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Neuroprotective potential of Marsilea quadrifolia Linn against monosodium glutamate-induced excitotoxicity in rats
No full textBackground: Excitotoxicity is a condition in which neurons are damaged/injured by the over-activation of glutamate receptors. Excitotoxins play a crucial part in the progression of several neurological diseases. Marsilea quadrifolia Linn (M. quadrifolia) is a very popular aquatic medicinal plant that has been utilised for a variety of therapeutic benefits since ancient times. Its chemical composition is diverse and includes phenolic compounds, tannins, saponins, flavonoids, steroids, terpenoids, alkaloids, carbohydrates and several others that possess antioxidant properties. Objective: The objective of the present study was to investigate the neuroprotective potential of M. quadrifolia against monosodium glutamate (MSG)-induced excitotoxicity in rats. Methods: A high-performance thin-layer chromatography (HPTLC) analysis of chloroform extract of M. quadrifolia (CEMQ) was conducted to identify the major constituents. Further, the in silico docking analysis was carried out on selected ligands. To confirm CEMQ's neuroprotective effects, the locomotor activity, non-spatial memory, and learning were assessed. Results and discussion: The present study confirmed that CMEQ contains quercetin and its derivatives in large. The in-silico findings indicated that quercetin has a better binding affinity (-7.9 kcal/mol) towards the protein target 5EWJ. Animals treated with MSG had 1) a greater reduction in the locomotor score and impairment in memory and learning 2) a greater increase in the blood levels of calcium and sodium and 3) neuronal disorganization, along with cerebral edema and neuronal degeneration in the brain tissues as compared to normal control animals. The changes were however, significantly improved in animals which received standard drug memantine (20 mg/kg) and CEMQ (200 and 400 mg/kg) as compared to the negative control. It is plausible that the changes seen with CEMQ may be attributed to the N-methyl-D-aspartate (NMDA) antagonistic properties. Conclusion: Overall, this study indicated that M. quadrifolia ameliorated MSG-induced neurotoxicity. Future investigations are required to explore the neuroprotective mechanism of M. quadrifolia and its active constituents, which will provide exciting insights in the therapeutic management of neurological disorders
Targeting the crosstalk of epigenetic modifications and immune evasion in nasopharyngeal cancer
No full textNasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer that is highly associated with Epstein-Barr virus (EBV) infection. EBV acts as an epigenetic driver in NPC tumorigenesis, reprogramming the viral and host epigenomes to regulate viral latent gene expression, and creating an environment conducive to the malignant transformation of nasopharyngeal epithelial cells. Targeting epigenetic mechanisms in pre-clinical studies has been shown promise in eradicating tumours and overcoming immune resistance in some solid tumours. However, its efficacy in NPC remains inclusive due to the complex nature of this cancer. In this review, we provide an updated understanding of the roles of epigenetic factors in regulating EBV latent gene expression and promoting NPC progression. We also explore the crosstalk between epigenetic mechanisms and immune evasion in NPC. Particularly, we discuss the potential roles of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors in reversing immune suppression and augmenting antitumour immunity. Furthermore, we highlight the advantages of combining epigenetic therapy and immune checkpoint inhibitor to reverse immune resistance and improve clinical outcomes. Epigenetic drugs have the potential to modulate both epigenetic mediators and immune factors involved in NPC. However, further research is needed to fully comprehend the diverse range of epigenetic modifications in NPC. A deeper understanding of the crosstalk between epigenetic mechanisms and immune evasion during NPC progression is crucial for the development of more effective treatments for this challenging disease
The Design, Synthesis, and Evaluation of Diaminopimelic Acid Derivatives as Potential dapF Inhibitors Preventing Lysine Biosynthesis for Antibacterial Activity
Get PDFWe created thiazole and oxazole analogues of diaminopimelic acid (DAP) by replacing its carboxyl groups and substituting sulphur for the central carbon atom. Toxicity, ADME, molecular docking, and in vitro antimicrobial studies of the synthesized compounds were carried out. These compounds displayed significant antibacterial efficacy, with MICs of 70–80 µg/mL against all tested bacteria. Comparative values of the MIC, MBC, and ZOI of the synthesized compound were noticed when compared with ciprofloxacin. At 200 µg/mL, thio-DAP (1) had a ZOI of 22.67 ± 0.58, while ciprofloxacin had a ZOI of 23.67 ± 0.58. To synthesize thio-DAP (1) and oxa-DAP (2), l-cysteine was used as a precursor for the L-stereocenter (l-cysteine), which is recognized by the dapF enzyme’s active site and selectively binds to the ligand’s L-stereocenter. Docking studies of these compounds were carried out using the programme version 11.5 Schrodinger to reveal the hydrophobic and hydrophilic properties of these complexes. The docking scores of compounds one and two were −9.823 and −10.098 kcal/mol, respectively, as compared with LL-DAP (−9.426 kcal/mol.). This suggests that compounds one and two interact more precisely with dapF than LL-DAP. Chemicals one and two were synthesized via the SBDD (structure-based drug design) approach and these act as inhibitors of the dapF in the lysine pathway of bacterial cell wall synthesis
The increasing importance of novel deep eutectic solvents as potential effective antimicrobials and other medicinal properties
No full textWith the rise of antibiotic resistance globally, coupled with evolving and emerging infectious diseases, there is an urgent need for the development of novel antimicrobials. Deep eutectic solvents (DES) are a new generation of eutectic mixtures that depict promising attributes with several biological implications. DES exhibit unique properties such as low toxicity, biodegradability, and high thermal stability. Herein, the antimicrobial properties of DES and their mechanisms of action against a range of microorganisms, including bacteria, amoebae, fungi, viruses, and anti-cancer properties are reviewed. Overall, DES represent a promising class of novel antimicrobial agents as well as possessing other important biological attributes, however, future studies on DES are needed to investigate their underlying antimicrobial mechanism, as well as their in vivo effects, for use in the clinic and public at large
Exploring the antibacterial mechanisms of chemically characterized essential oils from leaves and buds of Syzygium aromaticum (L.) Merr. et Perry against Staphylococcus aureus and Pseudomonas aeruginosa
No full textSyzygium aromaticum (L.) Merr. et Perry is a medicinal plant extensively used in international pharmacopeia to treat different ailments, including infectious diseases. In this study, we designed to determine the chemical constituents of S. aromaticum essential oils extracted from leaves (CEOL) and floral buds (CEOB) and their antibacterial mechanism of action against S. aureus and P. aeruginosa. The volatile components from CEOL and CEOB were detected using gas chromatography coupled to a mass spectrometer (GC/MS). The results indicated that eugenol was the major component for both CEOL (65.75%) and CEOB (74.03%). The antibacterial findings demonstrated the potent antibacterial activity of CEOL and CEOB. These oils exhibited significant zones of inhibition against all tested bacteria, including S. aureus ATCC 29213, K. aerogenes ATCC 13048, P. aeruginosa ATCC 27853, and E. coli ATCC 25922, surpassing the effects of antibiotics. Additionally, they displayed low minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs), indicating their bactericidal nature (MBC/MIC <4.0). Time-kill kinetics revealed that CEOB was more effective than CEOL at sub-MIC doses, eradicating S. aureus within 12 h and P. aeruginosa within 12–24 h. The cell membrane permeability test demonstrated that CEOL and CEOB treatment affected the relative conductivity of S. aureus and P. aeruginosa at both MIC and sub-MIC concentrations, indicating disruption of the bacterial membrane and influencing their growth and viability. Furthermore, the cell membrane integrity test showed that the addition of CEOL and CEOB to S. aureus and P. aeruginosa cultures led to significant protein release from the bacterial cells. The results of the anti-biofilm activity test confirmed the efficacy of S. aromaticum EOs, particularly CEOB, as potent anti-biofilm agents, suggesting its potential effect on inhibiting quorum sensing. Scanning electron microscope (SEM) microscopy further revealed significant alterations in bacterial cells treated with CEOB essential oil, including damage to the cell wall and distorted cell morphology, highlighting its impact on bacterial cell structure. Presented information suggests the use of clove EOs as natural alternatives for sustainable application in food and pharmaceutical industries
Current Updates on the Role of Microbiome in Endometriosis: A Narrative Review
Get PDFEndometriosis affects approximately 6 to 10% of reproductive-age women globally. Despite much effort invested, the pathogenesis that promotes the development, as well as the progression of this chronic inflammatory disease, is poorly understood. The imbalance in the microbiome or dysbiosis has been implicated in a variety of human diseases, especially the gut microbiome. In the case of endometriosis, emerging evidence suggests that there may be urogenital-gastrointestinal crosstalk that leads to the development of endometriosis. Researchers may now exploit important information from microbiome studies to design endometriosis treatment strategies and disease biomarkers with the use of advanced molecular technologies and increased computational capacity. Future studies into the functional profile of the microbiome would greatly assist in the development of microbiome-based therapies to alleviate endometriosis symptoms and improve the quality of life of women suffering from endometriosis
Identification and optimization of TDP1 inhibitors from anthraquinone and chalcone derivatives: consensus scoring virtual screening and molecular simulations
No full textVirtual screening aims to identify and rank compounds with drug/lead-like properties based on their affinity for the protein target. We developed a methodology that integrates structure- and ligand-based screening approaches to enhance hit rates against the TDP1 protein within a database of anthraquinone and chalcone derivatives, followed by evaluation of prioritized compounds through molecular simulations. This technique is particularly useful for training set imbalances. Four screening methods were used: QSAR, pharmacophore, shape similarity, and docking. Each method was individually trained to score compounds, and the scores were fused to create parallel Z-score fusion. The QSAR models exhibited satisfactory R2 values (0.84 to 0.75), whereas the pharmacophoric and shape similarity models demonstrated excellent performance (ROC:0.82–0.88). Docking enrichment analysis identified 6N0D as the optimal TDP1 crystal structure (ROC = 0.73). Remarkably, the consensus scoring method surpassed other screening methods, achieving the highest ROC value of 0.98. Docking screening prioritized compounds with binding modes resembling the co-crystallized ligands, whereas MMGBSA, consensus, and docking produced dynamic simulations that were as stable as the co-crystallized ligands. Additionally, the QSAR-selected compounds exhibited binding modes similar to those of commercially available TDP1 inhibitors. In this study, a strong correlation was found between the inhibitory concentrations and binding energy values of commercialized TDP1 inhibitors, indicating that the top-ranked compounds are expected to have potent inhibitory effects in the nano-/micromolar range. The results of this study establish that consensus scoring can be used as an adaptable mainstay virtual screening methodology, pending subsequent experimental validation for affirmation
Enhanced production of recombinant HALT-1 pore-forming toxin using two-step chromatographic procedure
Get PDFHydra actinoporin-like toxin-1 (HALT-1) has been isolated from Hydra magnipapillata and is highly cytolytic against various human cells including erythrocyte. Previously, recombinant HALT-1 (rHALT-1) was expressed in Escherichia coli and purified by the nickel affinity chromatography. In this study, we improved the purification of rHALT-1 by two-step purifications. Bacterial cell lysate containing rHALT-1 was subjected to the sulphopropyl (SP) cation exchange chromatography with different buffers, pHs, and NaCl concentrations. The results indicated that both phosphate and acetate buffers facilitated the strong binding of rHALT-1 to SP resins, and the buffers containing 150 mM and 200 mM NaCl, respectively, removed protein impurities but retain most rHALT-1 in the column. When combining the nickel affinity chromatography and the SP cation exchange chromatography, the purity of rHALT-1 was highly enhanced. In subsequent cytotoxicity assays, 50% of cells could be lysed at ∼18 and ∼22 µg/mL of rHALT-1 purified with phosphate and acetate buffers, respectively.
• HALT-1 is a soluble α-pore-forming toxin of 18.38 kDa.
• rHALT-1 was purified by nickel affinity chromatography followed by SP cation exchange chromatography.
• The cytotoxicity of purified rHALT-1 using 2-step purifications via either phosphate or acetate buffer was comparable to those previously reported
Streptomyces griseiviridis sp. nov., A Novel “Modern Actinobacteria” isolated from Malaysia Mangrove Soil
No full textA novel strain, Streptomyces griseiviridis MUM 136JT was recovered from a mangrove forest soil in Malaysia. The Gram-positive bacterium forms strong yellow aerial mycelium and moderate yellow substrate mycelium on ISP 2 agar. A polyphasic approach was used to determine the taxonomy status of strain MUM 136JT. The strain showed a spectrum of phylogenetic and chemotaxonomic properties consistent with those of the members of the genus Streptomyces. The cell wall peptidoglycan was determined to contain LL-diaminopimelic acid. The predominant menaquinones were identified as MK-9(H8) and MK-9(H6), while the identified polar lipids consisted of lipid, aminolipid, phospholipid, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, diphosphatidylglycerol, and phosphatidylinositolmannoside. The cell wall sugars consist of ribose, mannose, and galactose. The predominant cellular fatty acids (>10.0 %) were identified as iso-C16:0 (31.6 %), anteiso-C15:0 (14.8 %), iso-C15:0 (12.0 %), and anteiso-C17:0 (11.1 %). Phylogenetic analysis identified that closely related strains for MUM 136JT are Streptomyces leeuwenhoekii DSM 42122T (98.9 %), Streptomyces erythrogriseus JCM 9650T (98.4 %), Streptomyces griseoincarnatus JCM 4381T (98.5 %). The DNA-DNA relatedness values between MUM 136 JT and closely related type strains ranged from 13.3 ± 1.5 % to 17.4 ± 2.0 %. The name Streptomyces griseiviridis sp. nov. is proposed, and the type strain is MUM 136JT (= NBRC 114249T = MCCC 1K04199T)
Sunni Islamic perspectives on lab-grown sperm and eggs derived from stem cells–in vitro gametogenesis (IVG)
No full textAn exciting development in the field of assisted reproductive technologies is In Vitro Gametogenesis (IVG) that enables production of functional gametes from stem cells in the laboratory. Currently, development of this technology is still at an early stage and has demonstrated to work only in rodents. Upon critically examining the ethical dimensions of various possible IVG applications in human fertility treatment from a Sunni Islamic perspective, together with benefit-harm (maslahah-mafsadah) assessment; it is concluded that utilization of IVG, once its efficacy and safety are guaranteed, could be permissible by strictly adhering to Islamic ethical principles related to marriage, biological/genetic relatedness, sexual intercourse, and moral status of the embryo/fetus versus that of the gamete. As a result, IVG will be acceptable for treating primary infertility, age-related infertility, and preventing genetic diseases. However, it will be unacceptable for application in posthumous reproduction, donor gametes, genetic enhancement, and procreation in same-sex couples