Bacterial tyrosinases and their inhibitors.

Bacterial tyrosinase is a copper-containing metalloenzyme with diverse physio-chemical properties, that have been identified in various bacterial strains, including actinobacteria and proteobacteria. Tyrosinases are responsible for the rate-limiting catalytic steps in melanin biosynthesis and enzymatic browning. The physiological role of bacterial tyrosinases in melanin biosynthesis has been harnessed for the production of coloring and dyeing agents. Additionally, bacterial tyrosinases have the capability of cross-linking activity, demonstrated material functionalization applications, and applications in food processing with varying substrate specificities and stability features. These characteristics make bacterial tyrosinases a valuable alternative to well-studied mushroom tyrosinases. The key feature of substrate specificity of bacterial tyrosinase has been exploited to engineer biosensors that have the ability to detect the minimal amount of different phenolic compounds. Today, the world is facing the challenge of multi-drugs resistance in various diseases, especially antibiotic resistance, skin cancer, enzymatic browning of fruits and vegetables, and melanogenesis. To address these challenges, medicinal scientists are developing novel chemotherapeutic agents by inhibiting bacterial tyrosinases. To serve this purpose, heterocyclic compounds are of particular interest due to their vast spectrum of biological activities and their potential as effective tyrosinase inhibitors. In this chapter, a plethora of research explores applications of bacterial tyrosinases in different fields, such as the production of dyes and pigments, catalytic applications in organic synthesis, bioremediation, food and feed applications, biosensors, wool fiber coating and the rationalized synthesis, and structure-activity relationship of bacterial tyrosinase inhibitors.

Cholic Acid-Grafted Thiolated Chitosan-Enveloped Nanoliposomes for Enhanced Oral Bioavailability of Azathioprine: In Vitro and In Vivo Evaluation.

The purpose of the present study was to develop a cholic acid-grafted thiolated chitosan (CA-CS-TGA) polymeric biomaterial for attaining improved permeation via attaching thiol groups and cholic acid moieties. For this purpose, a CA-CS-TGA graft was prepared, and modification was confirmed via FTIR analysis. The prepared CA-CS-TGA graft was used to coat the azathioprine-loaded nanoliposomes (ENLs), with subsequent characterization in terms of zeta size, zeta potential, and SEM analysis. Pharmaceutical evaluation was carried out in terms of drug release studies, and ex vivo permeation and in vivo oral bioavailability were studied. The particle size and zeta potential of CA-CS-TGA coated nanoliposomal formulation CA-CS-TGA-NLs were found to be 245 ± 15.6 and +22.4 ± 0.58, respectively, compared to that of nonenveloped nanoliposomal formulation 165.7 ± 12.3 and -21.8 ± 0.14, respectively, indicating successful coating. CA-CS-TGA-NLs indicated 64% of drug release in 24 h at pH 7.4. Ex vivo permeation enhancement and relative oral bioavailability studies indicated a 2.84-fold enhanced permeation and 6-fold enhanced oral bioavailability of CA-CS-TGA-NLs compared to Azathioprine suspension. Based on the results, it can be concluded that grafting the CA-CS-TGA polymer onto nanoliposomes seems to be a promising strategy to enhance the oral bioavailability of Azathioprine.

Toxicological evaluation of copper oxide nanoparticles following their intraperitoneal injection to Wistar rats.

Background: Copper oxide (Cu2O) nanoparticles (CO NPs) are in extensive use during our everyday life as antimicrobial agent, lubricant, in manufacturing electrodes of lithium ion batteries as well as for photo catalytic degradation of organic pollutants. Due to extensive and diverse use Cu2O NPs, they are likely to accumulate in the environment and to affect the live forms. Present investigation was aimed to report the biocompatibility of CO NPs in Wistar rats in sex specific manner. CO NPs, having average diameter of 14.06 nm, were synthesized by co-precipitation method and scanning electron microscopy and X ray diffraction were used for their characterization. Methods: For 14 consecutive days, Wistar rats (6 weeks old) of both sexes were intraperitoneally injected with 10 mg/mL saline/Kg body weight of CO NPs, while the control groups intraperitoneally received saline solution for same duration. Behavioral tests (open field and novel object recognition), complete blood count, selected biomarkers of oxidative stress and Copper concentration in brain and liver were determined in all subjects. Results: High mortality rates [male 40% and female 60%] were observed in rats exposed to CO NPs. A sever decrease in body weight was also observed in both male and female rats exposed to CO NPs. Female rats treated with CO NPs spent significantly more time with novel object as compared to control [P = 0.05] during second trial of novel object test. CO NPs treated female rats had higher mean corpuscular hemoglobin [P < 0.001] levels and Copper concentration in liver [P = 0.04] than control. Male rats exposed to CO NPs had significantly higher mean corpuscular volume [P = 0.02] and superoxide dismutase [SOD] [P = 0.04] in lungs than their control group. All other studied parameters non significantly varied upon comparison between CO NPs treated and untreated rats of both sex. Conclusion: In conclusion, we are reporting that intraperitoneal injections of CO NPs for 14 days can disturb complete blood count and biomarkers of oxidative stress in lungs of Wistar rats.

Structure based functional identification of an uncharacterized protein from Coxiella burnetii involved in adipogenesis.

Coxiella burnetii, the causative agent of Q fever, is an intracellular pathogen posing a significant global public health threat. There is a pressing need for dependable and effective treatments, alongside an urgency for further research into the molecular characterization of its genome. Within the genomic landscape of Coxiella burnetii, numerous hypothetical proteins remain unidentified, underscoring the necessity for in-depth study. In this study, we conducted comprehensive in silico analyses to identify and prioritize potential hypothetical protein of Coxiella burnetii, aiming to elucidate the structure and function of uncharacterized protein. Furthermore, we delved into the physicochemical properties, localization, and molecular dynamics and simulations, and assessed the primary, secondary, and tertiary structures employing a variety of bioinformatics tools. The in-silico analysis revealed that the uncharacterized protein contains a conserved Mth938-like domain, suggesting a role in preadipocyte differentiation and adipogenesis. Subcellular localization predictions indicated its presence in the cytoplasm, implicating a significant role in cellular processes. Virtual screening identified ligands with high binding affinities, suggesting the protein's potential as a drug target against Q fever. Molecular dynamics simulations confirmed the stability of these complexes, indicating their therapeutic relevance. The findings provide a structural and functional overview of an uncharacterized protein from C. burnetii, implicating it in adipogenesis. This study underscores the power of in-silico approaches in uncovering the biological roles of uncharacterized proteins and facilitating the discovery of new therapeutic strategies. The findings provide valuable preliminary data for further investigation into the protein's role in adipogenesis.

An evaluation of inflammatory and endothelial dysfunction markers as determinants of peripheral arterial disease in those with diabetes mellitus.

The most serious long-term effects of diabetes is peripheral artery disease (PAD) which increases the chance of developing diabetic foot ulcers, gangrene and even lower limb amputation. The clinical manifestations of PAD which are typically not revealed until symptoms like intermittent claudication, rest pain and ischemic gangrene develop, are not present in majority of diabetes mellitus patients with PAD due to diabetic peripheral neuropathy. Therefore, current study is aimed to evaluate the inflammatory and endothelial dysfunction markers with their correlation to biomarkers that can help for in-time diagnosis and efficient prognosis of developing diabetes-associated PAD. Enzyme-linked immunosorbent assay was used to evaluate the interlukin-6, interlukin-8, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) in PAD with diabetes group, diabetic group and healthy individual group while biomarkers were measured by kit method. It was observed that serum IL-6, IL-8, ICAM and VCAM levels in type II diabetes mellitus (T2DM) with PAD patients were increased significantly (85.93, 597.08, 94.80 and 80.66) as compared to T2DM patients (59.52, 231.34, 56.88 and 50.19) and healthy individuals (4.81, 16.93, 5.55 and 5.16). The overall means for the parameters, IL-6, IL-8, ICAM, VCAM, urea, S/creatinine, CK-MB, AST, ALT, cholesterol, triglyceride, HDL, LDL, PT, aPTT, INR, HbA1C, and CRP within all groups were significantly (P < 0.05) different from each other. Therefore, it was concluded that the change in IL-6, IL-8, ICAM and VCAM can serve as an accurate diagnostic indicator and successful treatment.

Identification and prevalence of ticks infesting small ruminants of Fort Munro region in South Punjab, Pakistan.

Fort Munro is a hill station in Southern Punjab the residents of whom are heavily dependent upon livestock for their living but ticks are a big treat for the livestock. The purpose of this study was to ascertain the tick infestation among the small ruminants of Fort Munro. Ticks (N = 273) were collected from 333 animals (165 goats and 168 sheep) during August and September 2022. Two tick genera Hyalomma and Rhipicephalus were identified. Rhipicephalus was most abundant tick genera (78.02%) followed by Hyalomma (21.98%).Tick distribution significantly varied with the host: Rhipicephalus ticks were more frequently infesting goats while Hyalomma were more common on sheep. For both hosts, tick infestation varied with the sampling sites and male animals were significantly more infested than females. Five tick species were infesting goats with the following relative abundance: Rhipicephalus (R.) senegalensis (39.20%) > R. sanguineus (36.8%) > R. appendiculatus (10.40%) > R. turanicus (8%) > R. guilhoni (5.6%). Rhipicephalus senegalensis (41.22%) was also the most common tick species infesting sheep followed by Hyalomma (H.) marginatum (29.73%), R. guilhoni (18.24%), H. dromedarii (5.41%) and H. impeltatum (5.41%). Male ticks very more abundantly on both goats and sheep than female. Distribution of Hyalomma species also varied between the sampling sites. In conclusion, we are reporting the infestation of 3 Hyalomma and 5 Rhipicephalus in small ruminants of Fort Munro. The data generated through this study will help in developing appropriate tick control in the study area and will add to the existing knowledge regarding tick species that are infesting the small ruminants of Pakistan.

Facile Synthesis of 5-Bromo-N-Alkylthiophene-2-Sulfonamides and Its Activities Against Clinically Isolated New Delhi Metallo-ß-Lactamase Producing Klebsiella pneumoniae ST147.

Introduction: New Delhi Metallo-ß-lactamase producing Klebsiella pneumoniae (NDM-1-KP) sequence type (ST) 147 poses a significant threat in clinical settings due to its evolution into two distinct directions: hypervirulence and carbapenem resistance. Hypervirulence results from a range of virulence factors, while carbapenem resistance stems from complex biological mechanisms. The NDM-1-KP ST147 clone has emerged as a recent addition to the family of successful clones within the species. Methods: In this study, we successfully synthesized 5-bromo-N-alkylthiophene-2-sulfonamides (3a-c) by reacting 5-bromothiophene-2-sulfonamide (1) with various alkyl bromides (2) using LiH. We also synthesized a series of compounds (4a-g) from compound (3b) using the Suzuki-Miyaura cross-coupling reaction with fair to good yields (56-72%). Further, we screened the synthesized molecules against clinically isolated New Delhi Metallo-ß-lactamase producing Klebsiella pneumoniae ST147. Subsequently, we conducted in-silico tests on compound 3b against a protein extracted from NDM-KP ST147 with PDB ID: 5N5I. Results: The compound (3b) with favourable drug candidate status, MIC of 0.39 µg/mL, and MBC of 0.78 µg/mL. This low molecular weight compound exhibited the highest potency against the resistant bacterial strains. The in-silico tests revealed that the compound 3b against a protein extracted from NDM-KP ST147 with PDB ID: 5N5I demonstrated H-bond and hydrophobic interactions. Conclusion: The 5-bromo-N-alkylthiophene-2-sulfonamides displayed antibacterial efficacy against New Delhi Metallo-ß-lactamase producing Klebsiella pneumoniae ST147. After the in-vivo trial, this substance might offer an alternative therapeutic option.

Optimizing fungal treatment of lignocellulosic agro-industrial by-products to enhance their nutritional value.

This study delves into the dynamic interaction between various fungal strains, substrates, and treatment durations to optimize the nutritional value of these by-products. Six fungi, including Penicillium chrysogenum, Fusarium sp., Fusarium oxysporum, Fusarium solani, Penicillium crustosum, and Cosmospora viridescens, were evaluated across three substrates: wheat straw (WS), cedar sawdust (CW), and olive pomace (OP) over treatment periods of 4, 8, and 12 weeks. The study discerned profound impacts of these fungi across multiple parameters, including cellulose variation (C.var), lignin variation (L.var), and in vitro true digestibility variation (IVTD.var). Our results demonstrated that the various fungi had a significant effect on all parameters (p < .001). Noteworthy, F. oxysporum and F. solani emerged as exemplars, displaying notable lignin degradation, cellulose liberation, and IVTD enhancement. Importantly, P. crustosum demonstrated substantial cellulose degradation, exhibiting optimal efficacy in just 4 weeks for all substrates. Notably, F. sp. excelled, yielding favorable results when treating WS. P. chrysogenum achieved optimal outcomes with 8-week treatment for WS. Both Fusarium sp. and P. chrysogenum exhibited slight cellulose release, with remarkable reduction of WS lignin compared to other substrates. Especially, WS and OP displayed superior digestibility enhancements relative to CW. It should be noted that the treatment duration further shaped these outcomes, as prolonged treatment (12 weeks) fostered greater benefits in lignin degradation and digestibility, albeit with concomitant cellulose degradation. These findings underscore the intricate balance between fungal strains, substrates, and treatment durations in optimizing the nutritional value of lignocellulosic agro-industrial by-products. The outcomes of this study lead to the enhancement in the overall value of by-products, promoting sustainable livestock feed and advancing agricultural sustainability.

Effect of eugenol on cytochrome P450 1A2, 2C9, 2D6, and 3A4 activity in human liver microsomes.

This study aimed to provide an understanding of the influence of eugenol on CYP1A2, 2C9, 2D6, and 3A4 in human liver microsomes (HLM). Specific substrate for CYP1A2, 2C9, 2D6, and 3A4 were incubated in HLM with or without eugenol. The formation of their respective metabolites was assessed with HPLC analytical methods. Eugenol at 1, 10 and 100 µM levels inhibited the activity of CYP1A2 and CYP2C9 by 23.38 %, 23.57 %, 39.80 % and 62.82 %, 63.27 %, 67.70 % respectively. While, CYP2D6 and CYP3A4 activity was decreased by 40.70 %, 45.88 %, 62.68 % and 37.41 %, 42.58 % and 67.86 % at 1, 10 and 100 µM eugenol level respectively. The IC50 value of eugenol for CYP2D6 and CYP3A4 was calculated as 11.09 ± 3.49 µM and 13.48 ± 3.86 µM respectively. Potential herb-drug interactions was noted when eugenol is administered simultaneously with medications metabolized by these enzymes, most notably CYP2C9, CYP2D6 and CYP3A4.

In silico design of peptide inhibitors for Dengue virus to treat Dengue virus-associated infections.

Dengue virus is a single positive-strand RNA virus that is composed of three structural proteins including capsid, envelope, and precursor membrane while seven non-structural proteins (NS1, NS2A, NS2B, NS3A, NS3B, NS4, and NS5). Dengue is a viral infection caused by the dengue virus (DENV). DENV infections are asymptomatic or produce only mild illness. However, DENV can occasionally cause more severe cases and even death. There is no specific treatment for dengue virus infections. Therapeutic peptides have several important advantages over proteins or antibodies: they are small in size, easy to synthesize, and have the ability to penetrate the cell membranes. They also have high activity, specificity, affinity, and less toxicity. Based on the known peptide inhibitor, the current study designs peptide inhibitors for dengue virus envelope protein using an alanine and residue scanning technique. By replacing I21 with Q21, L14 with H14, and V28 with K28, the binding affinity of the peptide inhibitors was increased. The newly designed peptide inhibitors with single residue mutation improved the binding affinity of the peptide inhibitors. The inhibitory capability of the new promising peptide inhibitors was further confirmed by the utilization of MD simulation and free binding energy calculations. The molecular dynamics simulation demonstrated that the newly engineered peptide inhibitors exhibited greater stability compared to the wild-type peptide inhibitors. According to the binding free energies MM(GB)SA of these developed peptides, the first peptide inhibitor was the most effective against the dengue virus envelope protein. All peptide derivatives had higher binding affinities for the envelope protein and have the potential to treat dengue virus-associated infections. In this study, new peptide inhibitors were developed for the dengue virus envelope protein based on the already reported peptide inhibitor.

Human plasma derived exosomes: Impact of active and passive drug loading approaches on drug delivery.

The aim of the current study was to explore the potential of human plasma-derived exosomes as versatile carriers for drug delivery by employing various active and passive loading methods. Exosomes were isolated from human plasma using differential centrifugation and ultrafiltration method. Drug loading was achieved by employing sonication and freeze thaw methods, facilitating effective drug encapsulation within exosomes for delivery. Each approach was examined for its effectiveness, loading efficiency and ability to preserve membrane stability. Methotrexate (MTX), a weak acid model drug was loaded at a concentration of 2.2 µM to exosomes underwent characterization using various techniques such as particle size analysis, transmission electron microscopy and drug loading capacity. Human plasma derived exosomes showed a mean size of 162.15 ± 28.21 nm and zeta potential of -30.6 ± 0.71 mV. These exosomes were successfully loaded with MTX demonstrated a better drug encapsulation of 64.538 ± 1.54 % by freeze thaw method in comparison 55.515 ± 1.907 % by sonication. In-vitro drug release displayed 60 % loaded drug released within 72 h by freeze thaw method that was significantly different from that by sonication method i.e., 99 % within 72 h (p value 0.0045). Moreover, cell viability of exosomes loaded by freeze thaw method was significantly higher than that by sonication method (p value 0.0091) suggested that there was membrane disruption by sonication method. In conclusion, this study offers valuable insights into the potential of human plasma-derived exosomes loaded by freeze thaw method suggest as a promising carrier for improved drug loading and maintenance of exosomal membrane integrity.

Unveiling Therapeutic Avenues for Crohn's Disease Management: Exploring Inhibitors for Adherent-Invasive Escherichia coli Propanediol Dehydratase.

INTRODUCTION: Inflammatory Bowel Disease (IBD) encompasses a group of chronic disorders distinguished by inflammation of the gastrointestinal tract. Among these, Crohn's Disease (CD) stands out as a complex and impactful condition due to challenges for both diagnosis and management, making it a cynosure of research. METHODS: In CD, there is the predominance of proinflammatory bacteria, including the Adherentinvasive Escherichia coli (AIEC) with virulence-associated metabolic enzyme Propanediol Dehydratase (pduC), which has been identified as a therapeutic target for the management of CD. Herein, molecular modeling techniques, including molecular docking, Molecular Mechanics with Generalized Born and Surface Area (MMGBSA), drug-likeness, and pharmacokinetics profiling, were utilized to probe the potentials of eighty antibacterial compounds to serve as inhibitors of pduC. RESULTS: The results of this study led to the identification of five compounds with promising potentials; the results of the molecular docking simulation revealed the compounds as possessing better binding affinities for the target compared to the standard drug (sulfasalazine), while Lipinski's rule of five-based assessment of their drug-likeness properties revealed them as potential oral drugs. MMGBSA free energy calculation and Molecular Dynamics (MD) simulation of the complexes formed a sequel to molecular docking, revealing the compounds as stable binders in the active site of the protein. CONCLUSION: Ultimately, the results of this study have revealed five compounds to possess the potential to serve as inhibitors of pduC of AIEC. However, experimental studies are still needed to validate the findings of this study.

Predictive modeling for breast cancer classification in the context of Bangladeshi patients by use of machine learning approach with explainable AI.

Breast cancer has rapidly increased in prevalence in recent years, making it one of the leading causes of mortality worldwide. Among all cancers, it is by far the most common. Diagnosing this illness manually requires significant time and expertise. Since detecting breast cancer is a time-consuming process, preventing its further spread can be aided by creating machine-based forecasts. Machine learning and Explainable AI are crucial in classification as they not only provide accurate predictions but also offer insights into how the model arrives at its decisions, aiding in the understanding and trustworthiness of the classification results. In this study, we evaluate and compare the classification accuracy, precision, recall, and F1 scores of five different machine learning methods using a primary dataset (500 patients from Dhaka Medical College Hospital). Five different supervised machine learning techniques, including decision tree, random forest, logistic regression, naive bayes, and XGBoost, have been used to achieve optimal results on our dataset. Additionally, this study applied SHAP analysis to the XGBoost model to interpret the model's predictions and understand the impact of each feature on the model's output. We compared the accuracy with which several algorithms classified the data, as well as contrasted with other literature in this field. After final evaluation, this study found that XGBoost achieved the best model accuracy, which is 97%.

Ligand-based drug design against Herpes Simplex Virus-1 capsid protein by modification of limonene through in silico approaches.

The pharmacological effects of limonene, especially their derivatives, are currently at the forefront of research for drug development and discovery as well and structure-based drug design using huge chemical libraries are already widespread in the early stages of therapeutic and drug development. Here, various limonene derivatives are studied computationally for their potential utilization against the capsid protein of Herpes Simplex Virus-1. Firstly, limonene derivatives were designed by structural modification followed by conducting a molecular docking experiment against the capsid protein of Herpes Simplex Virus-1. In this research, the obtained molecular docking score exhibited better efficiency against the capsid protein of Herpes Simplex Virus-1 and hence we conducted further in silico investigation including molecular dynamic simulation, quantum calculation, and ADMET analysis. Molecular docking experiment has documented that Ligands 02 and 03 had much better binding affinities (- 7.4 kcal/mol and - 7.1 kcal/mol) to capsid protein of Herpes Simplex Virus-1 than Standard Acyclovir (- 6.5 kcal/mol). Upon further investigation, the binding affinities of primary limonene were observed to be slightly poor. But including the various functional groups also increases the affinities and capacity to prevent viral infection of the capsid protein of Herpes Simplex Virus-1. Then, the molecular dynamic simulation confirmed that the mentioned ligands might be stable during the formation of drug-protein complexes. Finally, the analysis of ADMET was essential in establishing them as safe and human-useable prospective chemicals. According to the present findings, limonene derivatives might be a promising candidate against the capsid protein of Herpes Simplex Virus-1 which ultimately inhibits Herpes Simplex Virus-induced encephalitis that causes interventions in brain inflammation. Our findings suggested further experimental screening to determine their practical value and utility.

Computational antigenic insights into the novel NADC-34-like Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) isolate YC-2020.

In this computational study, we advanced the understanding of the antigenic properties of the NADC-34-like isolate of the Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), named YC-2020, relevant in veterinary pathology. We utilized sequence comparison analyses of the M and N proteins, comparing them with those of NADC34, identifying substantial amino acid homology that allowed us to highlight conserved epitopes and crucial variants. Through the application of Clustal Omega for multiple sequence alignment and platforms like Vaxijen and AllerTOP for predicting antigenic and allergenic potential, our analyses revealed important insights into the conservation and variation of epitopes essential for the development of effective diagnostic tools and vaccines. Our findings, aligned with initial experimental studies, underscore the importance of these epitopes in the development of targeted immunodiagnostic platforms and significantly contribute to the management and control of PRRSV. However, further studies are required to validate the computational predictions of antigenicity for this new viral isolate. This approach underscores the potential of computational models to enable ongoing monitoring and control of PRRSV evolution in swine. While this study provides valuable insights into the antigenic properties of the novel PRRSV isolate YC-2020 through computational analysis, it is important to acknowledge the limitations inherent to in silico predictions, specifically, the absence of laboratory validation.

Molecular characterization of plasma virome of hepatocellular carcinoma (HCC) patients.

Hepatocellular carcinoma (HCC) stands as the most common cancer type, arising from various causes, and responsible for a substantial number of cancer-related fatalities. Recent advancements in viral metagenomics have empowered scientists to delve into the intricate diversity of the virosphere, viral evolution, interactions between viruses and their hosts, and the identification of viral causes behind disease outbreaks, the development of specific symptoms, and their potential role in altering the host's physiology. The present study had the objective of "Molecular Characterization of HBV, HCV, anelloviruses, CMV, SENV-D, SENV-H, HEV, and HPV viruses among individuals suffering from HCC." A total of 381 HCC patients contributed 10 cc of blood each for this study. The research encompassed the assessment of tumor markers, followed by molecular characterization of HBV, HCV, Anelloviruses (TTV, TTMV, and TTMDV), SENV-H and SENV-D viruses, HEV, CMV, and HPV, as well as histopathological examinations. The outcomes of this study revealed that majority of the HCC patients 72.4% (276/381) were male as compared to females. HCV infection, at 76.4% (291 out of 381), exhibited a significant association (p < 0.05) with HCC. Most patients displayed singular lesions in the liver, with Child Pugh Score Type B being the predominant finding in 45.2% of cases. Plasma virome analysis indicated the prevalence of TTMDV (75%), followed by TTMV (70%) and TTV (42.1%) among anelloviruses in HCC patients. Similarly, SENV-H (52%) was followed by SENV-D (20%), with co-infections at 15%. The presence of CMV and HEV among the HCC patients was recorded 5% each however 3.5% of the patients showed the presence of HPV. In conclusion, this study underscores that HCC patients serve as reservoirs for various pathogenic and non-pathogenic viruses, potentially contributing to the development, progression, and severity of the disease.

Revisiting methotrexate and phototrexate Zinc15 library-based derivatives using deep learning in-silico drug design approach.

Introduction: Cancer is the second most prevalent cause of mortality in the world, despite the availability of several medications for cancer treatment. Therefore, the cancer research community emphasized on computational techniques to speed up the discovery of novel anticancer drugs. Methods: In the current study, QSAR-based virtual screening was performed on the Zinc15 compound library (271 derivatives of methotrexate (MTX) and phototrexate (PTX)) to predict their inhibitory activity against dihydrofolate reductase (DHFR), a potential anticancer drug target. The deep learning-based ADMET parameters were employed to generate a 2D QSAR model using the multiple linear regression (MPL) methods with Leave-one-out cross-validated (LOO-CV) Q2 and correlation coefficient R2 values as high as 0.77 and 0.81, respectively. Results: From the QSAR model and virtual screening analysis, the top hits (09, 27, 41, 68, 74, 85, 99, 180) exhibited pIC50 ranging from 5.85 to 7.20 with a minimum binding score of -11.6 to -11.0 kcal/mol and were subjected to further investigation. The ADMET attributes using the message-passing neural network (MPNN) model demonstrated the potential of selected hits as an oral medication based on lipophilic profile Log P (0.19-2.69) and bioavailability (76.30% to 78.46%). The clinical toxicity score was 31.24% to 35.30%, with the least toxicity score (8.30%) observed with compound 180. The DFT calculations were carried out to determine the stability, physicochemical parameters and chemical reactivity of selected compounds. The docking results were further validated by 100 ns molecular dynamic simulation analysis. Conclusion: The promising lead compounds found endorsed compared to standard reference drugs MTX and PTX that are best for anticancer activity and can lead to novel therapies after experimental validations. Furthermore, it is suggested to unveil the inhibitory potential of identified hits via in-vitro and in-vivo approaches.

Chemical profiling of volatile compounds of the essential oil of grey-leaved rockrose (Cistus albidus L.) and its antioxidant, anti-inflammatory, antibacterial, antifungal, and anticancer activity in vitro and in silico.

Cistus albidus: L., also known as Grey-leaved rockrose and locally addressed as stab or tûzzâla lbîda, is a plant species with a well-established reputation for its health-promoting properties and traditional use for the treatment of various diseases. This research delves into exploring the essential oil extracted from the aerial components of Cistus albidus (referred to as CAEO), aiming to comprehend its properties concerning antioxidation, anti-inflammation, antimicrobial efficacy, and cytotoxicity. Firstly, a comprehensive analysis of CAEO's chemical composition was performed through Gas Chromatography-Mass Spectrometry (GC-MS). Subsequently, four complementary assays were conducted to assess its antioxidant potential, including DPPH scavenging, ß-carotene bleaching, ABTS scavenging, and total antioxidant capacity assays. The investigation delved into the anti-inflammatory properties via the 5-lipoxygenase assay and the antimicrobial effects of CAEO against various bacterial and fungal strains. Additionally, the research investigated the cytotoxic effects of CAEO on two human breast cancer subtypes, namely, MCF-7 and MDA-MB-231. Chemical analysis revealed camphene as the major compound, comprising 39.21% of the composition, followed by α-pinene (19.01%), bornyl acetate (18.32%), tricyclene (6.86%), and melonal (5.44%). Notably, CAEO exhibited robust antioxidant activity, as demonstrated by the low IC50 values in DPPH (153.92 ± 4.30 µg/mL) and ß-carotene (95.25 ± 3.75 µg/mL) assays, indicating its ability to counteract oxidative damage. The ABTS assay and the total antioxidant capacity assay also confirmed the potent antioxidant potential with IC50 values of 120.51 ± 3.33 TE µmol/mL and 458.25 ± 3.67 µg AAE/mg, respectively. In terms of anti-inflammatory activity, CAEO displayed a substantial lipoxygenase inhibition at 0.5 mg/mL. Its antimicrobial properties were broad-spectrum, although some resistance was observed in the case of Escherichia coli and Staphylococcus aureus. CAEO exhibited significant dose-dependent inhibitory effects on tumor cell lines in vitro. Additionally, computational analyses were carried out to appraise the physicochemical characteristics, drug-likeness, and pharmacokinetic properties of CAEO's constituent molecules, while the toxicity was assessed using the Protox II web server.