Antimalarial drug discovery against malaria parasites through haplopine modification: An advanced computational approach.

The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life-threatening infectious disease caused by Plasmodium spp., which includes Apicoplast DNA polymerase and Plasmodium falciparum cysteine protease falcipain-2. These components play a critical role in their life cycle and metabolic pathway, and are involved in the breakdown of erythrocyte hemoglobin in the host, making them promising targets for anti-malarial drug design. Our current study has been designed to explore the potential inhibitors from haplopine derivatives against these two targets using an in silico approach. A total of nine haplopine derivatives were used to perform molecular docking, and the results revealed that Ligands 03 and 05 showed strong binding affinity compared to the control compound atovaquone. Furthermore, these ligand-protein complexes underwent molecular dynamics simulations, and the results demonstrated that the complexes maintained strong stability in terms of RMSD (root mean square deviation), RMSF (root mean square fluctuation), and Rg (radius of gyration) over a 100 ns simulation period. Additionally, PCA (principal component analysis) analysis and the dynamic cross-correlation matrix showed positive outcomes for the protein-ligand complexes. Moreover, the compounds exhibited no violations of the Lipinski rule, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions yielded positive results without indicating any toxicity. Finally, density functional theory (DFT) and molecular electrostatic potential calculations were conducted, revealing that the mentioned derivatives exhibited better stability and outstanding performance. Overall, this computational approach suggests that these haplopine derivatives could serve as a potential source for developing new, effective antimalarial drugs to combat malaria. However, further in vitro or in vivo studies might be conducted to determine their actual effectiveness.

Exploring the cardioprotective effects of canagliflozin against cisplatin-induced cardiotoxicity: Role of iNOS/NF-κB, Nrf2, and Bax/cytochrome C/Bcl-2 signals.

Cardiotoxicity is a severe considerable side effect of cisplatin (CDDP) that requires much medical attention. The current study investigates the cardioprotective effects of canagliflozin (CA) against CDDP-induced heart toxicity. Rats were allocated to the control group; the CA group was administered CA 10 mg/kg/day orally for 10 days; the CDDP group was injected with 7 mg/kg, intraperitoneal as a single dose on the 5th day, and the CDDP + CA group. Compared to the CDDP-treated group, CA effectively attenuated CDDP-induced heart injury as evidenced by a decrease of serum aspartate aminotransferase, alkaline phosphatase, creatine kinase-MB, and lactate dehydrogenase enzymes and supported by the alleviation of histopathological changes in cardiac tissues. Biochemically, CA attenuated cardiac oxidative injury through upregulation of the nuclear factor-erythroid 2 related factor 2 (Nrf2) signal. CA suppressed inflammation by decreasing cardiac NO2 - , MPO, iNOS, nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha, and interleukin 1-beta levels. Besides, CA significantly upregulated cardiac levels of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and p-AKT proteins. Moreover, CA remarkably mitigated CDDP-induced apoptosis via modulation of Bax, cytochrome C, and Bcl-2 protein levels. Together, the present study revealed that CA could be a good candidate for preventing CDDP-induced cardiac injury by modulating iNOS/NF-κB, Nrf2, PI3K/AKT, and Bax/cytochrome C/Bcl-2 signals.

Neuroprotective effect of canagliflozin against cisplatin-induced cerebral cortex injury is mediated by regulation of HO-1/PPAR-γ, SIRT1/FOXO-3, JNK/AP-1, TLR4/iNOS, and Ang II/Ang 1-7 signals.

OBJECTIVES: Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor, is an anti-hyperglycemic drug that has been approved to treat diabetes. This study evaluated the beneficial effects of CAN on cerebral cortex intoxication induced by cisplatin (CIS). MATERIALS AND METHODS: Rats were allocated into four groups: normal control, CAN (10 mg/kg, P.O.) for 10 days, CIS (8 mg/kg, i.p.) as a single dose on the 5th day of the experiment, and CAN + CIS group. RESULTS: In comparison with CIS control rats, CAN significantly mitigated CIS-induced cortical changes in rats' behavior in the open field and forced swimming assessment as well as histological structure. Biochemically, CAN administration efficiently decreased lipid peroxidation biomarkers MDA and boosted the antioxidant status via a remarkable increase in the cortical reduced glutathione (GSH) content as well as enzymatic activities of antioxidant enzymes superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase (CAT), and glutathione peroxidase (GPx) mediated by up-regulation of heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptors (PPARγ), and silent information regulator (SIRT1)/forkhead box-O3 (FOXO-3) signals. Additionally, pretreatment with CAN significantly decreased cortical myeloperoxidase (MPO), nitrite (NO2-), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels. At the same time, it elevated the IL-10 level associated with the downregulation of Jun N-terminal kinase (JNK)/activator protein 1 (AP-1), TLR4/inducible nitric oxide synthase (iNOS)/nitric oxide (NO), and Ang II/Ang 1-7 signals. CONCLUSIONS: Due to the potent antioxidant and anti-inflammatory properties of CAN, our findings showed that CAN could be a good candidate for the protection against CIS-induced cortical intoxication in the patient receiving CIS.

A New Humanized Mouse Model Mimics Humans in Lacking α-Gal Epitopes and Secreting Anti-Gal Antibodies.

Mice have been used as accepted tools for investigating complex human diseases and new drug therapies because of their shared genetics and anatomical characteristics with humans. However, the tissues in mice are different from humans in that human cells have a natural mutation in the α1,3 galactosyltransferase (α1,3GT) gene and lack α-Gal epitopes on glycosylated proteins, whereas mice and other nonprimate mammals express this epitope. The lack of α-Gal epitopes in humans results in the loss of immune tolerance to this epitope and production of abundant natural anti-Gal Abs. These natural anti-Gal Abs can be used as an adjuvant to enhance processing of vaccine epitopes to APCs. However, wild-type mice and all existing humanized mouse models cannot be used to test the efficacy of vaccines expressing α-Gal epitopes because they express α-Gal epitopes and lack anti-Gal Abs. Therefore, in an effort to bridge the gap between the mouse models and humans, we developed a new humanized mouse model that mimics humans in that it lacks α-Gal epitopes and secretes human anti-Gal Abs. The new humanized mouse model (Hu-NSG/α-Galnull) is designed to be used for preclinical evaluations of viral and tumor vaccines based on α-Gal epitopes, human-specific immune responses, xenotransplantation studies, and in vivo biomaterials evaluation. To our knowledge, our new Hu-NSG/α-Galnull is the first available humanized mouse model with such features.

Construction of Adipogenic ceRNA Network Based on lncRNA Expression Profile of Adipogenic Differentiation of Human MSC Cells.

The Long non-coding RNA (lncRNA) expression profile data of ten samples including human Mesenchymal Stem Cell (MSC) adipogenic differentiation 0, 3, and 6 days from the GEO database, and then perform gene ID conversion, BLAST comparison, and annotation marking. Finally, group A (treatment group on day 3 of differentiation and control group on day 0 of differentiation) obtained a total of 1180 mRNA and 185 lncRNA; group B (treatment group on day 6 of differentiation and control group on day 0 of differentiation). A total of 1376 mRNA and 206 lncRNA were obtained. Finally, we processed the differential lncRNAs and mRNAs obtained in the two groups, and obtained 113 shared differential lncRNAs to further predict the targeted miRNA, a total of 815 lncRNA-miRNA pairs. The targeted mRNA was further predicted, and the grouped differential mRNAs were combined to obtain 64 differential mRNAs. In the end, we obtained 216 ceRNAs containing 26 lncRNAs, 27 miRNAs and 64 mRNAs. We found that the mRNAs in the ceRNA network were mainly enriched with 45 Gene Ontology (GO) terms, mainly including glucose homeostasis mechanism and insulin stimulation response. 69 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were mainly enriched. It mainly includes many pathways related to lipid metabolism such as Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), Rap1, cAMP, mitogen-activated protein kinase (MAPK), Ras, hypoxia inducible factor-1 (HIF-1), PI3K-Akt, insulin signaling and so on. In the end, we identified 216 ceRNA regulatory relationships related to obesity research. Our research provides a clearer direction for understanding the molecular mechanism of obesity, the screening and determination of drug targets biomarkers in the future.

Immunomodulatory Efficacy-Mediated Anti-HCV and Anti-HBV Potential of Kefir Grains; Unveiling the In Vitro Antibacterial, Antifungal, and Wound Healing Activities.

The utilization of fermented foods with health-promoting properties is becoming more popular around the world. Consequently, kefir, a fermented milk beverage made from kefir grains, was shown in numerous studies to be a probiotic product providing significant health benefits. Herein, we assessed the antibacterial and antifungal potential of kefir against a variety of pathogenic bacteria and fungi. This study also showed the effectiveness of kefir in healing wounds in human gastric epithelial cells (GES-1) by (80.78%) compared with control (55.75%) within 48 h. The quantitative polymerase chain reaction (qPCR) results of kefir-treated HCV- or HBV- infected cells found that 200 µg/mL of kefir can eliminate 92.36% of HCV and 75.71% of HBV relative to the untreated infected cells, whereas 800 µg/mL (the highest concentration) completely eradicated HCV and HBV. Moreover, the estimated IC50 values of kefir, at which HCV and HBV were eradicated by 50%, were 63.84 ± 5.81 µg/mL and 224.02 ± 14.36 µg/mL, correspondingly. Kefir can significantly suppress the elevation of TNF-α and upregulate IL-10 and INF-γ in both treated HCV- and HBV-infected cells. High-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) analysis of kefir revealed the presence of numerous active metabolites which mainly contribute to the antimicrobial, antiviral, and immunomodulatory activities. This study demonstrated, for the first time, the anti-HBV efficacy of kefir while also illustrating the immunomodulatory impact in the treated HBV-infected cells. Accordingly, kefir represents a potent antiviral agent against both viral hepatitis C and B, as well as having antimicrobial and wound healing potential.

Research on acute phase proteins and inflammatory cytokines biomarkers in dromedary camels (Camelus dromedarius) with clinical endometritis.

Uterine diseases are prevalent in camels and lead to economic losses because of decreased fertility. The aim of this study is to look into the expression patterns of acute-phase proteins (APPs) and inflammatory cytokines in dromedary camels with clinical endometritis (CE) to highlight their role in the immune pathogenesis of the disease. Moreover, to identify the use of these parameters as a complementary tool for CE screening as well as investigate the efficacy of ceftiofur antibiotic, APPs and inflammatory cytokines were estimated in camels with CE. Values of APPs (Hp, SAA, and Fg), pro-inflammatory (IFN-γ, TNF-α, IL-1α, IL-1ß, and IL-6), and anti-inflammatory cytokines (IL-10) were higher in camels with CE than in healthy controls (P < 0.05). The strongest correlations were observed between HP and IFN-γ (r = 0.73) and IL-1ß and IL-6 (r = 0.73), while the weakest correlations were observed between Fg and IFN-γ (r = 0.25). Corynebacterium pyogenes and Arcanobacterium pyogenes were the most common pathogens involved in the etiology of CE. All investigated biomarkers demonstrated a high degree of recognition between CE camel and healthy controls (AUC was > 0.90). A higher proportion of camels with CE that were treated with ceftiofur (90%, P < 0.0001) scored clinical cures after the first dose, while 10% required a second dose. In conclusion, CE causes increased APPs and inflammatory cytokine biomarkers, indicating a significant acute phase response in diseased camels with CE. These changes in biomarkers could be beneficial for understanding the immune pathogenesis of CE in dromedary camels, clinical practice, and basic clinical research.

Biosynthesis and Characterization of Extracellular Silver Nanoparticles from Streptomyces aizuneusis: Antimicrobial, Anti Larval, and Anticancer Activities.

The ability of microorganisms to reduce inorganic metals has launched an exciting eco-friendly approach towards developing green nanotechnology. Thus, the synthesis of metal nanoparticles through a biological approach is an important aspect of current nanotechnology. In this study, Streptomyces aizuneusis ATCC 14921 gave the small particle of silver nanoparticles (AgNPs) a size of 38.45 nm, with 1.342 optical density. AgNPs produced by Streptomyces aizuneusis were characterized by means of UV-VIS spectroscopy and transmission electron microscopy (TEM). The UV-Vis spectrum of the aqueous solution containing silver ion showed a peak between 410 to 430. Moreover, the majority of nanoparticles were found to be a spherical shape with variables between 11 to 42 nm, as seen under TEM. The purity of extracted AgNPs was investigated by energy dispersive X-ray analysis (EDXA), and the identification of the possible biomolecules responsible for the reduction of Ag+ ions by the cell filtrate was carried out by Fourier Transform Infrared spectrum (FTIR). High antimicrobial activities were observed by AgNPs at a low concentration of 0.01 ppm, however, no deleterious effect of AgNPs was observed on the development and occurrence of Drosophila melanogaster phenotype. The highest reduction in the viability of the human lung carcinoma and normal cells was attained at 0.2 AgNPs ppm.

Characterization of microbes associated with cervico-vaginal adhesion in the reproductive system of camels (Camelus dromedaries).

Vaginal and cervical adhesions are severe long-standing reproductive disorder in dromedaries and consequently result in a high culling rate. This study was designed to compare the microbial communities of the vaginae, cervices, and uteri of normal (n = 10) camels versus camels suffering from cervico-vaginal adhesion (n = 23). Vaginal, cervical, and uterine swab samples were collected from control and affected animals. Furthermore, serum samples were obtained for serological testing of Chlamydiosis and Coxiellosis. For bacteriological and fungal examination, swab samples were plated on Columbia and Saboraud's dextrose agar, respectively. Polymerase chain reaction (PCR) assay was applied to samples expressed seropositive for Chlamydiosis. Vaginal swab bacterial cultures showed that the affected animals were significantly infected with Staphylococcus aureus (P = 0.0322, CI: 0.25-0.95) than the control, while mycological cultures showed that both control and affected animals were infected with Cryptococcus and Candida albicans. Corynebacterium spp. (22.7%), Pseudomonas spp. (4.5%), Klebsiella spp. (9.1%), T. pyogenes (18.2%), and anaerobic bacteria (Fusobacterium necrophorum and Clostridium spp.; 34.78%) were also identified in affected animals. Cervical samples from affected animals were distinguished by the existence of S. aureus (27.8%), Klebsiella spp. (5.6%), Corynebacterium spp. (22.2%), Cryptococcus (16.7%), Proteus spp. (11.1% (, T. pyogenes (11.1%), Pseudomonas spp. (5.6%), and Fusobacterium necrophorum (17.4%). Uterine samples from affected animals were characterized by the presence of S. aureus (22.2%), Streptococcus (22.2%), Corynebacterium spp. (11.1%), E. coli (11.1%), and Pseudomonas spp. (11.1%). Anaerobic bacteria were not isolated from control nor affected animals. Enzyme immunoassays revealed that 50% and 34.8% of the control and affected animals were positive for Coxiella burnetii, respectively, Chlamydia was detected in 43.5% of samples from affected animals, only 60% of which were confirmed positive. These results show that microbial communities linked with cervico-vaginal adhesion in dromedary camels are likely to be polymicrobial. The findings of this study are helpful in designing antimicrobial therapies toward reducing the incidence for cervico-vaginal adhesion.

Impact of antibiotics on spermatozoa quality and bacterial load of chilled-stored camels (Camelus dromedarius) semen.

This experiment was conducted to assess the effect of different antibiotics in tris-fructose egg yolk-based diluent on bacterial load and sperm quality of dromedary camels during processing and cold storage. Ten semen ejaculates were collected from five male dromedary camels. Each sample was fractioned into four equally divided aliquots and diluted in one of four tris-fructose egg yolk. The first extender contained no antibiotic (NC). The second extender included streptomycin sulphate (1000 µg/ml) and benzyl penicillin (1000 IU/ml) (SP). The third extender was supplied with 250 µg/ml gentamicin sulphate (Gent). The fourth extender contained 500 µg/ml gentamicin sulphate,100 µg/ml tylosin tartrate, 300 µg/ml lincomycin hydrochloride and 600 µg/ml spectinomycin hydrochloride (GTLS). After dilution, the extended semen samples were cooled to 5 °C within 2 h and finally stored at 5 °C for 72 h. Microbial concentration, motility of spermatozoa, live spermatozoa, plasma membrane and acrosome integrity percentages were evaluated just after dilution at 35 °C, 0, 24, 48 and 72 h from the start of cooling to 5 °C. The results revealed that the diluent containing gentamicin had significantly (P<0.05) maximum motility percentage at the different examination intervals. The pattern of live spermatozoa percentage was varied between the different treatments at different examination intervals. The diluent supplied with Gent was distinguished with a significant peak percentage (P<0.05) of swelled spermatozoa among the other antibiotics supplied diluents. The number of colony-forming units isolated from the semen samples kept in diluent containing no antibiotics was significantly (P<0.05) higher than that isolated from the diluents supplemented with antibiotics. In conclusion, the semen diluents fortified with gentamicin generally keep the motility, acrosomal and plasma membrane integrity and live spermatozoa for 72-h preservation of dromedary semen.

A Simplified Numerical Approach to Examine the Sensitivity of Two-Electrode Capacitance Sensor Orientation to Capture Different Gas-Liquid Flow Patterns in a Small Circular Pipe.

This work involved the simulation of both a multiphase gas-liquid flow and the electromagnetic field representing a two-electrode capacitance sensor in a circular pipe. The simulation investigates in particular the sensitivity of the sensor orientation around the pipe (i.e., top-to-bottom or side-to-side) that best capture the induced flow patterns. The presented numerical work is a simplified simulation by COMSOL multi-physics which was validated by a systematic and an extensive experimental work, using (a) a specially designed simple capacitance sensor (i.e., concave two electrodes), (b) different gas-liquid superficial velocity combinations, (c) different flow section inclinations, and (d) high-speed camera images. The numerical modelling capacitance values were validated against the experimentally measured values which shows a satisfactory level of agreement with a deviation of less than ±2%. The quantity of finite points was between 280,000 and 340,000, which was influenced by the simulated flow pattern. The simulated cases captured the generated flow patterns and their variation inside the pipe, which was in a good agreement when compared to the experimental work as time-dependent values. It was found that the best orientation for the utilized two-electrode capacitance sensor was the top-to-bottom configuration. This is because the sensor's electrical field distribution was more sensitive, and capable of detecting a greater range of capacitance values. The sensitivity of the top-to-bottom configuration was 1.25-1.64 times greater than that of the side-to-side configuration. Therefore, for design purposes and performance optimization, it is recommended to use the top-to-bottom configuration.

Outcomes of patients with multiple sclerosis at a neurorehabilitation unit in Saudi Arabia.

OBJECTIVE: To assess the impact of inpatient multidisciplinary rehabilitation on a Saudi Arabian population of patients with multiple sclerosis (MS). METHODS: We retrospectively analyzed the data of patients with MS who underwent inpatient rehabilitation between 2009 and 2015 at King Fahad Medical City (KFMC). Differences in Functional Independence Measure (FIM) scores (used in rehabilitation settings to assess the functional independence of patients) and length of stay (LOS) were measured between patients of different ages, sexes, and types of MS and analyzed using the independent t-test. The Pearson correlation coefficient was used to investigate the correlation between FIM, LOS, and other variables. RESULTS: In total, 24 patients were identified, with an average age of 36 years. The average age at disease onset was 31 years. Disease duration ranged from 1-20 years, with a mean of 7 years. The most common type of MS was relapsing-remitting (45.8%). The mean FIM score at admission was 77.5 and at discharge 97.25. Functional independence measure gain ranged from 2-51, with a mean of 18.58. Functional independence measure efficiency (FIM gain divided by LOS) ranged between 0.09-0.95. The length of stay ranged between 21-95 days, with a mean of 37.79 days. There was a significant association between age and FIM efficiency (p=0.043). CONCLUSION: Inpatient rehabilitation is an important intervention that improves the functional independence of patients with chronic MS.

Adrenal medulla of AS/AGU rats: a histological and immunohistochemical study.

BACKGROUND: The outcome of the autograft therapy for Parkinson's disease including autologous cells from adrenal medulla was disappointing. This could be attributed to the pathological process in Parkinson's disease affecting cells of the adrenal medulla. This study was performed to investigate the histopathological changes in the adrenal medulla of AS/AGU rat, a model of Parkinson's disease, in comparison with Albino Swiss (AS) rats. MATERIALS AND METHODS: A total of 24 male AS rats were divided into four groups, each of 6 animals: AS W1 - AS rats aged 1 week; AS adult - AS adult rats; AS/ /AGU W1 - AS/AGU rats aged 1 week; and AS/AGU adult - AS/AGU adult rats. The rats were sacrificed and the adrenal glands were dissected and processed for histological staining with haematoxylin and eosin and periodic acid Schiff and for immunohistochemical staining for S100 protein, ubiquitin and tyrosine hydroxylase. RESULTS: The histological investigation of the adrenal medulla of AS/AGU rats showed vascular congestion, inflammatory cellular infiltration, pyknotic nuclei, necrotic chromaffin cells and medullary inclusion bodies. The immunohistochemical investigation of AS/AGU rats showed a statistically significant decrease in the expression of S100 protein, ubiquitin and tyrosine hydroxylase compared to AS rats. CONCLUSIONS: The histological and immunohistological changes in the adrenal medulla could explain the failure of outcome of adrenal autograft therapy in Parkinson's disease.

Epidemiological insights into paratuberculosis in camels in Saudi Arabia: Bayesian estimation of true prevalence and identification of risk factors.

Paratuberculosis, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a significant concern in the camel population of Saudi Arabia. This study aimed to provide epidemiological insights into the disease by estimating the true prevalence in camels in the Eastern Province and Riyadh, using a Bayesian estimation framework, and exploring the associated risk factors through a frequentist approach. A total of 1200 camel blood samples were collected and analyzed using an indirect ELISA method. The true herd-level prevalence was estimated at 0.7 (95% probability interval: 0.57 to 0.81), and the mean expected true animal-level prevalence was 0.17 (0.14 to 0.20). Risk factors associated with Map seropositivity were identified, including sex, breed, raising system, and production type. Females, single breed camels, and nomadic raising systems were found to have lower odds of seropositivity, while camels used for racing and show had significantly higher odds. The study's Bayesian approach, adjusting for the imperfect accuracy of MAP tests, provides a nuanced understanding of the disease's prevalence in the region. The integration of true prevalence estimates with risk factor analysis offers a comprehensive framework that can guide future policies and strategies in the fight against paratuberculosis in Saudi Arabia. The findings emphasize the importance of targeted control measures, underscoring the urgent need for interventions in Saudi Arabia's camel population. By understanding the true disease prevalence and its associated risk factors, we can enhance disease management strategies, offering valuable insights for future control and eradication efforts in the region.

Enumeration of olive derived lignan, pinoresinol for activity against recent Omicron variant spike protein for structure-based drug design, DFT, molecular dynamics simulations, and MMGBSA studies.

The coronavirus disease 2019 (COVID-19) was first found in Wuhan, China, in December 2019. Because the virus spreads quickly, it quickly became a global worry. Coronaviridae is the family that contains both SARS-CoV-2 and the viruses that came before (i.e., MERS-CoV and SARS-CoV). Recent sources portray that the COVID-19 virus has affected 344,710,576 people worldwide and killed about 5,598,511 people in the last 2 years. The B.1.1.529 strain, later called "Omicron," was named a Variant of Concern on November 24, 2021. The SARS-CoV-2 virus has gone through a never-ending chain of changes that have never happened before. As a result, it has many different traits. Most of these changes have occurred in the spike protein, where antibodies bind. Because of these changes, the Omicron type is very contagious and easy to pass on. There have been a lot of studies done to try to figure out this new challenge in the COVID-19 strains race, but there is still a lot that needs to be explained. This study focuses on virtual screening, docking, and molecular dynamic analysis; we aimed to identify therapeutic candidates for the SARS-CoV-2 variant Omicron based on their ability to inhibit non-structural proteins. We investigate the prediction of the properties of a substantial database of drug molecules obtained from the OliveNet™ database. Compounds that did not exhibit adequate gastrointestinal absorption and failed the Lipinski test are not considered for further research. The filtered compounds were coupled with our primary target, SARS-CoV-2 Omicron spike protein. We focused on SARS-CoV-2 Omicron spike protein and filtering potent olive compounds. Pinoresinol, the most likely candidate, is bound best (- 8.5 kcal/mol). Pinoresinol's strong interaction with the active site made the complex's dynamic structure more resilient. MD simulations explain the protein-ligand complex's stability and function. Pinoresinol may be a promising SARS-CoV-2 Omicron spike protein receptor lead drug, and additional research may assist the scientific community.

Revolutionizing Cancer Treatment: Unleashing the Power of Viral Vaccines, Monoclonal Antibodies, and Proteolysis-Targeting Chimeras in the New Era of Immunotherapy.

In the realm of cancer immunotherapy, a profound evolution has ushered in sophisticated strategies that encompass both traditional cancer vaccines and emerging viral vaccines. This comprehensive Review offers an in-depth exploration of the methodologies, clinical applications, success stories, and future prospects of these approaches. Traditional cancer vaccines have undergone significant advancements utilizing diverse modalities such as proteins, peptides, and dendritic cells. More recent innovations have focused on the physiological mechanisms enabling the human body to recognize and combat precancerous and malignant cells, introducing specific markers like peptide-based anticancer vaccines targeting tumor-associated antigens. Moreover, cancer viral vaccines, leveraging engineered viruses to stimulate immune responses against specific antigens, exhibit substantial promise in inducing robust and enduring immunity. Integration with complementary therapeutic methods, including monoclonal antibodies, adjuvants, and radiation therapy, has not only improved survival rates but also deepened our understanding of viral virulence. Recent strides in vaccine design, encompassing oncolytic viruses, virus-like particles, and viral vectors, mark the frontier of innovation. While these advances hold immense potential, critical challenges must be addressed, such as strategies for immune evasion, potential off-target effects, and the optimization of viral genomes. In the landscape of immunotherapy, noteworthy innovations take the spotlight from the use of immunomodulatory agents for the enhancement of innate and adaptive immune collaboration. The emergence of proteolysis-targeting chimeras (PROTACs) as precision tools for cancer therapy is particularly exciting. With a focus on various cancers, from melanoma to formidable solid tumors, this Review critically assesses types of cancer vaccines, mechanisms, barriers in vaccine therapy, vaccine efficacy, safety profiles, and immune-related adverse events, providing a nuanced perspective on the underlying mechanisms involving cytotoxic T cells, natural killer cells, and dendritic cells. The Review also underscores the transformative potential of cutting-edge technologies such as clinical studies, molecular sequencing, and artificial intelligence in advancing the field of cancer vaccines. These tools not only expedite progress but also emphasize the multidimensional and rapidly evolving nature of this research, affirming its profound significance in the broader context of cancer therapy.

Retraction: Superior Mesenteric Artery Thrombosis Following Severe COVID-19 Pneumonia.

[This retracts the article DOI: 10.7759/cureus.19954.].

Chronic hepatitis C genotype 1 patients with insulin resistance treated with pioglitazone and peginterferon alpha-2a plus ribavirin.

UNLABELLED: Patients with chronic hepatitis C and insulin resistance are less likely to respond to anti-hepatitis C virus (HCV) therapy and are at risk for more rapid fibrosis progression. Coadministration of pioglitazone with peginterferon/ribavirin improves insulin sensitivity and increases virologic response rates in insulin-resistant HCV genotype 4 patients, but it is unclear whether this finding applies to genotype 1 patients. For this reason we randomized treatment-naive HCV genotype 1 patients with insulin resistance to receive either standard care (peginterferon alpha-2a plus ribavirin for 48 weeks, n = 73) or pioglitazone 30-45 mg/day plus standard care (n = 77) in an open-label multicenter trial. Patients randomized to pioglitazone received the drug during a 16-week run-in phase, the 48-week standard-care phase, and the 24-week untreated follow-up phase. Pioglitazone treatment improved hemoglobin A1c (HbA1c), plasma glucose, insulin levels, and homeostasis model assessment of insulin resistance score and increased serum adiponectin levels during the 16-week run-in phase and maintained these improvements during the standard-care phase. However, we observed no statistically significant difference between the two groups in the primary efficacy endpoint, the decrease from baseline to Week 12 of peginterferon alpha-2a/ribavirin treatment in mean log(10) HCV RNA titer (-3.5 ± 1.71 and -3.7 ± 1.62 IU/mL in the pioglitazone and standard-care groups, respectively, Δ = 0.21 IU/mL, P = 0.4394). CONCLUSION: Treatment with pioglitazone before and during treatment with peginterferon alpha-2a plus ribavirin improved several indices of glycemic control in patients with chronic hepatitis C and insulin resistance, but did not improve virologic response rates compared with peginterferon alpha-2a plus ribavirin alone.

Impact of disease severity on healthcare costs in patients with chronic hepatitis C (CHC) virus infection.

UNLABELLED: Hepatitis C virus (HCV) infection increases total healthcare costs but the effect of the severity of liver disease associated with chronic hepatitis C (CHC) on healthcare costs has not been well studied. We analyzed the demographics, healthcare utilization, and healthcare costs of CHC patients in a large U.S. private insurance database (January, 2002 to August, 2010), with at least 1 year of baseline enrollment and 30 days of continuous follow-up. Patients were stratified by liver disease severity: noncirrhotic liver disease (NCD), compensated cirrhosis (CC), and endstage liver disease (ESLD), as defined by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9) codes. Mean all-cause and HCV-related healthcare costs per-patient-per-month (PPPM) during follow-up (mean 634 days) are reported in 2010 U.S.$ from the payer's perspective. A total of 53,796 patients with CHC were included (NCD: 41,858 [78%]; CC: 3,718 [7%]; and ESLD: 8,220 [15%]). Mean all-cause PPPM healthcare costs were 32% and 247% higher for patients with CC and ESLD compared to those with NCD ($1,870 and $4,931 versus $1,420; P < 0.001) and were independent of age or comorbid conditions. Pharmacy, ambulatory, and inpatient care collectively accounted for 90% of NCD costs and 93% of CC and ESLD costs. The largest cost components were inpatient costs for those with ESLD (56%) and ambulatory costs for those with CC and NCD (37% and 36%, respectively). Overall, 56% of costs were HCV-related and this proportion increased with severity (46%, 57%, and 71% for patients with NCD, CC, and ESLD, respectively). CONCLUSION: The direct healthcare costs associated with CHC are high, increase in association with the progression of liver disease, and are highest in those with ESLD.

Fusion of Magnetic Resonance Elastography Images With Computed Tomography and Magnetic Resonance Imaging Using the Human Visual System.

Magnetic resonance elastography (MRE) is used to assess the stiffness of the liver to rule out cirrhosis or fibrosis. The image, nevertheless, is regarded as shear-wave imaging and does not depict any anatomical features. Multimodality medical image fusion (MMIF), such as the fusion of MRE with computed tomography (CT) scan or magnetic resonance imaging (MRI), can help doctors optimize the advantages of each imaging technique. As a result, perceptions serve as valid and valuable assessment criteria. The contrast sensitivity function (CSF), which describes the rates of visual contrast sensitivity through the changing of spatial frequencies, is used mathematically to characterize the human visual system (HVS). As a result, we suggest novel methods for fusing images that use discrete wavelets transform (DWT) based on HVS and CSF models. Images from MRI or CT scan were combined with MRE images, and the outcomes were assessed both subjectively and objectively. Visual inspection of merging images was done throughout the qualitative analysis. The CT-MRE fused images in all four datasets were shown to be superior at maintaining bones and spatial resolution, despite the MRI-MRE being better at exhibiting soft tissues and contrast resolution. It is clear from all four datasets that the liver soft tissue in MRI and CT images mixed successfully with the red-colored stiffness distribution seen in MRE images. The proposed approach outperformed DWT, which produced visual artifacts such as signal loss. Quantitative evaluation using mean, standard deviation, and entropy showed that the generated images from the proposed technique performed better than the source images and DWT. Additionally, peak signal-to-noise ratio, mean square error, correlation coefficient, and structural similarity index measure were employed to compare the two fusion approaches, namely, MRI-MRE and CT-MRE. The comparison did not show the superiority of one approach over the other. In conclusion, both subjective and objective evaluation approaches revealed that the combined images contained more information and characteristics. Hence, the proposed method might be a useful procedure to diagnose and localize the stiffness regions on the liver soft tissue by fusion of MRE with MRI or CT.