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Objective: To investigate c-Src, a non-receptor tyrosine kinase dysregulated in various cancer types including colon, breast, and pancreatic cancers, as a potential drug target for cancer therapy. Methods: Ligand-based pharmacophore modeling and 3D-QSAR analysis on a dataset of 34c-Src tyrosine kinase inhibitors were employed. The established pharmacophore model (DDRRR_1) features two hydrogen bond donor (D) and three aromatic ring (R) features, exhibiting favorable parameters (R2 = 0.926; Q2 = 0.895; F value = 47.9). Hypothesis validation, enrichment analysis, and contour plot analysis were conducted, followed by virtual screening of a PubChem database using the optimized pharmacophore model and filtering based on the Lipinski rule of five. Results: The most promising inhibitors underwent multistep molecular docking, density Functional Theory (DFT) analysis, ADMET assessments, molecular dynamics simulation, and PCA. CID_70144047 emerged as the most promising hit with all the above favorable properties. Conclusion: The study provides a comprehensive approach for identifying novel c-Src tyrosine kinase inhibitors, highlighting CID_70144047 as a promising leads with potential therapeutic applications in cancer treatment.

Nitrite monitoring serves as a fundamental practice for protecting public health, preserving environmental quality, ensuring food safety, maintaining industrial safety standards, and optimizing agricultural practices. Although many nitrite sensing methods have been recently developed, the quantification of nitrite remains challenging due to sensitivity and selectivity limitations. In this context, we present the fabrication of enzymeless iron oxide nanoparticle-modified zinc oxide nanorod (α-Fe2O3-ZnO NR) hybrid nanostructure-based nitrite sensor fabrication. The α-Fe2O3-ZnO NR hybrid nanostructure was synthesized using a two-step hydrothermal method and characterized in detail utilizing x-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). These analyses confirm the successful synthesis of an α-Fe2O3-ZnO NR hybrid nanostructure, highlighting its morphology, purity, crystallinity, and elemental constituents. The α-Fe2O3-ZnO NR hybrid nanostructure was used to modify the SPCE (screen-printed carbon electrode) for enzymeless nitrite sensor fabrication. The voltammetric methods (i.e., cyclic voltammetry (CV) and differential pulse voltammetry (DPV)) were employed to explore the electrochemical characteristics of α-Fe2O3-ZnO NR/SPCE sensors for nitrite. Upon examination of the sensor’s electrochemical behavior across a range of nitrite concentrations (0 to 500 µM), it is evident that the α-Fe2O3-ZnO NR hybrid nanostructure shows an increased response with increasing nitrite concentration. The sensor demonstrates a linear response to nitrite concentrations up to 400 µM, a remarkable sensitivity of 18.10 µA µM−1 cm−2, and a notably low detection threshold of 0.16 µM. Furthermore, its exceptional selectivity, stability, and reproducibility make it an ideal tool for accurately measuring nitrite levels in serum, yielding reliable outcomes. This advancement heralds a significant step forward in the field of environmental monitoring, offering a potent solution for the precise assessment of nitrite pollution.

Chronic liver disease caused by hepatitis B virus (HBV) remains an important health issue. Though there are effective HBV-polymerase inhibitors (e.g., lamivudine), their prolonged use leads to emergence of drug-resistant (polymerase mutant) strains. Several herbal formulations and phytochemicals have been therefore, reported as potential anti-HBV agents with no sign of resistance in experimental and clinical settings. In this study, we assessed the anti-HBV as well as hepatoprotective salutations of solanopubamine, a rare alkaloid isolated from S. schimperianum. In cultured HepG2.2.15 cells, solanopubamine showed marked anti-HBV activity in a time and dose-dependent manner. Solanopubamine (30 μM) efficiently inhibited HBsAg and HBeAg expressions by 66.5%, 70.5%, respectively as compared to 82.5% and 86.5% respective inhibition by lamivudine (2 μM) at day 5. Molecular docking analyses of solanopubamine revealed formations of stable complexes with lamivudine-sensitive as well as lamivudine-resistant polymerase through interactions of catalytic ‘YMDD/YIDD’ motif residues. Moreover, solanopubamine attenuated DCFH-induced oxidative and apoptotic damage and restored HepG2 cell viability by 28.5%, and downregulated caspase-3/7 activations by 33%. Further docking analyses of solanopubamine showed formation of stable complexes with caspase-3/7. Taken together, our data demonstrates promising anti-HBV and anti-hepatotoxic therapeutic potential of solanopubamine, and warrants further molecular and pharmacological studies.

Elevation in hyperglycemia-associated methylglyoxal level can trigger vascular endothelial cells oxidative stress and apoptosis. The present work assesses the cell proliferative, anti-oxidative and anti-apoptotic potential of Suaeda monoica derived four new terpenes: a norsesquaterpenol (normonisesquaterpenol), a monocyclic triterpenoid (suaedanortriterpene dione), an aromatic monoterpenic ester and a labdane-type norditerpenic xyloside as well as two new phenols: an alkylated β-naphthol and a β-methoxy naphthalene in cultured human umbilical vein endothelial cells (HUVEC). Of these, suaedanortriterpenedione (53.7%), normonisesquaterpenol (51.4%) and norditerpenic xyloside (48%) showed the most promising cell proliferative activities compared to others. Moreover, normonisesquaterpenol, norditerpenic xyloside and suaedanortriterpenedione efficiently reversed the oxidative and apoptotic cell damage via downregulation of capase-3/7 by 44.3%, 42.2% and 39.4%, respectively against dichlorofluorescin, whereas by 46.2%, 43.5% and 42.5%, respectively against methylglyoxal. Aminoguanidine, the reference drug inhibited caspase-3/7 activity by 56.2% and 54.7% through attenuation of dichlorofluorescin and methylglyoxal, respectively. Further in silico molecular docking analysis revealed formation of stable complexes between the tested compounds and caspase-3/7. Conclusively, we for the first time demonstrate the growth stimulatory, anti-oxidative and anti-apoptotic salutations of S. monoica derived novel compounds in human endothelial cells. This warrants their further assessment as vascular cell protective and rejuvenating therapeutics, especially in hyperglycemic conditions.

Abstract Ethylene plays a crucial role throughout the life cycle of plants under optimal and stressful environments. The present study reports the involvement of exogenously sourced ethylene (as ethephon; 2-chloroethyl phosphonic acid) in the protection of the photosynthetic activity from glucose (Glu) sensitivity through its influence on the antioxidant system for adaptation of wheat (Triticum aestivum L.) plants under salt stress. Ten-day-old plants were subjected to control and 100 mM NaCl and treated with 200 µl L−1 ethephon on foliage at 20 days after seed sowing individually or in combination with 6% Glu. Plants receiving ethylene exhibited higher growth and photosynthesis through reduced Glu sensitivity in the presence of salt stress. Moreover, ethylene-induced reduced glutathione (GSH) production resulted in increased psbA and psbB expression to protect PSII activity and photosynthesis under salt stress. The use of buthionine sulfoximine (BSO), GSH biosynthesis inhibitor, substantiated the involvement of ethylene-induced GSH in the reversal of Glu-mediated photosynthetic repression in salt-stressed plants. It was suggested that ethylene increased the utilization of Glu under salt stress through its influence on photosynthetic potential and sink strength and reduced the Glu-mediated repression of photosynthesis.

Abstract Conserved telomere maintenance component 1 (CTC1) is an important component of the CST (CTC1-STN1-TEN1) complex, involved in maintaining the stability of telomeric DNA. Several non-synonymous single-nucleotide polymorphisms (nsSNPs) in CTC1 have been reported to cause Coats plus syndrome and Dyskeratosis congenital diseases. Here, we have performed sequence and structure analyses of nsSNPs of CTC1 using state-of-the-art computational methods. The structure-based study focuses on the C-terminal OB-fold region of CTC1. There are 11 pathogenic mutations identified, and detailed structural analyses were performed. These mutations cause a significant disruption of noncovalent interactions, which may be a possible reason for CTC1 instability and consequent diseases. To see the impact of such mutations on the protein conformation, all-atom molecular dynamics (MD) simulations of CTC1-wild-type (WT) and two of the selected mutations, R806C and R806L for 200 ns, were carried out. A significant conformational change in the structure of the R806C mutant was observed. This study provides a valuable direction to understand the molecular basis of CTC1 dysfunction in disease progression, including Coats plus syndrome.

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus capable of causing coronavirus disease 2019 (COVID-19), was declared as a global public health emergency on January 30, 2020, by the World Health Organization. In this devastating situation, precautionary measures, early diagnosis, and repurposed drugs appear to be timely and decisive factors by which to handle this problem until the discovery of an effective, dedicated vaccine or medicine is made. Currently, some researchers and clinicians have claimed evidence exists in favor of the use of some antimalarial drugs (chloroquine, hydroxychloroquine) antiviral drugs (remdesivir, favipiravir, lopinavir, ritonavir, umifenovir) vitamins, traditional Chinese medicines, and herbal medicines against SARS-CoV-2 infection. Based on the available literature, this review article sought to highlight the current understanding of the origin, transmission, diagnosis, precautionary measures, infection and drug action mechanisms, therapeutic role, and toxicities of targeted drugs for the prevention and cure of COVID-19. This review may be useful for developing further strategies as a blueprint and understanding the mentioned drugs’ mechanisms to elucidate the possible target of action by which to successfully freeze the replication of the SARS-CoV-2 virus.

Context Traditionally, Inula racemosa Hook. f. (Asteraceae) has been reported to be effective in cancer treatment which motivated the authors to explore the plant for novel anticancer compounds. Objective To isolate and characterize new cytotoxic phytoconstituents from I. racemosa roots. Materials and methods The column chromatography of I. racemosa ethyl acetate extract furnished a novel sesquiterpene lactone whose structure was established by NMR (1D/2D), ES-MS and its cytotoxic properties were assessed on HeLa, MDAMB-231, and A549 cell lines using MTT and LDH (lactate dehydrogenase) assays. Further, morphological changes were analyzed by flow cytometry, mitochondrial membrane potential, AO-EtBr dual staining, and comet assay. Molecular docking and simulation were performed using Glide and Desmond softwares, respectively, to validate the mechanism of action. Results The isolated compound was identified as racemolactone I (compound 1). Amongst the cell lines tested, considerable changes were observed in HeLa cells. Compound 1 (IC50 = 0.9 µg/mL) significantly decreased cell viability (82%) concomitantly with high LDH release (76%) at 15 µg/mL. Diverse morphological alterations along with significant increase (9.23%) in apoptotic cells and decrease in viable cells were observed. AO-EtBr dual staining also confirmed the presence of 20% apoptotic cells. A gradual decrease in mitochondrial membrane potential was observed. HeLa cells showed significantly increased comet tail length (48.4 µm), indicating broken DNA strands. In silico studies exhibited that compound 1 binds to the active site of Polo-like kinase-1 and forms a stable complex. Conclusions Racemolactone I was identified as potential anticancer agent, which can further be confirmed by in vivo investigations.

AbstractIntroduction Alzheimer's disease (AD), the most predominant cause of dementia, has evolved tremendously with an escalating frequency, mainly affecting the elderly population. An effective means of delaying, preventing, or treating AD is yet to be achieved. The failure rate of dementia drug trials has been relatively higher than in other disease-related clinical trials. Hence, multi-targeted therapeutic approaches are gaining attention in pharmacological developments.Aims As an extension of our earlier reports, we have performed docking and molecular dynamic (MD) simulation studies for the same 13 potential ligands against beta-site APP cleaving enzyme 1 (BACE-1) and γ-secretase as a therapeutic target for AD. The In-silico screening of these ligands as potential inhibitors of BACE-1 and γ-secretase was performed using AutoDock enabled PyRx v-0.8. The protein-ligand interactions were analyzed in Discovery Studio 2020 (BIOVIA). The stability of the most promising ligand against BACE-1 and γ-secretase was evaluated by MD simulation using Desmond-2018 (Schrodinger, LLC, NY, USA).Results The computational screening revealed that the docking energy values for each of the ligands against both the target enzymes were in the range of −7.0 to −10.1 kcal/mol. Among the 13 ligands, 8 (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed binding energies of ≤−8 kcal/mol against BACE-1 and γ-secretase. For the selected enzyme targets, BACE-1 and γ-secretase, 6Z5 displayed the lowest binding energy of −10.1 and −9.8 kcal/mol, respectively. The MD simulation study confirmed the stability of BACE-6Z5 and γ-secretase-6Z5 complexes and highlighted the formation of a stable complex between 6Z5 and target enzymes.Conclusion The virtual screening, molecular docking, and molecular dynamics simulation studies revealed the potential of these multi-enzyme targeted ligands. Among the studied ligands, 6Z5 seems to have the best binding potential and forms a stable complex with BACE-1 and γ-secretase. We recommend the synthesis of 6Z5 for future in-vitro and in-vivo studies.

Increasing incidence of multi-drug resistant bacterial pathogens, especially in clinical settings, has been developed into a grave health situation. The drug resistance problem demands the necessity for alternative unique therapeutic policies. One such tactic is targeting the quorum sensing (QS) controlled virulence and biofilm production. In this study, we evaluated a marine steroid Siphonocholin (Syph-1) isolated from Siphonochalina siphonella against Chromobacterium violaceum (CV) 12472, Pseudomonas aeruginosa (PAO1), Methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii (BAA) for biofilm and pellicle formation inhibition, and anti-QS property. MIC of Syph-1 against MRSA, CV, PAO1 was found as 64 µg/mL and 256 µg/mL against BAA. At selected sub-MICs, Syph-1 significantly (P ≤ 0.05) decreased the production of QS regulated virulence functions of CV12472 (violacein) and PAO1 [elastase, total protease, pyocyanin, chitinase, exopolysaccharides, and swarming motility]. The Syph-1 significantly decreased (p = 0.005) biofilm formation ability of tested bacterial pathogens, at sub-MIC level (PAO1 > MRSA > CV > BAA) and pellicle formation in A. baumannii (at 128 µg/mL). Molecular docking and simulation results indicated that Siph-1 was bound at the active site of BfmR N-terminal domain with high affinity. This study highlights the anti-QS and anti-biofilm activity of Syph-1 against bacterial pathogens reflecting its broad spectrum anti-infective potential.

Abstract The current study was carried out on dominant fish Oreochromis niloticus and water collected from the polluted Yamuna River, Agra, India. The heavy metals in water, recorded as follows: Fe > Mn > Zn > Cu > Ni > Cr > Cd and all were found to be above the prescribed limits. According to metal pollution index, exposed muscle (49.86), kidney (47.68) and liver (45.26) have been recorded to have higher bioaccumulation. The blood biochemical analysis of exposed O. niloticus indicated significant increase in activities of aspartate aminotransferase (+ 343.5%), alkaline phosphatase (+ 673.6%), alanine aminotransferase (+ 309.1%), and creatinine (+ 494.3%) over the reference. However, a significant decrease in albumin (A): globulins (G) ratio (− 87.86%) was observed. Similarly, the exposed fish also showed significant increase in total leucocyte count (+ 121%), differential leucocyte count, respiratory burst (+ 1175%), and nitric oxide synthase (+ 420%). The histological examination of liver and kidney showed tissue injury. Moreover, micronuclei (0.95%), kidney shaped nuclei (1.2%), and lobed nuclei (0.6%) along with DNA damage in the form of mean tail length in the liver (20.7 µm) and kidney (16.5 µm) was observed in the exposed O. niloticus. Potential health risk assessments based on estimated daily intake, target hazard quotient, hazard index, and target cancer risk indicated health risks associated with the consumption of these contaminated fishes. In conclusion, the present study showed that exposure to heavy metals contaminated water can alter immunological response; induce histopathological alterations and DNA damage in the studied fish. The consumption of this contaminated water or fish could have serious impact on human health.

Active herbal or natural compounds have high chemical diversity and specificity than synthetic drugs. Recently, we have validated the hypoglycemic salutation of Oncocalyx glabratus in rodent model, and demonstrated the activation of PPARα/γ by its newly ioslated flavan derivative Oncoglabrinol C (5,3′-Dihydroxyflavan 7-4′-O-digallate) in liver cells (HepG2). Here we evaluated the potential of Oncoglabrinol C against Dichlorofluorescin (DCFH) and Methylglyoxal (MGO) induced endothelial cells (HUVEC) oxidative and apoptotic damage, including activation of PXR-mediated hepatic CYP3A4. Our MTT assay showed protection of ~57% and ~63.5% HUVEC cells by 10 and 20 μg/ml doses of Oncoglabrinol C, respectively through attenuating DCFH triggered free-radicals. Also, the two doses effectively protected ~53% and ~65.5% cells, respectively by reversing MGO toxicity. In DCFH and MGO treated cells, Oncoglabrinol C (20 μg/ml) effectively downregulated caspase 3/7 activity by ~33% and ~43.5%, respectively. Moreover, in reporter gene (dual-luciferase) assay, Oncoglabrinol C (20 μg/ml) moderately activated hepatic CYP3A4. Molecular docking of Oncoglabrinol C indicated its strong interactions with cellular caspase 3/7, PPARα/γ and PXR proteins, which supported its anti-apoptotic (antagonistic) as well as pro-hypoglycemic and PXR/CYP activating (agonistic) activities. Taken together, our findings demonstrated the potential of Oncoglabrinol C in reversing the endothelial oxidative and apoptotic damage as well as in the activation of hepatic CYP3A4. This warrants further evaluations of Oncoglabrinol C and related compounds towards developing effective and safe drugs against diabetes associated cardiovascular disorders.

Polyphenols has attained pronounced attention due to their beneficial values of health and found to prevent several chronic diseases. Here, we elucidated binding mechanism between frequently consumed polyphenol “tea catechin” and milk protein bovine beta-lactoglobulin (β-Lg). We investigated the conformational changes of β-Lg due to interaction with catechin using spectroscopic and in silico studies. Fluorescence quenching data (Stern-Volmer quenching constant) revealed that β-Lg interacted with catechin via dynamic quenching. Thermodynamic data revealed that the interaction between β-Lg and catechin is endothermic and spontaneously interacted mainly through hydrophobic interactions. The UV-Vis absorption and far-UV circular dichroism (CD) spectroscopy exhibited that the tertiary as well as secondary structure of β-Lg distorted after interaction with catechin. Molecular docking and simulation studies also confirm that catechin binds at the central cavity of β-Lg with high affinity (~105 M−1) and hydrophobic interactions play significant role in the formation of a stable β-Lg-catechin complex. Keywords: Polyphenol, Catechin, Beta-Lactoglobulin, Protein and proteinligand, interaction

Myrrh is an oleo-gum-resin produced in the stem of Commiphora myrrha (Burseraceae) and used for centuries for different medicinal purposes. The present work was designed to evaluate the cytotoxic and antioxidant properties of seventeen myrrh samples (S1–S17) obtained from different retail markets of Saudi Arabia and Yemen regions, along with two furanosesquiterpenoids (CM-1 and CM-2). The cytotoxicity assay was carried out on HepG2, MCF-7 and HUVEC cell lines. S2, S5, S10, S12, CM-1, CM-2 exhibited significant cytotoxicity against HepG2/MCF-7 cell lines [IC50 (μg/mL): 13.8/10, 14/10, 14.5/11.3, 18/13.2, 9.5/12.5, 10/15.8, respectively) compare to vinblastin (IC50 (μg/mL): 2/2.5) whereas the remaining samples were found as mild active or inactive. The antioxidant properties of the samples were tested by β-carotene-bleaching and DPPH free radical scavenging methods where the samples S8 (1000 μg/mL) exhibited the highest β-carotene bleaching (76.2%) and free radical scavenging activity (79.8%). The HPTLC analysis was performed on NP-HPTLC plate using toluene, chloroform and glacial acetic acid as mobile phase in ratio of 7:2.9:0.1 (V/V/V). The validated HPTLC method furnished sharp, intense and compact peaks of CM-1 and CM-2 at Rf = 0.39 and 0.44, respectively. The highest/lowest content of CM-1 and CM-2 were found in S12/S5 and S5/S17, respectively. The molecular docking studies of CM-1 and CM-2 with human DNA topoisomerase IIα have shown that both the compounds were bound the active sites of the respective enzymes. Molecular dynamics simulation studies further confirmed that the interactions of CM-1 and CM-2 with topoisomerase were stable in nature. This study will help us in selection of appropriate myrrh sample for the greater benefits of the population in the Middle East region. Keywords: Myrrh, Furanosesquiterpenoids, Cytotoxicity, Antioxidant, HPTLC, Molecular docking

The present study demonstrates the miquelianin or quercetin 3-O-glucuronide (compound 1) isolated from aerial parts of Euphorbia schimperi exhibited significant results for antioxidant and antidiabetic potential. The compound 1 along with kaempferol 3-O-glucuronide (compound 2) and quercetin 3-O-rhamnoside (compound 3) isolated from the same source were quantified by validated HPTLC method. Antioxidant activity was determined by chemical means in terms of ABTS radical cation and DPPH radical scavenging activity. Compound 1 showed significant scavenging activity in both ABTS and DPPH assays as compared to standard BHA. In ABTS method IC50 values of compound 1 and standard BHA is found to be 58.90 ± 3.40 µg/mL and 28.70 ± 5.20 µg/mL respectively while in DPPH assay IC50 values of Compound 1 and standard BHA is 47.20 ± 4.90 µg/mL and 34.50 ± 6.20 µg/mL respectively. Antidiabetic effect was studied through α-amylase and α-glucosidase inhibitory activity. The mechanistic approach through molecular modelling also support the strong binding sites of compound 1 which showed significant α-amylase and α-glucosidase inhibitory activities with IC50 values 128.34 ± 12.30 and 89.20 ± 9.20 µg/mL respectively as compared to acarbose 64.20 ± 5.60 and 52.40 ± 4.60 µg/mL respectively. The results of validated RP-HPTLC analyses revealed the concentration of compound 1 found to be 16.39 µg/mg and for compound 2 and compound 3 as 3.92 and 14.98 µg/mg of dried extract, respectively. Keywords: Miquelianin, Antidiabetic, Antioxidant, HPTLC, Quantification

Despite high anti-HBV efficacies, while the nucleoside analogs (e.g., lamivudine) lead to the emergence of drug-resistance, interferons (e.g., IFN-α causes adverse side-effects. Comparatively, various natural or plant products have shown similar or even better efficacy. Hence, new antiviral strategies must focus not only on synthetic molecules but also on potential natural compounds. In this report, we have combined the in vitro cell culture and in silico molecular docking methods to assess the novel anti-HBV activity and delineate the inhibitory mechanism of selected plant-derived pure compounds of different classes. Of the tested (2.5-50 μg/ml) twelve non-cytotoxic compounds, ten (10 μg/ml) were found to maximally inhibit HBsAg production at day 5. Compared to quercetin (73%), baccatin III (71%), psoralen (67%), embelin (65%), menisdaurin (64%) and azadirachtin (62%) that showed high inhibition of HBeAg synthesis, lupeol (52%), rutin (47%), β-sitosterol (43%) and hesperidin (41%) had moderate efficacies against HBV replication. Further assessment of quercetin in combination with the highly active compounds, enhanced its anti-HBV activity up to 10%. Being the most important drug target, a 3-D structure of HBV polymerase (Pol/RT) was modeled and docked with the active compounds, including lamivudine as standard. Docking of lamivudine indicated strong interaction with the modeled HBV Pol active-site residues that formed stable complex (∆G = −5.2 kcal/mol). Similarly, all the docked antiviral compounds formed very stable complexes with HBV Pol (∆G = −6.1 to −9.3 kcal/mol). Taken together, our data suggest the anti-HBV potential of the tested natural compounds as novel viral Pol/RT inhibitors. : Keywords, Hepatitis B virus, Antiviral, HBV polymerase, Natural compounds, Molecular docking, Pol/RT inhibitors

The oleo-gum-resin of Commiphora myrrha is one of the most known natural antimicrobial agents, mainly due to its furanosesquiterpenes. A validated method based on sample extraction by matrix solid-phase dispersion (MSPD) followed by high-performance column chromatography (HPLC) determination is applied to analyze two furanosesquiterpenoids, namely, 2-methoxyfuranodiene (CM-1) and 2-acetoxyfuranodiene (CM-2), existing in C. myrrha. The trial parameters that controlled the extraction prospective were studied and optimized. These include the nature of dispersant, mass ratio of sample to the dispersant, and the volume of elution solvent. A comparative antimicrobial study that used the Minimum Inhibitory Concentration Assay (MIC) method between MSPD, ultrasonic, and Soxhlet of myrrh extracts was also conducted. The optimal MSPD parameters used were (i) 15 mL of methanol applied as elution solvent; (ii) silica gel/sample mass at a 2 : 1 ratio; and (iii) a dispersing sorbent selected as silica gel. Technique retrievals were regulated from 96.87% to 100.54%, with relative standard deviations (RSDs) from 1.24% to 4.45%. Commiphora myrrha-MSPD (CM-MSPD) extract showed the highest antibacterial activity against gram-positive and gram-negative bacteria (156.25 μg/mL and 312.5 μg/mL, respectively) and antifungal activity (156.25 μg/mL). Yields acquired through the MSPD technique were larger than yields from other extraction techniques (sonication and traditional reflux extraction methods) with less consumption of time, sample, and solvent. The mode of antibacterial action of CM-1 and CM-2 was elucidated by performing molecular docking with bacterial DNA gyrase. Both the compounds interacted with key residues of DNA gyrase.

The human CST complex (CTC1–STN1–TEN1) is associated with telomere functions including genome stability. We have systemically analyzed the sequence of STN and performed structure analysis to establish its association with the Coat Plus (CP) syndrome. Many deleterious non-synonymous SNPs have been identified and subjected for structure analysis to find their pathogenic association and aggregation propensity. A 100-ns all-atom molecular dynamics simulation of WT, R135T, and D157Y structures revealed significant conformational changes in the case of mutants. Changes in hydrogen bonds, secondary structure, and principal component analysis further support the structural basis of STN1 dysfunction in such mutations. Free energy landscape analysis revealed the presence of multiple energy minima, suggesting that R135T and D157Y mutations destabilize and alter the conformational dynamics of STN1 and thus may be associated with the CP syndrome. Our study provides a valuable direction to understand the molecular basis of CP syndrome and offer a newer therapeutics approach to address CP syndrome.

Parthenolide, a strong cytotoxic compound found in different parts of Tarchonanthus camphoratus which motivated the authors to develop an optimized microwave-assisted extraction (MEA) method using Box–Behnken design (BBD) for efficient extraction of parthenolide from the stem of T. camphoratus and its validation by high-performance thin-layer chromatography (HPTLC) and cytotoxic analysis. The optimized parameters for microwave extraction were determined as: 51.5 °C extraction temperature, 50.8 min extraction time, and 211 W microwave power. A quadratic polynomial model was found the most suitable model with R2 of 0.9989 and coefficient of variation (CV) of 0.2898%. The high values of adjusted R2 (0.9974), predicted R2 (0.9945), and signal-to-noise ratio (74.23) indicated a good correlation and adequate signal, respectively. HPTLC analyzed the parthenolide (Rf = 0.16) content in T. camphoratus methanol extract (TCME) at λmax = 575 nm and found it as 0.9273% ± 0.0487% w/w, which was a higher than expected yield (0.9157% w/w). The TCME exhibited good cytotoxicity against HepG2 and MCF-7 cell lines (IC50 = 30.87 and 35.41 µg/mL, respectively), which further supported our findings of high parthenolide content in TCME. This optimized MAE method can be further applied to efficiently extract parthenolide from marketed herbal supplements containing different Tarconanthus species.

A new dimeric sesquiterpene named disesquicin (compound 1) was isolated from Inula racemosa roots by normal-phase MPLC (Medium Pressure Liquid Chromatography), and its structure was established by using extensive spectral analysis. Compound 1, when tested on different human cancer cell lines, showed marked cytotoxic activity (IC50 (µg/mL): 5.99 (MDA-MB), 9.10 (HeLa), and 12.47 (A549)). Docking study revealed that it binds at the catalytic domain of PLK-1 and interacts with catalytic site residues Leu59, Gly60, Lys61, Gly62, Cys67, Ala80, Lys82, Leu130, Arg136, Ser137, Leu139, Glu140, Lys178, Gly180, Asn181, Phe183, and Asp194. The binding of compound 1 to PLK-1 is spontaneous in nature as evident by a free energy of—8.930 kcal mol−1, corresponding to a binding affinity of 3.54 × 106 M−1. Results showed that compound 1 exhibited cytotoxic potential that was further confirmed by in vivo investigations.

Aging represents a significant biological process having strong associations with cancer, diabetes, and neurodegenerative and cardiovascular disorders, which leads to progressive loss of cellular functions and viability. Astonishingly, age-related disorders share several genetic and molecular mechanisms with the normal aging process. Over the last three decades, budding yeast Saccharomyces cerevisiae has emerged as a powerful yet simple model organism for aging research. Genetic approaches using yeast RLS have led to the identification of hundreds of genes impacting lifespan in higher eukaryotes. Numerous interventions to extend yeast lifespan showed an analogous outcome in multi-cellular eukaryotes like fruit flies, nematodes, rodents, and humans. We collected and analyzed a multitude of observations from published literature and provide the contribution of yeast in the understanding of aging hallmarks most applicable to humans. Here, we discuss key pathways and molecular mechanisms that underpin the evolutionarily conserved aging process and summarize the current understanding and clinical applicability of its trajectories. Gathering critical information on aging biology would pave the way for future investigation targeted at the discovery of aging interventions.

Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC50 values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation.

Cancer and the associated secondary bacterial infections are leading cause of mortality, due to the paucity of effective drugs. Here, we have synthesized silver nanoparticles (AgNPs) from organic resource and confirmed their anti-cancer and anti-microbial potentials. Microwave irradiation method was employed to synthesize AgNPs using Pandanus odorifer leaf extract. Anti-cancer potential of AgNPs was evaluated by scratch assay on the monolayer of rat basophilic leukemia (RBL) cells, indicating that the synthesized AgNPs inhibit the migration of RBL cells. The synthesized AgNPs showed MIC value of 4–16 μg/mL against both Gram +ve and Gram -ve bacterial strains, exhibiting the anti-microbial potential. Biofilm inhibition was recorded at sub-MIC values against Gram +ve and Gram -ve bacterial strains. Violacein and alginate productions were reduced by 89.6 and 75.6%, respectively at 4 and 8 μg/mL of AgNPs, suggesting anti-quorum sensing activity. Exopolysaccharide production was decreased by 61–79 and 84% for Gram -ve and Gram +ve pathogens respectively. Flagellar driven swarming mobility was also reduced significantly. Furthermore, In vivo study confirmed their tolerability in mice, indicating their clinical perspective. Collective, we claim that the synthesized AgNPs have anti-metastasis as well as anti-microbial activities. Hence, this can be further tested for therapeutic options to treat cancer and secondary bacterial infections.

Microtubule affinity-regulating kinase (MARK4) plays a key role in Alzheimer’s disease (AD) development as its overexpression is directly linked to increased tau phosphorylation. MARK4 is a potential drug target of AD and is thus its structural features are employed in the development of new therapeutic molecules. Donepezil (DP) and rivastigmine tartrate (RT) are acetylcholinesterase (AChE) inhibitors and are used to treat symptomatic patients of mild to moderate AD. In keeping with the therapeutic implications of DP and RT in AD, we performed binding studies of these drugs with the MARK4. Both DP and RT bound to MARK4 with a binding constant (K) of 107 M−1. The temperature dependency of binding parameters revealed MARK−DP complex to be guided by static mode while MARK−RT complex to be guided by both static and dynamic quenching. Both drugs inhibited MARK4 with IC50 values of 5.3 μM (DP) and 6.74 μM (RT). The evaluation of associated enthalpy change (ΔH) and entropy change (ΔS) implied the complex formation to be driven by hydrogen bonding making it seemingly strong and specific. Isothermal titration calorimetry further advocated a spontaneous binding. In vitro observations were further complemented by the calculation of binding free energy by molecular docking and interactions with the functionally-important residues of the active site pocket of MARK4. This study signifies the implications of AChE inhibitors, RT, and DP in Alzheimer’s therapy targeting MARK4.

Studying drug−protein interactions has gained significant attention lately, and this is because the majority of drugs interact with proteins, thereby altering their structure and, moreover, their functionality. Rivastigmine tartrate (RT) is a drug that is in use for mild to moderate Alzheimer therapy. This study was targeted to characterize the interaction between human transferrin (hTf) and RT by employing spectroscopy, isothermal titration calorimetry (ITC), and molecular docking studies. Experimental results of fluorescence quenching of hTf induced by RT implied the formation of a static complex between hTf and RT. Further elucidation of the observed fluorescence data retorting Stern−Volmer and modified Stern−Volmer resulted in binding constants for hTf−RT complex of the order 104 M−1 over the studied temperatures. Thermodynamic parameters of hTf−RT interaction were elucidated further by employing these obtained binding constant values. It was quite evident from obtained thermodynamic attributes that RT spontaneously binds to hTf with a postulated existence of hydrogen bonding or Van der Waals forces. Further, Circular dichroism spectroscopy (CD) also confirmed RT−hTf complex formation owing to upward movement of CD spectra in the presence of RT. ITC profiles advocated the existence of reaction to be spontaneous. Moreover, molecular docking further revealed that the important residues play a pivotal role in RT−hTf interaction. The findings of this study can be of a significant benefit to the drug-designing industry in this disease-prone era.

Three new transition metal complexes, Cu(II) 1, Co(II) 2, and Zn(II) 3 with ligand “bimnap” derived from 1-methyl-2-aminobenzimidazole and 2-hydroxynapthaldehyde were synthesized and characterized. The structure of the ligand was determined by single X-ray crystallography. All the three complexes, 1–3, were examined for the mode of interaction with biomolecule viz., calf thymus-DNA (CT-DNA) using various spectroscopic methods. The nuclease activity was performed against pBR322 DNA that exhibited concentration-dependent degradation of the nucleic acid. The mechanism of DNA cleavage was studied by the electrophoretic pattern in the presence of the radical scavengers. Also, the complexes 1–3 were analyzed for groove binding affinity. Moreover, in vitro cytotoxicities of the complexes 1–3 were tested against the five human cancer cell lines, i.e., HeLa, SK-MEL-1, HepG2, HT108, and MDA-MB 231. Also, the cell adhesion and migration properties upon treatment of cell lines with complexes 1–3, and consequently, their cell death pathway via apoptosis and necrosis were analyzed. Further, complexes 1–3 were studied in vivo for their toxicities and tolerabilities in mice. In sum, the complexes 1–3 showed merits of an effective anticancer agent in cell lines–based study while minor side effects were observed in vivo.