mol). The inhibition constant value for cynarin and chlorogenic acid were calculated at the picomolar scale and assigned as the most potent MMP-9 inhibitor from the cinnamic acid derivatives. The root-mean-square deviations for cynarin and chlorogenic acid were below 2 Å in the 10 ns simulation. Cynarin, chlorogenic acid, and rosmarinic acid might be considered drug candidates for MMP-9 inhibition.

Prognostic biomarkers and molecular pathways mediating Helicobacter pylori-induced gastric cancer: a network-biology approach.

Cancer of the stomach is the second most frequent cancer-related death worldwide. The survival rate of patients with gastric cancer (GC) remains fragile. There is a requirement to discover biomarkers for prognosis approaches. Helicobacter pylori in the stomach is closely associated with the progression of GC. We identified the genes associated with poor/favorable prognosis in H. pylori-induced GC. Multivariate statistical analysis was applied on the Gene Expression Omnibus (GEO) dataset GSE54397 to identify differentially expressed miRNAs (DEMs) in gastric tissues with H. pylori-induced cancer compared with the H. pylori-positive with non-cancerous tissue. A protein interaction map (PIM) was built and subjected to DEMs targets. The enriched pathways and biological processes within the PIM were identified based on substantial clusters. Thereafter, the most critical genes in the PIM were illustrated, and their prognostic impact in GC was investigated. Considering p-value less than 0.01 and |Log2 fold change| as >1, five microRNAs demonstrated significant changes among the two groups. Gene functional analysis revealed that the ubiquitination system, neddylation pathway, and ciliary process are primarily involved in H. pylori-induced GC. Survival analysis illustrated that the overexpression of DOCK4, GNAS, CTGF, TGF-b1, ESR1, SELE, TIMP3, SMARCE1, and TXNIP was associated with poor prognosis, while increased MRPS5 expression was related to a favorable prognosis in GC patients. DOCK4, GNAS, CTGF, TGF-b1, ESR1, SELE, TIMP3, SMARCE1, TXNIP, and MRPS5 may be considered prognostic biomarkers for H. pylori-induced GC. However, experimental validation is necessary in the future.

Flavonoids as Strong Inhibitors of MAPK3: A Computational Drug Discovery Approach.

Background: Mitogen-activated protein kinase 3 (MAPK3) mediates the onset, progression, metastasis, drug resistance, and poor prognosis in various malignancies, including glioma, liver, ovarian, thyroid, lung, breast, gastric, and oral cancers. Negative regulation of MAPK3 expression using miRNAs has led to therapeutic effects in cancer. Objectives: The present study performed molecular docking and dynamics simulation to identify potential MAPK3 inhibitors from natural flavonoids, possibly leading to drug development in cancer therapy. Methods: A computational drug discovery approach was performed using the AutoDock tool to identify potential MAPK3 inhibitors from 46 plant-based flavonoids. A cross-validation study was executed using the Schrödinger Maestro docking tool. Molecular dynamics (MD) was executed to evaluate the stability of docked poses between the top-ranked compounds and the MAPK3 catalytic domain. Interactions among the most potent MAPK3 inhibitors and residues within the receptor's active site were studied using the BIOVIA Discovery Studio Visualizer before and after 100 ns MD simulations. Results: Kaempferol 3-rutinoside-4'-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 exhibited a magnificent binding affinity to the receptor's active site. In addition, the stability of the docked poses of these compounds seemed to be stable after ∼45 ns computer simulations. Conclusion: The present study suggests that kaempferol 3-rutinoside-4'-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 could strongly bind to the MAPK3 catalytic site and could be assigned as a potent inhibitor for MAPK3. These findings may be helpful in the treatment of various cancers. However, further validation experiments are needed.

Pathogenesis and prognosis of primary oral squamous cell carcinoma based on microRNAs target genes: a systems biology approach.

Oral squamous cell carcinoma (OSCC) is the most prevalent head and neck malignancy, with frequent cervical lymph-node metastasis, leading to a poor prognosis in OSCC patients. The present study aimed to identify potential markers, including microRNAs (miRNAs) and genes, significantly involved in the etiology of early-stage OSCC. Additionally, the main OSCC's dysregulated Gene Ontology annotations and significant signaling pathways were identified. The dataset GSE45238 underwent multivariate statistical analysis in order to distinguish primary OSCC tissues from healthy oral epithelium. Differentially expressed miRNAs (DEMs) with the criteria of p-value < 0.001 and |Log2 fold change| > 1.585 were identified in the two groups, and subsequently, validated targets of DEMs were identified. A protein interaction map was constructed, hub genes were identified, significant modules within the network were illustrated, and significant pathways and biological processes associated with the clusters were demonstrated. Using the GEPI2 database, the hub genes' predictive function was assessed. Compared to the healthy controls, main OSCC had a total of 23 DEMs. In patients with head and neck squamous cell carcinoma (HNSCC), upregulation of CALM1, CYCS, THBS1, MYC, GATA6, and SPRED3 was strongly associated with a poor prognosis. In HNSCC patients, overexpression of PIK3R3, GIGYF1, and BCL2L11 was substantially correlated with a good prognosis. Besides, "proteoglycans in cancer" was the most significant pathway enriched in the primary OSCC. The present study results revealed more possible mechanisms mediating primary OSCC and may be useful in the prognosis of the patients with early-stage OSCC.

Potential Biomarkers and Signaling Pathways Associated with the Pathogenesis of Primary Ameloblastoma: A Systems Biology Approach.

Objective: Ameloblastoma is a benign odontogenic tumor that may lead to ameloblastic carcinoma. This study aimed to determine potential signaling pathways and biological processes, critical genes and their regulating transcription factors (TFs), and miRNAs, as well as protein kinases involved in the etiology of primary ameloblastoma. Methods: The dataset GSE132472 was obtained from the GEO database, and multivariate statistical analyses were applied to identify differentially expressed genes (DEGs) in primary ameloblastoma tissues compared to the corresponding normal gingiva samples. A protein-protein interaction (PPI) map was built using the STRING database. The Cytoscape software identified significant modules and the hub genes within the PPI network. Gene Ontology annotation and signaling pathway analyses were executed by employing the DAVID and Reactome databases, respectively. Significant TFs and miRNAs acting on the hub genes were identified using the iRegulon plugin and MiRWalk 2.0 database, respectively. A protein kinase enrichment analysis was conducted using the online Kinase Enrichment Analysis 2 (KEA2) web server. The approved drugs acting on the hub genes were also found. Results: A total of 1,629 genes were differentially expressed in primary ameloblastoma (P value <0.01 and |Log2FC| > 1). HRAS, CDK1, MAPK3, ERBB2, COL1A1, CYCS, and BRCA1 demonstrated high degree and betweenness centralities in the PPI network. E2F4 was the most significant TF acting on the hub genes. BTK was the protein kinase significantly enriched by the TFs. Cholesterol biosynthesis was considerably involved in primary ameloblastoma. Conclusions: This study provides an intuition into the potential mechanisms involved in the etiology of ameloblastoma.

Aptamer-conjugated nanoliposomes containing COL1A1 siRNA sensitize CRC cells to conventional chemotherapeutic drugs.

COL1A1 is an important extracellular matrix component that is associated with poor prognosis in cancers. In this study, As1411 aptamer-conjugated liposomes were used for targeted siRNA delivery against the COL1A1 gene in colorectal cancer (CRC) cells. Cationic liposomes were synthesized and siRNA loading and conjugation of aptamer were confirmed by gel shift assay and spectrophotometry method. Release of siRNA from liposomes was assessed using dialysis method. Binding and uptake of aptamer-conjugated liposomes to and into cancer cells was assessed by fluorescence microscopy and flowcytometry. Gene expression was evaluated using qRT-PCR. Cell viability, chemosensitivity and apoptosis were determined by MTT assay and Annexin/PI kit. Cellular studies showed that liposomal transfer of COL1A1 siRNA into HCT116 and HEK293 cells significantly reduced the expression level of corresponding gen and cell viability, and significantly increased the sensitivity to chemotherapy drugs while free siRNA had no such effects. Aptamer conjugation was associated with increased cellular effects in HCT116 cells, but not in HEK293 cells. Our study revealed that delivery of COL1A1 siRNA via AS1411-targeted liposomes is a promising therapeutic approach to overcome treatment resistance in CRC.

Methicillin-Resistant Staphylococcus aureus: Docking-Based Virtual Screening and Molecular Dynamics Simulations to Identify Potential Penicillin-Binding Protein 2a Inhibitors from Natural Flavonoids.

Staphylococcus aureus (S. aureus) is responsible for several disorders including skin and soft tissue infections, bacteremia, pulmonary infections, septic arthritis, osteomyelitis, meningitis, gastroenteritis, toxic-shock syndrome, and urinary tract infections. Methicillin-resistant S. aureus (MRSA) contains penicillin-binding protein 2a (SauPBP2a) responsible for catalyzing the peptidoglycan production within the bacterial cell wall. The binding affinity of SauPBP2a to beta-lactam antibiotics is low, and thus, it is necessary to discover new effective SauPBP2a inhibitors to combat mortality and morbidity in patients affected by MRSA. The binding affinity of 46 natural flavonoids to the SauPBP2a active site was examined via molecular docking analysis. The stability of docked poses associated with the top-ranked flavonoids was tested by performing molecular dynamics (MD) in 10 nanoseconds (ns) computer simulations. Kaempferol 3-rutinoside-7-sophoroside and rutin demonstrated a considerable binding affinity to the SauPBP2a active site (ΔG binding < -11 kcal/mol). Their docked poses were found to be stable for 10 ns MD simulations. Kaempferol 3-rutinoside-7-sophoroside and rutin also exhibited salient binding affinity to the enzyme's allosteric site. This study suggests that kaempferol 3-rutinoside-7-sophoroside and rutin may be considered as drug candidates for therapeutic aims in several human infections associated with MRSA. Nevertheless, in vitro and in vivo confirmations are warranted.

Molecular Docking and Dynamics Simulation of Natural Phenolic Compounds with GSK-3ß: A Putative Target to Combat Mortality in Patients with COVID-19.

OBJECTIVE: In this study, molecular docking analysis was performed to evaluate the binding affinity of 52 plant-based phenolics with the GSK-3ß active sites. Moreover, Molecular Dynamics (MD) simulation was conducted to investigate the stability of interactions between the topranked phenolics and residues within the GSK-3ß active sites. METHODS: Molecular docking and MD simulations were performed using AutoDock and Discovery Studio Client software, respectively. Thereafter, pharmacokinetic and toxicological properties of top inhibitors were predicted using bioinformatics web tools. This study aimed to identify the most effective amino acids involved in the inhibition of GSK-3ß based on the most stabilizing interactions between the residues and compounds, and also by considering the degree centrality in the ligand- amino acid interaction network for GSK-3ß. RESULTS: It was observed that procyanidin and amentoflavone could bind to the GSK-3ß active sites at the picomolar (pM) scale as well as the binding affinity of ΔG binding < -13 kcal/mol, while the inhibition constant for theaflavin 3'-gallate, procyanidin B4, and rutin was calculated at the nanomolar (nM) scale, suggesting that these phenolic compounds can be considered as potential effective GSK-3ß inhibitors. Furthermore, Val70, Ala83, Val135, and Tyr134 were found to be the most important amino acids involved in the inhibition of GSK-3ß. CONCLUSION: The results of the current study may be useful in the prevention of several human disorders, including COVID-19, cancers, Alzheimer's disease, diabetes mellitus, and cardiovascular diseases. However, wet-lab experiments need to be performed in the future.

Identification of Prognostic Biomarkers in Papillary Thyroid Cancer and Developing Non-Invasive Diagnostic Models Through Integrated Bioinformatics Analysis.

BACKGROUND: Papillary thyroid cancer (PTC) is the most frequent subtype of thyroid carcinoma, mainly detected in patients with benign thyroid nodules (BTN). Due to the invasiveness of accurate diagnostic tests, there is a need to discover applicable biomarkers for PTC. So, in this study, we aimed to identify the genes associated with prognosis in PTC. Besides, we performed a machine learning tool to develop a non-invasive diagnostic approach for PTC. METHODS: For the study purposes, the miRNA dataset GSE130512 was downloaded from the GEO database and then analyzed to identify the common differentially expressed miRNAs in patients with non-metastatic PTC (nm-PTC)/metastatic PTC (m-PTC) compared with BTNs. The SVM was also applied to differentiate patients with PTC from those patients with BTN using the common DEMs. A protein-protein interaction network was also constructed based on the targets of the common DEMs. Next, functional analysis was performed, the hub genes were determined, and survival analysis was then executed. RESULTS: A total of three common miRNAs were found to be differentially expressed among patients with nm-PTC/m-PTC compared with BTNs. In addition, it was established that the autophagosome maturation, ciliary basal body-plasma membrane docking, antigen processing as ubiquitination & proteasome degradation, and class I MHC mediated antigen processing & presentation are associated with the pathogenesis of PTC. Furthermore, it was illustrated that RPS6KB1, CCNT1, SP1, and CHD4 might serve as new potential biomarkers for PTC prognosis. CONCLUSION: RPS6KB1, CCNT1, SP1, and CHD4 may be considered new potential biomarkers used for prognostic aims in PTC. However, performing validation tests is inevitable in the future.

Identification of Key Gene Targets for Sensitizing Colorectal Cancer to Chemoradiation: an Integrative Network Analysis on Multiple Transcriptomics Data.

PURPOSE: Colorectal cancer (CRC) is a main cause of morbidity and mortality in the world. Chemoradioresistance is a major problem in CRC treatment. Identification of novel therapeutic targets in order to overcome treatment resistance in CRC is necessary. METHODS: In this study, gene expression omnibus (GEO) database was searched to find microarray datasets. Data normalization/analyzing was performed using ExAtlas. The gene ontology (GO) and pathway enrichment analysis was performed using g:Profiler. Protein-protein interaction network (PPIN) was constructed by Search Tool for the Retrieval of Interacting Genes (STRING) and analyzed using Cytoscape. Survival analysis was done using Kaplan-Meier curve method. RESULTS: Forty-one eligible datasets were included in study. A total of 12,244 differentially expressed genes (DEGs) and 7337 unique DEGs were identified. Among them, 1187 DEGs were overlapped in ≥ 3 datasets. Fifty-five overlapped genes were considered as hub genes. Common hub genes in chemo/radiation/chemoradiation datasets were chosen as the essential candidate genes (n = 13). Forty-one hub gene and 7 essential candidate genes were contributed in the significant modules. The modules were mainly enriched in the signaling pathways of senescence, autophagy, NF-κB, HIF-1, stem cell pluripotency, notch, neovascularization, cell cycle, p53, chemokine, and PI3K-Akt. NGFR, FGF2, and PROM1 genes were significantly predictors of CRC patient's survival. CONCLUSION: Our study revealed three-gene signatures as potential therapeutic targets and also candidate molecular markers in CRC chemoradioresistance.