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During evolution Orientia tsutsugamushi became a smarter obligate bacterium to establish as intracellular pathogens. O. tsutsugamushi is a human pathogenic bacterium responsible for 1 billion infections of scrub typhus. Several novel mechanisms make this bacterium unique (cell wall, genetic constitutions, secretion system, etc.). In 2007, O. tsutsugamushi Boryong was pioneer strain for whole-genome sequencing. But the fundamental biology of this bacterial cell is a mystery till date. The unusual biology makes this organism as model for host cell interaction. Only a few antibiotics are effective against this intracellular pathogen but emergence of less susceptibility toward antibiotics make the situation alarming. The review was captivated to highlight the unusual aspects of adaptation, antibiotics, and drugs beyond antibiotics.
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Antibacterianos , Orientia tsutsugamushi , Tifo por Ácaros , Orientia tsutsugamushi/genética , Orientia tsutsugamushi/efeitos dos fármacos , Tifo por Ácaros/microbiologia , Tifo por Ácaros/tratamento farmacológico , Antibacterianos/farmacologia , Humanos , Adaptação Fisiológica , AnimaisRESUMO
Developing new chemotherapeutics that are structurally and mechanistically unique is needed due to the rapid rise of the cancer incidence across the globe. Here, we report the identification of irreversible, thiol-reactive diazepam derivatives as GPX4 modifiers and nanomolar inducers of ferroptosis in liver cancer cells.
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Ferroptose , Neoplasias Hepáticas , Humanos , Linhagem Celular , Diazepam , Compostos de Sulfidrila , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
Dementia is reported to be common in those with type 2 diabetes mellitus. Type 2 diabetes contributes to common molecular mechanisms and an underlying pathology with dementia. Brain cells becoming resistant to insulin leads to elevated blood glucose levels, impaired synaptic plasticity, microglial overactivation, mitochondrial dysfunction, neuronal apoptosis, nutrient deprivation, TAU (Tubulin-Associated Unit) phosphorylation, and cholinergic dysfunction. If insulin has neuroprotective properties, insulin resistance may interfere with those properties. Risk factors have a significant impact on the development of diseases, such as diabetes, obesity, stroke, and other conditions. Analysis of risk factors of importance for the association between diabetes and dementia is important because they may impede clinical management and early diagnosis. We discuss the pathological and physiological mechanisms behind the association between Type 2 diabetes mellitus and dementia, such as insulin resistance, insulin signaling, and sporadic forms of dementia; the relationship between insulin receptor activation and TAU phosphorylation; dementia and mRNA expression and downregulation of related receptors; neural modulation due to insulin secretion and glucose homeostasis; and neuronal apoptosis due to insulin resistance and Type 2 diabetes mellitus. Addressing these factors will offer clinical outcome-based insights into the mechanisms and connection between patients with type 2 diabetes and cognitive impairment. Furthermore, we will explore the role of brain insulin resistance and evidence for anti-diabetic drugs in the prevention of dementia risk in type 2 diabetes.
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Demência , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Resistência à Insulina/fisiologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Demência/complicações , Demência/tratamento farmacológicoRESUMO
Nanoformulation-based combinational drug delivery systems are well known to overcome drug resistance in cancer management. Among them, nanoemulsions are well-known and thermodynamically stable drug delivery systems suitable for carrying hydrophobic drugs and phytoconstituents to tackle drug-resistant cancers. In the present study, we have investigated the effect of paclitaxel in combination with erucin (natural isothiocyanate isolated from the seeds of Eruca sativa) loaded in the frankincense oil-based nanoemulsion formulation. The choice of frankincense oil for the current study was based on reported research investigations stating its magnificient therapeutic potential against breast cancer. Optimized nanoemulsion of paclitaxel (PTX) and erucin (ER) combination (EPNE) provided sustained release and exhibited enhanced cytotoxicity towards human epithelial breast cancer cells (T-47D) as compared to individual ER and PTX. EPNE was further assessed for its antitumor activity in the 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer mice model. EPNE significantly decreased the levels of hepatic and renal parameters along with oxidative stress in breast cancer mice. Furthermore, EPNE also showed decreased levels of inflammatory cytokines TNF-α, IL-6. Histopathological examinations revealed restoration of the tumorous breast to normal tissues in EPNE-treated breast cancer mice. Therefore, EPNE can act as a viable lead and therapeutic option for drug-resistant breast cancer.
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Worldwide, since ages and nowadays, traditional medicine is well known, owing to its biodiversity, which immensely contributed to the advancement and development of complementary and alternative medicines. There is a wide range of spices, herbs, and trees known for their medicinal uses. Chilli peppers, a vegetable cum spice crop, are bestowed with natural bioactive compounds, flavonoids, capsaicinoids, phytochemicals, phytonutrients, and pharmacologically active compounds with potential health benefits. Such compounds manifest their functionality over solo-treatment by operating in synergy and consortium. Co-action of these compounds and nutrients make them potentially effective against coagulation, obesity, diabetes, inflammation, dreadful diseases, such as cancer, and microbial diseases, alongside having good anti-oxidants with scavenging ability to free radicals and oxygen. In recent times, capsaicinoids especially capsaicin can ameliorate important viral diseases, such as SARS-CoV-2. In addition, capsaicin provides an ability to chilli peppers to ramify as topical agents in pain-relief and also benefitting man as a potential effective anesthetic agent. Such phytochemicals involved not only make them useful and a much economical substitute to wonder/artificial drugs but can be exploited as obscene drugs for the production of novel stuffs. The responsibility of the TRPV1 receptor in association with capsaicin in mitigating chronic diseases has also been justified in this study. Nonetheless, medicinal studies pertaining to consumption of chilli peppers are limited and demand confirmation of the findings from animal studies. In this artifact, an effort has been made to address in an accessible format the nutritional and biomedical perspectives of chilli pepper, which could precisely upgrade and enrich our pharmaceutical industries towards human well-being.
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Tratamento Farmacológico da COVID-19 , Capsicum , Animais , Antioxidantes/farmacologia , Capsaicina/farmacologia , Capsicum/química , Flavonoides , Humanos , Oxigênio , SARS-CoV-2RESUMO
Antimicrobial resistance (AMR) is a global health concern. Targetting AMR, we present an in situ lactonization mechanism generating 4-nitroisobenzofuran-1(3H)-one (IITK2020), an exclusive S. aureus inhibitor at 2-4 µg mL-1 MIC including multidrug-resistant S. aureus clinical strains, that prevents peptidoglycan biosynthesis.
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Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Peptidoglicano , Staphylococcus aureusRESUMO
Poly [adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are members of a family of 17 enzymes that performs several fundamental cellular processes. Aberrant activity (mutation) in PARP12 has been linked to various diseases including inflammation, cardiovascular disease, and cancer. Herein, a large library of compounds (ZINC-FDA database) has been screened virtually to identify potential PARP12 inhibitor(s). The best compounds were selected on the basis of binding affinity scores and poses. Molecular dynamics (MD) simulation and binding free energy calculation (MMGBSA) were carried out to delineate the stability and dynamics of the resulting complexes. To this end, root means deviations, relative fluctuation, atomic gyration, compactness, covariance, residue-residue contact map, and free energy landscapes were studied. These studies have revealed that compounds ZINC03830332, ZINC03830554, and ZINC03831186 are promising agents against mutated PARP12.
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1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only 7 and 8 showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds 7 and 8 exhibited docking scores of -7.089 and -8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential.
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Multiple variants of SARS-CoV-2 have emerged and are now prevalent at the global level. Currently designated variants of concern (VOCs) are B.1.1.7, B1.351, P.1, B.1.617.2 variants and B.1.1.529. Possible options for VOC are urgently required as they carry mutations in the virus spike protein that allow them to spread more easily and cause more serious illness. The primary targets for most therapeutic methods against SARS-CoV-2 are the S (Spike) protein and RBD (Receptor-Binding Domain), which alter the binding to ACE2 (Angiotensin-Converting Enzyme 2). The most popular of these strategies involves the use of drug development targeting the RBD and the NTD (N-terminal domain) of the spike protein and multiple epitopes of the S protein. Various types of mutations have been observed in the RBDs of B.1.1.7, B1.351, P. and B.1.620. The incidence of RBD mutations increases the binding affinity to the ACE2 receptor. The high binding affinity of RBD and ACE2 has provided a structural basis for future evaluation of antibodies and drug development. Here we discuss the variants of SARS-CoV-2 and recent updates on the clinical evaluation of antibody-based treatment options. Presently, most of the antibody-based treatments have been effective in patients with SARS-CoV-2. However, there are still significant challenges in verifying independence, and the need for further clinical evaluation.
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Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Humanos , Mutação , Ligação Proteica , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Resultado do TratamentoRESUMO
Fighting against the emergent coronavirus disease (COVID-19) remains a big challenge at the front of the world communities. Recent research has outlined the potential of various medicinal herbs to counteract the infection. This study aimed to evaluate the interaction of artemisinin, a sesquiterpene lactone extracted from the Artemisia genus, and its derivatives with the SARS-CoV-2 main protease. To assess their potential use against COVID-19, the interactions of the main active principle of Artemisia with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) was investigated through in silico probing. Our results showed that artemesinin and its derivatives manifested good oral absorption and bioavailability scores (0.55). They potently bound to the Mpro site of action-specifically, to its Cys145 residue. The selected compounds established two to three conventional hydrogen bonds with binding affinities ranging between -5.2 and -8.1 kcal/mol. Furthermore, artemisinin interactions with angiotensin converting enzyme 2 (ACE2) were dependent on the ACE2 allelic variants. The best score was recorded with rs961360700. A molecular dynamic simulation showed sufficient stability of the artemisinin-Mpro complex on the trajectory of 100 ns simulation frame. These binding interactions, together with drug-likeness and pharmacokinetic findings, confirmed that artemisinin might inhibit Mpro activity and explain the ethnopharmacological use of the herb and its possible antiviral activity against SARS-CoV-2 infection inducing COVID-19. Nevertheless, it interacted differently with the various ACE2 allelic variants reported to bind with the SARS-CoV-2 spike protein.
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BACKGROUND: Several natural/synthetic molecules having a structure similar to 1H-isochromen- 1-ones have been reported to display promising antioxidants and platelet aggregation inhibitory activity. Isocoumarin (1H-2-benzopyran-1-one) skeleton, either whole or as a part of the molecular framework, has been explored for its antioxidant or antiplatelet activities. INTRODUCTION: Based on the literature, a new prototype, i.e., 3-phenyl-1H-isochromen-1-ones based compounds, has been rationalized to possess both antioxidant as well as antiplatelet activities. Consequently, no reports are available regarding its inhibition either by cyclooxygenase-1 (COX-1) enzyme or by arachidonic acid (AA)-induced platelet aggregation. This prompted us to investigate 3-phenyl-1H-isochromen-1-ones towards antioxidant and antiplatelet agents. METHODS: The goal of this work was to identify new 3-phenyl-1H-isochromen-1-ones based compounds via synthesis of a series of analogues, followed by performing in vitro antioxidant as well as AA-induced antiplatelet activities. Then, identification of potent compounds by SAR and molecular docking studies was carried out. RESULTS: Out of all synthesized 3-phenyl-1H-isochromen-1-ones analogues, five compounds showed 7-fold to 16-fold more highly potent antioxidant activities than ascorbic acid. Altogether, ten 3-phenyl-1H-isochromen- 1-one analogues displayed antioxidant activities in 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Almost all the 3-phenyl-1H-isochromen-1-one analogues exhibited potent AA-induced antiplatelet activity; few of them displayed 7-folds more activity as compared to aspirin. Further, in silico analysis validated the wet results. CONCLUSION: We disclose the first detailed study for the identification of 3-phenyl-1H-isochromen-1-one analogues as highly potent antioxidant as well as antiplatelet agents. The article describes the scaffold designing, synthesis, bioevaluation, structure-activity relationship, and in silico studies of a pharmaceutically privileged bioactive 3-phenyl-1H-isochromen-1-one class of heterocycles.
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Antioxidantes , Benzopiranos/química , Produtos Biológicos , Antioxidantes/química , Benzopiranos/farmacologia , Produtos Biológicos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Relação Estrutura-AtividadeRESUMO
Recent times have seen a strong surge in therapeutically targeting the hedgehog (HH)/GLI signaling pathway in cervical cancer. HH signaling pathway is reported to be a crucial modulator of carcinogenesis in cervical cancer and is also associated with recurrence and development of chemoresistance. Moreover, our previous reports have established that carvacrol (CAR) inhibited the proliferation of prostate cancer cells via inhibiting the Notch signaling pathway and thus, it was rational to explore its antiproliferative effects in cervical cancer cell lines. Herein, the present study aimed to investigate the anticancer and apoptotic potential of CAR on C33A cervical cancer cells and further explore the underlying mechanisms. We found that CAR significantly suppressed the growth of C33A cells, induced cell cycle arrest, and enhanced programmed cell death along with augmentation in the level of ROS, dissipated mitochondrial membrane potential, activation of caspase cascade, and eventually inhibited the HH signaling cascade. In addition, CAR treatment increased the expression of pro-apoptotic proteins (Bax, Bad, Fas-L, TRAIL, FADDR, cytochrome c) and concomitantly reduced the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL) in C33A cells. CAR mediates the activation of caspase-9 and -3 (intrinsic pathway) and caspase-8 (extrinsic pathway) accompanied by the cleavage of PARP in cervical cancer cells. Thus, CAR induced apoptosis by both the intrinsic and extrinsic apoptotic pathways. CAR efficiently inhibited the growth of cervical cancer cells via arresting the cell cycle at G0/G1 phase and modulated the gene expression of related proteins (p21, p27, cyclin D1 and CDK4). Moreover, CAR inhibited the HH/GLI signaling pathway by down regulating the expression of SMO, PTCH and GLI1 proteins in cervical carcinoma cells. With evidence of the above results, our data revealed that CAR treatment suppressed the growth of HPV-C33A cervical cancer cells and further elucidated the mechanistic insights into the functioning of CAR.
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We explored the antibacterial potential (alone and combination) against multidrug resistant (MDR) Pseudomonas aeruginosa isolates KG-P2 using synthesized thieno[3,2-c]pyran-2-ones in combination with different antibiotics. Out of 14 compounds, two compounds (3g and 3l) abridged the MIC of tetracycline (TET) by 16 folds. Compounds was killing the KG-P2 cells, in time dependent manner, lengthened post-antibiotic effect (PAE) of TET and found decreased the mutant prevention concentration (MPC) of TET. In ethidium bromide efflux experiment, two compounds repressed the drug transporter (efflux pumps) which is further supported by molecular docking of these compounds with efflux complex MexAB-OprM. In another study, these compounds inhibited the synthesis of biofilm.
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Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pironas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Quimioterapia Combinada , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pironas/síntese química , Pironas/química , Relação Estrutura-Atividade , Tetraciclina/farmacologia , Fatores de TempoRESUMO
Herein, we have synthesized a series of lipophilic, halogenated-arylvinyl-1,2,4-trioxanes 8a-g (28 compounds) and assessed for their in vitro anti-plasmodial activity in Plasmodium falciparum culture using SYBRgreen-I fluorescence assay against chloroquine-resistant Pf INDO and artemisinin-resistant Pf Cam 3.1R539T (MRA-1240) strains. Alongside, the cell cytotoxic potential of 8a-g has also been determined against the HEK293 cell line in vitro. Out of twenty-eight halogenated-arylvinyl-1,2,4-trioxanes; ten analogues (8a2, 8a4, 8b2, 8b4, 8d4, 8e1, 8e2, 8e4,8f2, and 8g4) have shown potent in vitro antiplasmodial activity with IC50 < 27 nM (IC50 range = 4.48-26.58 nM). Also, the selectivity index (SI) for these ten analogues were found in the range of 72.00-3972.50 which indicates their selective potential towards Plasmodium cells. Results of the cell cycle stage specificity with two of the most potent compounds 8a4 {(IC50 = 4.48 nM; SI = 3972.50) more potent than chloroquine (IC50 = 546 nM; SI = 36.64) and artesunate (IC50 = 6.6 nM; SI = 4333.33)} and 8e2 (IC50 = 9.69 nM; SI = 1348) against Pf INDO indicated all three stages to be the target of the action of 8e2 while only rings and trophozoites appeared to be targeted by 8a4. Ring stage survival assay against artemisinin-resistant Pf Cam 3.1R539T indicated that 8a4 may be well suited to replace artemisinin from current ACTs which are experiencing in vivo delayed parasite clearance. With intraperitoneal (i.p.) and oral (p.o.) route at the dose of 50 mg/kg/day × 4 days; 8a4 has also shown 100% suppression of parasitemia in P. berghei ANKA infected Balb C mice. Further, the in vitro anticancer activity of 8a-g performed against human lung (A549) and liver (HepG2) cancer cell lines as also against immortalized normal lung (BEAS-2B) and liver (LO2) cell lines has revealed that most of the derivatives are endowed also with promising anticancer activity (IC50 = 0.69-15 µM; SI = 1.02-20.61) in comparison with standard drugs such as chloroquine (IC50 = 100 µM; SI = 0.03), artemisinin (IC50 = 100 µM), and artesunic acid (IC50 = 9.85 µM; SI = 0.76), respectively. All the derivatives have shown moderate anticancer activity against liver (HepG2) cancer cell lines. Arylvinyl-1,2,4-trioxanes 8f2 (IC50 = 0.69 µM; SI = 16.66), the most active compound of the series, has shown â¼145 fold more cytotoxic potential with higher selectivity in comparison to reference drugs chloroquine (IC50 = 100 µM; SI = 0.03) and artemisinin (IC50 = 100 µM), respectively against the lung (A549) cancer cell line. Finally, the in-silico docking studies of the potent halogenated 1,2,4-trioxanes along with reference drug molecules against epidermal growth factor receptor (EGFR; PDB ID: 1M17) have demonstrated the strong virtual interaction.
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Antimaláricos/síntese química , Antineoplásicos/síntese química , Compostos Heterocíclicos/química , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Artesunato/farmacologia , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/química , Receptores ErbB/metabolismo , Células HEK293 , Halogenação , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Parasitemia/tratamento farmacológico , Parasitemia/patologia , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Endophyte is considered a source of natural bioactive secondary metabolites that provides an array of bioactive lead compounds. The present study was aimed to determine the antimicrobial and anti-inflammatory potential of fungal endophytes isolated from Catharanthus roseus. METHODS: A total of seven fungal endophytes crude extract were screened against bacterial pathogens. Of these, Curvularia geniculata CATDLF7 crude extract exhibited the most potent inhibitory activity against bacterial pathogens. Hence, CATDLF7 crude extract was subjected to chromatographic separation. This purification leads to the isolation of six pure compounds (1PS - 6PS). Of these, 3PS was found to be a major constituent and most effective against clinical isolates of methicillin- resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) values ranging from 100 to 200 µg/ml. Based on the spectroscopic data, 3PS was characterized as α,ß- dehydrocurvularin. This compound also showed synergistic interaction with norfloxacin and reduced its MIC up to 32-folds with a fractional inhibitory concentration index (FICI) of 0.09. RESULTS: To understand the possible antibacterial mechanism of action, α,ß-dehydrocurvularin alone (100 µg/ml) exhibited efflux pump inhibitory potential by 0.84 fold decreasing in ethidium bromide (EtBr) fluorescence. In addition, α,ß-dehydrocurvularin inhibited inflammatory cytokines TNF-α and IL-6 production, which is further validated by molecular docking scores -4.921 and -5.641, respectively, for understanding orientation and binding affinity. CONCLUSION: Overall, the results highlighted identifying bioactive compound α,ß-dehydrocurvularin, which could be used as an antimicrobial and anti-inflammatory agent.
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Anti-Infecciosos/isolamento & purificação , Anti-Inflamatórios/isolamento & purificação , Catharanthus/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Zearalenona/análogos & derivados , Animais , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Endófitos/metabolismo , Feminino , Humanos , Interleucina-6/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Norfloxacino/farmacologia , Extratos Vegetais/farmacologia , Ligação Proteica , Transdução de Sinais , Relação Estrutura-Atividade , Zearalenona/isolamento & purificação , Zearalenona/farmacologiaRESUMO
BACKGROUND: In the present study, we have explored the utility of QSAR modelling, in silico ADMET, docking, chemical semi-synthesis, and in vitro evaluation studies for the identification of active camptothecin (CPT) derivatives against cancer-targeting human liver (HepG2) and lung (A549) cancer cell lines. METHODS: Two QSAR models were developed as screenings tools using the multiple linear regression (MLR) method followed by ADMET and docking studies. The regression coefficient (r2) and cross-validation regression coefficients (rCV2T) of the QSAR model for the HepG2 cell line was 0.95 and 0.90, respectively, and for the A549 cell line, it was 0.93 and 0.81, respectively. RESULTS: In silico studies show that CPT derivatives (CPT-1 and CPT-6) possess drug-like properties. Docking performed on DNA Topoisomerase-I showed significant binding affinity. Finally, predicted active derivatives were chemically semi synthesized, spectroscopically characterized, and evaluated in-vitro for cytotoxic/anticancer activity against HepG2 and A549 cell lines. CONCLUSION: The experimental results are consistent with the predicted results. These findings may be of immense importance in the anticancer drug development from an inexpensive and widely available natural product, camptothecin.
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Antineoplásicos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Camptotecina/isolamento & purificação , Magnoliopsida/química , Extratos Vegetais/isolamento & purificação , Células A549 , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Camptotecina/farmacologia , DNA Topoisomerases Tipo I/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Modelos Lineares , Simulação de Acoplamento Molecular/métodos , Extratos Vegetais/farmacologia , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Transdução de SinaisRESUMO
Brain function activity is regulated by several mechanisms of genetic and epigenetic factors such as histone modelling, DNA methylation, and non-coding RNA. Alterations in these regulatory mechanisms affect the normal development of neurons that causes Neuropsychiatric Disorders (ND). However, it is required to analyse the functional significance of neuropsychiatric disorders associated with a molecular mechanism to bring about therapeutic advances in early diagnosis and treatment of the patients. The CRISPR/Cas 9 (Clustered Regularly Interspaced Short Palindromic Repeats) genome editing tools have revolutionized multiple genome and epigenome manipulation targets the same time. This review discussed the possibilities of using CRISPR/Cas 9 tools during molecular mechanism in the ND as a therapeutic approach to overcome ND that is caused due to genetic and epigenetic abnormalities.
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Sistemas CRISPR-Cas/genética , Epigênese Genética/genética , Transtornos Mentais/terapia , Transtornos Neurocognitivos/terapia , Animais , Metilação de DNA , Edição de Genes/métodos , Regulação da Expressão Gênica , Terapia Genética/métodos , Histonas/genética , Humanos , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Bacteria employ numerous resistance mechanisms against structurally distinct drugs by the process of multidrug resistance. A study was planned to discover the antibacterial potential of a graphene oxide nanosheet (GO), a graphene oxide-zinc oxide nanocomposite (GO/ZnO), a graphene oxide-chitosan nanocomposite (GO-CS), a zinc oxide decorated graphene oxide-chitosan nanocomposite (GO-CS/ZnO), and zinc oxide nanoparticles (ZnO) alone and in a blend with antibiotics against a PS-2 isolate of Pseudomonas aeruginosa. These nanocomposites reduced the MIC of tetracycline (TET) from 16 folds to 64 folds against a multidrug-resistant clinical isolate. Efflux pumps were interfered, as evident by an ethidium bromide synergy study with nanocomposites, as well as inhibiting biofilm synthesis. These nanoparticles/nanocomposites also decreased the mutant prevention concentration (MPC) of TET. To the best of our knowledge, this is the first report on nanomaterials as a synergistic agent via inhibition of efflux and biofilm synthesis.
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Biomembranes and lipid systems are rich in unsaturated lipid components and are subject to photo-induced lipid peroxidation. The peroxidized lipid products in cellular systems are known to affect the structural organization and function of the biomembrane. We employed molecular dynamics simulations to study the effects of phospholipid peroxidation on membrane properties and the permeability of different reactive species. The results suggest that when the lipids are peroxidized, the peroxide group moves toward the membrane surface, which causes the membrane system to expand laterally and increase in area. The permeability profile revealed that nitrogen species can easily permeate through the native and peroxidized system in comparison to oxygen species, suggesting its importance in plasma-based treatment. Thus, by breaching the energy barrier with lower energy, they can traverse the cell membrane and induce oxidative stress, which leads to apoptosis.Communicated by Ramaswamy H. Sarma.
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Simulação de Dinâmica Molecular , Fosfolipídeos , Membrana Celular/metabolismo , Peroxidação de Lipídeos , Permeabilidade , Espécies Reativas de Oxigênio/metabolismoRESUMO
The coronavirus (SARS-CoV-2) pandemic is a rapidly transmitting and highly pathogenic disease. The spike protein of SARS-CoV-2 binds to the surface of angiotensin-converting enzyme-2 (ACE2) receptors along the upper respiratory tract and intestinal epithelial cells. SARS-CoV-2 patients develop acute respiratory distress, lymphocytic myocarditis, disseminated intravascular coagulation, lymphocytic infiltration, and other serious complications. A SARS-CoV-2 diagnosis is conducted using quantitative reverse-transcription PCR and computed tomography (CT) imaging. In addition, IgM or IgG antibodies are used to identify acute and convalescent illness. Recent clinical data have been generated by health workers and researchers and have shown that there is an urgent requirement in the effective clinical and treatment of patients, as well as other developments for dealing with SARS-CoV-2 infection. A broad spectrum of clinical trials of different vaccines and drug treatment has been evaluated for use against SARS-CoV-2. This review includes the emergence of SARS-CoV-2 pneumonia as a way to recognize and eliminate any barriers that affect rapid patient care and public health management against the SARS-CoV-2 epidemic based on the natural history of the disease, its transmission, pathogenesis, immune response, epidemiology, diagnosis, clinical presentation, possible treatment, drug and vaccine development, prevention, and future perspective.