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Protein kinases are key targets for cancer therapies, with the c-Met receptor tyrosine kinase (MET) and its ligand, hepatocyte growth factor, playing a role in various cancers, including non-small cell lung cancer, gastric cancer, and hepatocellular carcinoma. Although small-molecule inhibitors have been designed to target MET, the development of drug resistance remains a significant challenge to advancing therapeutic strategies. In this study, we employed virtual screening of plant-based compounds sourced from the IMPPAT 2.0 databank to identify potent inhibitors of MET. Preliminary filtering based on the physicochemical parameters following Lipinski's rule of five and pan-assay interference compounds criteria were applied to prioritize hits. Subsequent molecular docking, pharmacokinetic evaluation, prediction of activity spectra for biologically active substances, and specificity assessments facilitated the identification of two promising phytochemicals, neogitogenin and samogenin. Both phytochemicals exhibited considerable drug-like properties with notable binding affinity and selectivity toward MET. Molecular dynamics simulation studies showed the conformational stability of MET with neogitogenin and samogenin. Taken together, these findings suggest that neogitogenin and samogenin hold potential as lead molecules for the development of MET-targeted therapeutics. We call for further evaluations of these phytochemicals in preclinical and experimental studies for anticancer drug discovery and development.

Duchenne muscular dystrophy (DMD) is a genetic disorder that causes muscle weakness and degeneration. In this study, we identified potential biomarkers and drug targets for DMD through a comprehensive meta-analysis of mRNA profiles. We conducted an in-depth analysis of three microarray datasets from the GEO database, utilizing the Affymetrix platform. A rigorous data pre-processing pipeline encompassed background correction, normalization, log2 transformation and probe-to-gene symbol mapping. Robust multi-array average method followed by Limma package in R was employed to ensure differential expression analysis within individual datasets, yielding gene-specific p-values. We identified 63 genes exhibiting statistically significant differential expression across the three datasets (p < 0.05) and an absolute log fold change > 1.5. Functional enrichment analyses of these differentially expressed genes were done, followed by pathway analyses. Our results suggested pertinent biological processes, molecular functions and cellular components associated with DMD. Finally, eight hub genes-COL6A3, COL1A1, COL3A1, COL1A2, POSTN, TIMP1, THBS2 and SPP1-were pinpointed as central players in the network. Two differentially expressed genes with substantial absolute log-fold changes, namely, DMD, downregulated and MYH3, upregulated, were identified as potential therapeutic candidates. In light of these findings, our work contributes not only to understanding DMD at the molecular level but also presents potential targets for therapeutic strategies. Finally, our study facilitates the development of therapeutic interventions that can effectively control and mitigate the impact of DMD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Mast/Stem cell growth factor receptor Kit (c-Kit), a Proto-oncogene c-Kit, is a tyrosine-protein kinase involved in cell differentiation, proliferation, migration, and survival. Its role in developing certain cancers, particularly gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML), makes it an attractive therapeutic target. Several small molecule inhibitors targeting c-Kit have been developed and approved for clinical use. Recent studies have focused on identifying and optimizing natural compounds as c-Kit inhibitors employing virtual screening. Still, drug resistance, off-target side effects, and variability in patient response remain significant challenges. From this perspective, phytochemicals could be an important resource for discovering novel c-Kit inhibitors with less toxicity, improved efficacy, and high specificity. This study aimed to uncover possible c-Kit inhibitors by utilizing a structure-based virtual screening of active phytoconstituents from Indian medicinal plants. Through the screening stages, two promising candidates, Anilinonaphthalene and Licoflavonol, were chosen based on their drug-like features and ability to bind to c-Kit. These chosen candidates were subjected to all-atom molecular dynamics (MD) simulations to evaluate their stability and interaction with c-Kit. The selected compounds Anilinonaphthalene from Daucus carota and Licoflavonol from Glycyrrhiza glabra showed their potential to act as selective binding partners of c-Kit. Our results suggest that the identified phytoconstituents could serve as a starting point to develop novel c-Kit inhibitors for developing new and effective therapies against multiple cancers, including GISTs and AML. The use of virtual screening and MD simulations provides a rational approach to discovering potential drug candidates from natural sources.Communicated by Ramaswamy H. Sarma.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disorder characterized by progressive and severe muscle weakening and degeneration. Among the various forms of muscular dystrophy, it stands out as one of the most common and impactful, predominantly affecting boys. The condition arises due to mutations in the dystrophin gene, a key player in maintaining the structure and function of muscle fibers. The manuscript explores the structural features of dystrophin protein and their pivotal roles in DMD. We present an in-depth analysis of promising therapeutic approaches targeting dystrophin and their implications for the therapeutic management of DMD. Several therapies aiming to restore dystrophin protein or address secondary pathology have obtained regulatory approval, and many others are ongoing clinical development. Notably, recent advancements in genetic approaches have demonstrated the potential to restore partially functional dystrophin forms. The review also provides a comprehensive overview of the status of clinical trials for major therapeutic genetic approaches for DMD. In addition, we have summarized the ongoing therapeutic approaches and advanced mechanisms of action for dystrophin restoration and the challenges associated with DMD therapeutics., 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 © 2024 Elsevier B.V. All rights reserved.)

Humans are constantly at high risk of emerging pandemics caused by viral and bacterial infections. The emergence of new pandemics is mainly caused by evolved viruses and bacteria that are highly resistant to existing medications. The rapid evolution of infectious agents demands the urgent investigation of new therapeutic strategies to prevent and treat these infections at an early stage. One of these therapeutic strategies includes the use of medicinal herbs for their antibacterial and antiviral properties. The use of herbal medicines as remedies is very ancient and has been employed for centuries. Many studies have confirmed the antimicrobial activities of herbs against various pathogens in vitro and in vivo. The therapeutic effect of medicinal herbs is mainly attributed to the natural bioactive molecules present in these plants such as alkaloids, flavonoids, and terpenoids. Different mechanisms have been proposed for how medicinal herbs enhance the immune system and combat pathogens. Such mechanisms include the disruption of bacterial cell membranes, suppression of protein synthesis, and limitation of pathogen replication through the inhibition of nucleic acid synthesis. Medicinal herbs have been shown to treat a number of infectious diseases by modulating the immune system's components. For instance, many medicinal herbs alleviate inflammation by reducing pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha (TNF-α), interleukin-1, IL-6) while promoting the production of anti-inflammatory cytokines (e.g., IL-10). Medicinal herbs also play a role in defense against viral and intracellular infections by enhancing the proliferation and functions of natural killer cells, T-helper-1 cells, and macrophages. In this review, we will explore the use of the most common herbs in preventing and treating infectious and non-infectious diseases. Using current and recently published studies, we focus on the immunomodulatory and therapeutic effects induced by medicinal herbs to enhance immune responses during diseases.

Cyclin-dependent kinase 9 (CDK9) is a transcription-associated protein involved in controlling the cell cycle and is often deregulated in stress conditions. CDK9 is being studied as a well-known druggable target for developing effective therapeutics against a wide range of cancer, cardiac dysfunction and inflammatory diseases. Owing to the significance of CDK9 in the etiology of hematological and solid malignancies, its structure, biological activity, regulation and its pharmacological inhibition are being explored for therapeutic management of cancer. We employed a structure-based virtual high-throughput screening of bioactive compounds from the IMPPAT database to discover potential bioactive inhibitors of CDK9. The preliminary results were obtained from the Lipinski criteria, ADMET parameters and sorting compounds without any PAINS patterns. Subsequently, binding affinity and selectivity analyses were used to find effective CDK9 hits. This screening resulted in the identification of two natural compounds, Glabrene and Guggulsterone with high affinity and specificity for the CDK9 binding site. Both compounds exhibit drug-like characteristics, as projected by ADMET analysis, physicochemical data and PASS evaluation. Both compounds preferentially bind to the ATP-binding pocket of CDK9 and interact with functionally important residues. Further, the dynamics and consistency of CDK9 interaction with Glabrene and Guggulsteron were evaluated through all-atom molecular dynamic (MD) simulations which suggested the stability of both complexes. The results might be deployed to introduce novel CDK9 inhibitors that may treat life-threatening diseases, including cancer.Communicated by Ramaswamy H. Sarma.

Lung cancer remains a formidable global health challenge, necessitating the exploration of novel therapeutic approaches. This study investigates the potential of Cuscuta reflexa Roxb. stem extract as an anticancer agent against human lung cancer, focusing on its antioxidative and ROS-dependent apoptotic effects. Utilizing a combination of network pharmacology and in-vitro experimental validation, we delineate the multifaceted molecular mechanisms underlying the observed effects. The antioxidant potential of C. reflexa stem extract was evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH • ), 2,2-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS •+ ) and ferric reducing/antioxidant power (FRAP), hydroxyl free radical scavenging, reactive nitrogen oxide scavenging and super oxide anion radical scavenging assays. Furthermore, the antiproliferative and proapoptotic effect of C. reflexa stem extract was evaluated against A549 lung adenocarcinoma cell line using the consecrated sulforhodamine B (SBR) and Annexin V-PI assays. Additionally, the mitochondrial membrane potential (MMP) and the total reactive oxygen species (ROS) estimation assays were performed. As a result, network pharmacology analysis revealed a complex interaction network between the bioactive constituents of C. reflexa and key proteins implicated in lung cancer progression. The C. reflexa stem extract showed dose-dependent antioxidant activity against DPPH • (IC 50 - 87.38 µg/mL), reactive nitrogen oxide (IC 50 - 318.34 µg/mL), FRAP (IC 50 - 359.96 µg/mL), hydroxy free radicals (IC 50 - 526.12 µg/mL) than ABTS ●+ (IC 50 - 698.45 µg/mL) and super oxide anion (IC 50 - 892.71 µg/mL) as well as cytotoxic activity against A549 cells (IC 50 - 436.80 µg/mL). Observations of morphological features in treated cells have revealed hallmark of apoptosis properties. Furthermore, as a result of treatment with C. reflexa stem extract, ROS generation and mitochondrial depolarization were increased in A549 cells, suggesting that this treatment has significant apoptotic properties. . These findings highlight the potential utility of this natural extract as an innovative therapeutic strategy for lung cancer treatment. The integration of network pharmacology and experimental validation enhances our understanding of the underlying mechanisms and provide the way for further translational research.Communicated by Ramaswamy H. Sarma.

Honokiol (HNK) is a natural polyphenolic compound extracted from the bark and leaves of Magnolia grandiflora. It has been traditionally used as a medicinal compound to treat inflammatory diseases. HNK possesses numerous health benefits with a minimal level of toxicity. It can cross the blood-brain barrier and blood-cerebrospinal fluid, thus having significant bioavailability in the neurological tissues. HNK is a promising bioactive compound possesses neuroprotective, antimicrobial, anti-tumorigenic, anti-spasmodic, antidepressant, analgesic, and antithrombotic features . HNK can prevent the growth of several cancer types and haematological malignancies. Recent studies suggested its role in COVID-19 therapy. It binds effectively with several molecular targets, including apoptotic factors, chemokines, transcription factors, cell surface adhesion molecules, and kinases. HNK has excellent pharmacological features and a wide range of chemotherapeutic effects, and thus, researchers have increased interest in improving the therapeutic implications of HNK to the clinic as a novel agent. This review focused on the therapeutic implications of HNK, highlighting clinical and pharmacological features and the underlying mechanism of action.Communicated by Ramaswamy H. Sarma.

Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine-threonine protein kinase vital for neuronal cell cycle arrest and differentiation. It activates by binding with p35 and p39 and is important for the functioning of the nervous system. A growing body of evidence suggests that CDK5 contributes to the onset and progression of neurodegeneration and tumorigenesis and represents itself as a potential therapeutic target. Our research illustrates virtual screening of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) library to search for potential inhibitors of CDK5. Initially, the compounds from the parent library were filtered out via their physicochemical properties following the Lipinski rule of five. Then sequentially, molecular docking-based virtual screening, PAINS filter, ADMET, PASS analysis, and molecular dynamics (MD) simulation were done using various computational tools to rule out adversities that can cause hindrances in the identification of potential inhibitors of CDK5. Finally, two compounds were selected via the extensive screening showing significant binding with CDK5 ATP-binding pocket and ultimately were selected as potent ATP-competitive inhibitors of CDK5. Finally, we propose that the elucidated compounds Desmodin and Isopongachromene can be used further in the drug discovery process and act as therapeutics in the medical industry to treat certain complex diseases, including cancer and neurodegeneration.Communicated by Ramaswamy H. Sarma.

Rho-associated protein kinase 1 (ROCK1) is a member of the AGC family which plays crucial roles in inflammatory diseases and cancer progression. Elevated expression of ROCK1 has been reported in multiple cancer types, and thus it has emerged as a potential drug target for cancer therapeutics. In this study, we performed a structure-based virtual screening of the natural compounds taken from the IMPPAT database to find some potential molecules as inhibitors of ROCK1. For the first step, we selected the compounds based on the Lipinski rule of five, and then we filtered them based on their ADMET properties and PAINS value. After this, other parameters like binding affinities, docking score, biological properties and selectivity were calculated to find appropriate hits against ROCK1. Finally, we identified two natural compounds, Isoononin and Candidissiol, with appreciable binding affinity and selectivity towards ROCK1. Furthermore, all-atom molecular dynamics simulations were carried out on ROCK1 with the elucidated compounds, which suggested stability throughout the simulated trajectories of 100 ns. Taken together, Isoononin and Candidissiol could be considered as potential inhibitors of ROCK1 for developing anticancer therapeutics.Communicated by Ramaswamy H. Sarma.

Objective: The goal of this study was to look at the patterns of thyroid tumors and how thyroid cancer markers showed up in immunohistochemistry in Northern Saudi Arabia., Patients and Methods: This study investigated retrospectively 190 patients who attended with thyroid complaints. About 140 thyroid biopsies were diagnosed in the Department of Pathology at King Salman Hospital, Ha'il, from November 2019 to November 2020., Results: Out of the 190 patients who attended with thyroid complaints, 140/190 (73.7%) were detected with thyroid lesions (58 malignant and 82 benign). Benign lesions included goiter 49/82 (60%), follicular adenoma 17/82 (21%), Hashimoto's thyroiditis 13/82 (16%), and toxic goiter 3/82 (3%). 5/6 (83.3%) of males with benign lesions had goiters. CK19 was positive in 68.5% of the cases; 71.8% were papillary, 66.7% were follicular, and 100% were undifferentiated carcinomas. Out of the 26/54 (48%) CD56-positive cases, 18/39 (46%) were papillary, 7/12 (58.3%) were follicular, and 3/3 (100%) were undifferentiated carcinomas. Out of the 35/54 (64.8%) Galectin-3-positive cases, 69.2% were papillary, 7/12 (58.3%) were follicular, and 3/3 (100%) were undifferentiated carcinomas., Conclusions: Thyroid cancer is prevalent in northern Saudi Arabia, with the predominant type being papillary thyroid carcinoma. Most patients are female and younger. The combined use of CK19, CD56, and Galectin-3 tumor markers assists in the accurate differential diagnosis of thyroid neoplasms.

Immunotherapies, including immune checkpoint inhibitors, have limitations in their effective treatment of malignancies. The immunosuppressive environment associated with the tumor microenvironment may prevent the achievement of optimal outcomes for immune checkpoint inhibitors alone, and nanotechnology-based platforms for delivery of immunotherapeutic agents are increasingly being investigated for their potential to improve the efficacy of immune checkpoint blockade therapy. In this manuscript, nanoparticles were designed with appropriate size and surface characteristics to enhance their retention of payload so that they can transmit their loaded drugs to the tumor. We aimed to enhance immune cell stimulation by a small molecule inhibitor of PD-1/PD-L1 (BMS202) using nanodiamonds (ND). Melanoma cells with different disease stages were exposed to bare NDs, BMS202-NDs or BMS202 alone for 6 h. Following this, melanoma cells were co-cultured with freshly isolated human peripheral blood mononuclear cells (hPBMCs). The effects of this treatment combination on melanoma cells were examined on several biological parameters including cell viability, cell membrane damage, lysosomal mass/pH changes and expression of γHA2X, and caspase 3. Exposing melanoma cells to BMS202-NDs led to a stronger than normal interaction between the hPBMCs and the melanoma cells, with significant anti-proliferative effects. We therefore conclude that melanoma therapy has the potential to be enhanced by non-classical T-cell Immune responses via immune checkpoint inhibitors delivered by nanodiamonds-based nanoparticles., (© 2023. The Author(s).)

Microtubule-affinity regulating kinase 4 (MARK4) is linked with the development of cancer, diabetes and neurodegenerative diseases. Due to its direct role in the hyperphosphorylation of tau protein, MARK4 is considered as an attractive target to fight Alzheimer's disease (AD) and neuroinflammation. In the present study, we have selected Harmaline (HAR), an alkaloid of Paganum harmala, to investigate its MARK4 inhibitory potential and its binding mechanism. Molecular docking and fluorescence binding studies were carried out to estimate the binding affinity of the HAR with the MARK4. We observed an excellent binding affinity of HAR to the MARK4 (K = 10 7  M -1 ), further complemented by isothermal titration calorimetric measurements. In addition, HAR significantly inhibits the kinase activity of MARK4 (IC 50 value of 4.46 μM). Structural investigations suggested that HAR binds to the active site pocket and forms several non-covalent interactions with biologically important residues of MARK4. All-atom molecular dynamics simulation studies further advocated that the MARK4-HAR complex is stabilized throughout the trajectory of 200 ns and causes a little conformational change. All these findings suggest that HAR is a potential MARK4 inhibitor that can be implicated in managing MARK4-associated diseases, including AD., 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.)

Traditional treatment of cancer has been plagued by a number of obstacles, such as multiple drug resistance, toxicity and financial constraints. In contrast, phytochemicals that modulate a variety of molecular mechanisms are garnering increasing interest in complementary and alternative medicine. Therefore, an approach based on network pharmacology was used in the present study to explore possible regulatory mechanisms of 6-shogaol as a potential treatment for cervical cancer (CC). A number of public databases were screened to collect information on the target genes of 6-shogaol (SuperPred, Targetnet, Swiss target prediction and PharmMapper), while targets pertaining to CC were taken from disease databases (DisGeNet and Genecards) and gene expression omnibus (GEO) provided expression datasets. With STRING and Cytoscape, protein-protein interactions (PPI) were generated and topology analysis along with CytoNCA were used to identify the Hub genes. The Gene Ontology (GO) database Enrichr was used to annotate the target proteins, while, using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, signaling pathway enrichment analysis was conducted. Molecular docking and survival analysis for the Hub genes revealed four genes (HSP90AA1, HRAS, ESR1 and EGFR) with lowest binding energy and majority of the Hub genes (EGFR, SRC, CASP-3, HSP90AA1, MTOR, MAPK-1, MDM2 and ESR1) were linked with the overall survival of CC patients. In conclusion, the present study provides the scientific evidence which strongly supports the use of 6-shogoal as an inhibitor of cellular proliferation, growth, migration as well as inducer of apoptosis via targeting the hub genes involved in the growth of CC.Communicated by Ramaswamy H. Sarma.

Sphingosine kinase 1 (SphK1) dysfunction is well-known to be linked to various severe diseases, including breast, lung, prostate, and hematological cancers. Due to its crucial function in the onset of cancer and its progression, it is considered a notable drug target for anticancer therapy. Small molecule inhibitors with high specificity and efficacy towards SphK1 are needed for their therapeutic use. In order to find possible SphK1 inhibitors, we conducted a stepwise structure-based virtual screening of plant-based molecules available from the IMPPAT library. A multi-step virtual screening, including physicochemical and ADMET evaluation, PAINS, molecular docking, PASS analysis followed by molecular dynamics (MD) simulation and principal component analysis, identifies two compounds, Gummadiol and Isoarboreol, against SphK1. All-atom MD simulations were performed for 100 ns which examined the structural changes and stability of the docked complexes in the aqueous environment. The time evolution data of structural deviations and compactness, PCA and free energy landscapes suggested that the binding of Gummadiol and Isoarboreol with SphK1 is considerably stable throughout the trajectory. The study highlighted the use of phytochemicals in anticancer therapeutics and presented Gummadiol and Isoarboreol as promising inhibitors of SphK1.Communicated by Ramaswamy H. Sarma.

Fungal infections caused by Candida species have attracted great interest due to their resistance to commercial antifungal agents. Essential oils from aromatic and medicinal plants have many bioactive compounds that are known for their important biological activities, mainly their antimicrobial effects. In the present study, we aimed to evaluate the antifungal ability of Elettaria cardamomum essential oil (EO) against different clinical Candida isolates. Then, we investigated the anti-phospholipase, anti-protease, and anti-biofilm activity of E. cardamomum EO against the selected isolates. Twenty-four Candida strains (clinical and reference) were tested for virulence factors such as biofilm formation, protease, and phospholipase activity. The minimum inhibitory (MIC) and fungicidal (MFC) concentrations of E. cardamomum were determined, and their effects were tested against all Candida strains. Our results revealed that E. cardamomum EO was rich in α-terpinyl acetate (56.5%), limonene (12.6%), and mentha-2.4(8)-diene (7.65%). The tested EO showed activity against all tested Candida strains in their planktonic form and against exoenzymes and biofilm production. Based on our findings, we promote the use of E. cardamomum EO as a treatment against clinical Candida isolates active on the virulence factors of this fungus.

Metabolic reprogramming is a key attribute of cancer progression. An altered expression of pyruvate kinase M2 (PKM2), a phosphotyrosine-binding protein is observed in many human cancers. PKM2 plays a vital role in metabolic reprogramming, transcription and cell cycle progression and thus is deliberated as an attractive target in anticancer drug development. The expression of PKM2 is essential for aerobic glycolysis and cell proliferation, especially in cancer cells, facilitating selective targeting of PKM2 in cell metabolism for cancer therapeutics. We have screened a virtual library of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database of Indian medicinal plants to identify potential activators of PKM2. The initial screening was carried out for the physicochemical properties of the compounds, and then structure-based molecular docking was performed to select compounds based on their binding affinity towards PKM2. Subsequently, the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties, PAINS (Pan-assay interference compounds) patterns, and PASS evaluation were carried out to find more potent hits against PKM2. Here, Tuberosin was identified from the screening process bearing appreciable binding affinity toward the PKM2-binding pocket and showed a worthy set of drug-like properties. Finally, molecular dynamics simulation for 100 ns was performed, which showed decent stability of the protein-ligand complex and relatival conformational dynamics throughout the trajectory. The study suggests that modulating PKM2 with natural compounds is an attractive approach in treating human malignancy after required validation.

Objective: This study aimed to associate the expression of P53, BCL2, PTEN, and HER2/neu tumor markers in specific breast cancer lesions., Methods: This study analyzed the immunohistochemical expression of P53, BCL2, PTEN, and HER2/neu tumor markers for 306 patients who presented with lesions. Tissue blocks and patients' identification data were retrieved from the department of pathology, AL Madinah Almonwarah hospital, Al Madinah, UAE., Results: Of the 306 patients, 104 had benign lesions and 202 had malignancy (including 194 females and 6 males). Most females were presented with invasive ductal carcinoma (IDC), followed by infiltrating ductal carcinoma, and invasive lobular carcinoma (ILC), representing 70%, 23.2%, and 3.7%, respectively. Positive P53, BCL2, PTEN, and HER2 were identified in 20.8%, 11.9%, 91%, and 18.3%, respectively., Conclusion: : The expression of P53, BCL2, PTEN, and HER2/neu tumor markers among Saudi patients with breast cancer is relatively similar in many parts of the world., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Mohamed Ahmed Bealy et al.)

Recently, there has been significant interest in bio-based degradable plastics owing to their potential as a green and sustainable alternative to synthetic plastics due to their biodegradable properties. Polyhydroxybutyrate (PHB) is a biodegradable polymer that is produced by bacteria and archaea as carbon and energy reserves. Due to its rapid degradation in natural environments, it can be considered a biodegradable plastic alternative. In the present study, a dye-based procedure was used to screen PHB-producing bacteria isolated from mangrove soil samples. Among the seven isolates, Agromyces indicus ( A. indicus) , identified by means of 16S rRNA analysis, accumulated the highest amount of PHB. The extracted polymer was characterized by a UV-Vis spectrophotometer, Fourier-transform infrared (FTIR) spectroscopy, and for the presence of the phbB gene, which confirmed the structure of the polymer as PHB. The maximum PHB production by A. indicus was achieved after 96 h of incubation at a pH of 8.0 and 35 °C in the presence of 2% NaCl, with glucose and peptone as the carbon and nitrogen sources, respectively. The strain was found to be capable of accumulating PHB when various cheap agricultural wastes, such as rice, barley, corn, and wheat bran, were used as the carbon sources. The response surface methodology (RSM) through the central composite design (CCD) for optimizing the PHB synthesis was found to be highly efficient at augmenting the polymer yields. As a result of the optimum conditions obtained from the RSM, this strain can increase the PHB content by approximately 1.4-fold when compared with an unoptimized medium, which would substantially lower the production cost. Therefore, the isolate A. indicus strain B2 may be regarded as one of the best candidates for the industrial production of PHB from agricultural wastes, and it can remove the environmental concerns associated with synthetic plastic.

Effluents discharged by poultry meat industries are heavily polluted with raw materials, such as fat, blood residues, and proteins. Thus, untreated effluents directly discharged into the environment may constitute a public health threat. This study aims to evaluate the bacterial diversity of three water qualities: industrial poultry wastewater (PWW), tap water (TW), and PWW diluted with TW (50 : 50) (V/V) (TWPWW) by the combination of culture-independent and culture-dependent approaches. The total bacterial DNA was extracted using phenol/chloroform method. The hypervariable 16S rRNA region V3-V5 was amplified by PCR using universal primers. The amplicons were separated by vertical electrophoresis on a polyacrylamide gel of increasing denaturing gradient according to their richness in GC bases. Selected bands were reamplified and sequenced. Pure isolated bacteria from nutrient agar medium were characterized according to their morphological and biochemical characteristics. Genomic DNA from pure strains was extracted by boiling method, and a molecular amplification of the 16S-23S ITS region of the 16S rRNA gene was performed using the universal primers. Selected isolates were identified by sequencing. Results showed a high bacterial load and diversity in PWW in comparison with TW and TWPWW. A collection of 44 strains was obtained, and 25 of them were identified by sequencing. Proteobacteria represented 76% of isolated bacteria Gamma-Proteobacteria was the predominate isolate (68%). Other isolates were Firmicutes (8%), Bacteroidetes (12%), and Actinobacteria (8%). These isolates belong to different genera, namely, Pseudomonas , Acinetobacter , Proteus , Empedobacter , Corynebacterium , Enterobacter , Comamonas , Frondibacter , Leclercia , Staphylococcus , Atlantibacter , Klebsiella , and Microbacterium ., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Amira Oueslati et al.)

This study aimed at optimizing conditions for increased withanolide production in Withania somnifera . The elicitors used for the foliar spray on the aerial parts of the plant were salicylic acid, jasmonic acid, and chitosan for the enhancement of withanolides in Withania somnifera under different environmental regimes. Three different elicitors, i.e., chitosan, jasmonic acid and salicylic acid, were applied on the plants through foliar route every 15th day for 6 months, and later plants were used for sample preparation. Further, the elicitors were used in different concentration, i.e., jasmonic acid (50, 200 and 400 ppm), chitosan (10, 50 and 100 ppm) and salicylic acid (0.5, 1 and 2 ppm). The elicitors were sprayed on the foliar parts of the plant between 10:00-11:00 a.m. on application days. For elicitor spray, a calibrated sprayer was used. The withanolide A/withaferin A was quantified through HPLC. It was found that in an open environment, maximum withaferin A content, i.e., 0.570 mg/g (DW), was recorded with jasmonic acid (50 ppm) treatment in comparison to control (0.067 mg/g DW). Thus, there was an 8.5-fold increase in the withaferin A content. Maximum withanolide A content of 0.352 mg/g (DW) was recorded when chitosan (50 ppm) was sprayed, while in the control, withanolide A content was recorded to be 0.031 mg/g (DW); thus, chitosan application increased the production of withanolide A by 11.3-fold. Under controlled conditions, maximum withaferin A content of 1.659 mg/g (DW) was recorded when plants were sprayed with chitosan (100 ppm), which was 8.1 times greater than the control content of 0.203 mg/g (DW). Maximum withanolide A content of 0.460 mg/g (DW) was recorded when chitosan (100 ppm) was applied, whereas in the control, withanolide A content was found to be 0.061 mg/g (DW). Thus, foliar spraying of elicitors in very low concentrations can serve as a low-cost, eco-friendly, labor-intensive and elegant alternative approach that can be practiced by farmers for the enhancement, consistent production and improved yield of withanolide A/withaferin A. This can be a suitable way to enhance plant productivity, thus increasing the availability of withanolide A and withaferin A for the health and pharma industry.

The 3-phosphoinositide-dependent protein kinase 1 (PDPK1) has a significant role in cancer progression and metastasis as well as other inflammatory disorders, and has been proposed as a promising therapeutic target for several malignancies. In this work, we conducted a systematic virtual screening of natural compounds from the IMPPAT database to identify possible PDPK1 inhibitors. Primarily, the Lipinski rules, ADMET, and PAINS filter were applied and then the binding affinities, docking scores, and selectivity were carried out to find effective hits against PDPK1. Finally, we identified two natural compounds, 11-Hydroxytephrosin and Torosaflavone A, bearing substantial affinity with PDPK1. Both compounds showed drug-likeness as predicted by the ADMET analysis and their physicochemical parameters. These compounds preferentially bind to the ATP-binding pocket of PDPK1 and interact with functionally significant residues. The conformational dynamics and complex stability of PDPK1 with the selected compounds were then studied using interaction analysis and molecular dynamics (MD) simulations for 100 ns. The simulation results revealed that PDPK1 forms stable docked complexes with the elucidated compounds. The findings show that the newly discovered 11-Hydroxytephrosin and Torosaflavone A bind to PDPK1 in an ATP-competitive manner, suggesting that they could one day be used as therapeutic scaffolds against PDPK1-associated diseases including cancer.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase molecular target with broad importance for drug discovery, especially in the field of cancer therapeutics. ALK belongs to the insulin receptor superfamily that is involved in various malignancies, including non-small cell lung cancer, anaplastic large cell lymphoma, and neuroblastoma. ALK has been shown to play a role in cancer progression and metastasis, making it one of the prime targets to develop novel anticancer therapeutics. In this context, natural compounds can be an important resource to unravel novel ALK inhibitors. In this study, we report a structure-based virtual screening of natural compounds from the ZINC database, with an eye to potential inhibitors of ALK. Molecular docking was performed on a natural compound library, and top hits holding good binding affinity, docking score, and specificity toward ALK were selected. The hits were further evaluated based on the PAINS (pan-assay interference compounds) filter, ADMET (absorption, distribution, metabolism, excretion, toxicity) properties, PASS (prediction of activity spectra for substances) analysis, and two-dimensional interaction of protein-ligand complexes. Importantly, two natural compounds (ZINC03845566 and ZINC03999625) were identified as potential candidates for ALK, having appreciable affinity and specificity toward the ALK binding pocket and depicting drug-like properties as predicted from ADMET analysis and their physicochemical parameters. An all-atom molecular dynamics simulation for 100 ns on ALK promised stable ALK-ligand complexes. Hence, we conclude that ZINC03845566 and ZINC03999625 can act as potential ALK inhibitors against cancers where ALK plays a role, for example, in lung cancer, among others. All in all, these findings inform future discovery and translational research for ALK inhibitors as anticancer drugs.

Cancer is one of the major causes of global deaths and needs immediate therapeutic development. So far, several strategies have been undertaken to prevent cancer, including kinase targeting by small-molecule inhibitors. Cyclin dependent kinase 6 (CDK6) plays an essential role in cancer progression and development as its overexpression is associated with tumor development and progression. The present study demonstrated that Naringenin (NAG) binds strongly to CDK6 with a binding affinity of -7.51 kcal/mol. ATPase assay of CDK6 in the presence of NAG shows that it inhibits CDK6 with an IC 50  = 3.13 μM. Fluorescence and isothermal titration calorimetry studies demonstrated that NAG binds to CDK6 with the binding constant (K) values of 3.55 × 10 6  M -1 and 7.06 ± 2.70 × 10 6  M -1 , respectively. The cell-based functional studies showed that NAG decreases the cell viability of human cancer cell lines, induces apoptosis, and reduces their colonization ability. Outcomes of the present in silico and in vitro studies highlighted the significance of NAG for the development of anti-cancer leads in terms of CDK6 inhibitors and provided future implications for combinatorial anti-cancer therapies., (Copyright © 2022. Published by Elsevier B.V.)

Plant bioactive compounds, particularly apigenin, have therapeutic potential and functional activities that aid in the prevention of infectious diseases in many mammalian bodies and promote tumor growth inhibition. Apigenin is a flavonoid with low toxicities and numerous bioactive properties due to which it has been considered as a traditional medicine for decades. Apigenin shows synergistic effects in combined treatment with sorafenib in the HepG2 human cell line (HCC) in less time and statistically reduces the viability of tumor cells, migration, gene expression and apoptosis. The combination of anti-cancerous drugs with apigenin has shown health promoting potential against various cancers. It can prevent cell mobility, maintain the cell cycle and stimulate the immune system. Apigenin also suppresses mTOR activity and raises the UVB-induced phagocytosis and reduces the cancerous cell proliferation and growth. It also has a high safety threshold, and active (anti-cancer) doses can be gained by consuming a vegetable and apigenin rich diet. Apigenin also boosted autophagosome formation, decreased cell proliferation and activated autophagy by preventing the activity of the PI3K pathway, specifically in HepG2 cells. This paper provides an updated overview of apigenin's beneficial anti-inflammatory, antibacterial, antiviral, and anticancer effects, making it a step in the right direction for therapeutics. This study also critically analyzed the effect of apigenin on cancer cell signaling pathways including the PI3K/AKT/MTOR, JAK/STAT, NF-κB and ERK/MAPK pathways.

Death-associated protein kinase 3 (DAPK3) is a serine/threonine protein kinase that regulates apoptosis, autophagy, transcription, and actin cytoskeleton reorganization. DAPK3 induces morphological alterations in apoptosis when overexpressed, and it is considered a potential drug target in antihypertensive and anticancer drug development. In this article, we report new findings from a structure-guided virtual screening for discovery of phytochemicals that could modulate the elevated expression of DAPK3, and with an eye to anticancer drug discovery. We used the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT), a curated database, as part of the methodology. The potential initial hits were identified based on their physicochemical properties and binding affinity toward DAPK3. Subsequently, various filters for drug likeness followed by interaction analysis and molecular dynamics (MD) simulations for 100 nsec were performed to explore the conformational sampling and stability of DAPK3 with the candidate molecules. Notably, the data from all-atom MD simulations and principal component analysis suggested that DAPK3 forms stable complexes with ketanserin and rotenone. In conclusion, this study supports the idea that ketanserin and rotenone bind to DAPK3, and show stability, which can be further explored as promising scaffolds in drug development and therapeutics innovation in clinical contexts such as hypertension and various types of cancer.

Oral squamous cell carcinoma (OSCC) is a major cause of death in developing countries because of high tobacco consumption. RAC-alpha serine-threonine kinase (AKT1) is considered as an attractive drug target because its prolonged activation and overexpression are associated with cancer progression and metastasis. In addition, several AKT1 inhibitors are being developed to control OSCC and other associated forms of cancers. We performed a screening of the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database to discover promising AKT1 inhibitors which pass through various important filters such as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, physicochemical properties, PAINS (pan-assay interference compounds) filters, PASS (prediction of activity spectra for substances) analysis, and specific interactions with AKT1. Molecules bearing admirable binding affinity and specificity towards AKT1 were selected for further analysis. Initially, we identified 30 natural compounds bearing appreciable affinity and specific interaction with AKT1. Finally, tuberosin and villosol were selected as potent and selective AKT1 inhibitors. To obtain deeper insights into binding mechanism and selectivity, we performed an all-atom molecular dynamics (MD) simulation and principal component analysis (PCA). We observed that both tuberosin and villosol strongly bind to AKT1, and their complexes were stable throughout the simulation trajectories. Our in-depth structure analysis suggested that tuberosin and villosol could be further exploited in the therapeutic targeting of OSCC and other cancers after further clinical validations.

In the present study, we investigated the cytotoxic effects of Athyrium hohenackerianum ethanolic extract (AHEE) on the proliferation of breast, lung, and colon cancer cells. The AHEE was tested for its effect on the progression of the cell cycle, followed by induction of apoptosis determination by flow cytometry. Real-time qRT-PCR was also utilized to observe the initiation of apoptosis. In addition, GC-MS was performed in order to identify the active phytochemicals present in the AHEE. A cytotoxic activity with an IC 50 value of 123.90  μ g/mL against HCT-116 colon cancer cells was exhibited by AHEE. Following propidium iodide staining, annexin-V/PI, and clonogenic assays, AHEE treatment results in cell arrest in the S phase, causing an increase in the early and late phases of apoptosis and displaying antiproliferative potential, respectively. The morphological alterations were further monitored using acridine orange/ethidium bromide (AO/EB) staining. When compared with the control cells, features of apoptotic cell death, including nuclear fragmentation, in the AHEE-treated cells were noticed. The apoptosis was also confirmed by detecting the increased expression of p53 and caspase-3 along with the downregulation of Bcl-2 . GC-MS analysis revealed that trans-linalool oxide, loliolide, phytol, 4,8,12,16-tetramethylheptadecan-4-olide, and gamma-sitosterol were the major phytochemical constituents. Based on these findings, it can be suggested that AHEE causes cellular death via apoptosis, which should be further explored for the identification of active compounds responsible for these observed effects. Therefore, AHEE can be used in the pharmaceutical development of anticancer agents for cancer therapeutics., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Abdelbaset Mohamed Elasbali et al.)

The aim of this study was to investigate the phytochemical composition of dried Roselle calyx ( Hibiscus sabdariffa L.) using both ethanolic and aqueous extracts. We report the antimicrobial activities against a wide range of bacteria, yeast, and fungi. The antioxidant activities were tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl, and 2-2'-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) radical scavenging assays. We report also for the first time the effect of the swarming motility in Pseudomonas aeruginosa PAO1. Our results showed that the tested two extracts were a rich source of phenols, flavonoids, and tannins with different degrees. Additionally, eleven phytoconstituents were identified by LC/MS technique ( Hibiscus acid: 3-caffeoylquinic acid, 5-caffeoylquinic acid, 5-feruloylquinic acid, cyanidin 3-o-glucoside, myricetin, quercetin 7-o-rutinoside, quercetin 3-o-glucoside, delphinidin 3-o-sambubioside, and kaempferol 3-o-p-coumaroyl-glucoside). Also, it was shown that the calyx extract can scavenge 86% of the DPPH radical, while the rate of 53% and 23% of inhibition of the DPPH was obtained only at the concentration of 125 and 50  µ g/mL, and a small inhibition was made at a concentration of 5  μ g/mL. Roselle extracts inhibited the growth of the selected microorganisms at low concentrations, while higher concentrations are needed to completely kill them. However, no activity against CVB-3 was recorded for both extracts. In addition, the obtained extracts reduced the swarming motility of P. aeruginosa at 2.5 mg/ml. The docking simulation showed acceptable binding affinities (up to -9.6 kcal/mol) and interaction with key residues of 1JIJ, 2QZW, and 2UVO. The obtained results highlighted the potential use of Roselle extract as a source of phytoconstituents with promising antimicrobial, antioxidant, and anti-quorum sensing activities., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Bechr Hamrita et al.)

Objective: Breast cancer (BC) tumor markers have an important implication in the subsequent BC management and survival determinants. Thus, the present study aimed to formulate the expression of ER, PR, HER2, and E-cadherin tumor markers in a series of Saudi patients with BC., Patients and Methods: About 133 BC biopsies were retrieved from the Department of Pathology at King Salman Hospital, Hai'l, Northern Saudi Arabia, from November 2019 to November 2020. Out of the 133 biopsies, 50 (37.6%) were diagnosed with BC, including 46 ductal carcinoma, 2 lobular carcinomas, and 2 papillary carcinomas., Results: ER was expressed in 30/44 (68.2%), 2/2 (100%), 2/2 (100%) of the cases of DC, LC, and PC, respectively. PR was expressed in 27/43 (63%), 2/2 (100%), 2/2 (100%) of the cases of DC, LC, and PC, correspondingly. HER2 was expressed in 13/31 (42%), 0%, and 0% of DC, LC, and PC cases, respectively. Correspondingly, E-cadherin was expressed in 11/21 (52.4%), 0%, 1/1 (100%) of the cases of DC, LC, and PC., Conclusions: Triple-negative BC and HER2+ve among Saudi women are among the higher globally reported ranges, associated with poorer response to treatment and prognosis. Luckily, only one patient was found with ER-ve PR+ve, the subtype usually associated with poorer survival outcomes. E-cadherin loss is lower among Saudi BC patients, which suggests a less rate of invasion in these patients. The current study's findings may help improve Saudi guidelines for the treatment of breast cancer.

Saccharomyces cerevisiae var. boulardii is best known for its treatment efficacy against different gastrointestinal diseases. This probiotic yeast can significantly protect the normal microbiota of the human gut and inhibit the pathogenicity of different diarrheal infections. Several clinical investigations have declared S. cerevisiae var. boulardii a biotherapeutic agent due to its antibacterial, antiviral, anti-carcinogenic, antioxidant, anti-inflammatory and immune-modulatory properties. Oral or intramuscular administration of S. cerevisiae var. boulardii can remarkably induce health-promoting effects in the host body. Different intrinsic and extrinsic factors are responsible for its efficacy against acute and chronic gut-associated diseases. This review will discuss the clinical and beneficial effects of S. cerevisiae var. boulardii in the treatment and prevention of different metabolic diseases and highlight some of its health-promising properties. This review article will provide fundamental insights for new avenues in the fields of biotherapeutics, antimicrobial resistance and one health.

Non-small cell lung carcinoma (NSCLC) comprises 80%-85% of lung cancer cases. EGFR is involved in several cancer developments, including NSCLC. The EGFR pathway regulates the Bax/Bcl-2 cascade in NSCLC. Increasing understanding of the molecular mechanisms of fundamental tumor progression has guided the development of numerous antitumor drugs. The development and improvement of rationally planned inhibitors and agents targeting particular cellular and biological pathways in cancer have been signified as a most important paradigm shift in the strategy to treat and manage lung cancer. Newer approaches and novel chemotherapeutic agents are required to accompany present cancer therapies for improving efficiency. Using natural products as a drug with an effective delivery system may benefit therapeutics. Naturally originated compounds such as phytochemicals provide crucial sources for novel agents/drugs and resources for tumor therapy. Applying the small-molecule inhibitors (SMIs)/phytochemicals has led to potent preclinical discoveries in various human tumor preclinical models, including lung cancer. In this review, we summarize recent information on the molecular mechanisms of the Bax/Bcl-2 cascade and EGFR pathway in NSCLC and target them for therapeutic implications. We further described the therapeutic potential of Bax/Bcl-2/EGFR SMIs, mainly those with more potent and selectivity, including gefitinib, EGCG, ABT-737, thymoquinone, quercetin, and venetoclax. In addition, we explained the targeting EGFR pathway and ongoing in vitro and in vivo and clinical investigations in NSCLC. Exploration of such inhibitors facilitates the future treatment and management of NSCLC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alam, Alam, Shamsi, Adnan, Elasbali, Al-Soud, Alreshidi, Hawsawi, Tippana, Pasupuleti and Hassan.)

Caffeic acid (CA) is found abundantly in fruits, vegetables, tea, coffee, oils, and more. CA and its derivatives have been used for many centuries due to their natural healing and medicinal properties. CA possesses various biological and pharmacological activities, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. The potential therapeutic effects of CA are mediated via repression and inhibition of transcription and growth factors. CA possesses potential anticancer and neuroprotective effects in human cell cultures and animal models. However, the biomolecular interactions and pathways of CA have been described highlighting the target binding proteins and signaling molecules. The current review focuses on CA's chemical, physical, and pharmacological properties, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. We further described CA's characteristics and therapeutic potential and its future directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alam, Ahmed, Elasbali, Adnan, Alam, Hassan and Pasupuleti.)

Background: Prolactin inducible protein (PIP) is a small secretary glycoprotein present in most biological fluids and contributes to various cellular functions, including cell growth, fertility, antitumor, and antifungal activities. Objectives: The present study evaluated the antibacterial activities of recombinant PIP against multiple broad-spectrum MDR bacterial strains. Methods: The PIP gene was cloned, expressed and purified using affinity chromatography. Disk diffusion, broth microdilution, and growth kinetic assays were used to determine the antibacterial activities of PIP. Results : Disk diffusion assay showed that PIP has a minimum and maximum zone of inhibition against E. coli and P. aeruginosa , respectively, compared to the reference drug ampicillin. Furthermore, growth kinetics studies also suggested that PIP significantly inhibited the growth of E. coli and P. aeruginosa . The minimum inhibitory concentration of PIP was 32 µg/mL for E. coli (443), a standard bacterial strain, and 64 µg/mL for Bacillus sp. (LG1), an environmental multidrug-resistant (MDR) strain. The synergistic studies of PIP with ampicillin showed better efficacies towards selected bacterial strains having MDR properties. Conclusion: Our findings suggest that PIP has a broad range of antibacterial activities with important implications in alleviating MDR problems.

The unexpected emergence of the new Coronavirus disease (COVID-19) has affected more than three hundred million individuals and resulted in more than five million deaths worldwide. The ongoing pandemic has underscored the urgent need for effective preventive and therapeutic measures to develop anti-viral therapy. The natural compounds possess various pharmaceutical properties and are reported as effective anti-virals. The interest to develop an anti-viral drug against the novel severe acute respiratory syndrome Coronavirus (SARS-CoV-2) from natural compounds has increased globally. Here, we investigated the anti-viral potential of selected promising natural products. Sources of data for this paper are current literature published in the context of therapeutic uses of phytoconstituents and their mechanism of action published in various reputed peer-reviewed journals. An extensive literature survey was done and data were critically analyzed to get deeper insights into the mechanism of action of a few important phytoconstituents. The consumption of natural products such as thymoquinone, quercetin, caffeic acid, ursolic acid, ellagic acid, vanillin, thymol, and rosmarinic acid could improve our immune response and thus possesses excellent therapeutic potential. This review focuses on the anti-viral functions of various phytoconstituent and alkaloids and their potential therapeutic implications against SARS-CoV-2. Our comprehensive analysis provides mechanistic insights into phytoconstituents to restrain viral infection and provide a better solution through natural, therapeutically active agents., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cyclin-dependent kinase 6 (CDK6) is an important protein kinase that regulates cell growth, development, cell metabolism, inflammation, and apoptosis. Its overexpression is associated with reprogramming glucose metabolism through alternative pathways and apoptosis, which ultimately plays a significant role in cancer development. In the present study, we have investigated the structural and conformational changes in CDK6 at varying pH employing a multi-spectroscopic approach. Circular dichroism (CD) spectroscopy revealed at extremely acidic conditions (pH 2.0-4.0), the secondary structure of CDK6 got significantly disrupted, leading to aggregates formation. These aggregates were further characterized by employing Thioflavin T (ThT) fluorescence. No significant secondary structural changes were observed over the alkaline pH range (pH 7.0-11.0). Further, fluorescence and UV spectroscopy revealed that the tertiary structure of CDK6 was disrupted under extremely acidic conditions, with slight alteration occurring in mild acidic conditions. The tertiary structure remains intact over the entire alkaline range. Additionally, enzyme assay provided an insight into the functional aspect of CDK at varying pH; CDK6 activity was optimal in the pH range of 7.0-8.0. This study will provide a platform that provides newer insights into the pH-dependent dynamics and functional behavior of CDK6 in different CDK6 directed diseased conditions, viz. different types of cancers where changes in pH contribute to cancer development., Competing Interests: The authors have declared that no competing interests exist.

Parkinsonism-associated deglycase-PARK7/DJ-1 (PARK7) is a multifunctional protein having significant roles in inflammatory and immune disorders and cell protection against oxidative stress. Mutations in PARK7 may result in the onset and progression of a few neurodegenerative disorders such as Parkinson's disease. This study has analyzed the non-synonymous single nucleotide polymorphisms (nsSNPs) resulting in single amino acid substitutions in PARK7 to explore its disease-causing variants and their structural dysfunctions. Initially, we retrieved the mutational dataset of PARK7 from the Ensembl database and performed detailed analyses using sequence-based and structure-based approaches. The pathogenicity of the PARK7 was then performed to distinguish the destabilizing/deleterious variants. Aggregation propensity, noncovalent interactions, packing density, and solvent accessible surface area analyses were carried out on the selected pathogenic mutations. The SODA study suggested that mutations in PARK7 result in aggregation, inducing disordered helix and altering the strand propensity. The effect of mutations alters the number of hydrogen bonds and hydrophobic interactions in PARK7, as calculated from the Arpeggio server. The study indicated that the alteration in the hydrophobic contacts and frustration of the protein could alter the stability of the missense variants of the PARK7, which might result in disease progression. This study provides a detailed understanding of the destabilizing effects of single amino acid substitutions in PARK7.

The purpose of this study was to evaluate for the first time the phytochemical constituents and biological properties of three (ethanol, acetone, and hexane) Arthrocnemum indicum (Willd.) Moq. ( A. indicum ) extracts. Quantitative analysis revealed the significantly ( p < 0.05) dominance of ethanolic extract on total polyphenol (TPC; 303.67 ± 4.16 mg GAE/g DR) and flavonoid (TFC; 55.33 ± 2.52 mg CE/g DR) contents than the other extracts, also displaying high and equipotent condensed tannin (TCTC) contents as the acetone extract. The qualitative HPLC-MS analysis elucidates 19 and 18 compounds in ethanolic and acetonic extracts, respectively, belonging to the phenolics and flavonoids chemical classes. The extracts were also screened for their in vitro antioxidant activities using 1,1-diphenyl-2-picrylhydrazyl, superoxide anion, and ferric ion (Fe 3+ ) reducing antioxidant power (FRAP), demonstrating the potent antioxidant activity of ethanolic extract, due to its stronger scavenging DPPH • (IC 50 = 7.17 ± 1.26 μg/mL) which is not significantly ( p > 0.05) different from the positive control, BHT (IC 50 = 10.70 ± 0.61 μg/mL), however moderate activity through FRAP and superoxide anion radicals have been observed. Four Gram-positive, four Gram-negative bacteria, and four pathogenic fungi were used for the antimicrobial activity. In addition, S. epidermidis, M. luteus, E. faecalis, C. glabrata, C. parapsilosis, C. krusei were found to be the most susceptible strains towards ethanolic extract. Cytotoxicity values against human colon adenocarcinoma cells (HT29) and human epidermoid cancer cells (Hep2), and one continuous cell lineage control (Vero) revealed that the HT29 cancer cell line was the most responsive to A. indicum shoot extract treatment and significantly ( p < 0.05) different from the other cancer cells. Moreover, when tested for their antidiabetic inhibitory effect, ethanol extract recorded the highest antidiabetic effect with IC 50 = 13.17 ± 1.04 mg/mL, which is 8.4-fold higher than acetone extract. Therefore, the present study provides new findings on the use of A. indicum shoot ethanolic extract to cure many incurable diseases.

Background: Protein sequence and structure analyses have been essential components of bioinformatics and structural biology. They provide a deeper insight into the physicochemical properties, structure, and subsequent functions of a protein. Advanced computational approaches and bioinformatics utilities help solve several issues related to protein analysis. Still, beginners and non-professional may struggle when encountering a wide variety of computational tools and the sheer number of input parameter variables required by each tool., Methods: We introduce a free-to-access graphical user interface (GUI) named PyPAn 'Python-based Protein Analysis' for varieties of protein sequence/structure analyses. PyPAn serves as a universal platform to analyze protein sequences, structure, and their properties. PyPAn facilitates onboard analysis of each task in just a single click. It can be used to calculate the physicochemical properties, including instability index and molar extinction coefficient, for a protein. PyPAn is one of the few computational tools that allow users to generate a Ramachandran plot and calculate solvent accessibility and the radius of gyration (Rg) of proteins at once. In addition, it can refine the protein model along with computation and minimization of its energy., Results: PyPAn can generate a recommendation for an appropriate structure modelling method to employ for a query protein sequence. PyPAn is one of the few, if not the only, Python-based computational GUI tools with an array of options for the user to employ as they see fit., Conclusion: PyPAn aims to unify many successful academically significant proteomic applications and is freely available for academic and industrial research uses at https://hassanlab.org/pypan., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Diagnostic radiology has been linked to several health consequences. Thus, the present study aimed to assess the practice, knowledge, and awareness of the diverse effects of diagnostic radiology among radiology staff and students in Saudi Arabia., Methodology: In this study, 107 participants were recruited from August to December 2020. The study included 56 radiology personnel (staff from Hail City Hospitals) and 51 radiology medical students (students from the University of Ha'il)., Results: To the question, "Have you ever been informed of radiation and its effects?" about 6/107 (5.6 %) answered "No," among which 5/6 (83.3 %) were the staff. In response to the question, "In your opinion, how hazardous is radiation to your body?" about 8/104 (7.7 %) indicated it as nonhazardous (3 were staff and 5 were students). To the question, "Do you believe that radiation in medical sites is harmful?" about 20/104 (19.2 %) answered, "No" (8 were staff and 12 were students)., Conclusion: There is a lack of awareness, knowledge, and practice towards ionizing radiation protection measures among radiology medical students and radiology department staff in Northern Saudi Arabia. The paper notifies the health system advisors to include stressing guidelines regarding radiation hazards. More actions are deemed necessary for the safety of patients and radiation workers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Since the emergence of yellow fever in the Americas and the devastating 1918 influenza pandemic, biologists and clinicians have been drawn to human infecting viruses to understand their mechanisms of infection better and develop effective therapeutics against them. However, the complex molecular and cellular processes that these viruses use to infect and multiply in human cells have been a source of great concern for the scientific community since the discovery of the first human infecting virus. Viral disease outbreaks, such as the recent COVID-19 pandemic caused by a novel coronavirus, have claimed millions of lives and caused significant economic damage worldwide. In this study, we investigated the mechanisms of host-virus interaction and the molecular machinery involved in the pathogenesis of some common human viruses. We also performed a phylogenetic analysis of viral proteins involved in host-virus interaction to understand the changes in the sequence organization of these proteins during evolution for various strains of viruses to gain insights into the viral origin's evolutionary perspectives., Competing Interests: The authors have declared that no competing interests exist.

Amyotrophic lateral sclerosis (ALS) is a fatal, incurable neurodegenerative disease described by progressive degeneration of motor neurons. The most common familial form of ALS (fALS) has been associated with mutations in the Cu/Zn superoxide dismutase ( SOD1 ) gene. Mutation-induced misfolding and aggregation of SOD1 is often found in ALS patients. In this work, we probe the aggregation properties of peptides derived from the SOD1. To examine the source of SOD1 aggregation, we have employed a computational algorithm to identify four peptides from the SOD1 protein sequence that aggregates into a fibril. Aided by computational algorithms, we identified four peptides likely involved in SOD1 fibrillization. These four aggregation-prone peptides were 14 VQGIINFE21, 30 KVWGSIKGL38, 101 DSVISLS 107 , and 147 GVIGIAQ 153 . In addition, the formation of fibril propensities from the identified peptides was investigated through different biophysical techniques. The atomic structures of two fibril-forming peptides from the C-terminal SOD1 showed that the steric zippers formed by 101 DSVISLS 107 and 147 GVIGIAQ 153 vary in their arrangement. We also discovered that fALS mutations in the peptide 147 GVIGIAQ 153 increased the fibril-forming propensity and altered the steric zipper's packing. Thus, our results suggested that the C-terminal peptides of SOD1 have a central role in amyloid formation and might be involved in forming the structural core of SOD1 aggregation observed in vivo ., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Ursolic acid (UA) is a pentacyclic triterpenoid frequently found in medicinal herbs and plants, having numerous pharmacological effects. UA and its analogs treat multiple diseases, including cancer, diabetic neuropathy, and inflammatory diseases. UA inhibits cancer proliferation, metastasis, angiogenesis, and induced cell death, scavenging free radicals and triggering numerous anti- and pro-apoptotic proteins. The biochemistry of UA has been examined broadly based on the literature, with alterations frequently having been prepared on positions C-3 (hydroxyl), C12-C13 (double bonds), and C-28 (carboxylic acid), leading to several UA derivatives with increased potency, bioavailability and water solubility. UA could be used as a protective agent to counter neural dysfunction via anti-oxidant and anti-inflammatory effects. It is a potential therapeutic drug implicated in the treatment of cancer and diabetic complications diseases provide novel machinery to the anti-inflammatory properties of UA. The pharmacological efficiency of UA is exhibited by the therapeutic theory of one-drug → several targets → one/multiple diseases. Hence, UA shows promising therapeutic potential for cancer and diabetic neuropathy diseases. This review aims to discuss mechanistic insights into promising beneficial effects of UA. We further explained the pharmacological aspects, clinical trials, and potential limitations of UA for the management of cancer and diabetic neuropathy diseases.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a Ser/Thr protein kinase involved in regulating cell survival, growth, proliferation, and migration. Its elevated expression and dysfunction are reported in breast, prostate, hepatocellular, lung adenoma, and renal carcinomas. We have analyzed the SGK1 mutations to explore their impact at the sequence and structure level by utilizing state-of-the-art computational approaches. Several pathogenic and destabilizing mutations were identified based on their impact on SGK1 and analyzed in detail. Three amino acid substitutions, K127M, T256A, and Y298A, in the kinase domain of SGK1 were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic (MD) simulations for 200 ns. MD results indicate substantial conformational alterations in SGK1, thus its functional loss, particularly upon T256A mutation. This study provides meaningful insights into SGK1 dysfunction upon mutation, leading to disease progression, including cancer, and neurodegeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 AlAjmi, Khan, Choudhury, Mohammad, Noor, Hussain, Lu, Eapen, Chimankar, Hansbro, Sohal, Elasbali and Hassan.)

The study aimed to screen for PIK3CA gene mutations among Saudi women with Ovarian Cancer. The study included 298 Saudi women with epithelial ovarian cancers (EOC). DNA sequence analysis was employed to screen for the mutations. DNA sequence analysis of a coding region of exon 9 and 20 of PIK3CA gene revealed mutations in 37/298 (12.4%) EOC patients. About 21/37(56.8%) somatic mutations were identified in exons 9, and 16/37(43.2%) in exon 20. All analysed mutations were missense mutations, the frequencies of which varied from 2.7% to 43.2%. PIK3CA mutation was found to be significantly associated with age ( p  = .023), grade ( p  = .001) and histological types ( p  = .032). Only 6.6% of serous carcinomas and 3.8% of endometrioid had PIK3CA mutation. The Mutated PIK3CA gene was significantly involved in the pathogenesis of EOC among Saudi women. PIK3CA gene mutation and overexpression represent important clinical implications for diagnosis, and prognosis, which can be utilised for better EOC management.Impact statement What is already known on this subject? The detailed molecular and genetic phenomenon underlying the progression of these tumours is still unclear. Recently, the pathogenesis of ovarian cancer has been attributed to mutations of PIK3CA. What do the results of this study add? Mutation in the PIK3CA gene leads to altered PI3K/AKT signalling pathways responsible for the progression of the epithelial ovarian cancer. What are the implications of these findings for clinical practice and/or further research? The Mutated PIK3CA gene was significantly involved in the pathogenesis of EOC among Saudi women. PIK3CA gene mutation and overexpression represent important clinical implications for diagnosis, and prognosis, which can be utilised for better EOC management.

Human papillomavirus (HPV) is a widely dispersed DNA double-stranded carcinogenic virus worldwide. Many cancers have been attributed to HPV subtypes as a major aetiological factor. Around 90% of cervical cancers have been attributed to the HPV infection, in addition to other cancers such as head and neck cancer, breast cancer and other cancers. As the carcinogenic high risk and low-risk, HPV subtypes are sexually transmitted viruses, and the Saudi community is religiously conservative, lots of measures of the precise burden of the HPV and its related cancers are still obscure. With the absence of cervical-screening programmes and in-depth research in HPV-related cancers, there a lack of literature except for literature pertained to awareness and perceptions. Consequently, the present review is deemed to explore the present state of the HPV-related issues, the future perspective in light of the current scientific evidence, as well as, Saudi community practices, and health policies in this regard. Making accessible data on HPV-related cancers can assist in designing HPV-related early detection and control sustainable programmes. Therefore, this review aimed to discuss the most important magnitudes related to the HPV, concerning the available literature from Saudi Arabia and the data in the neighbouring Arab countries interrelated to Saudi Arabia. The review depended on searching Electronic databases using strongly considered indexes including PubMed, Medline, Web of Science, Scopus, ABSCO, EMBASE, and others. In conclusion, though Saudi Arabia is pronounced as a conservative community with low sexual transmitted diseases, there is an alarming menace of HPV-attributable diseases necessitating a quick intervention.

Background: Although there is an emergent increase in the epidemiology of skin cancer in Saudi Arabia, yet knowledge, attitude, and awareness towards skin cancer prevention measures is still poor. Therefore, the present study aimed to assess the knowledge and attitudes and practice towards skin cancer among the Saudi population, as well as, to evaluate the level of awareness relating to exposure to sunlight., Methods: This cross-sectional survey involved 438 participants who were randomly selected from Riyadh city, Saudi Arabia. A standard questionnaire was used to collect data regarding skin cancer. The questionnaire focused on three main aspects knowledge, attitude, and practice. The skin cancer quality of life impact tool (SCQOLIT) was employed., Results: The present study included 438 participants, aged 18 to 55 years old. The response in the present study was 81.9%. Regarding the causes and effects of skin cancer, 61.2% of the respondents have prior knowledge about it. The positive attitude about skin cancer was exhibited by 68.9%, and only 31.1% showed a negative attitude towards it., Conclusion: In conclusion, Knowledge, attitude, and practice towards skin cancer still under the desired level to prevent skin cancer and its related conditions in Saudi Arabia. Greater emphasis should be made through awareness campaigns and available media to raise the knowledge about implications related to prolonged exposure to sunlight., Competing Interests: None., (IJBT Copyright © 2021.)

Background: Cancer is emerging as a major global health-care system challenge with a growing burden worldwide. Due to the inconsistent cancer registry system in Saudi Arabia, the epidemiology of cancer is still dispersed in the country. Consequently, this review aimed to assemble the epidemiological metrics of cancer in Saudi Arabia in light of the available published data during the period from (2010-2019)., Methods: Published literature from Saudi Arabia relating to cancer incidence, prevalence, risk factors, and other epidemiological metrics were accessed through electronic search in Medline/PubMed, Cochrane, Scopus, Web of Knowledge, Google Scholar, and public database that meet the inclusion criteria. Relevant keywords were used during the electronic search about different types of cancers in Saudi Arabia. No filters were used during the electronic searches. Data were pooled and odds ratios (ORs) and 95% confidence interval (95%CI) were calculated. A random-effects meta-analysis was performed to assess the well-determined risk factors associated with different types of cancers., Results: The most common cancers in Saudi Arabia are breast, colorectal, prostate, brain, lymphoma, kidney and thyroid outnumbering respectively. Their prevalence rates and OR (95%CI) as follow: breast cancer 53% and 0.93 (0.84-1.00); colon-rectal cancer (CRC) 50.9% and 1.2 (0.81-1.77); prostate cancer 42.6% and 3.2 (0.88-31.11); brain/Central Nervous System cancer 9.6% and 2.3 (0.01-4.2); Hodgkin and non-Hodgkin's lymphoma 9.2% and 3.02 (1.48-6.17); kidney cancer 4.6% and 2.05 (1.61-2.61), and thyroid cancer 12.9% and 6.77 (2.34-19.53)., Conclusion: Within the diverse cancers reported from Saudi Arabia, the epidemiology of some cancers magnitude 3-fold in the latest years. This increase might be attributed to the changing in the Saudi population lifestyle (adopting western model), lack of cancer awareness, lack of screening & early detection programs, social barriers toward cancer investigations. Obesity, genetics, sedentary lifestyle, tobacco use, viral infection, and iodine & Vit-D deficiency represent the apparent cancer risk factors in Saudi Arabia., Competing Interests: Conflict of interest: The authors declared no competing interests. The authors had full responsibility for data collection, data interpretation, and writing of the report., (© 2020 the Author(s), licensee AIMS Press.)

Background: In recent years, there is an emerging increase in the prevalence of oral and oropharyngeal cancers (O-OPCs) across the Arabian Gulf Cooperation Council (GCC) countries. Consequently, this review aimed to explore the epidemiology and possible risk factors of O-OPCs in GCC countries., Methods: Data published after 2008 related to O-OPCs in GCC countries were obtained through electronic searches in Medline/PubMed, Scopus, Web of Science, EMBASE and Google Scholar. Keywords related to the association between O-OPCs metrics (epidemiology and risk factors) and GCC countries were used for electronic searches., Results: The overall prevalence of OPCs increased significantly over time (40-51%) in some countries (Saudi Arabia and Arab Emigrated) of the Gulf regions. The pooled risk factor was 3.4 (2.5 - 4.7). Among the risk factors, human papillomavirus and the use of smoke and smokeless tobacco revealed odds ratio (OR) 3.31 (3.13 - 4.5) and 0.60 (0.45 - 0.80) at 95% confidence interval (CI)., Conclusion: A positive correlation between factors like age, diet, hygiene, genetics, viral and bacterial infection, consumption of alcohol and tobacco products with OPC-MFC is suggested., Competing Interests: The authors declare that there is no conflict of interest., (Copyright 2020, Alqahtani et al.)