Design, classification, and adverse effects of NSAIDs: A review on recent advancements.

Inflammation is a hallmark of many diseases, including cancer, neurodegenerative diseases like Alzheimer's, type II diabetes, rheumatoid arthritis, and asthma. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been a cornerstone in the management of various inflammatory, pain, and fever-related conditions. As a result, NSAIDs have found their applications in new therapeutic areas. NSAIDs are known to act by inhibiting the cyclooxygenase (COX) pathway. In recent years, new strategies have been proposed to counter inflammation and develop safer COX inhibitors. This review discusses the design of new COX inhibitors, the derivatization of conventional NSAIDs, and their biological applications. The review also presents an integrated classification of NSAIDs incorporating both traditional chemical-based and function-based approaches, including a brief overview of the NSAIDs of natural origins. Additionally, the review addresses adverse effects associated with different NSAIDs, including effects associated with cardiovascular, renal, and hepatic complications emphasizing the need for the development of new and safer COX inhibitors.

Mechanistic elucidation of Juglanthraquinone C targeting breast Cancer: A network Pharmacology-based investigation.

Breast cancer is the leading cause of death among women worldwide. Despite the recent treatment options like surgery, chemotherapy etc. the lethality of breast cancer is alarming. Natural compounds are considered a better treatment option against breast carcinoma because of their lower side effects and specificity in targeting important proteins involved in the aberrant activation of pathways in breast cancer. A recently discovered compound called Juglanthraquinone C, which is found in the bark of the Juglans mandshurica Maxim (Juglandaceae) tree has shown promising cytotoxicity in hepatocellular carcinoma. However, not much data is available on the molecular mechanisms followed by this compound. Therefore, we aimed to investigate the molecular mechanism followed by Juglanthraquinone C against breast cancer. We used the network pharmacology technique to analyse the mechanism of action of Juglanthraquinone C in breast cancer and validated our study by applying various computational tools such as UALCAN, cBioportal, TIMER, docking and simulation. The results showed the compound and breast cancer target network shared 31 common targets. Moreover, we observed that Juglanthraquinone C targets multiple deregulated genes in breast cancer such as TP53, TGIF1, IGF1R, SMAD3, JUN, CDC42, HBEGF, FOS and signaling pathways such as PI3K-Akt pathway, TGF-ß signaling pathway, MAPK pathway and HIPPO signaling pathway. A docking examination revealed that the investigated drug had a high affinity for the primary target TGIF1 protein. A stable protein-ligand combination was generated by the best hit molecule, according to molecular dynamics modeling. The main aim of this study was to examine Juglanthraquinone C's significance as a prospective breast cancer treatment and to better understand the molecular mechanism this substance uses in breast cancer since there is a need to discover new therapeutics to decrease the load on current therapeutics which also are currently ineffective due to several side effects and development of drug resistance.

Novel landmarks on the journey from natural products to pharmaceutical formulations: Phytochemical, biological, toxicological and computational activities of Satureja hortensis L.

This study examined the ethanolic extract of the Satureja hortensis L. plant's aerial parts to describe its phytochemical makeup, biological functions, toxicity tests, and in-silico molecular docking tests. The GC-MS analysis was used to evaluate the phytochemical composition of the tested extract, and the ABTS and hydrogen peroxide antioxidant assays were used to measure antioxidant activity. Aspergillus fumigatus, Candida albicans, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Proteus vulgaris were tested for antimicrobial potential. On cell lines such as HepG-2, MCF-7, A-549, and Panc-1, the in-vitro toxicity was also examined. The A-549 cell line was also used for flow cytometry analysis of apoptosis and cell cycle. Additionally, the compounds discovered by the GC-MS analysis were used in silico tests against biological targets. Eight different phytocompounds were tentatively identified as a result of the GC-MS analysis. The compounds also demonstrated significant antioxidant potential for the ABTS and H2O2 assays (IC50: 2.44 and 28.04 µg/ml, respectively). The tested extract was found to have a range of inhibition zones and to be significantly active against the tested bacterial and fungal strains. Apoptosis and cell cycle analysis for the A-549 cell line showed that the cell cycle was arrested at S-phase, and the extract was also found to be most active against this cell line with an IC50 value of 113.05 µg/ml. The docking studies have emphasized the compounds' interactions and binding scores with the EGFR-TK target as determined by the GC-MS.

A network pharmacology-based investigation of brugine reveals its multi-target molecular mechanism against Breast Cancer.

Breast cancer represents the leading cause of mortality among women worldwide. Since the complexity of breast cancer as a disease resides in its heterogeneity as it consists of several subtypes such as hormone receptor-positive subtypes: Luminal A, Luminal B, Her2- overexpressed, basal-like and hormone receptor-negative subtype: TNBC. Among all the subtypes, triple negative breast cancer (TNBC) is the most lethal and complex subtype. Moreover, the available treatment options like surgery, radiation therapy, and chemotherapy are not sufficient because of the associated side effects and drug resistance development. Therefore, discovery of new effective natural compounds with anti-tumor activity is required. In this pursuit, marine organisms provide a plentiful supply of such chemicals compounds. A marine compound Brugine found in the bark and stem of mangrove species Bruguiera sexangula is a potential anti-cancer compound. It has shown its cytotoxic activity against sarcoma 180 and lewis lung cancer. The molecular processes, however, are currently unknown. So, in order to research the molecular pathways this compound utilizes, we sought to apply a network pharmacology approach. The network pharmacology strategy we used in this investigation to identify and evaluate possible molecular pathways involved in the treatment of breast cancer with brugine was supported by simulation and molecular docking experiments. The study was conducted using various databases such as the cancer genome atlas (TCGA) for the genetic profile study of breast cancer, Swiss ADME for studying the pharmacodynamic study of brugine, Gene cards for collection of information of genes, STRING was used to study the interaction among proteins, AutoDock vina was to study the binding efficacy of brugine with the best fit protein. The results showed that the compound and breast cancer target network shared 90 common targets. According to the functional enrichment analysis brugine exhibited its effects in breast cancer via modulating certain pathways such as cAMP signaling pathway, JAK/STAT pathway, HIF-1 signaling pathway PI3K-Akt pathway, calcium signaling pathway, and Necroptosis. Molecular docking investigations demonstrated that the investigated marine compound has a high affinity for the key target, protein kinase A (PKA). A stable protein-ligand combination was created by the best hit molecule, according to molecular dynamics modeling. The purpose of this research was to examine the importance of brugine as a potentially effective treatment for breast cancer and to obtain knowledge of the molecular mechanism used by this substance in breast cancer.

Inhibitory Potential of the Ocimum sanctum Phytochemicals on Bruton's Tyrosine Kinase, a Well-Known Drug Target for Treatment of Chronic Lymphocytic Leukemia: An In Silico Investigation.

Chronic lymphocytic leukemia (CLL) is an incurable neoplasm of B-lymphocytes, which accounts for about one-third of all leukemias. Ocimum sanctum, an herbaceous perennial, is considered as one of the important sources of drugs for the treatment of various diseases, including cancers and autoimmune diseases. The present study was designed to screen various phytochemicals of O. sanctum for discovering their potential to inhibit Bruton's tyrosine kinase (BTK), a well-known drug target of CLL. Various phytochemicals of O. sanctum were screened for their potential to inhibit BTK using several in silico protocols. First, the molecular docking approach was used to calculate the docking scores of the selected phytochemicals. Then, the selected top-ranked phytochemicals were screened for their physicochemical characteristics using ADME analysis. Finally, the stability of the selected compounds in their corresponding docking complexes with BTK was analysed using molecular dynamics simulations. Primarily, our observations revealed that, out of the 46 phytochemicals of O. sanctum, six compounds possessed significantly better docking scores (ranging from -9.2 kcal/mol to -10 kcal/mol). Their docking scores were comparable to those of the control inhibitors, acalabrutinib (-10.3 kcal/mol), and ibrutinib (-11.3 kcal/mol). However, after ADME analysis of these top-ranked six compounds, only three compounds (Molludistin, Rosmarinic acid, and Vitexin) possessed drug likeliness characteristics. During the MD analysis, the three compounds Molludistin, Rosmarinic acid, and Vitexin were found to remain stable in the binding pocket in their corresponding docking complexes with BTK. Therefore, among the 46 phytochemicals of O. sanctum tested in this study, the three compounds, Molludistin, Rosmarinic acid, and Vitexin are the best inhibitors of BTK. However, these findings need to be confirmed by biological experiments in the laboratory.

Antimicrobial, Antibiofilm, and Antioxidant Potentials of Four Halophytic Plants, Euphorbia chamaesyce, Bassia arabica, Fagonia mollis, and Haloxylon salicornicum, Growing in Qassim Region of Saudi Arabia: Phytochemical Profile and In Vitro and In Silico Bioactivity Investigations.

The current study aimed to investigate the phytochemical contents and antioxidant, antimicrobial, and antibiofilm activities of four halophytic plants, namely, Euphorbia chamaesyce, Bassia arabica, Fagonia mollis, and Haloxylon salicornicum, native to central Saudi Arabia. The alcoholic extract of E. chamaesyce was found to be the most potent in various bioactivities-based evaluations and rich in polyphenols and flavonoid secondary metabolites, with 68.0 mg/g and 39.23 mg/g gallic acid and quercetin equivalents, respectively. Among all plants' extracts, the alcoholic extract of E. chamaesyce had the highest DPPH scavenging and metal chelating antioxidant activities at 74.15 Trolox equivalents and 16.28 EDTA equivalents, respectively. The highest antimicrobial activity of E. chamaesyce extract was found to be against Shigella flexneri, with a mean zone of inhibition diameter of 18.1 ± 0.2 mm, whereas the minimum inhibitory concentration, minimum biocidal concentration, minimum biofilm inhibitory concentration, and minimum biofilm eradication concentration values were 12.5, 25, 25, and 50 mg/mL, respectively. The LC-ESI-MS/MS analysis of the E. chamaesyce extract showed the presence of six flavonoids and ten phenolic constituents. The in silico binding of the E. chamaesyce extract's constituents to Staphylococcus aureus tyrosyl-tRNA synthetase enzyme displayed -6.2 to -10.1 kcal/mol binding energy values, suggesting that these constituents can contribute to the antimicrobial properties of the plant extract, making it an essential medicinal ingredient. In conclusion, these results warrant further investigation to standardize the antimicrobial profiles of these plant extracts.

Alternatively Spliced Isoforms of MUC4 and ADAM12 as Biomarkers for Colorectal Cancer Metastasis.

There is a pertinent need to develop prognostic biomarkers for practicing predictive, preventive and personalized medicine (PPPM) in colorectal cancer metastasis. The analysis of isoform expression data governed by alternative splicing provides a high-resolution picture of mRNAs in a defined condition. This information would not be available by studying gene expression changes alone. Hence, we utilized our prior data from an exon microarray and found ADAM12 and MUC4 to be strong biomarker candidates based on their alternative splicing scores and pattern. In this study, we characterized their isoform expression in a cell line model of metastatic colorectal cancer (SW480 & SW620). These two genes were found to be good prognostic indicators in two cohorts from The Cancer Genome Atlas database. We studied their exon structure using sequence information in the NCBI and ENSEMBL genome databases to amplify and validate six isoforms each for the ADAM12 and MUC4 genes. The differential expression of these isoforms was observed between normal, primary and metastatic colorectal cancer cell lines. RNA-Seq analysis further proved the differential expression of the gene isoforms. The isoforms of MUC4 and ADAM12 were found to change expression levels in response to 5-Fluorouracil (5-FU) treatment in a dose-, time- and cell line-dependent manner. Furthermore, we successfully detected the protein isoforms of ADAM12 and MUC4 in cell lysates, reflecting the differential expression at the protein level. The change in the mRNA and protein expression of MUC4 and ADAM12 in primary and metastatic cells and in response to 5-FU qualifies them to be studied as potential biomarkers. This comprehensive study underscores the importance of studying alternatively spliced isoforms and their potential use as prognostic and/or predictive biomarkers in the PPPM approach towards cancer.

Target-based virtual screening and molecular interaction studies for lead identification of natural olive compounds against glioblastoma multiforme.

Glioblastoma multiforme, a rare traumatic brain disorder, is at the research climax for its uncontrolled growth leading to a catastrophic outcome. Throwing light on the target-based virtual screening of drugs using natural phytocompounds is a striking cornerstone in glioblastoma-based drug discovery, accelerating with leaps and bounds. This project aims to develop promising lead compounds against glioblastoma brain cancer using OliveNet™, an open-source database. In this pursuit, our rationale for selecting molecules was based on their capability to pass through the blood-brain barrier. Out of 51 derivative molecules from flavonoids and polyphenols, 17 molecules were screened out bearing the best ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, alongside fulfilling our rationale of lead selection. Two polyphenols, 3,4,5-trimethoxybenzoic acid and 4-ethyl guaiacol, have binding affinity for the antioxidant flavonoid luteolin of -5.1 and -4.3 kcal/mol, respectively. According to docking studies, the residues ASN1960, ASN1966, ASN1960, PHE1984, TYR1896, VAL1911, and LYS1966 make both polar and nonpolar interactions with 3,4,5-trimethoxybenzoic acid and 4-ethylguanidine, respectively. LD50 values of toxicity screening using TOX Pro brought to limelight the excellent safety profile of polyphenols and flavonoids. Furthermore, studies using in silico cytotoxicity prediction and molecular modelling have decisively shown that these polyphenols are likely to be effective brain cancer inhibitors and promising future lead candidates against glioblastoma multiforme.

Comparative Anticancer Potentials of Taxifolin and Quercetin Methylated Derivatives against HCT-116 Cell Lines: Effects of O-Methylation on Taxifolin and Quercetin as Preliminary Natural Leads.

Six flavonoids present in Pulicaria jaubertii, i.e., 7,3'-di-O-methyltaxifolin (1), 3'-O-methyltaxifolin (2), 7-O-methyltaxifolin (3), taxifolin (4), 3-O-methylquercetin (5), and quercetin (6), were tested for their anticancer activities. The methylated flavonoids, compounds 1-3 and 5, were evaluated for their anticancer activities in comparison to the non-methylated parent flavonoids taxifolin (4) and quercetin (6). The structures of the known compounds were reconfirmed by spectral analyses using 1H and 13C NMR data comparisons and HRMS spectrometry. The anticancer activity of these compounds was evaluated in colon cancer, HCT-116, and noncancerous, HEK-293, cell lines using the MTT antiproliferative assays. The caspase-3 and caspase-9 expressions and DAPI (4', 6-diamidino-2-phenylindole) staining assays were used to evaluate the apoptotic activity. All the compounds exhibited antiproliferative activity against the HCT-116 cell line with IC50 values at 33 ± 1.25, 36 ± 2.25, 34 ± 2.15, 32 ± 2.35, 34 ± 2.65, and 36 ± 1.95 µg/mL for compounds 1 to 6, respectively. All the compounds produced a significant reduction in HCT-116 cell line proliferation, except compounds 2 and 6. The viability of the HEK-293 normal cells was found to be significantly higher than the viability of the cancerous cells at all of the tested concentrations, thus suggesting that all the compounds have better inhibitory activity on the cancer cell line. Apoptotic features such as chromatin condensation and nuclear shrinkage were also induced by the compounds. The expression of caspase-3 and caspase-9 genes increased in HCT-116 cell lines after 48 h of treatment, suggesting cell death by the apoptotic pathways. The molecular docking studies showed favorable binding affinity against different pro- and antiapoptotic proteins by these compounds. The docking scores were minimum as compared to the caspase-9, caspase-3, Bcl-xl, and JAK2.

Therapeutic application of carvacrol: A comprehensive review.

Carvacrol is a major natural constituent and is significantly present as an essential oil in aromatic plants and is well known for its numerous biological activities. Therapeutic properties of carvacrol have been demonstrated as anti-oxidant, anticancer, diabetes prevention, cardioprotective, anti-obesity, hepatoprotective and reproductive role, antiaging, antimicrobial, and immunomodulatory properties. The carvacrol biosynthesis has been mediated through mevalonate pathway. Carvacrol has the anticancer ability against malignant cells via decreasing the expressions of matrix metalloprotease 2 and 9, inducing apoptosis, enhancing the expression of pro-apoptotic proteins, disrupting mitochondrial membrane, suppressing extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signal transduction, and also decreasing the phosphoinositide 3-kinase/protein kinase B. It also decreased the concentrations of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase, and gamma-glutamyl transpeptidase as well as also restored liver function, insulin level, and plasma glucose level. Carvacrol also has been found to exert antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Coagulase-negative staphylococcus, Salmonella spp., Enterococcus sp. Shigella, and Escherichia coli. The current review article summarizes the health-promoting perspectives of carvacrol through various pathways.

In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is an incurable malignancy of B-cells. In this study, bioinformatics analyses were conducted to identify possible pathogenic roles of CK2α, which is a protein encoded by CSNK2A1, in the progression and aggressiveness of CLL. Furthermore, various computational tools were used to search for a competent inhibitor of CK2α from fungal metabolites that could be proposed for CLL therapy. In CLL patients, high-expression of CSNK2A1 was associated with early need for therapy (n = 130, p < 0.0001) and short overall survival (OS; n = 107, p = 0.005). Consistently, bioinformatics analyses showed CSNK2A1 to associate with/play roles in CLL proliferation and survival-dependent pathways. Furthermore, PPI network analysis identified interaction partners of CK2α (PPI enrichment p value = 1 × 10-16) that associated with early need for therapy (n = 130, p < 0.003) and have been known to heavily impact on the progression of CLL. These findings constructed a rational for targeting CK2α for CLL therapy. Consequently, computational analyses reported 35 fungal metabolites out of 5820 (filtered from 19,967 metabolites) to have lower binding energy (ΔG: - 10.9 to - 11.7 kcal/mol) and better binding affinity (Kd: 9.77 × 107 M-1 to 3.77 × 108 M-1) compared with the native ligand (ΔG: - 10.8, Kd: 8.3 × 107 M--1). Furthermore, molecular dynamics simulation study established that Butyl Xanalterate-CK2α complex continuously remained stable throughout the simulation time (100 ns). Moreover, Butyl Xanalterate interacted with most of the catalytic residues, where complex was stabilized by more than 65% hydrogen bond interactions, and a significant hydrophobic interaction with residue Phe113. Here, high-expression of CSNK2A1 was implicated in the progression and poor prognosis of CLL, making it a potential therapeutic target in the disease. Butyl Xanalterate showed stable and strong interactions with CK2α, thus we propose it as a competitive inhibitor of CK2α for CLL therapy.

State-of-the-art Tools to Elucidate the Therapeutic Potential of TAT-peptide (TP) Conjugated Repurposing Drug Against SARS-CoV-2 Spike Glycoproteins.

BACKGROUND: In late 2019, a highly infectious and pathogenic coronavirus was recognized as Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2), which causes acute respiratory disease, threatening human health and public safety. A total of 448,327,303 documented cases and 6,028,576 deaths have been reported as of March 8th 2022. The COVID-19 vaccines currently undergoing clinical trials or already in use should provide at least some protection against SARS-CoV-2; however, the emergence of new variations as a result of mutations may lessen the effectiveness of the currently available vaccines. Since the efficacy of available drugs and vaccines against COVID-19 is notably lower, there is an urgent need to develop a potential drug to treat this deadly disease. The SARS-CoV-2 spike (SCoV-SG) is the foremost drug target among coronaviruses. OBJECTIVE: The major objectives of the current study are to conduct a molecular docking study investigation of TAT-peptide47-57(GRKKRRQRRRP)-conjugated remodified therapeutics such as ritonavir (RTV), lopinavir (LPV), favipiravir (FPV), remdesivir (RMV), hydroxychloroquine (HCQ), molnupiravir (MNV) and nirmatrelvir (NMV) with (SCoV-SG) structure. METHODS: Molecular docking analysis was performed to study the interaction of repurposed drugs and drugs conjugated with the TAT-peptide with target SARS-CoV-2 spike glycoprotein (PDB ID: 6VYB) using Auto- Dock. Further docking investigation was completed with PatchDock and was visualized by the discovery of the studio visualizer 2020. RESULTS: TAT-peptides are well-characterized immune enhancers that are used in intracellular drug delivery. The results of molecular docking analysis showed higher efficiency and significantly enhanced and improved interactions between TP-conjugated repurposed drugs and the target sites of the SCoV-SG structure. CONCLUSION: The study concluded that TP-conjugated repurposed drugs may be effective in preventing COVID- 19, and therefore, in vitro, in vivo, and clinical trial studies are required in detail.

In Silico Pharmacokinetic Profiling of the Identified Bioactive Metabolites of Pergularia tomentosa L. Latex Extract and In Vitro Cytotoxic Activity via the Induction of Caspase-Dependent Apoptosis with S-Phase Arrest.

The in vitro cytotoxic efficacy of plant latex from Pergularia tomentosa L. was studied using five human cancer cell lines: HeLa cells (cervical carcinoma cells), A-549 (lung carcinoma), Panc-1 (pancreatic carcinoma cells), MDA-MB-231 (metastatic mammary adenocarcinoma), and MRC-5 (lung fibroblast cell line) cells. The phytonutrient content of plant latex was identified using the liquid chromatography/mass spectra-quadrupole time of flight (LC/MS-QTOF) technique. In silico studies of polyphenols were carried out to clarify the potential mode of action of the plant latex's constituents. The treatment of different tumor cell lines with different concentrations of plant latex revealed a potent efficacy on the human lung carcinoma cell line (A-549) (IC50 = 3.89 µg/mL) compared with that with vinblastine as a positive control (IC50 = 7.12 µg/mL). The effect of the potent concentration of plant latex on the A-549 cell line induced cell arrest, upregulated the expression of pre-apoptotic markers, and downregulated the expression of antiapoptotic markers. Seven identified polyphenols were selected for the in silico study. A docking assessment using the epidermal growth factor receptor kinase (EGFRk) and eltronib as a positive control showed a higher affinity for the enzyme receptor of the selected polyphenols, except for methyl orsellinate and ginkgotoxin. The ADMET assessment demonstrated the inhibitory effect of the polyphenols on CYP450, except for ouabagenin and xanthyletine. The selected polyphenols obey Lipinski's drug-likeness with no significant toxicity effect. In conclusion, the plant latex of P. tomentosa L. showed cytotoxic activity on the A-549 cell line, and the selected polyphenols showed a promising prodrug agent with a low profile of toxicity in the study.

Classification of Skin Cancer Lesions Using Explainable Deep Learning.

Skin cancer is among the most prevalent and life-threatening forms of cancer that occur worldwide. Traditional methods of skin cancer detection need an in-depth physical examination by a medical professional, which is time-consuming in some cases. Recently, computer-aided medical diagnostic systems have gained popularity due to their effectiveness and efficiency. These systems can assist dermatologists in the early detection of skin cancer, which can be lifesaving. In this paper, the pre-trained MobileNetV2 and DenseNet201 deep learning models are modified by adding additional convolution layers to effectively detect skin cancer. Specifically, for both models, the modification includes stacking three convolutional layers at the end of both the models. A thorough comparison proves that the modified models show their superiority over the original pre-trained MobileNetV2 and DenseNet201 models. The proposed method can detect both benign and malignant classes. The results indicate that the proposed Modified DenseNet201 model achieves 95.50% accuracy and state-of-the-art performance when compared with other techniques present in the literature. In addition, the sensitivity and specificity of the Modified DenseNet201 model are 93.96% and 97.03%, respectively.

Colorectal cancer in patients with SARS-CoV-2: a systematic review and meta-analysis.

BACKGROUND: Patients with colorectal cancer (CRC) are more likely to develop severe course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and experience increased risk of mortality compared to SARS-CoV-2 patients without CRC. OBJECTIVES: To estimate the prevalence of SARS-CoV-2 infection in CRC patients and analyse the demographic parameters, clinical characteristics and treatment outcomes in CRC patients with COVID-19 illness. METHODS: For this systematic review and meta-analysis, we searched Proquest, Medline, Embase, Pubmed, CINAHL, Wiley online library, Scopus and Nature for studies on the incidence of SARS-CoV-2 infection in CRC patients, published from December 1, 2019 to December 31, 2021, with English language restriction. Effect sizes of prevalence were pooled with 95% confidence intervals (CIs). Sub-group analyses were performed to minimize heterogeneity. Binary logistic regression model was used to explore the effect of various demographic and clinical characteristics on patient's final treatment outcome (survival or death). RESULTS: Of the 472 papers that were identified, 69 articles were included in the systematic review and meta-analysis (41 cohort, 16 case-report, 9 case-series, 2 cross-sectional, and 1 case-control studies). Studies involving 3362 CRC patients with confirmed SARS-CoV-2 (all patients were adults) were analyzed. The overall pooled proportions of CRC patients who had laboratory-confirmed community-acquired and hospital-acquired SARS-CoV-2 infections were 8.1% (95% CI 6.1 to 10.1, n = 1308, 24 studies, I2 98%, p = 0.66), and 1.5% (95% CI 1.1 to 1.9, n = 472, 27 studies, I2 94%, p < 0.01). The median patient age ranged from 51.6 years to 80 years across studies. The majority of the patients were male (n = 2243, 66.7%) and belonged to White (Caucasian) (n = 262, 7.8%), Hispanic (n = 156, 4.6%) and Asian (n = 153, 4.4%) ethnicity. The main source of SARS-CoV-2 infection in CRC patients was community-acquired (n = 2882, 85.7%; p = 0.014). Most of those SARS-CoV-2 patients had stage III CRC (n = 725, 21.6%; p = 0.036) and were treated mainly with surgical resections (n = 304, 9%) and chemotherapies (n = 187, 5.6%), p = 0.008. The odd ratios of death were significantly high in patients with old age (≥ 60 years) (OR 1.96, 95% CI 0.94-0.96; p < 0.001), male gender (OR 1.44, 95% CI 0.41-0.47; p < 0.001) CRC stage III (OR 1.54, 95% CI 0.02-1.05; p = 0.041), CRC stage IV (OR 1.69, 95% CI 0.17-1.2; p = 0.009), recent active treatment with chemotherapies (OR 1.35, 95% CI 0.5-0.66; p = 0.023) or surgical resections (OR 1.4, 95% CI 0.8-0.73; p = 0.016) and admission to ICU (OR 1.88, 95% CI 0.85-1.12; p < 0.001) compared to those who survived. CONCLUSION: SARS-CoV-2 infection in CRC patient is not uncommon and results in a mortality rate of 26.2%. Key determinants that lead to increased mortality in CRC patients infected with COVID-19 include older age (≥ 60 years old); male gender; Asian and Hispanic ethnicity; if SARS-CoV-2 was acquired from hospital source; advanced CRC (stage III and IV); if patient received chemotherapies or surgical treatment; and if patient was admitted to ICU, ventilated or experienced ARDS.

Disease specific symptoms indices in patients with celiac disease-A hardly recognised entity.

Background: Celiac disease (CD) was considered a rare disease before and was perceivably only limited to children but now affects almost 1-2% of the global population. This abrupt increase in prevalence is due to advancements in diagnostic criteria and medical facilities but still many countries lack the basic data that can assess the severity of this health issue. The present study was conducted with the aim to assess the common but rarely diagnosed condition with the identification of its underlying secondary ailments. Materials and methods: Patients visiting public sector hospitals were recruited and tested for clinical symptoms secondary to gluten-containing foods (wheat and barley, etc.), followed by serological testing for immunoglobulin A, tissue transglutaminase A, and anti-endomysial antibodies. Only seropositive candidates were included in the endoscopic and biopsy examination for the features of villous atrophy and intestinal cell damage. The secondary ailments including anemia, growth retardation, and gastrointestinal symptoms were also documented for the tested positive patients. The modified European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) criterion was followed throughout the study. Results: From 647 suspected cases from March 2018 to July 2019, 113 were confirmed with CD while 58% were female children and 42% were male children. The majority of them were from a lower class (75%) and 26% of them had a positive family history of CD. A total of 67% of patients with CD were underweight while wasting was observed in 38%, and 80% were stunted as well. Of the positively tested patients with CD, 49% had moderate anemia with 15% having severe anemia. Approximately 33% had hypoalbuminemia as well. The majority of them had a mild to severe range of gastrointestinal symptoms, such as abdominal pain, diarrhea, flatus, eructation, diarrhea, and steatorrhea. Conclusion: The study finding indicates an increased number of patients diagnosed with CD with an excessive sum of secondary ailments, such as anemia, growth failure, growth retardation, malnutrition, and gastrointestinal symptoms.

Risk factors of SARS-CoV-2 infection in cancer patients pre- and post-vaccination.

BACKGROUND: Severe complications from COVID-19 and poor responses to SARS-CoV-2 vaccination were commonly reported in cancer patients compared to those without cancer. Therefore, the identification of predisposing factors to SARS-CoV-2 infection in cancer patients would assist in the prevention of COVID-19 and improve vaccination strategies. The literature lacks reports on this topic from the Kingdom of Saudi Arabia (KSA). Therefore, we studied clinical and laboratory data of 139 cancer patients from King Abdulaziz Medical City, Riyadh, KSA. METHODS: The cancer patients fall into three categories; (i) uninfected with SARS-CoV-2 pre-vaccination and remained uninfected post-vaccination (control group; n = 114; 81%), (ii) pre-vaccination infected group (n = 16; 11%), or (iii) post-vaccination infected group (n = 9; 6%). Next, the clinical and lab data of the three groups of patients were investigated. RESULTS: Comorbidity factors like diabetes and hemodialysis were associated with the risk of infection in cancer patients before the vaccination (p<0.05). In contrast to breast cancer, papillary thyroid cancer was more prevalent in the infected patients pre- and post-vaccination (p<0.05). Pre-vaccination infected group had earlier cancer stages compared with the control group (p = 0.01). On the other hand, combined therapy was less commonly administrated to the infected groups versus the control group (p<0.05). Neutrophil to lymphocyte ratio was lower in the post-vaccination infected group compared to the control group (p = 0.01). CONCLUSION: Collectively, this is the first study from KSA to report potential risk factors of SARS-CoV-2 infection in cancer patients pre- and post-vaccination. Further investigations on these risk factors in a larger cohort are worthwhile to draw a definitive conclusion about their roles in predisposing cancer patients to the infection.

Inhibition of MARK4 by serotonin as an attractive therapeutic approach to combat Alzheimer's disease and neuroinflammation.

Mitogen-activated protein kinases (MAPKs) govern various cellular programs and crucial intermediate pathways in signaling. Microtubule affinity-regulating kinase 4 (MARK4) is a part of the kinase family recognized for actively phosphorylating neural microtubule-associated proteins (MAPs) like MAP2, MAP4 and most importantly, tau. The Ser/Thr kinase MARK4 overexpression is associated with various life-threatening conditions such as neurodegenerative disorders, diabetic neuropathy, and cancer. Functionally, MARK4 is correlated with many important signaling cascades and transcription factors contributing to neurodegeneration and cancer onset and progression. Serotonin is a key molecule associated with regulating mood, stress, and various behavioral aspects. Low serotonin levels promote the progression of neurological and psychotic disorders, which is also a consequence of tau accumulation. MARK4 being a major contributor to phosphorylating tau, leading to its accumulation, and contributing to tauopathy, is targeted for inhibition by serotonin. The study deals with the inhibition of MARK4 by serotonin using combined computational and experimental studies. The results presented in this paper provide strong evidence for the direct physical binding of serotonin to recombinant MARK4 and subsequent inhibition of its kinase activity. In addition, we have performed molecular docking, followed by 100 ns MD simulations of MARK4 in the presence of serotonin, to estimate the stability of the protein-ligand complex. Since MARK4 is a potential drug target and can be exploited for drug design and discovery for cancer and neurodegenerative disorders, the results presented here are of interest and may be further exploited for Alzheimer's disease (AD) and other neurodegenerative diseases.

Investigating the impact of RNA integrity variation on the transcriptome of human leukemic cells.

High RNA integrity is essential for good quality of transcriptomics profiling. Nevertheless, in some cases samples with low RNA integrity is the only available material to study. This work was set to investigate the impact of thermal-induced RNA degradation on the transcriptomic profiles of human leukemic cells. DNA microarray-based transcriptomics was conducted on two groups of samples; high RNA integrity samples (n = 4) and low RNA integrity samples (n = 5). RNA degradation caused limited but noticeable changes in the transcriptomes. Only 1945 (6.7%) of 29,230 genes showed altered quantitation (fold change ≥ two-fold, p value ≤ 0.03, corrected p value ≤ 0.05). RNA degradation had the most impact on short transcripts and those with short distance between their 5'end and the probe binding position. Overall, the present work identified the genes whose relative quantification is sensitive to RNA degradation. Therefore, altered expression of these genes should be interpreted with caution when studied in low integrity RNA samples. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03223-1.

Zingiberene exerts chemopreventive activity against 7,12-dimethylbenz(a)anthracene-induced breast cancer in Sprague-Dawley rats.

Breast cancer is the primary cause of cancer-related death in females, wherein increased mortality of breast cancer patients is recorded worldwide. Zingiberene is a monocyclic sesquiterpene from the ginger plant and has many pharmacological benefits. In this exploration, we assessed the anticancer actions of Zingiberene against the 7,12-dimethylbenz(a)anthracene (DMBA)-stimulated mammary carcinogenesis in rats and MDA-MB-231 cells. Breast cancer was induced in the Female Sprague-Dawley rats through the 25 mg/kg of DMBA in 0.5 ml of corn oil and then treated with 20 and 40 mg/kg of Zingiberene, respectively. The body weight of animals and tumor volume was measured. Hematological parameters, transaminases, lipid profile, lipid peroxidation, and antioxidants status were scrutinized using standard techniques. The estrogen receptor-α and inflammatory markers were inspected by using respective assay kits. Histological damage scores were determined. In vitro experiments were conducted to scrutinize Zingiberene's effect on cell viability and apoptotic cell death in MDA-MB-231 cells. Zingiberene substantially modulated the DMBA-stimulated physiological and hematological changes and decreased the transaminases, and lipid peroxidation in the DMBA-stimulated animals. Zingiberene also elevated the antioxidant level and suppressed the inflammatory markers. Histological study revealed the protective effects of Zingiberene. The viability of MDA-MB-231 cells was noticeably diminished by the Zingiberene, thus inducing apoptotic cell death. Overall, our findings reliably proved the anticancer potential of Zingiberene against the DMBA-stimulated mammary tumorigenesis, and it could be a promising chemotherapeutic agent.