The NLR family pyrin domain containing 3 (NLRP3) inflammasome is responsible for the sensation of various pathogenic and non-pathogenic damage signals and has a vital role in neuroinflammation and ...neural diseases. Various stimuli, such as microbial infection, misfolded protein aggregates, and aberrant deposition of proteins can induce NLRP3 inflammasome in neural cells. Once triggered, the NLRP3 inflammasome leads to the activation of caspase-1, which in turn activates inflammatory cytokines, such as interleukin-1β and interleukin -18, and induces pyroptotic cell death. Mitochondria are critically involved in diverse cellular processes and are involved in regulating cellular redox status, calcium levels, inflammasome activation, and cell death. Mitochondrial dysfunction and subsequent accumulation of mitochondrial reactive oxygen species, mitochondrial deoxyribonucleic acid, and other mitochondria-associated proteins and lipids play vital roles in the instigation of the NLRP3 inflammasome. In addition, the processes of mitochondrial dynamics, such as fission and fusion, are essential in the maintenance of mitochondrial integrity and their imbalance also promotes NLRP3 inflammasome activation. In this connection, mitophagy-mediated maintenance of mitochondrial homeostasis restricts NLRP3 inflammasome hyperactivation and its consequences in various neurological disorders. Hence, mitophagy can be exploited as a potential strategy to target damaged mitochondria induced NLRP3 inflammasome activation and its lethal consequences. Therefore, the identification of novel mitophagy modulators has promising therapeutic potential for NLRP3 inflammasome-associated neuronal diseases.
•Selective functionalization of ferrocenyl Cp rings using rice husk ash (RHA) as solid support.•Fluorescence based sensing and signaling behavior with metal cations in the intracellular matrix.•Mode ...of interaction of the unsymmetrical ferrocene based rhodaminyl organometallic receptor has been established by DFT study.
Selective funtionalization of ferrocenyl species with fluorescent active rhodamine moiety using a solvent free solid state method led to the synthesis of 1,1’- unsymmetrical ferrocene based turn-on fluorescent hydrazone molecular system, 1,1’-CH3C(O)(η5-C5H4)Fe{(η5-C5H4)C(CH3)N-NC(O)-X}, (X = Rhodamine-6G) (1) and 1,1’-HC(O)(η5-C5H4)Fe{(η5-C5H4)C(H)N-NC(O)-X}, (X = Rhodamine-6G (2), Rhodamine-B (3)). The unsymmetrical molecular system was structurally characterized by single crystal X-ray diffraction crystallography. Their fluorescence based signaling and sensing behavior has been explored with metal cations to observe remarkable fluorescence enhancement capabilities in the intracellular matrix. The interaction behavior of the unsymmetrical ferrocene based rhodaminyl organometallic receptor has been established by DFT study and spectroscopic analysis. The study showed some significant intracellular metal recognition and imaging characteristics to understand their potential in applications related to bioimaging of heavy metal ions. Molecular logic Gate property was also studied corresponding to INHIBIT, OR and a combinational logic operations using the fluorometric molecular compound.
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A solvent free synthetic method using rice husk ash (RHA) as solid support has been designed for selective functionalization and preparation of novel 1,1′- unsymmetrically bi-functionalized ...ferrocenyl compounds. The selectively functionalized intermediate compound, Ferrocenyl-1-acetyl-1′-thiosemicarbazone, has been structurally characterized using single crystal X-ray diffraction technique which revealed distinct inter-molecular hydrogen bonding interactions across the thiosemicarbazone chains. Cytotoxic evaluation of five different unsymmetrically bi-functionalized thiosemicarbazone - hydrazone compounds showed potent activity against human leukemia (THP-1) cell line. The unsymmetrical ferrocenyl compounds also showed strong BSA and DNA binding interactions and reversible redox properties.
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•Selective functionalization of ferrocenyl Cp rings using rice husk ash (RHA) as solid support.•Solvent free multicomponent synthetic method for unsymmetrical functionalization of ferrocenyl derivatives.•Potent cytotoxicity for the unsymmetrically bi-functionalized thiosemicarbazone - hydrazone compounds.
Antibiotic resistance development and pathogen cross-dissemination are both considered essential risks to human health on a worldwide scale. Antimicrobial resistance genes (AMRs) are acquired, ...expressed, disseminated, and traded mainly through integrons, the key players capable of transferring genes from bacterial chromosomes to plasmids and their integration by integrase to the target pathogenic host. Moreover, integrons play a central role in disseminating and assembling genes connected with antibiotic resistance in pathogenic and commensal bacterial species. They exhibit a large and concealed diversity in the natural environment, raising concerns about their potential for comprehensive application in bacterial adaptation. They should be viewed as a dangerous pool of resistance determinants from the “One Health approach.” Among the three documented classes of integrons reported viz., class-1, 2, and 3, class 1 has been found frequently associated with AMRs in humans and is a critical genetic element to serve as a target for therapeutics to AMRs through gene silencing or combinatorial therapies. The direct method of screening gene cassettes linked to pathogenesis and resistance harbored by integrons is a novel way to assess human health. In the last decade, they have witnessed surveying the integron-associated gene cassettes associated with increased drug tolerance and rising pathogenicity of human pathogenic microbes. Consequently, we aimed to unravel the structure and functions of integrons and their integration mechanism by understanding horizontal gene transfer from one trophic group to another. Many updates for the gene cassettes harbored by integrons related to resistance and pathogenicity are extensively explored. Additionally, an updated account of the assessment of AMRs and prevailing antibiotic resistance by integrons in humans is grossly detailed—lastly, the estimation of AMR dissemination by employing integrons as potential biomarkers are also highlighted. The current review on integrons will pave the way to clinical understanding for devising a roadmap solution to AMR and pathogenicity.
Graphical Abstract
The graphical abstract displays how integron-aided AMRs to humans: Transposons capture integron gene cassettes to yield high mobility integrons that target res sites of plasmids. These plasmids, in turn, promote the mobility of acquired integrons into diverse bacterial species. The acquisitions of resistant genes are transferred to humans through horizontal gene transfer.
Tumour-promoting inflammation is a critical hallmark in cancer development, and inflammasomes are well-known regulators of inflammatory processes within the tumour microenvironment. Different ...inflammasome components along with the adaptor, apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC), and the effector, caspase-1, have a significant influence on tumorigenesis but in a tissue-specific and stage-dependent manner. The downstream products of inflammasome activation, that is the proinflammatory cytokines such as IL-1β and IL-18, regulate tissue homeostasis and induce antitumour immune responses, but in contrast, they can also favour cancer growth and proliferation by directing various oncogenic signalling pathways in cancer cells. Moreover, different epigenetic mechanisms, including DNA methylation, histone modification and noncoding RNAs, control inflammasomes and their components by regulating gene expression during cancer progression. Furthermore, autophagy, a master controller of cellular homeostasis, targets inflammasome-induced carcinogenesis by maintaining cellular homeostasis and removing potential cancer risk factors that promote inflammasome activation in support of tumorigenesis. Here, in this review, we summarize the effect of inflammasome activation in cancers and discuss the role of epigenetic and autophagic regulatory mechanisms in controlling inflammasomes. A proper understanding of the interactions among these key processes will be useful for developing novel therapeutic regimens for targeting inflammasomes in cancer.
Diclofenac is a highly prescribed non-steroidal anti-inflammatory drug (NSAID) that relieves inflammation, pain, fever, and aches, used at different doses depending on clinical conditions. This drug ...inhibits cyclooxygenase-1 and cyclooxygenase-2 enzymes, which are responsible for the generation of prostaglandin synthesis. To improve current diclofenac-based therapies, we require new molecular systematic therapeutic approaches to reduce complex multifactorial effects. However, the critical challenge that appears with diclofenac and other drugs of the same class is their side effects, such as signs of stomach injuries, kidney problems, cardiovascular issues, hepatic issues, and diarrhea. In this article, we discuss why defining diclofenac-based mechanisms, pharmacological features, and its medicinal properties are needed to direct future drug development against neurodegeneration and imperfect ageing and to improve cancer therapy. In addition, we describe various advance molecular mechanisms and fundamental aspects linked with diclofenac which can strengthen and enable the better designing of new derivatives of diclofenac to overcome critical challenges and improve their applications.
Tuberculosis (TB) is a global health concern, and this situation has further worsened due to the emergence of drug-resistant strains and the failure of BCG vaccine to impart protection. There is an ...imperative need to develop highly sensitive, specific diagnostic tools, novel therapeutics, and vaccines for the eradication of TB. In the present study, a chemical screen of a pharmacologically active compound library was performed to identify antimycobacterial compounds. The phenotypic screen identified a few novel small-molecule inhibitors, including NU-6027, a known CDK-2 inhibitor. We demonstrate that NU-6027 inhibits
BCG growth
and also displayed cross-reactivity with
protein kinase D (PknD) and protein kinase G (PknG). Comparative structural and sequence analysis along with docking simulation suggest that the unique binding site stereochemistry of PknG and PknD accommodates NU-6027 more favorably than other
Ser/Thr protein kinases. Further, we also show that NU-6027 treatment induces the expression of proapoptotic genes in macrophages. Finally, we demonstrate that NU-6027 inhibits
growth in both macrophage and mouse tissues. Taken together, these results indicate that NU-6027 can be optimized further for the development of antimycobacterial agents.
In its myriad devastating forms, Tuberculosis (TB) has existed for centuries, and humanity is still affected by it. Mycobacterium tuberculosis (M. tuberculosis), the causative agent of TB, was the ...foremost killer among infectious agents until the COVID-19 pandemic. One of the key healthcare strategies available to reduce the risk of TB is immunization with bacilli Calmette-Guerin (BCG). Although BCG has been widely used to protect against TB, reports show that BCG confers highly variable efficacy (0-80%) against adult pulmonary TB. Unwavering efforts have been made over the past 20 years to develop and evaluate new TB vaccine candidates. The failure of conventional preclinical animal models to fully recapitulate human response to TB, as also seen for the failure of MVA85A in clinical trials, signifies the need to develop better preclinical models for TB vaccine evaluation. In the present review article, we outline various approaches used to identify protective mycobacterial antigens and recent advancements in preclinical models for assessing the efficacy of candidate TB vaccines.
We determined whether human NK cells could contribute to immune defenses against Mycobacterium tuberculosis through production of IL-22. CD3(-)CD56(+) NK cells produced IL-22 when exposed to ...autologous monocytes and gamma-irradiated M. tuberculosis, and this depended on the presence of IL-15 and IL-23, but not IL-12 or IL-18. IL-15-stimulated NK cells expressed 10.6 times more DAP10 mRNA compared with control NK cells, and DAP10 siRNA inhibited IL-15-mediated IL-22 production by NK cells. Soluble factors produced by IL-15-activated NK cells inhibited growth of M. tuberculosis in macrophages, and this effect was reversed by anti-IL-22. Addition of rIL-22 to infected macrophages enhanced phagolysosomal fusion and reduced growth of M. tuberculosis. We conclude that NK cells can contribute to immune defenses against M. tuberculosis through production of IL-22, which inhibits intracellular mycobacterial growth by enhancing phagolysosomal fusion. IL-15 and DAP-10 elicit IL-22 production by NK cells in response to M. tuberculosis.
Delphinium roylei
Munz is an indigenous medicinal plant to India where its activity against cancer has not been previously investigated, and its specific interactions of bioactive compounds with ...vulnerable breast cancer drug targets remain largely unknown. Therefore, in the current study, we aimed to evaluate the anti-breast cancer activity of different extracts of
D. roylei
against breast cancer and deciphering the molecular mechanism by Network Pharmacology combined with Molecular Docking and
in vitro
verification. The experimental plant was extracted with various organic solvents according to their polarity index. Phytocompounds were identified by High resolution-liquid chromatography-mass spectrometry (HR-LC/MS) technique, and SwissADME programme evaluated their physicochemical properties. Next, target(s) associated with the obtained bioactives or breast cancer-related targets were retrieved by public databases, and the Venn diagram selected the overlapping targets. The networks between overlapping targets and bioactive were visualized, constructed, and analyzed by STRING programme and Cytoscape software. Finally, we implemented a molecular docking test (MDT) using AutoDock Vina to explore key target(s) and compound(s). HR-LC/MS detected hundreds of phytocompounds, and few were accepted by Lipinski’s rules after virtual screening and therefore classified as drug-like compounds (DLCs). A total of 464 potential target genes were attained for the nine quantitative phytocompounds and using Gene Cards, OMIM and DisGeNET platforms, 12063 disease targets linked to breast cancer were retrieved. With Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment, a total of 20 signalling pathways were manifested, and a hub signalling pathway (PI3K-Akt signalling pathway), a key target (Akt1), and a key compound (8-Hydroxycoumarin) were selected among the 20 signalling pathways via molecular docking studies. The molecular docking investigation revealed that among the nine phytoconstituents, 8-hydroxycoumarin showed the best binding energy (−9.2 kcal/mol) with the Akt1 breast cancer target. 8-hydroxycoumarin followed all the ADME property prediction using SwissADME, and 100 nanoseconds (ns) MD simulations of 8-hydroxycoumarin complexes with Akt1 were found to be stable. Furthermore,
D. roylei
extracts also showed significant antioxidant and anticancer activity through
in vitro
studies. Our findings indicated for the first time that
D. roylei
extracts could be used in the treatment of BC.
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