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Garlic’s main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC10, IC25, and IC35 of DATSL with the IC10 of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC50 doses by more than 8- and 14-fold, respectively. However, the DATSL IC10, IC25, and IC35 showed escalating chemosensitivity, and treated the cells in combination with DOXL IC10. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of −4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer.

Diallyl disulfide (DADS) is one of the main bioactive organosulfur compounds of garlic, and its potential against various cancer models has been demonstrated. The poor solubility of DADS in aqueous solutions limits its uses in clinical application. The present study aimed to develop a novel formulation of DADS to increase its bioavailability and therapeutic potential and evaluate its role in combination with oxaliplatin (OXA) in the colorectal cancer system. We prepared and characterized PEGylated, DADS (DCPDD), and OXA (DCPDO) liposomes. The anticancer potential of these formulations was then evaluated in HCT116 and RKO colon cancer cells by different cellular assays. Further, a molecular docking-based computational analysis was conducted to determine the probable binding interactions of DADS and OXA. The results revealed the size of the DCPDD and DCPDO to be 114.46 nm (95% EE) and 149.45 nm (54% EE), respectively. They increased the sensitivity of the cells and reduced the IC50 several folds, while the combinations of them showed a synergistic effect and induced apoptosis by 55% in the cells. The molecular docking data projected several possible targets of DADS and OXA that could be evaluated more precisely by these novel formulations in detail. This study will direct the usage of DCPDD to augment the therapeutic potential of DCPDO against colon cancer in clinical settings.

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated sequence (CRISPR/Cas) system is a cutting-edge genome-editing tool employed to explore the functions of normal and disease-related genes. The CRISPR/Cas system has a remarkable diversity in the composition and architecture of genomic loci and Cas protein sequences. Owing to its excellent efficiency and specificity, this system adds an outstanding dimension to biomedical research on genetic manipulation of eukaryotic cells. However, safe, efficient, and specific delivery of this system to target cells and tissues and their off-target effects are considered critical bottlenecks for the therapeutic applications. Recently discovered anti-CRISPR proteins (Acr) play a significant role in limiting the effects of this system. Acrs are relatively small proteins that are highly specific to CRISPR variants and exhibit remarkable structural diversity. The in silico approaches, crystallography, and cryo-electron microscopy play significant roles in elucidating the mechanisms of action of Acrs. Acrs block the CRISPR/Cas system mainly by employing four mechanisms: CRISPR/Cas complex assembly interruption, target-binding interference, target cleavage prevention, and degradation of cyclic oligonucleotide signaling molecules. Engineered CRISPR/Cas systems are frequently used in gene therapy, diagnostics, and functional genomics. Understanding the molecular mechanisms underlying Acr action may help in the safe and effective use of CRISPR/Cas tools for genetic modification, particularly in the context of medicine. Thus, attempts to regulate prokaryotic CRISPR/Cas surveillance complexes will advance the development of antimicrobial drugs and treatment of human diseases. In this review, recent updates on CRISPR/Cas systems, especially CRISPR/Cas9 and Acrs, and their novel mechanistic insights are elaborated. In addition, the role of Acrs in the novel applications of CRISPP/Cas biotechnology for precise genome editing and other applications is discussed., Competing Interests: The authors declare no competing interests in this work., (© 2024 Allemailem et al.)

Silver nanoparticles (AgNPs) are leading the way in nanotechnological innovation, combining the captivating properties of silver with the accuracy of nanoscale engineering, thus revolutionizing material science. Three main techniques arise within the alchemical domains of AgNP genesis: chemical, physical, and biological synthesis. Each possesses its distinct form of magic for controlling size, shape, and scalability-key factors necessary for achieving expertise in the practical application of nanoparticles. The story unravels, describing the careful coordination of chemical reduction, the environmentally sensitive charm of green synthesis utilizing plant extracts, and the precise accuracy of physical techniques. AgNPs are highly praised in the field of healthcare for their powerful antibacterial characteristics. These little warriors display a wide-ranging attack against bacteria, fungi, parasites, and viruses. Their critical significance in combating hospital-acquired and surgical site infections is highly praised, serving as a beacon of hope in the fight against the challenging problem of antibiotic resistance. In addition to their ability to kill bacteria, AgNPs are also known to promote tissue regeneration and facilitate wound healing. The field of cancer has also observed the adaptability of AgNPs. The review documents their role as innovative carriers of drugs, specifically designed to target cancer cells with accuracy, minimizing harm to healthy tissues. Additionally, it explores their potential as cancer therapy or anticancer agents capable of disrupting the growth of tumors. In the food business, AgNPs are utilized to enhance the durability of packing materials and coatings by infusing them with their bactericidal properties. This results in improved food safety measures and a significant increase in the duration that products can be stored, thereby tackling the crucial issue of food preservation. This academic analysis recognizes the many difficulties that come with the creation and incorporation of AgNPs. This statement pertains to the evaluation of environmental factors and the effort to enhance synthetic processes. The review predicts future academic pursuits, envisioning progress that will enhance the usefulness of AgNPs and increase their importance from being new to becoming essential within the realms of science and industry. Besides, AgNPs are not only a subject of scholarly interest but also a crucial component in the continuous effort to tackle some of the most urgent health and conservation concerns of contemporary society. This review aims to explore the complex process of AgNP synthesis and highlight their numerous uses, with a special focus on their growing importance in the healthcare and food business sectors. This review invites the scientific community to explore the extensive possibilities of AgNPs in order to fully understand and utilize their potential.

Dengue fever poses a significant global health threat, with symptoms including dengue hemorrhagic fever and dengue shock syndrome. Each year, India experiences fatal dengue outbreaks with severe manifestations. The primary cause of severe inflammatory responses in dengue is a cytokine storm. Individuals with a secondary dengue infection of a different serotype face an increased risk of complications due to antibody-dependent enhancement. Therefore, it is crucial to identify potential risk factors and biomarkers for effective disease management. In the current study, we assessed the prevalence of dengue infection in and around Aligarh, India, and explored the role of cytokines, including CXCL5, CXCL9, and CCL17, in primary and secondary dengue infections, correlating them with various clinical indices. Among 1,500 suspected cases, 367 tested positive for dengue using Real-Time PCR and ELISA. In secondary dengue infections, the serum levels of CXCL5, CXCL9, and CCL17 were significantly higher than in primary infections (P < 0.05). Dengue virus (DENV)-2 showed the highest concentrations of CXCL5 and CCL17, whereas DENV-1 showed the highest concentrations of CXCL9. Early detection of these cytokines could serve as potential biomarkers for diagnosing severe dengue, and downregulation of these cytokines may prove beneficial for the treatment of severe dengue infections.

Apigenin is a powerful flavone compound found in numerous fruits and vegetables, and it offers numerous health-promoting benefits. Many studies have evidenced that this compound has a potential role as an anti-inflammatory and antioxidant compound, making it a promising candidate for reducing the risk of pathogenesis. It has also been found to positively affect various systems in the body, such as the respiratory, digestive, immune, and reproductive systems. Apigenin is effective in treating liver, lung, heart, kidney, neurological diseases, diabetes, and maintaining good oral and skin health. Multiple studies have reported that this compound is capable of suppressing various types of cancer through the induction of apoptosis and cell-cycle arrest, suppressing cell migration and invasion, reduction of inflammation, and inhibiting angiogenesis. When used in combination with other drugs, apigenin increases their efficacy, reduces the risk of side effects, and improves the response to chemotherapy. This review broadly analyzes apigenin's potential in disease management by modulating various biological activities. In addition, this review also described apigenin's interaction with other compounds or drugs and the potential role of nanoformulation in different pathogeneses. Further extensive research is needed to explore the mechanism of action, safety, and efficacy of this compound in disease prevention and treatment.

The genome editing approach by clustered regularly interspaced short palindromic repeats (CRISPR)/associated protein 9 (CRISPR/Cas9) is a revolutionary advancement in genetic engineering. Owing to its simple design and powerful genome-editing capability, it offers a promising strategy for the treatment of different infectious, metabolic, and genetic diseases. The crystal structure of Streptococcus pyogenes Cas9 (SpCas9) in complex with sgRNA and its target DNA at 2.5 Å resolution reveals a groove accommodating sgRNA:DNA heteroduplex within a bilobate architecture with target recognition (REC) and nuclease (NUC) domains. The presence of a PAM is significantly required for target recognition, R-loop formation, and strand scission. Recently, the spatiotemporal control of CRISPR/Cas9 genome editing has been considerably improved by genetic, chemical, and physical regulatory strategies. The use of genetic modifiers anti-CRISPR proteins, cell-specific promoters, and histone acetyl transferases has uplifted the application of CRISPR/Cas9 as a future-generation genome editing tool. In addition, interventions by chemical control, small-molecule activators, oligonucleotide conjugates and bioresponsive delivery carriers have improved its application in other areas of biological fields. Furthermore, the intermediation of physical control by using heat-, light-, magnetism-, and ultrasound-responsive elements attached to this molecular tool has revolutionized genome editing further. These strategies significantly reduce CRISPR/Cas9's undesirable off-target effects. However, other undesirable effects still offer some challenges for comprehensive clinical translation using this genome-editing approach. In this review, we summarize recent advances in CRISPR/Cas9 structure, mechanistic action, and the role of small-molecule activators, inhibitors, promoters, and physical approaches. Finally, off-target measurement approaches, challenges, future prospects, and clinical applications are discussed., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Allemailem et al.)

Natural products and their bioactive compounds have been used for centuries to prevent and treat numerous diseases. Kaempferol, a flavonoid found in vegetables, fruits, and spices, is recognized for its various beneficial properties, including its antioxidant and anti-inflammatory potential. This molecule has been identified as a potential means of managing different pathogenesis due to its capability to manage various biological activities. Moreover, this compound has a wide range of health-promoting benefits, such as cardioprotective, neuroprotective, hepatoprotective, and anti-diabetic, and has a role in maintaining eye, skin, and respiratory system health. Furthermore, it can also inhibit tumor growth and modulate various cell-signaling pathways. In vivo and in vitro studies have demonstrated that this compound has been shown to increase efficacy when combined with other natural products or drugs. In addition, kaempferol-based nano-formulations are more effective than kaempferol treatment alone. This review aims to provide detailed information about the sources of this compound, its bioavailability, and its role in various pathogenesis. Although there is promising evidence for its ability to manage diseases, it is crucial to conduct further investigations to know its toxicity, safety aspects, and mechanism of action in health management.

Biofilms, which consist of microorganisms enclosed in an extracellular polymeric material (EPS), hold immense importance in the fields of environmental research, industry, and medicine. They play a significant role in ecosystem dynamics and stability, but they also pose issues such as biofouling, corrosion, and pollution. Biofilms in medical environments are linked to persistent infections and elevated healthcare expenses. The EPS matrix plays a crucial role in maintaining the structural integrity and antibiotic resistance of these structures. The research primarily investigates the role of the EPS matrix in facilitating horizontal gene transfer among biofilm communities, with a particular emphasis on EPS and its impact on this process. The process is recognized as a pivotal mechanism in the emergence of antibiotic resistance, underscoring the crucial function of EPS in the dynamics of biofilms. The analysis also highlights the significant financial constraints caused by biofilms in several industries. Biofilm-associated infections in the healthcare sector result in escalated treatment expenses and extended hospitalization periods. In an industrial context, biofilms have a role in increasing maintenance expenses and product contamination, emphasizing the need for efficient management solutions. This review presents the most recent progress in biofilm research, emphasizing the utilization of sophisticated imaging tools and molecular methodologies. In addition to conventional imaging techniques, the research explores the utilization of sophisticated molecular tools, such as DNA and RNA sequencing, in conjunction with proteomics. These approaches are essential for assessing the genetic and metabolic mechanisms that regulate biofilm development and antibiotic resistance. The review underscores the significance of employing an interdisciplinary methodology in the study of biofilms. By incorporating a range of approaches, such as sophisticated imaging and molecular analysis, a comprehensive understanding of biofilm dynamics may be achieved. This approach also opens up possibilities for developing novel solutions to address the negative impacts of biofilms on health, industry, and the environment., Competing Interests: The author declares no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Luteolin, a flavonoid, is mainly found in various vegetables and fruits, including carrots, cabbages, onions, parsley, apples, broccoli, and peppers. Extensive research in vivo and in vitro has been performed to explore its role in disease prevention and treatment. Moreover, this compound possesses the ability to combat cancer by modulating cell-signaling pathways across various types of cancer. The studies have confirmed that luteolin can inhibit cancer-cell survival and proliferation, angiogenesis, invasion, metastasis, mTOR/PI3K/Akt, STAT3, Wnt/β-catenin, and cell-cycle arrest, and induce apoptosis. Further, scientific evidence describes that this compound plays a vital role in the up/down-regulation of microRNAs (miRNAs) in cancer therapy. This review aims to outline the anti-cancer mechanisms of this compound and its molecular targets. However, a knowledge gap remains regarding the studies on its safety and efficacy and clinical trials. Therefore, it is essential to conduct more research based on safety, efficacy, and clinical trials to explore the beneficial role of this compound in disease management, including cancer.

Triple negative breast cancers (TNBC) are clinically heterogeneous but mostly aggressive malignancies devoid of expression of the estrogen, progesterone, and HER2 (ERBB2 or NEU) receptors. It accounts for 15-20% of all cases. Altered epigenetic regulation including DNA hypermethylation by DNA methyltransferase 1 (DNMT1) has been implicated as one of the causes of TNBC tumorigenesis. The antitumor effect of DNMT1 has also been explored in TNBC that currently lacks targeted therapies. However, the actual treatment for TNBC is yet to be discovered. This study is attributed to the identification of novel drug targets against TNBC. A comprehensive docking and simulation analysis was performed to optimize promising new compounds by estimating their binding affinity to the target protein. Molecular dynamics simulation of 500 ns well complemented the binding affinity of the compound and revealed strong stability of predicted compounds at the docked site. Calculation of binding free energies using MMPBSA and MMGBSA validated the strong binding affinity between compound and binding pockets of DNMT1. In a nutshell, our study uncovered that Beta-Mangostin, Gancaonin Z, 5-hydroxysophoranone, Sophoraflavanone L, and Dorsmanin H showed maximum binding affinity with the active sites of DNMT1. Furthermore, all of these compounds depict maximum drug-like properties. Therefore, the proposed compounds can be a potential candidate for patients with TNBC, but, experimental validation is needed to ensure their safety.Communicated by Ramaswamy H. Sarma.

Despite advanced diagnosis and detection technologies, prostate cancer (PCa) is the most prevalent neoplasms in males. Dysregulation of the androgen receptor (AR) is centrally involved in the tumorigenesis of PCa cells. Acquisition of drug resistance due to modifications in AR leads to therapeutic failure and relapse in PCa. An overhaul of comprehensive catalogues of cancer-causing mutations and their juxta positioning on 3D protein can help in guiding the exploration of small drug molecules. Among several well-studied PCa-specific mutations, T877A, T877S and H874Y are the most common substitutions in the ligand-binding domain (LBD) of the AR. In this study, we combined structure as well as dynamics-based in silico approaches to infer the mechanistic effect of amino acid substitutions on the structural stability of LBD. Molecular dynamics simulations allowed us to unveil a possible drug resistance mechanism that acts through structural alteration and changes in the molecular motions of LBD. Our findings suggest that the resistance to bicalutamide is partially due to increased flexibility in the H 12 helix, which disturbs the compactness, thereby reducing the affinity for bicalutamide. In conclusion, the current study helps in understanding the structural changes caused by mutations and could assist in the drug development process.Communicated by Ramaswamy H. Sarma.

COVID-19 is a highly infectious disease caused by a new type of extremely contagious coronavirus called SARS-CoV-2. The virus's main protease enzyme, SARS-CoV-2 Mpro, is essential for its replication and transcription processes. Targeting this enzyme presents a promising avenue for antiviral drug development. Researchers have explored the intricate three-dimensional configurations of the enzyme, analyzing its interactions with various inhibitors. These findings provide a foundation for designing specific and powerful inhibitors targeting SARS-CoV-2 Mpro. Certain plants possess medicinal attributes due to the presence of bioactive compounds that inhibit pathogens. The olive tree ( Olea europaea ) has served as a source of food and medicine, containing bioactive compounds in its leaves that hinder the proliferation of various pathogens including viruses. This study explores the potential of bioactive compounds from olive leaf extract (OLE) to inhibit SARS-CoV-2 Mpro. In-silico study was conducted to predict the pharmacokinetic and toxicity profiles of these compounds. Molecular docking was utilized to assess their binding affinity to SARS-CoV-2 Mpro and their potential interference with its function. The top three compounds, apigenin (Api), luteolin-7-O-glucoside (Lut) and rutin (Rut), were chosen based on their favorable drug-like properties and strong binding affinities to Mpro. Detailed molecular dynamics simulations demonstrated the stability of SARS-CoV-2 Mpro in conjunction with these compounds, showing minimal structural alterations over the simulation period. Particularly, Lut and Rut formed bonds with critical amino acid residues His41 and Cys145 of Mpro, suggesting their potential inhibitory effect. These findings suggest that these compounds hold promise as natural drug candidates for combating COVID-19.Communicated by Ramaswamy H. Sarma.

Cancer is a major public health concern worldwide in terms of mortality. The exact reason behind the development of cancer is not understood clearly, but it is evidenced that alcohol consumption, radiation, and exposure to chemicals are main players in this pathogenesis. The current mode of treatments such as surgery, chemotherapy, and radiotherapy are effective, but, still, cancer is a major problem leading to death and other side effects. However, safer and effective treatment modules are needed to overcome the adverse effects of current treatment modules. In this regard, natural compounds have been recognized to ameliorate diseases by exerting anti-inflammatory, anti-oxidative, and anti-tumor potential through several mechanisms. Mangiferin, a xanthone C-glucoside, is found in several plant species including Mangifera indica (mango), and its role in disease prevention has been confirmed through its antioxidant and anti-inflammatory properties. Furthermore, its anti-cancer-potential mechanism has been designated through modulation of cell signaling pathways such as inflammation, angiogenesis, PI3K/AKT, apoptosis, and cell cycle. This article extensively reviews the anticancer potential of mangiferin in different cancers through the modulation of cell signaling pathways. Moreover, the synergistic effects of this compound with some commonly used anti-cancer drugs against different cancer cells are discussed. More clinical trials should be performed to reconnoiter the anti-cancer potential of this compound in human cancer treatment. Further, understanding of mechanisms of action and the safety level of this compound can help to manage diseases, including cancer.

Congestive cardiac failure (CCF) is a pathophysiologic state when the heart is not able to maintain its cardiac output to meet the demand of metabolising tissues. CCF is responsible for approximately 2.9 million deaths worldwide. The heterogeneous nature of CCF draws the attention of researchers to find more enthralling and promising diagnostic and treatment options. Terminalia arjuna (Arjuna) is an evergreen, deciduous tree exhibited various astringent, anti-bacterial, and anti-microbial properties. T. arjuna is being used in various regions for anginal pain, hypertension, congestive heart failure, and dyslipidemia. Although previous in vitro studies have demonstrated the therapeutic potential of T. arjuna , the exact molecular mechanism underlying its protective effect on the heart remains unclear. In this study, a network pharmacology technique was used to explore the active ingredients, potential targets in T. arjuna for the treatment of CCF. In the framework of this study, we explored the active ingredient-target-pathway network and figured out that oleanolic acid, arjunolic acid, luteolin, kaempferol, cholesterol, ellagic acid 4-O-xylopyranoside 3,3'-dimethyl ether, and cyclohexyl (2,4-dimethyl phenyl) methanone contributed significantly to the development of CCF by affecting AKT1, MAPK14, TNF, IL6, ESR1, and HSP90AA1 genes. Molecular docking analysis further validated the activities of these compounds against potential targets. To sum up, integrated network pharmacology and docking analysis revealed that T. arjuna exerts its cardioprotective effect by acting on various signalling pathways, including the thyroid hormone, VEGF signalling pathway, AGE-RAGE signalling pathway in diabetic complications, HIF signalling pathway, sphingolipid signalling pathway, and oestrogen signalling pathways. Overall, this study provides valuable insights into the molecular mechanism of T. arjuna in CCF and highlights its potential as a promising preventive treatment for this condition.

Proteus mirabilis is a gram-negative bacterium particularly known for its unique swarming ability. The swarming gives the bacteria ability to enhance adherence to the catheter surface and epithelium cells of the urethra to cause catheter associated urinary tract infections. P. mirabilis has evolved resistant to antibiotics. Additionally, there is an approved vaccine against P. mirabilis , thus demanding for identification of new vaccine targets. This gram-negative bacterium consists of 19,502 core proteins, out of which 19,063 are redundant proteins and remaining 439 are non-redundant proteins. The non-redundant proteins have 21 proteins present on the cell surface out of which 11 proteins are virulent. Antigenicity analysis predicted only 2 proteins as antigenic (fimbrial biogenesis outer membrane usher protein and ligand-gated channel protein). Four and seven B-cells epitopes were predicted from the former and later proteins, respectively. The predicted B-cells epitopes were used for T- cells epitopes prediction. The predicted epitopes were linked to each other through GPGPG linkers and joined with cholera toxin beta subunit adjuvant. A multi-epitopes vaccine construct consisting of 226 residues was docked with MHC-I, MHC-II and TLR-4. The best docked complex in each case has binding energy of -714.6, -744.6 and -829.5 kcal/mol, respectively. Moreover, the docking results were validated through molecular dynamics simulation and binding free energies estimation. The net energy of -137.2 kcal/mol was calculated for vaccine-MHC-I complex, -133.39 kcal/mol for vaccine-MHC-II and -158.68 kcal/mol for vaccine-TLR-4 complex. The designed vaccine construct could provoke immune responses against targeted pathogen and may be used in experimental testing.Communicated by Ramaswamy H. Sarma.

The recent developments in the study of clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9) system have revolutionized the art of genome-editing and its applications for cellular differentiation and immune response behavior. This technology has further helped in understanding the mysteries of cancer progression and possible designing of novel antitumor immunotherapies. CRISPR/Cas9-based genome-editing is now often used to engineer universal T-cells, equipped with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR). In addition, this technology is used in cytokine stimulation, antibody designing, natural killer (NK) cell transfer, and to overcome immune checkpoints. The innovative potential of CRISPR/Cas9 in preparing the building blocks of adoptive cell transfer (ACT) immunotherapy has opened a new window of antitumor immunotherapy and some of them have gained FDA approval. The manipulation of immunogenetic regulators has opened a new interface for designing, implementation and interpretation of CRISPR/Cas9-based screening in immuno-oncology. Several cancers like lymphoma, melanoma, lung, and liver malignancies have been treated with this strategy, once thought to be impossible. The safe and efficient delivery of CRISPR/Cas9 system within the immune cells for the genome-editing strategy is a challenging task which needs to be sorted out for efficient immunotherapy. Several targeting approaches like virus-mediated, electroporation, microinjection and nanoformulation-based methods have been used, but each procedure offers some limitations. Here, we elaborate the recent updates of cancer management through immunotherapy in partnership with CRISPR/Cas9 technology. Further, some innovative methods of targeting this genome-editing system within the immune system cells for reprogramming them, as a novel strategy of anticancer immunotherapy is elaborated. In addition, future prospects and clinical trials are also discussed., Competing Interests: The authors declare no conflicts of interest in this work., (© 2023 Allemailem et al.)

Monkeypox is a viral zoonotic disease that is caused by the monkeypox virus (MPXV) and is mainly transmitted to human through close contact with an infected person, animal, or fomites which is contaminated by the virus. In the present research work, reverse vaccinology and several other bioinformatics and immunoinformatics tools were utilized to design multi-epitopes-based vaccine against MPXV by exploring three probable antigenic extracellular proteins: cupin domain-containing protein, ABC transporter ATP-binding protein and DUF192 domain-containing protein. Both cellular and humoral immunity induction were the main concerning qualities of the vaccine construct, hence from selected proteins both B and T-cells epitopes were predicted. Antigenicity, allergenicity, toxicity, and water solubility of the predicted epitopes were assessed and only probable antigenic, non-allergic, non-toxic and good water-soluble epitopes were used in the multi-epitopes vaccine construct. The developed vaccine was found to be potentially effective against MPXV and to be highly immunogenic, cytokine-producing, antigenic, non-toxic, non-allergenic, and stable. Additionally, to increase stability and expression efficiency in the host E. coli, disulfide engineering, codon adaptation, and in silico cloning were employed. Molecular docking and other biophysical approaches were utilized to evaluate the binding mode and dynamic behavior of the vaccine construct with TLR-2, TLR-4, and TLR-8. The outcomes of the immune simulation demonstrated that both B and T cells responded more strongly to the vaccination component. The detailed in silico analysis concludes that the proposed vaccine will induce a strong immune response against MPXV infection, making it a promising target for additional experimental trials.Communicated by Ramaswamy H. Sarma.

Liver cancer is a malignant tumor that grows on the surface or inside the liver. The leading cause is a viral infection with hepatitis B or C virus. Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer. A list of studies evidences the therapeutic efficacy of Bacopa monnieri against liver cancer, but the precise molecular mechanism is yet to be discovered. This study combines data mining, network pharmacology, and molecular docking analysis to potentially revolutionize liver cancer treatment by identifying effective phytochemicals. Initially, the information on active constituents of B. monnieri and target genes of both liver cancer and B. monnieri were retrieved from literature as well as from publicly available databases. Based on the matching results between B. monnieri potential targets and liver cancer targets, the protein-protein interaction (PPI) network was constructed using the STRING database and imported into Cytoscape for screening of hub genes based on their degree of connectivity. Later, the interactions network between compounds and overlapping genes was constructed using Cytoscape software to analyze the network pharmacological prospective effects of B. monnieri on liver cancer. Gene Ontology (GO) and KEGG pathway analysis of hub genes revealed that these genes are involved in the cancer-related pathway. Lastly, the expression level of core targets was analyzed using microarray data (GSE39791, GSE76427, GSE22058, GSE87630, and GSE112790). Further, the GEPIA server and PyRx software were used for survival and molecular docking analysis, respectively. In summary, we proposed that quercetin, luteolin, apigenin, catechin, epicatechin, stigmasterol, beta-sitosterol, celastrol, and betulic acid inhibit tumor growth by affecting tumor protein 53 (TP53), interleukin 6 (IL6), RAC-alpha serine/threonine protein kinases 1 (AKT1), caspase-3 (CASP3), tumor necrosis factor (TNF), jun proto-oncogene (JUN), heat shot protein 90 AA1 (HSP90AA1), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), and SRC proto-oncogene (SRC). Through, microarray data analysis, the expression level of JUN and IL6 were found to be upregulated while the expression level of HSP90AA1 was found to be downregulated. Kaplan-Meier survival analysis indicated that HSP90AA1 and JUN are promising candidate genes that can serve as diagnostic and prognostic biomarkers for liver cancer. Moreover, the molecular docking and molecular dynamic simulation of 60ns well complemented the binding affinity of the compound and revealed strong stability of predicted compounds at the docked site. Calculation of binding free energies using MMPBSA and MMGBSA validated the strong binding affinity between the compound and binding pockets of HSP90AA1 and JUN. Despite that, in vivo and in vitro studies are mandatory to unveil pharmacokinetics and biosafety profiles to completely track the candidature status of B. monnieri in liver cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cancer is one of the main causes of death in all developed and developing countries. Various factors are involved in cancer development and progression, including inflammation and alterations in cellular processes and signaling transduction pathways. Natural compounds have shown health-promoting effects through their antioxidant and anti-inflammatory potential, having an important role in the inhibition of cancer growth. In this regard, formononetin, a type of isoflavone, plays a significant role in disease management through the modulation of inflammation, angiogenesis, cell cycle, and apoptosis. Furthermore, its role in cancer management has been proven through the regulation of different signal transduction pathways, such as the signal transducer and activator of transcription 3 (STAT 3), Phosphatidyl inositol 3 kinase/protein kinase B (PI3K/Akt), and mitogen activating protein kinase (MAPK) signaling pathways. The anticancer potential of formononetin has been reported against various cancer types, such as breast, cervical, head and neck, colon, and ovarian cancers. This review focuses on the role of formononetin in different cancer types through the modulation of various cell signaling pathways. Moreover, synergistic effect with anticancer drugs and methods to improve bioavailability are explained. Thus, detailed studies based on clinical trials are required to explore the potential role of formononetin in cancer prevention and treatment.

Cancer is a major public health concern worldwide and main burden of the healthcare system. Regrettably, most of the currently used cancer treatment approaches such as targeted therapy, chemotherapy, radiotherapy and surgery usually cause adverse complications including hair loss, bone density loss, vomiting, anemia and other complications. However, to overcome these limitations, there is an urgent need to search for the alternative anticancer drugs with better efficacy as well as less adverse complications. Based on the scientific evidences, it is proven that naturally occurring antioxidants present in medicinal plants or their bioactive compounds might constitute a good therapeutic approach in diseases management including cancer. In this regard, myricetin, a polyhydroxy flavonol found in a several types of plants and its role in diseases management as anti-oxidant, anti-inflammatory and hepato-protective has been documented. Moreover, its role in cancer prevention has been noticed through modulation of angiogenesis, inflammation, cell cycle arrest and induction of apoptosis. Furthermore, myricetin plays a significant role in cancer prevention through the inhibition of inflammatory markers such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2). Moreover, myricetin increases the chemotherapeutic potential of other anticancer drugs through modulation of cell signaling molecules activity. This review elaborates the information of myricetin role in cancer management through modulating of various cell-signaling molecules based on in vivo and in vitro studies. In addition, synergistic effect with currently used anticancer drugs and approaches to improve bioavailability are described. The evidences collected in this review will help different researchers to comprehend the information about its safety aspects, effective dose for different cancers and implication in clinical trials. Moreover, different challenges need to be focused on engineering different nanoformulations of myricetin to overcome the poor bioavailability, loading capacity, targeted delivery and premature release of this compound. Furthermore, some more derivatives of myricetin need to be synthesized to check their anticancer potential.

Cancer is the principal cause of death and its incidence is increasing continuously worldwide. Various treatment approaches are in practice to treat cancer, but these treatment strategies may be associated with severe side effects and also produce drug resistance. However, natural compounds have established their role in cancer management with minimal side effects. In this vista, kaempferol, a natural polyphenol, mainly found in vegetables and fruits, has been revealed to have many health-promoting effects. Besides its health-promoting potential, its anti-cancer potential has also been described in in vivo as well as in in vitro studies. The anti-cancer potential of kaempferol has been proven through modulation of cell signaling pathways in addition to the induction of apoptosis and cell cycle arrest in cancer cells. It leads to the activation of tumor suppressor genes, inhibition of angiogenesis, PI3K/AKT pathways, STAT3, transcription factor AP-1, Nrf2 and other cell signaling molecules. Poor bioavailability of this compound is one of the major limitations for its proper and effective disease management actions. Recently, some novel nanoparticle-based formulations have been used to overcome these limitations. The aim of this review is to provide a clear picture regarding the mechanism of action of kaempferol in different cancers through the modulation of cell signaling molecules. Besides this, strategies to improve the efficacy and synergistic effects of this compound have also been described. However, more studies are needed based on clinical trials to fully explore the therapeutic role of this compound, especially in cancer treatment.

The innovative advances in transforming clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) into different variants have taken the art of genome-editing specificity to new heights. Allosteric modulation of Cas9-targeting specificity by sgRNA sequence alterations and protospacer adjacent motif (PAM) modifications have been a good lesson to learn about specificity and activity scores in different Cas9 variants. Some of the high-fidelity Cas9 variants have been ranked as Sniper-Cas9, eSpCas9 (1.1), SpCas9-HF1, HypaCas9, xCas9, and evoCas9. However, the selection of an ideal Cas9 variant for a given target sequence remains a challenging task. A safe and efficient delivery system for the CRISPR/Cas9 complex at tumor target sites faces considerable challenges, and nanotechnology-based stimuli-responsive delivery approaches have significantly contributed to cancer management. Recent innovations in nanoformulation design, such as pH, glutathione (GSH), photo, thermal, and magnetic responsive systems, have modernized the art of CRISPR/Cas9 delivery approaches. These nanoformulations possess enhanced cellular internalization, endosomal membrane disruption/bypass, and controlled release. In this review, we aim to elaborate on different CRISPR/Cas9 variants and advances in stimuli-responsive nanoformulations for the specific delivery of this endonuclease system. Furthermore, the critical constraints of this endonuclease system on clinical translations towards the management of cancer and prospects are described.

Breast cancer is a silent killer malady among women and a serious economic burden in health care management. A case of breast cancer is diagnosed among women every 19 s, and every 74 s, a woman dies of breast cancer somewhere in the world. Despite the pop-up of progressive research, advanced treatment approaches, and preventive measures, breast cancer remains amplifying ailment. The nuclear factor kappa B (NF-κB) is a key transcription factor that links inflammation with cancer and is demonstrated as being involved in the tumorigenesis of breast cancer. The NF-κB transcription factor family in mammals consists of five proteins; c-Rel, RelA(p65), RelB, NF-κB1(p50), and NF-κB2(p52). The antitumor effect of NF-κB has also been explored in breast cancer, however, the actual treatment for breast cancer is yet to be discovered. This study is attributed to the identification of novel drug targets against breast cancer by targeting c-Rel, RelA(p65), RelB, NF-κB1(p50), and NF-κB2(p52) proteins. To identify the putative active compounds, a structure-based 3D pharmacophore model to the protein active site cavity was generated followed by virtual screening, molecular docking, and molecular dynamics (MD) simulation. Initially, a library of 45000 compounds were docked against the target protein and five compounds namely Z56811101, Z653426226, Z1097341967, Z92743432, and Z464101066 were selected for further analysis. The relative binding affinity of Z56811101, Z653426226, Z1097341967, Z92743432, and Z464101066 with NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel proteins were -6.8, -8, -7.0, -6.9, and -7.2 kcal/mol, respectively which remained stable throughout the simulations of 200 ns. Furthermore, all of these compounds depict maximum drug-like properties. Therefore, the proposed compounds can be a potential candidate for patients with breast cancer, but, experimental validation is needed to ensure their safety.Communicated by Ramaswamy H. Sarma.

The hepatitis E virus (HEV) is a long-ignored virus that has spread globally with time. It ranked 6th among the top risk-ranking viruses with high zoonotic spillover potential; thus, considering its viral threats is a pressing priority. The molecular pathophysiology of HEV infection or the underlying cause is limited. Therefore, we incorporated an unbiased, systematic methodology to get insights into the biological heterogeneity associated with the HEV. Our study fetched 93 and 2016 differentially expressed genes (DEGs) from chronic HEV (CHEV) infection in kidney-transplant patients, followed by hub module selection from a weighted gene co-expression network (WGCN). Most of the hub genes identified in this study were associated with interferon (IFN) signaling pathways. Amongst the genes induced by IFNs, the 2'-5'-oligoadenylate synthase 3 ( OAS3 ) protein was upregulated. Protein-protein interaction (PPI) modular, functional enrichment, and feed-forward loop (FFL) analyses led to the identification of two key miRNAs, i.e., miR-222-3p and miR-125b-5p, which showed a strong association with the OAS3 gene and TRAF-type zinc finger domain containing 1 ( TRAFD1 ) transcription factor (TF) based on essential centrality measures. Further experimental studies are required to substantiate the significance of these FFL-associated genes and miRNAs with their respective functions in CHEV. To our knowledge, it is the first time that miR-222-3p has been described as a reference miRNA for use in CHEV sample analyses. In conclusion, our study has enlightened a few budding targets of HEV, which might help us understand the cellular and molecular pathways dysregulated in HEV through various factors. Thus, providing a novel insight into its pathophysiology and progression dynamics.

Pro-inflammatory macrophage polarization is crucial in acute inflammatory diseases like Acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Prostaglandin E2 (PGE2) is believed to promote inflammation in such cases. Therefore, our study aimed to deliver anti-prostaglandin E synthase 2 small interfering RNA antibodies (anti-PGE2-siRNA) through lipid nanoparticles (LNPs) in RAW264.7 (The murine macrophage cell line) to find a possible cure to the acute inflammatory diseases. LNPs were synthesized by using thin layer evaporation method and were characterized by dynamic light scattering (DLS), Zeta potential, SEM and TEM analysis. The obtained NPs were spherical with an average size of 73 nm and zeta potential +29mV. MTT assay revealed that these NPs were non-toxic in nature. Gel retardation assay displayed 5:2 ratio of siRNA and NPs as the best siRNA:LNPs ratio for the delivery of siRNA into cells. After siRNA delivery by using LNPs, real time gene expression analysis revealed significant decrease in the expression of PGE2. Western blot results confirmed that silencing of PGE2 gene influence inducible nitric oxide synthase (iNOS) and interlukin-1β (1L-1β), markers involved in pro-inflammatory macrophage polarization. Our study revealed that LNPs synthesized in present study can be one of the effective methods to deliver anti-PGE2-siRNA to control pro-inflammatory macrophage polarization for the treatment of acute inflammatory response.

Cancer is a main culprit and the second-leading cause of death worldwide. The current mode of treatment strategies including surgery with chemotherapy and radiation therapy may be effective, but cancer is still considered a major cause of death. Plant-derived products or their purified bioactive compounds have confirmed health-promoting effects as well as cancer-preventive effects. Among these products, flavonoids belong to polyphenols, chiefly found in fruits, vegetables and in various seeds/flowers. It has been considered to be an effective antioxidant, anti-inflammatory and to play a vital role in diseases management. Besides these activities, flavonoids have been revealed to possess anticancer potential through the modulation of various cell signaling molecules. In this regard, fisetin, a naturally occurring flavonoid, has a confirmed role in disease management through antioxidant, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential. As well, its cancer-preventive effects have been confirmed via modulating various cell signaling pathways including inflammation, apoptosis, angiogenesis, growth factor, transcription factor and other cell signaling pathways. This review presents an overview of the anti-cancer potential of fisetin in different types of cancer through the modulation of cell signaling pathways based on in vivo and in vitro studies. A synergistic effect with anticancer drugs and strategies to improve the bioavailability are described. More clinical trials need to be performed to explore the anti-cancer potential and mechanism-of-action of fisetin and its optimum therapeutic dose.

Clustered regularly interspaced short palindromic repeats-associated protein (CRISPR/Cas9), an adaptive microbial immune system, has been exploited as a robust, accurate, efficient and programmable method for genome targeting and editing. This innovative and revolutionary technique can play a significant role in animal modeling, in vivo genome therapy, engineered cell therapy, cancer diagnosis and treatment. The CRISPR/Cas9 endonuclease system targets a specific genomic locus by single guide RNA (sgRNA), forming a heteroduplex with target DNA. The Streptococcus pyogenes Cas9/sgRNA:DNA complex reveals a bilobed architecture with target recognition and nuclease lobes. CRISPR/Cas9 assembly can be hijacked, and its nanoformulation can be engineered as a delivery system for different clinical utilizations. However, the efficient and safe delivery of the CRISPR/Cas9 system to target tissues and cancer cells is very challenging, limiting its clinical utilization. Viral delivery strategies of this system may have many advantages, but disadvantages such as immune system stimulation, tumor promotion risk and small insertion size outweigh these advantages. Thus, there is a desperate need to develop an efficient non-viral physical delivery system based on simple nanoformulations. The delivery strategies of CRISPR/Cas9 by a nanoparticle-based system have shown tremendous potential, such as easy and large-scale production, combination therapy, large insertion size and efficient in vivo applications. This review aims to provide in-depth updates on Streptococcus pyogenic CRISPR/Cas9 structure and its mechanistic understanding. In addition, the advances in its nanoformulation-based delivery systems, including lipid-based, polymeric structures and rigid NPs coupled to special ligands such as aptamers, TAT peptides and cell-penetrating peptides, are discussed. Furthermore, the clinical applications in different cancers, clinical trials and future prospects of CRISPR/Cas9 delivery and genome targeting are also discussed., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

The roles of medicinal plants or their purified bioactive compounds have attracted attention in the field of health sciences due to their low toxicity and minimal side effects. Baicalein is an active polyphenolic compound, isolated from Scutellaria baicalensis, and plays a significant role in the management of different diseases. Epidemiologic studies have proven that there is an inverse association between baicalein consumption and disease severity. Baicalein is known to display anticancer activity through the inhibition of inflammation and cell proliferation. Additionally, the anticancer potential of baicalein is chiefly mediated through the modulation of various cell-signaling pathways, such as the induction of apoptosis, autophagy, cell cycle arrest, inhibition of angiogenesis, signal transducer and activator of transcription 3, and PI3K/Akt pathways, as well as the regulation of other molecular targets. Therefore, the current review aimed to explore the role of baicalein in different types of cancer along with mechanisms of action. Besides this, the synergistic effects with other anti-cancerous drugs and the nano-formulation based delivery of baicalein have also been discussed., Competing Interests: The authors declare no conflict of interest.

Cancer is one of the leading global causes of death in both men and women. Colorectal cancer (CRC) alone accounts for ∼10 % of total new global cases and poses an over 4% lifetime risk of developing cancer. Recent advancements in the field of biotechnology and microbiology concocted novel microbe-based therapies to treat various cancers, including CRC. Microbes have been explored for human use since centuries, especially for the treatment of various ailments. The utility of microbes in cancer therapeutics is widely explored, and various bacteria, fungi, and viruses are currently in use for the development of cancer therapeutics. The human gut hosts about 100 trillion microbes that release their metabolites in active, inactive, or dead conditions. Microbial secondary metabolites, proteins, immunotoxins, and enzymes are used to target cancer cells to induce cell cycle arrest, apoptosis, and death. Various approaches, such as dietary interventions, the use of prebiotics and probiotics, and fecal microbiota transplantation have been used to modulate the gut microbiota in order to prevent or treat CRC pathogenesis. The present review highlights the role of the gut microbiota in CRC precipitation, the potential mechanisms and use of microorganisms as CRC biomarkers, and strategies to modulate microbiota for the prevention and treatment of CRC., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cancer is the utmost common disease-causing death worldwide, characterized by uncontrollable cell division with the potential of metastasis. Overexpression of the Inhibitors of Apoptosis proteins (IAPs) and autophagy correlates with tumorigenesis, therapeutic resistance, and reoccurrence after anticancer therapies. This study illuminates the role and efficacy of smac mimetic compound BV6 alone and in co-treatment with death ligands such as TRAIL and TNFα in the regulation of cell death mechanisms, i.e., apoptosis and autophagy. In this study, MTT assays, wound healing assays, and cellular and nuclear morphological studies were done. DAPI staining, AO/EtBr staining and AnnexinV/PI FACS was done to study the apoptosis. The expression of IAPs and autophagy biomarkers was analyzed using Real time-PCR and western blotting. Meanwhile, TEM demonstrated autophagy and cellular autophagic vacuoles in response to the BV6. The result shows a promising anti-cancer effect of BV6 alone as well as in combinational treatment with TRAIL and TNFα, compared to the lone treatment of TRAIL and TNFα in both breast cancer cell lines. The smac mimetic compound might provide an alternative combinational therapy with conventional anticancer therapies to tackle their inefficiency at the advanced stage of cancer, cancer resistance, and reoccurrence. Also, IAPs and autophagic proteins could act as potent target molecules for the development of novel anti-cancer drugs in pathogenesis and the betterment of regimens for cancer.

(1) Background: SARS-CoV-2 Omicron BA.1 is the most common variation found in most countries and is responsible for 99% of cases in the United States. To overcome this challenge, there is an urgent need to discover effective inhibitors to prevent the emerging BA.1 variant. Natural products, particularly flavonoids, have had widespread success in reducing COVID-19 prevalence. (2) Methods: In the ongoing study, fifteen compounds were annotated from Echium angustifolium and peach (Prunus persica), which were computationally analyzed using various in silico techniques. Molecular docking calculations were performed for the identified phytochemicals to investigate their efficacy. Molecular dynamics (MD) simulations over 200 ns followed by molecular mechanics Poisson-Boltzmann surface area calculations (MM/PBSA) were performed to estimate the binding energy. Bioactivity was also calculated for the best components in terms of drug likeness and drug score. (3) Results: The data obtained from the molecular docking study demonstrated that five compounds exhibited remarkable potency, with docking scores greater than -9.0 kcal/mol. Among them, compounds 1, 2 and 4 showed higher stability within the active site of Omicron BA.1, with ΔG binding values of -49.02, -48.07, and -67.47 KJ/mol, respectively. These findings imply that the discovered phytoconstituents are promising in the search for anti-Omicron BA.1 drugs and should be investigated in future in vitro and in vivo research.

Introduction: Brain tumors are one of the major causes of death and morbidity around the world. A prospective existential retrospective observational population-cohort study based on the comprehensive research work on brain tumors in the Saudi population was conducted, with statistics drawn from the Saudi Cancer Registry data collected and published by the Ministry of Health, Saudi Arabia, which is a national document prepared and maintained by the National Health Information Center, from 2006 to 2016. For the analysis of the brain tumor distribution and trends in Saudi Arabian inhabitants, the current study outlined the brain tumor incident rates in the age-standardized incidence rates (ASIRs) and crude incidence rates (CIRs) in the inhabitants of Saudi Arabia by distinct age cohorts, the year of diagnosis, and the core administrative regions of Saudi Arabia., Method: Statistical tools, such as GraphPad Prism and SPSS 2.0, were used for the analyses of the t -test, Kruskal-Wallis test, and descriptive statistics, including the sex ratio and other demographic features. Between 2006 and 2016, Saudi Arabia recorded 1854 and 1293 cases of brain tumors in males and females, respectively., Results: The highest percentage and mean number of brain tumor cases were recorded among males and females in the age group 0-4 years, and the lowest proportion of brain tumor cases were reported among males and females in the higher age group (55-69 years). The highest mean CIR and ASIR were found in the male and female populations of the Riyadh region, and the highest CIR and ASIR sex ratios were found in the Baha and Naj regions of Saudi Arabia, respectively. Males in the Jazan region had the lowest average CIRs and ASIRs. The Baha and Jazan regions of Saudi Arabia recorded the lowest mean CIR and ASIR among females., Conclusion: The Riyadh region had the most significant increases in ASIRs and CIRs for brain tumors in males and females from 2006 to 2016, whereas the Jazan region had the least significant changes in the ASIRs in males and females.

Cancer is the leading cause of death worldwide. In spite of advances in the treatment of cancer, currently used treatment modules including chemotherapy, hormone therapy, radiation therapy and targeted therapy causes adverse effects and kills the normal cells. Therefore, the goal of more effective and less side effects-based cancer treatment approaches is still at the primary position of present research. Medicinal plants or their bioactive ingredients act as dynamic sources of drugs due to their having less side effects and also shows the role in reduction of resistance against cancer therapy. Apigenin is an edible plant-derived flavonoid that has received significant scientific consideration for its health-promoting potential through modulation of inflammation, oxidative stress and various other biological activities. Moreover, the anti-cancer potential of apigenin is confirmed through its ability to modulate various cell signalling pathways, including tumor suppressor genes, angiogenesis, apoptosis, cell cycle, inflammation, apoptosis, PI3K/AKT, NF-κB, MAPK/ERK and STAT3 pathways. The current review mainly emphases the potential role of apigenin in different types of cancer through the modulation of various cell signaling pathways. Further studies based on clinical trials are needed to explore the role of apigenin in cancer management and explain the possible potential mechanisms of action in this vista.

Background: A good understanding of the possible risk factors for coronavirus disease 19 (COVID-19) severity could help clinicians in identifying patients who need prioritized treatment to prevent disease progression and adverse outcome. In the present study, we aimed to correlate clinical and laboratory characteristics of hospitalized COVID-19 patients to disease outcome in Saudi Arabia., Materials and Methods: The present study included 199 COVID-19 patients admitted to King Fahd Specialist Hospital, Buraydah, Qassim, Saudi Arabia, from April to December 2020. Patients were followed-up until discharge either for recovery or death. Demographic data, clinical data and laboratory results were retrieved from electronic patient records., Results: Critical COVID-19 cases showed higher mean of age and higher prevalence of co-morbid conditions. Fifty-five patients died during the observation period. Risk factors for in hospital death for COVID 19 patients were leukocytosis (OR 1.89, 95% CI 1.008-3.548, p = 0.081), lymphocytopenia (OR 2.152, 95% CI 1.079-4.295, p = 0.020), neutrophilia (OR 1.839, 95% CI 0.951-3.55, p = 0.047), thrombocytopenia (OR 2.152, 95% CI 0.852-5.430, p = 0.085), liver injury (OR 2.689, 95% CI 1.373-4.944, p = 0.003), acute kidney injury (OR 1.248, 95% CI 0.631-2.467 p = 0.319), pancreatic injury (OR 1.973, 95% CI 0.939-4.144, p = 0.056) and high D dimer (OR 2.635, 95% CI 0.747-9.287, p = 0.091)., Conclusion: Clinical and laboratory data of COVID-19 patients may help understanding the pathogenesis of the disease and subsequently improve of the outcome of patients by determination of the associated risk factors and recognition of high risk group who are more liable for complications and in hospital death. The present study put an eye on some parameters (laboratory and clinical) that should be alarming signs that the patient is at high risk bad prognosis., Competing Interests: The authors report no conflicts of interest in relation to this work., (© 2022 El-Kady et al.)

The rise of antimicrobial resistance (AMR) impacts public health due to the diminished potency of existing antibiotics. The microbiome plays an important role in the host's immune system activity and shows the history of exposure to antimicrobials and its manipulation in combating antimicrobial resistance. Advancements in gene technologies, DNA sequencing, and computational biology have emerged as powerful platforms to better understand the relationship between animals and microorganisms (MOs). The past few years have witnessed an increase in the use of nanotechnology, both in industry and in academia, as tools to tackle antimicrobial resistance. New strategies of microbiome manipulation have been developed, such as the use of prebiotics, probiotics, peptides, antibodies, an appropriate diet, phage therapy, and the use of various nanotechnological techniques. Owing to the research outcomes, targeted delivery of antimicrobials with some modifications with nanoparticles can lead to the destruction of resistant microbial cells. In addition, nanoparticles have been studied for their potential antimicrobial effects both in vitro and in vivo. In this review, we highlight key opportunistic areas for applying nanotechnologies with the aim of manipulating the microbiome for the treatment of antimicrobial resistance. Besides providing a detailed review on various nanomaterials, technologies, opportunities, technical needs, and potential approaches for the manipulation of the microbiome to address these challenges, we discuss future challenges and our perspective., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: Although trastuzumab (TZB)-induced cardiotoxicity is well documented and allicin (one of the main active garlic ingredients) has ameliorating effects against numerous causes of toxicities; however, the influence of allicin on TZB-induced cardiotoxicity has not been investigated yet. Therefore, the current work explored the potential cardioprotective structural, biochemical, and molecular mechanisms of allicin against TZB-induced cardiotoxicity in a rat's model., Methods: Forty rats were divided into four equal groups and treated for five weeks. The control group (G1) received PBS, the allicin group (G2) received allicin (9 mg/kg/day), the TZB group (G3) received TZB (6 mg/kg/week), and the allicin+TZB group (G4) received 9 mg of allicin/kg/day +6 mg of TZB/kg/week. Heart specimens and blood samples were processed for histopathological, immunohistochemical, biochemical, and molecular investigations to determine the extent of cardiac injury in all groups., Key Findings: The myocardium of G3 revealed significant increases in the numbers of inflammatory and apoptotic cells and the area percentage of collagen fibers and TNF-α immunoexpression compared with G1 and G2. Besides, qRT-PCR analysis exhibited significant reductions of SOD3, GPX1, and CAT expressions with significant increases in TNFα, IL-1β, IL-6, cTnI, cTnT, and LDH expressions. Additionally, flow cytometry analysis demonstrated a significant elevation in the apoptotic and ROS levels. In contrast, allicin+TZB cotherapy in G4 ameliorated all previous changes compared with G3., Significance: The current study proves that allicin could be used as a novel supplementary cardioprotective therapy to avoid TZB-induced cardiotoxicity via its anti-inflammatory, antifibrotic, antioxidant, antihyperlipidemic, and antiapoptotic properties., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Antimicrobial resistance has become a significant health issue because of the misuse of antibiotics in our daily lives, resulting in high rates of morbidity and mortality. Hafnia alvei is a rod-shaped, Gram-negative and facultative anaerobic bacteria. The medical community has emphasized H. alvei 's possible association with gastroenteritis. As of now, there is no licensed vaccine for H. alvei , and as such, computer aided vaccine design approaches could be an ideal approach to highlight the potential vaccine epitopes against this bacteria. By using bacterial pan-genome analysis (BPGA), we were able to study the entire proteomes of H. alvei with the aim of developing a vaccine. Based on the analysis, 20,370 proteins were identified as core proteins, which were further used in identifying potential vaccine targets based on several vaccine candidacy parameters. The prioritized vaccine targets against the bacteria are; type 1 fimbrial protein, flagellar hook length control protein (FliK), flagellar hook associated protein (FlgK), curli production assembly/transport protein (CsgF), fimbria/pilus outer membrane usher protein, fimbria/pilus outer membrane usher protein, molecular chaperone, flagellar filament capping protein (FliD), TonB-dependent hemoglobin /transferrin/lactoferrin family receptor, Porin (OmpA), flagellar basal body rod protein (FlgF) and flagellar hook-basal body complex protein (FliE). During the epitope prediction phase, different antigenic, immunogenic, non-Allergenic, and non-Toxic epitopes were predicted for the above-mentioned proteins. The selected epitopes were combined to generate a multi-epitope vaccine construct and a cholera toxin B subunit (adjuvant) was added to enhance the vaccine's antigenicity. Downward analyses of vaccines were performed using a vaccine three-dimensional model. Docking studies have confirmed that the vaccine strongly binds with MHC-I, MHC-II, and TLR-4 immune cell receptors. Additionally, molecular dynamics simulations confirmed that the vaccine epitopes were exposed to nature and to the host immune system and interpreted strong intermolecular binding between the vaccine and receptors. Based on the results of the study, the model vaccine construct seems to have the capacity to produce protective immune responses in the host, making it an attractive candidate for further in vitro and in vivo studies.

Camel milk (CM) constitutes an important dietary source in the hot and arid regions of the world. CM is a colloidal mixture of nutritional components (proteins, carbohydrates, lipids, vitamins, and minerals) and non-nutritional components (hormones, growth factors, cytokines, immunoglobulins, and exosomes). Although the majority of previous research has been focused on the nutritional components of CM; there has been immense interest in the non-nutritional components in the recent past. Reckoning with these, in this review, we have provided a glimpse of the recent trends in CM research endeavors and attempted to provide our perspective on the therapeutic efficacy of the nutritional and non-nutritional components of CM. Interestingly, with concerted efforts from the research fraternities, convincing evidence for the better understanding of the claimed traditional health benefits of CM can be foreseen with great enthusiasm and is indeed eagerly anticipated.

Objectives: Here, we prepared a liposome-based vaccine formulation containing Middle East Respiratory Syndrome Coronavirus papain-like protease (MERS-CoV-PLpro)., Methods: A persistent leukopenic condition was induced in mice by injecting cyclophosphamide (CYP) three days before each dose of immunization. Mice were immunized on days 0, 14 and 21 with α-GalCer-bearing MERS-CoV PLpro-encapsulated DPPC-liposomes (α-GalCer-MERS-PLpro-liposomes or MERS-CoV PLpo-encapsulated DPPC-liposomes (MERS-PLpro-liposomes), whereas the antigen emulsified in Alum (MERS-PLpro-Alum) was taken as a control. On day 26, the blood was taken from the immunized mice to analyze IgG titer, whereas the splenocytes were used to analyze the lymphocyte proliferation and the level of cytokines. In order to assess the memory immune response, mice were given a booster dose after 150 days of the last immunization., Results: The higher levels of MERS-CoV-PLpro-specific antibody titer, IgG2a and lymphocyte proliferation were noticed in mice immunized with α-GalCer-MERS-PLpro-liposomes. Besides, the splenocytes from mice immunized with α-GalCer-MERS-PLpro-liposomes produced larger amounts of IFN-γ as compared to the splenocytes from MERS-PLpro-liposomes or MERS- PLpro-Alum immunized mice. Importantly, an efficient antigen-specific memory immune response was observed in α-GalCer-MERS-PLpro-liposomes immunized mice., Conclusions: These findings suggest that α-GalCer-MERS-PLpro-liposomes may substantiate to be a successful vaccine formulation against MERS-CoV infection, particularly in immunocompromised individuals., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

The Rift Valley fever virus (RVFV) is a zoonotic arbovirus and pathogenic to both humans and animals. Currently, no proven effective RVFV drugs or licensed vaccine are available for human or animal use. Hence, there is an urgent need to develop effective treatment options to control this viral infection. RVFV glycoprotein N (GN), glycoprotein C (GC), and nucleocapsid (N) proteins are attractive antiviral drug targets due to their critical roles in RVFV replication. In present study, an integrated docking-based virtual screening of more than 6000 phytochemicals with known antiviral activities against these conserved RVFV proteins was conducted. The top five hit compounds, calyxin C, calyxin D, calyxin J, gericudranins A, and blepharocalyxin C displayed optimal binding against all three target proteins. Moreover, multiple parameters from the molecular dynamics (MD) simulations and MM/GBSA analysis confirmed the stability of protein-ligand complexes and revealed that these compounds may act as potential pan-inhibitors of RVFV replication. Our computational analyses may contribute toward the development of promising effective drugs against RVFV infection., (© 2022. The Author(s).)

Enterobacter cloacae (EC) is a significant emerging pathogen that is occasionally associated with lung infection, surgical site infection, urinary infection, sepsis, and outbreaks in neonatal intensive care units. In light of the fact that there is currently no approved vaccine or therapeutic option for the treatment of EC, the current study was developed to concentrate on applications based on modern computational approaches to design a multi-epitope-based E. cloacae peptide vaccine (MEBEPV) expressing the antigenic determinants prioritized from the EC genome. Integrated computational analyses identified two potential protein targets (phosphoporin protein-PhoE and putative outer-membrane porin protein) for further exploration on the basis of pangenome subtractive proteomics and immunoinformatic in-depth examination of the core proteomes. Then, a multi-epitope peptide vaccine was designed, which comprised shortlisted epitopes that were capable of eliciting both innate and adaptive immunity, as well as the cholera toxin's B-subunit, which was used as an adjuvant in the vaccine formulation. To ensure maximum expression, the vaccine's 3D structure was developed and the loop was refined, improving the stability by disulfide engineering, and the physicochemical characteristics of the recombinant vaccine sequence were found to be ideal for both in vitro and in vivo experimentation. Blind docking was then used for the prediction of the MEBEPV predominant blinding mode with MHCI, MHCII, and TLR3 innate immune receptors, with lowest global energy of -18.64 kJ/mol, -48.25 kJ/mol, and -5.20 kJ/mol for MHC-I, MHC-II, and TLR-4, respectively, with docked complexes considered for simulation. In MD and MMGBSA investigations, the docked models of MEBEPV-TLR3, MEBEPV-MHCI, and MEBEPV-MHCII were found to be stable during the course of the simulation. MM-GBSA analysis calculated -122.17 total net binding free energies for the TLR3-vaccine complex, -125.4 for the MHC I-vaccine complex, and -187.94 for the MHC II-vaccine complex. Next, MM-PBSA analysis calculated -115.63 binding free energy for the TLR3-vaccine complex, -118.19 for the MHC I-vaccine complex, and -184.61 for the MHC II-vaccine complex. When the vaccine was tested in silico, researchers discovered that it was capable of inducing both types of immune responses (cell mediated and humoral) at the same time. Even though the suggested MEBEPV has the potential to be a powerful contender against E. cloacae -associated illnesses, further testing in the laboratory will be required before it can be declared safe and immunogenic.

Introduction: In recent decades, the rate of infection with dengue virus (DENV) has risen significantly, now affecting nearly 400 million individuals annually. Dengue fever among humans is caused via specific mosquito vectors bites. Sporadic cases have been reported in Egypt. The goal of this study was to identify the serotype of the DENV outbreak in both human and mosquito vector along the coast of the Red Sea, Upper Egypt, in 2017. Identification of the serotype of the virus may help identify its source and assist in applying epidemiological and control measures., Materials and Methods: The current study was carried out in El Quseir City, Red Sea Governorate, Upper Egypt, on 144 patients complaining of symptoms indicative of dengue fever at the time of the 2017 Egypt outbreak. Human blood samples and the mosquito reservoirs were identified as having dengue virus infection serologically and molecularly., Results: Overall, 97 (67.4%) patients were positive for dengue virus IgM antibodies. Molecular examination of the human samples and pools of mosquitoes revealed that DENV-2 virus was the serotype responsible for the outbreak. Only one pool of female mosquitoes containing Aedes aegypti was infected with dengue fever virus (DENV-2)., Conclusion: This was the first serotyping of the DENV responsible for dengue virus outbreak in Egypt in 2017. Determining the serotype of dengue virus can help to avoid and monitor outbreaks. The serotype identified in this study was DENV-2, while DENV-1 was the serotype found in the previous outbreak in 2015 in the province of Assiut. This study thus raises concerns that a new dengue serotype could have been introduced into Egypt. It is necessary for a comprehensive risk assessment to be carried out in the country, including an entomological survey, to assess the presence and potential geographical expansion of mosquito vectors there., Competing Interests: The authors declare that they have no conflicts of interest., (© 2022 El-Kady et al.)

Rift valley fever virus (RVFV) is the causative agent of a viral zoonosis that causes a significant clinical burden in domestic and wild ruminants. Major outbreaks of the virus occur in livestock, and contaminated animal products or arthropod vectors can transmit the virus to humans. The viral RNA-dependent RNA polymerase (RdRp; L protein) of the RVFV is responsible for viral replication and is thus an appealing drug target because no effective and specific vaccine against this virus is available. The current study reported the structural elucidation of the RVFV-L protein by in-depth homology modeling since no crystal structure is available yet. The inhibitory binding modes of known potent L protein inhibitors were analyzed. Based on the results, further molecular docking-based virtual screening of Selleckchem Nucleoside Analogue Library (156 compounds) was performed to find potential new inhibitors against the RVFV L protein. ADME (Absorption, Distribution, Metabolism, and Excretion) and toxicity analysis of these compounds was also performed. Besides, the binding mechanism and stability of identified compounds were confirmed by a 50 ns molecular dynamic (MD) simulation followed by MM/PBSA binding free energy calculations. Homology modeling determined a stable multi-domain structure of L protein. An analysis of known L protein inhibitors, including Monensin, Mycophenolic acid, and Ribavirin, provide insights into the binding mechanism and reveals key residues of the L protein binding pocket. The screening results revealed that the top three compounds, A-317491, Khasianine, and VER155008, exhibited a high affinity at the L protein binding pocket. ADME analysis revealed good pharmacodynamics and pharmacokinetic profiles of these compounds. Furthermore, MD simulation and binding free energy analysis endorsed the binding stability of potential compounds with L protein. In a nutshell, the present study determined potential compounds that may aid in the rational design of novel inhibitors of the RVFV L protein as anti-RVFV drugs.

Honey is the principal premier product of beekeeping familiar to Homo for centuries. In every geological era and culture, evidence can be traced to the potential usefulness of honey in several ailments. With the advent of recent scientific approaches, honey has been proclaimed as a potent complementary and alternative medicine for the management and treatment of several maladies including various neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, etc. In the literature archive, oxidative stress and the deprivation of antioxidants are believed to be the paramount cause of many of these neuropathies. Since different types of honey are abundant with certain antioxidants, primarily in the form of diverse polyphenols, honey is undoubtedly a strong pharmaceutic candidate against multiple neurological diseases. In this review, we have indexed and comprehended the involved mechanisms of various constituent polyphenols including different phenolic acids, flavonoids, and other phytochemicals that manifest multiple antioxidant effects in various neurological disorders. All these mechanistic interpretations of the nutritious components of honey explain and justify the potential recommendation of sweet nectar in ameliorating the burden of neurological disorders that have significantly increased across the world in the last few decades.

Introduction: Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is one of the leading causes of death in the world. The resource constraints make it difficult to diagnose and monitor the cases of MDR-TB. GeneXpert is a recognized tool used to diagnose the patients of pulmonary tuberculosis in clinical settings across the globe., Methodology: The present one-year cross-sectional study was conducted to estimate the occurrence of MDR-TB in patients with pulmonary TB. A total of 1000 patients suspected of pulmonary tuberculosis were included in this study. A random convenient sampling technique was done to collect the sputum samples (twice) from the patients. Samples were processed for the detection of Mycobacterium tuberculosis using conventional detection methods like the Ziehl Nelson staining method and fluorescent microscopy. Additionally, Cepheid GeneXpert was used for molecular detection of MDR-TB in smear-positive samples of pulmonary tuberculosis by amplifying the rifampicin resistance determining region (RRDR; rpoB gene). All the tests were performed in the biosafety level III lab of District Headquarters Hospital Nankana Sahib., Results: It was observed that 103 (10.3%) individuals were diagnosed as positive for tuberculosis among 1000 patients. Among these 103 TB positive cases, there were 11 (10.7%) patients diagnosed with rifampicin resistance gene (RR-Gene) of Mycobacterium tuberculosis., Conclusions: Overall findings of the study showed that MDR-TB is prevalent in pulmonary TB patients and GeneXpert is the most sensitive technique for early diagnosis of the disease, which may be very helpful in the treatment and control of this public health menace in low and middle-income countries., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2022 Azhar Iqbal, Muhammad Shafique, Muhammad Asif Zahoor, Saima Muzammil, Zeeshan Nawaz, Abdul Jabbar, Mohsin Khurshid, Riaz Hussain, Md. Akhttarul Islam, Ahmad Almatroudi, Khaled Saleh Allemailem, Muhammad Hidayat Rasool, Bilal Aslam.)

Due to the misuse of antibiotics in our daily lives, antimicrobial resistance (AMR) has become a major health problem. Penicillin, the first antibiotic, was used in the 1930s and led to the emergence of AMR. Due to alterations in the microbe's genome and the evolution of new resistance mechanisms, antibiotics are losing efficacy against microbes. There are high rates of mortality and morbidity due to antibiotic resistance, so addressing this major health issue requires new approaches. Staphylococcus auricularis is a Gram-positive cocci and is capable of causing opportunistic infections and sepsis. S. auricularis is resistant to several antibiotics and does not currently have a licensed vaccine. In this study, we used bacterial pan-genome analysis (BPGA) to study S. auricularis pan-genome and applied a reverse immunology approach to prioritize vaccine targets against S. auricularis . A total of 15,444 core proteins were identified by BPGA analysis, which were then used to identify good vaccine candidates considering potential vaccine filters. Two vaccine candidates were evaluated for epitope prediction including the superoxide dismutase and gamma-glutamyl transferase protein. The epitope prediction phase involved the prediction of a variety of B-Cell and T-cell epitopes, and the epitopes that met certain criteria, such as antigenicity, immunogenicity, non-allergenicity, and non-toxicity were chosen. A multi-epitopes vaccine construct was then constructed from all the predicted epitopes, and a cholera toxin B-subunit adjuvant was also added to increase vaccine antigenicity. Three-dimensional models of the vaccine were used for downward analyses. Using the best-modeled structure, binding potency was tested with MHC-I, MHC-II and TLR-4 immune cells receptors, proving that the vaccine binds strongly with the receptors. Further, molecular dynamics simulations interpreted strong intermolecular binding between the vaccine and receptors and confirmed the vaccine epitopes exposed to the host immune system. The results support that the vaccine candidate may be capable of eliciting a protective immune response against S. auricularis and may be a promising candidate for experimental in vitro and in vivo studies.