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Norovirus (HNoV) is a leading cause of gastroenteritis globally, and there are currently no treatment options or vaccines available to combat it. RNA-dependent RNA polymerase (RdRp), one of the viral proteins that direct viral replication, is a feasible target for therapeutic development. Despite the discovery of a small number of HNoV RdRp inhibitors, the majority of them have been found to possess a little effect on viral replication, owing to low cell penetrability and drug-likeness. Therefore, antiviral agents that target RdRp are in high demand. For this purpose, we used in silico screening of a library of 473 natural compounds targeting the RdRp active site. The top two compounds, ZINC66112069 and ZINC69481850, were chosen based on their binding energy (BE), physicochemical and drug-likeness properties, and molecular interactions. ZINC66112069 and ZINC69481850 interacted with key residues of RdRp with BEs of -9.7, and -9.4 kcal/mol, respectively, while the positive control had a BE of -9.0 kcal/mol with RdRp. In addition, hits interacted with key residues of RdRp and shared several residues with the PPNDS, the positive control. Furthermore, the docked complexes showed good stability during the molecular dynamic simulation of 100 ns. ZINC66112069 and ZINC69481850 could be proven as potential inhibitors of the HNoV RdRp in future antiviral medication development investigations.
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Gastroenterite , Norovirus , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica , RNA Polimerase Dependente de RNA/metabolismo , Antivirais/farmacologia , Simulação de Acoplamento MolecularRESUMO
Industrial effluents containing dyes are the dominant pollutants, making the drinking water unfit. Among the dyes, methylene orange (MO) dye is mutagenic, carcinogenic and toxic to aquatic organisms. Therefore, its removal from water bodies through effective and economical approach is gaining increased attention in the last decades. Photocatalytic degradation has the ability to convert economically complex dye molecules into non-toxic and smaller species via redox reactions, by using photocatalysts. g-C3N4 is a metal-free n-type semiconductor, typical nonmetallic and non-toxici polymeric photocatalyst. It widely used in photocatalytic materials, due to its easy and simple synthesis, fascinating electronic band structure, high stability and abundant availability. As a photocatalyst, its major drawbacks are its limited efficiency in separating photo-excited electron-hole pairs, high separated charge recombination, low specific surface area, and low absorption coefficient. In this review, we report the recent modification strategies adopted for g-C3N4 for the efficient photodegradation of MO dye. The different modification approaches, such as nanocomposites and heterojunctions, as well as doping and defect introductions, are briefly discussed. The mechanism of the photodegradation of MO dye by g-C3N4 and future perspectives are discussed. This review paper will predict strategies for the fabrication of an efficient g-C3N4-based photocatalyst for the photodegradation of MO dye.
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Replication of Human Cytomegalovirus (HCMV) requires the presence of a metal-dependent endonuclease at the C-terminus of pUL89, in order to properly pack and cleave the viral genome. Therefore, pUL89 is an attractive target to design anti-CMV intervention. Herein, we used integrated structure-based and ligand-based virtual screening approaches in combination with MD simulation for the identification of potential metal binding small molecule antagonist of pUL89. In this regard, the essential chemical features needed for the inhibition of pUL89 endonuclease domain were defined and used as a 3D query to search chemical compounds from ZINC and ChEMBL database. Thereafter, the molecular docking and ligand-based shape screening were used to narrow down the compounds based on previously identified pUL89 antagonists. The selected virtual hits were further subjected to MD simulation to determine the intrinsic and ligand-induced flexibility of pUL89. The predicted binding modes showed that the compounds reside well in the binding site of endonuclease domain by chelating with the metal ions and crucial residues. Taken in concert, the in silico investigation led to the identification of potential pUL89 antagonists. This study provided promising starting point for further in vitro and in vivo studies.
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Citomegalovirus , Endonucleases , Humanos , Endonucleases/metabolismo , Citomegalovirus/metabolismo , Proteínas Virais/metabolismo , Simulação de Acoplamento Molecular , Ligantes , Endodesoxirribonucleases/metabolismo , Simulação de Dinâmica MolecularRESUMO
Background and Objectives: We have recently reported that stains have calcium channel blocking activity in isolated jejunal preparations. In this study, we examined the effects of atorvastatin and fluvastatin on blood vessels for a possible vasorelaxant effect. We also studied the possible additional vasorelaxant effect of atorvastatin and fluvastatin, in the presence of amlodipine, to quantify its effects on the systolic blood pressure of experimental animals. Materials and Methods: Atorvastatin and fluvastatin were tested in isolated rabbits' aortic strip preparations using 80mM Potassium Chloride (KCl) induced contractions and 1 micro molar Norepinephrine (NE) induced contractions. A positive relaxing effect on 80 mM KCl induced contractions were further confirmed in the absence and presence of atorvastatin and fluvastatin by constructing calcium concentration response curves (CCRCs) while using verapamil as a standard calcium channel blocker. In another series of experiments, hypertension was induced in Wistar rats and different test concentrations of atorvastatin and fluvastatin were administered in their respective EC50 values to the test animals. A fall in their systolic blood pressure was noted using amlodipine as a standard vasorelaxant drug. Results: The results show that fluvastatin is more potent than amlodipine as it relaxed NE induced contractions where the amplitude reached 10% of its control in denuded aortae. Atorvastatin relaxed KCL induced contractions with an amplitude reaching 34.4% of control response as compared to the amlodipine response, i.e., 39.1%. A right shift in the EC50 (Log Ca++ M) of Calcium Concentration Response Curves (CCRCs) implies that statins have calcium channel blocking activity. A right shift in the EC50 of fluvastatin with relatively less EC50 value (-2.8 Log Ca++ M) in the presence of test concentration (1.2 × 10-7 M) of fluvastatin implies that fluvastatin is more potent than atorvastatin. The shift in EC50 resembles the shift of Verapamil, a standard calcium channel blocker (-1.41 Log Ca++ M). Conclusions: Atorvastatin and fluvastatin relax the aortic strip preparations predominantly through the inhibition of voltage gated calcium channels in high molar KCL induced contractions. These statins also inhibit the effects of NE induced contractions. The study also confirms that atorvastatin and fluvastatin potentiate blood pressure lowering effects in hypertensive rats.
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Bloqueadores dos Canais de Cálcio , Inibidores de Hidroximetilglutaril-CoA Redutases , Ratos , Coelhos , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Fluvastatina/farmacologia , Fluvastatina/uso terapêutico , Vasodilatadores/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anlodipino/farmacologia , Anlodipino/uso terapêutico , Cálcio , Pressão Sanguínea , Ratos Wistar , Verapamil/farmacologia , Canais de Cálcio/farmacologia , Cloreto de Potássio/farmacologiaRESUMO
The multidrug-resistant (MDR) human immunodeficiency virus 1 (HIV-1) infection is an unmet medical need. HIV-1 capsid plays an important role at different stages of the HIV-1 replication cycle and is an attractive drug target for developing therapies against MDR HIV-1 infection. Lenacapavir (LEN) is the first-in-class HIV-1 capsid inhibitor approved by the USFDA, EMA, and Health Canada for treating MDR HIV-1 infection. This article highlights the development, pharmaceutical aspects, clinical studies, patent literature, and future directions on LEN-based therapies. The literature for this review was collected from PubMed, authentic websites (USFDA, EMA, Health Canada, Gilead, and NIH), and the free patent database (Espacenet, USPTO, and Patent scope). LEN has been developed by Gilead and is marketed as Sunlenca (tablet and subcutaneous injection). The long-acting and patient-compliant LEN demonstrated a low level of drug-related mutations, is active against MDR HIV-1 infection, and does not reveal cross-resistance to other anti-HIV drugs. LEN is also an excellent drug for patients having difficult or limited access to healthcare facilities. The literature has established additive/synergistic effects of combining LEN with rilpivirine, cabotegravir, islatravir, bictegravir, and tenofovir. HIV-1 infection may be accompanied by opportunistic infections such as tuberculosis (TB). The associated diseases make HIV treatment complex and warrant drug interaction studies (drug-drug, drug-food, and drug-disease interaction). Many inventions on different aspects of LEN have been claimed in patent literature. However, there is a great scope for developing more inventions related to the drug combination of LEN with anti-HIV/anti-TB drugs in a single dosage form, new formulations, and methods of treating HIV and TB co-infection. Additional research may provide more LEN-based treatments with favorable pharmacokinetic parameters for MDR HIV-1 infections and associated opportunistic infections such as TB.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Infecções Oportunistas , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Humanos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Capsídeo , Antituberculosos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
BACKGROUND: The aim of this study was to evaluate renal function by urinalysis in COVID-19 patients following the administration of vancomycin. METHODS: A retrospective observational study was performed between October 2020 and January 2021, during which time patients were hospitalized in the Prince Mohammed Bin Abdulaziz Hospital in Riyadh, Saudi Arabia. The patients were free of kidney disease. Urinalysis was performed by an automated laboratory system, and the collected results were based upon age, gender, diabetic status, whether the patients had received vancomycin, the mortality rate, and the urinalysis panel including coinfection by bacteria and yeast. RESULTS: A total of 227 patients were included in this study, 147 (64.75%) of whom were male and 80 (35.25%) of whom were female; 54.63% were diabetic, 11.89% were prediabetic, and 33.48% were non-diabetic patients. Proteinuria, hematuria, glycosuria, coinfection, and ketonuria were detected among all participants within the study group, specifically among diabetic patients. The mortality rate was 16.2% among the study group; 6.6% had re-ceived vancomycin, and 9.6% had not received vancomycin. No significant correlation was found between nephrotoxicity and abnormalities in the urine and the mortality rate among members of our study group. CONCLUSIONS: Proteinuria, hematuria, glycosuria, ketonuria, and coinfection were common among members of our study group, especially in the diabetic group. Urinalysis abnormalities were less frequent in the vancomycin group than in the others, except the prediabetic group. No correlation between mortality and vancomycin was identified.
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COVID-19 , Coinfecção , Glicosúria , Cetose , Estado Pré-Diabético , Feminino , Hematúria , Humanos , Rim/fisiologia , Masculino , Proteinúria , Estudos Retrospectivos , Urinálise , Vancomicina/efeitos adversosRESUMO
BACKGROUND: This study evaluates the seroprevalence of immunoglobulin M (IgM) and G (IgG) antibodies against SARS-CoV-2 after two doses of Pfizer-BioNTech COVID-19 vaccination from women with breast cancer in Jazan city Kingdom of Saudi Arabia, antibody detections were performed one month and three months after the administration of the second dose. METHODS: Overall, 103 breast cancer patients were included. Individuals who had had two doses of Pfizer-BioNTech vaccine, patients who were earlier diagnosed with COVID-19 infection, had not finalized immunization plan, or who received the second dose recently were excluded from the study. The antibodies detection test was run according to the manufacturer's directions of Viva Diag™ SARS-CoV-2 IgM/IgG Rapid Test (COVID-19 IgM/IgG Rapid Test). RESULTS: This study included 62 (60.2%) and 41 (39.8%) patients with invasive ductal carcinoma and invasive lobular carcinoma, respectively. The age, median and interquartile range (IQR) was 54.0 (26) years. Regarding reactivity of antibodies, after one month IgM antibody showed 64 (62.1%) positive and 39 (37.9%) negative while IgG antibody showed positive results in all patients. After three months IgM antibody showed 44 (42.7%) positive and 59 (57.3%) negative, while IgG showed 87 (84.5%) positive and 16 (15.5%) negative. There were significant differences in the IgM and IgG seropositivity. There were 19.3% patients with ductal carcinoma who were positive and then turned negative versus 17.7% who were positive and then turned negative, respectively (p < 0.001). There were significant differences in IgM antibody positivity among different age groups. CONCLUSIONS: Our results recommend the importance of screening for an antibody response for breast cancer patient after immunization in order to reveal persons who need early and late extra enhancing vaccine dose. Upcoming studies recommended to estimate different methods that raise cancer patients' immune response.
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Neoplasias da Mama , COVID-19 , Carcinoma Ductal , Humanos , Feminino , Pessoa de Meia-Idade , SARS-CoV-2 , Imunoglobulina M , Estudos Soroepidemiológicos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacina BNT162 , Vacinas contra COVID-19 , Anticorpos Antivirais , Imunoglobulina GRESUMO
The severe acute respiratory syndrome coronavirus 2, also known as SARS-CoV-2, is the causative agent of the COVID-19 global pandemic. SARS-CoV-2 has a highly conserved non-structural protein 12 (NSP-12) involved in RNA-dependent RNA polymerase (RdRp) activity. For the identification of potential inhibitors for NSP-12, computational approaches such as the identification of homologous proteins that have been previously targeted by FDA-approved antivirals can be employed. Herein, homologous proteins of NSP-12 were retrieved from Protein DataBank (PDB) and the evolutionary conserved sequence and structure similarity of the active site of the RdRp domain of NSP-12 was characterized. The identified homologous structures of NSP-12 belonged to four viral families: Coronaviridae, Flaviviridae, Picornaviridae, and Caliciviridae, and shared evolutionary conserved relationships. The multiple sequences and structural alignment of homologous structures showed highly conserved amino acid residues that were located at the active site of the RdRp domain of NSP-12. The conserved active site of the RdRp domain of NSP-12 was evaluated for binding affinity with the FDA-approved antivirals, i.e., Sofosbuvir and Dasabuvir in a molecular docking study. The molecular docking of Sofosbuvir and Dasabuvir with the active site that contains conserved motifs (motif A-G) of the RdRp domain of NSP-12 revealed significant binding affinity. Furthermore, MD simulation also inferred the potency of Sofosbuvir and Dasabuvir. In conclusion, targeting the active site of the RdRp domain of NSP-12 with Dasabuvir and Sofosbuvir might reduce viral replication and pathogenicity and could be further studied for the treatment of SARS-CoV-2.
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Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Humanos , Reposicionamento de Medicamentos , Sofosbuvir , Simulação de Acoplamento Molecular , RNA Polimerase Dependente de RNA/genética , Antivirais/farmacologia , Antivirais/uso terapêuticoRESUMO
Commiphora gileadensis (CG) is a small tree distributed throughout the Middle East. It was traditionally used in perfumes in countries in this area. In Saudi Arabia, it was used to treat wounds burns and as an antidote to scorpion stings. This study aimed to evaluate the antimicrobial activity and cutaneous wound healing efficiency of the CG extracts using microbiological tests, rate of wound contraction and histopathological changes. CG plant were extracted using the methanol extraction technique; then, the methanolic extract was characterized using liquid chromatography coupled with mass spectrometry (LC−MS). Afterwards, a six-millimetre (mm) excision wound was induced in 60 male Balb/c mice. Mice were classified into two classes; each class consisted of three groups of 10 mice. In the non-infected wound class, the group I was assigned as control and received normal saline. Group II received gentamicin treatment, and group III treated with CG-methanolic extract. In the Staphylococcus aureus-infected class, group IV received normal saline, and groups V and VI were treated with gentamicin and CG-methanolic extract, respectively. The colonization of infected wounds was determined using colony-forming units (CFUs), and the percentage of wound contraction was measured in all groups. Finally, the histopathologic semi-quantitative determination of wound healing was evaluated by inflammatory cell infiltration, the presence of collagen fibres and granulation tissue, and the grade of re-epithelization. Composition analysis of the methanolic extract confirmed the presence of a high amount of ceramide (69%) and, to a lesser extent, hexosylceramide (18%) and phosphatidylethanolamine (7%) of the total amount. Additionally, there was a statistically significant difference between the percentage of wound contraction in the CG-treated and control groups in both Staphylococcus aureus-infected and non-infected wounds (p < 0.01). The colonization of the infected wounds was lower in the group treated with CG than in the control group (p < 0.01). In both non-infected and infected wounds, the CG-treated group showed significant statistical differences in inflammatory cell infiltration, collagen fibres, re-epithelization and granulation tissue formation compared with the control group (p < 0.01). The CG extract possesses antibacterial and anti-inflammatory properties that induce wound healing.
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Antibacterianos , Commiphora , Extratos Vegetais , Infecções Estafilocócicas , Infecção dos Ferimentos , Animais , Antibacterianos/farmacologia , Colágeno/farmacologia , Commiphora/química , Gentamicinas/farmacologia , Masculino , Metanol , Camundongos , Extratos Vegetais/farmacologia , Solução Salina/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus , Cicatrização , Infecção dos Ferimentos/tratamento farmacológicoRESUMO
Medical researchers have paid close attention to the green synthesis of oxazine and thiazine derivatives since they provided a lead molecule for the creation of numerous possible bioactive compounds. This review provides more information on green synthesis, which will be very helpful to researchers in creating the most effective, affordable, and clinically significant thiazine and oxazine derivatives that are anticipated to have strong pharmacological effects. This has resulted in the identification of several substances with a wide range of intriguing biological functions. This article's goal is to examine the numerous green chemical processes used to create oxazine and thiazine derivatives and their biological activity. We anticipate that researchers interested in oxazine and thiazine chemicals will find this material to be useful. We anticipate that medicinal chemists looking for new active medicinal components for drug discovery and advance progress will find this review of considerable interest.
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BACKGROUND: Due to the biological importance of the benzoxazole derivatives, some 1-(benzo[d]oxazol-2-yl)-3,5-diphenyl-formazans (4a-f) were synthesized and screened for in-silico studies and in-vitro antibacterial activity. METHODS: The benzo[d]oxazole-2-thiol (1) was prepared by reacting with 2-aminophenol and carbon disulfide in the presence of alcoholic potassium hydroxide. Then 2-hydrazinylbenzo[d]oxazole (2) was synthesized from the reaction of compound 1 with hydrazine hydrate in the presence of alcohol. Compound 2 was reacted with aromatic aldehydes to give Schiff base, 2-(2-benzylidene-hydrazinyl)benzo[d]oxazole derivatives (3a-f). The title compounds, formazan derivatives (4a-f), were prepared by a reaction of benzene diazonium chloride. All compounds were confirmed by their physical data, FTIR, 1H-NMR, and 13CNMR spectral data. All the prepared title compounds were screened for in-silico studies and in-vitro antibacterial activity on various microbial strains. RESULTS: Molecular docking against the 4URO receptor demonstrated that molecule 4c showed a maximum dock score of (-) 8.0 kcal/mol. MD simulation data reflected the stable ligand-receptor interaction. As per MM/PBSA analysis, the maximum free binding energy of (-) 58.831 kJ/mol was exhibited by 4c. DFT calculation data confirmed that most of the molecules were soft molecules with electrophilic nature. CONCLUSION: The synthesized molecules were validated using molecular docking, MD simulation, MMPBSA analysis, and DFT calculation. Among all the molecules, 4c showed maximum activity. The activity profile of the synthesized molecules against tested micro-organisms was found to be 4c>4b>4a>4e>4f>4d.
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OBJECTIVES: To assess the different side effects of COVID-19 vaccines at different scenarios in Saudi Arabia. METHODS: This cross-sectional study sought to investigate the side effects of COVID-19 vaccines through an online survey of 2,718 participants in Saudi Arabia. RESULTS: People can manage their expectations about vaccine side effects and deal with symptoms better by knowing beforehand that they are likely to experience mild side effects for a short period, symptoms that are manifested regardless of age, and infection before or after vaccination. There are certain uncommon side effects that affect more people who got infected, and not before vaccination; there are side effects that disproportionately impact women, and also the side effects that wane after the second dose. CONCLUSION: These findings can assist in evaluating the concerns regarding vaccine acceptance. The public should be made aware that they are likely to experience at least one side effect, with temporary post-injection inflammation, musculoskeletal pain, fever, and headache as the most commonly reported side effects across the board. However, the common symptoms are mild to moderate, and the side effects last for a short period for most people.
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Vacinas contra COVID-19 , COVID-19 , Feminino , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Estudos Transversais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Arábia Saudita/epidemiologiaRESUMO
Background This study aimed to analyze the health and demographic characteristics of blood donors in Makkah, Saudi Arabia, and assess the prevalence and correlation of two markers related to hepatitis B infection: hepatitis B virus surface antigen (HBsAg) and anti-hepatitis B virus surface antibody (HBsAb). Materials and methods The study used a retrospective design and collected data from the Central Blood Bank in Makkah, Saudi Arabia, in 2022. The sample size was 7,875 blood donors. The study used various methods, such as serological testing, nucleic acid testing (NAT), and statistical analysis. The data were analyzed using Pearson correlation to examine the relationships between different variables. Results The predominant age group was 29-39 years, accounting for 46.9% of the total donors. In terms of blood types, O+ve was the most common, representing 40.3% of the donors. The investigation into infectious markers revealed overall low levels of reactivity among donors. For HBsAg, a marker of active hepatitis B infection, only 0.36% of the units were reactive. Conversely, the anti-HBsAb, which indicates immunity to hepatitis B, was reactive in 6.83% of the units. The correlation analysis illuminated some critical relationships. The total number of units tested had a statistically significant, albeit weak, positive relationship with HBsAg reactivity, shown by a Pearson correlation coefficient of 0.030 and a p-value of 0.008. Conversely, the total number of units tested and anti-HBsAb reactivity showed a moderate negative correlation, with a Pearson correlation coefficient of -0.437 and a p-value of less than 0.001. However, no significant correlation was identified between HBsAg and anti-HBsAb reactivity, indicating that active infection and immunity status might not be directly linked. Conclusion This extensive study provides in-depth insights into the sociodemographic characteristics of blood donors and the prevalence of key infectious markers within this population. It underlines the imperative of rigorous screening of blood units, particularly given the low immunity levels to hepatitis B identified. Also, the study showed the importance of screening blood units and vaccinating people against hepatitis B. It also suggested the need for more research on blood safety and infection-immunity relationships.
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OBJECTIVES: To evaluate the levels of total lymphocytes, B-lymphocytes (CD19+), T-lymphocytes (CD3+), natural killer (NK) cells (CD3-/CD56+), and monocyte subsets in type 2 diabetes mellitus (T2DM) patients in Saudi Arabia. In addition, this study aimed to evaluate whether B- and T-lymphocyte subsets are frequently altered in patients with T2DM. METHODS: A case-control study included 95 participants recruited in the study: 62 patients with T2DM and 33 healthy individuals. All the patients were admitted to the Diabetic Centre in Taif, Saudi Arabia. Blood samples were collected between April and August 2022. The hemoglobin A1c (HbA1c) level was evaluated in all patients. Flow cytometry was used to measure the expression of B-lymphocyte, T-lymphocyte, NK cells, and monocyte markers. The unpaired t-test was carried out to evaluate the differences in these markers between T2DM patients and healthy individuals. RESULTS: Patients with T2DM were associated with a lower percentage of total lymphocytes, higher percentage of B-lymphocytes, naive, and memory B subsets. In addition, patients with T2DM showed lower percentage of total T-lymphocytes (CD3+) and CD4 T-cells, but higher CD8 T-cell expression. Also, the NK-cell level was reduced in patients with T2DM, and the levels of monocyte subsets were altered. CONCLUSION: These data suggested that levels of lymphocytes and monocytes are impaired in T2DM patients, and this might be associated with the higher risk of infections observed in these patients.
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Diabetes Mellitus Tipo 2 , Monócitos , Humanos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Arábia Saudita , Linfócitos B/metabolismo , Citometria de FluxoRESUMO
Chemical signal molecules are used by bacteria to interact with one another. Small hormone-like molecules known as autoinducers are produced, released, detected, and responded to during chemical communication. Quorum Sensing (QS) is the word for this procedure; it allows bacterial populations to communicate and coordinate group behavior. Several research has been conducted on using inhibitors to prevent QS and minimize the detrimental consequences. Through the enzymatic breakdown of the autoinducer component, by preventing the formation of autoinducers, or by blocking their reception by adding some compounds (inhibitors) that can mimic the autoinducers, a technique known as "quorum quenching" (QQ) disrupts microbial communication. Numerous techniques, including colorimetry, electrochemistry, bioluminescence, chemiluminescence, fluorescence, chromatography-mass spectroscopy, and many more, can be used to test QS/QQ. They all permit quantitative and qualitative measurements of QS/QQ molecules. The mechanism of QS and QQ, as well as the use of QQ in the prevention of biofilms, are all elaborated upon in this writing, along with the fundamental study of nanoparticle (NP)in QQ. Q.
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Rett syndrome (RTT) is a rare disability causing female-oriented pediatric neurodevelopmental unmet medical need. RTT was recognized in 1966. However, over the past 56 years, the United States Food and Drug Administration (USFDA) has authorized no effective treatment for RTT. Recently, Trofinetide was approved by the USFDA on 10 March 2023 as the first RTT treatment. This article underlines the pharmaceutical advancement, patent literature, and prospects of Trofinetide. The data for this study were gathered from the PubMed database, authentic websites (Acadia Pharmaceuticals, Neuren Pharmaceuticals, and USFDA), and free patent databases. Trofinetide was first disclosed by Neuren Pharmaceuticals in 2000 as a methyl group containing analog of the naturally occurring neuroprotective tripeptide called glycine-proline-glutamate (GPE). The joint efforts of Acadia Pharmaceuticals and Neuren Pharmaceuticals have developed Trofinetide. The mechanism of action of Trofinetide is not yet well established. However, it is supposed to improve neuronal morphology and synaptic functioning. The patent literature revealed a handful of inventions related to Trofinetide, providing excellent and unexplored broad research possibilities with Trofinetide. The development of innovative Trofinetide-based molecules, combinations of Trofinetide, patient-compliant drug formulations, and precise MECP2-mutation-related personalized medicines are foreseeable. Trofinetide is in clinical trials for some neurodevelopmental disorders (NDDs), including treating Fragile X syndrome (FXS). It is expected that Trofinetide may be approved for treating FXS in the future. The USFDA-approval of Trofinetide is one of the important milestones for RTT therapy and is the beginning of a new era for the therapy of RTT, FXS, autism spectrum disorder (ASD), brain injury, stroke, and other NDDs.
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Magnesium oxide nanostructured particles (NP) were prepared using a simple solution combustion technique using different leaf extracts such as Mangifera indica (Mango - Ma), Azadirachta indica (Neem-Ne), and Carica papaya (Papaya-Pa) as surfactants. The highly crystalline phase of MgO nanostructures was confirmed by PXRD and FTIR studies for 2 h 500°C calcined samples. To analyze the characteristics of obtained material-MaNP, NeNP, and PaNP for dosimetry applications, thermoluminescence (TL) studies were carried out for Co-60 gamma rays irradiated samples in the dose range 10-50 KGy; PaNP and NeNP exhibited well-defined glow curve when compared with MaNP samples. In addition, it was observed that the TL intensity decreases, with increase in gamma dose and the glow peak temperature is shifted towards the higher temperature with the increase in heating rate. The glow peak was segregated using glow curve deconvolution and thermal cleaning method. Kinetic parameters estimated using Chen's method, trap depth (E), and frequency factor (s) were found to be 0.699, 7.408, 0.4929, and 38.71, 11.008, and 10.71 for PaNP, NeNP, and MaNP respectively. The well-resolved glow curve, good linear behavior in the dose range of 10-50, KGy, and less fading were observed in PaNP as compared with MaNP and NeNP. Further, the antibacterial activity was checked against human pathogens such as Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. A visible zone of clearance was observed at 200 and 100 µg/mL by the PaNP and NeNP, indicating the death of colonies by the nanoparticles. Therefore, PaNP nanomaterial is a potential phosphor material for dosimetry and antibacterial application compared to NeNP and MaNP.
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Clinical epidemiological studies have reported that viral infections cause autoimmune pathology in humans. Host-pathogen protein sequences and structure-based molecular mimicry cause autoreactive T cells to cross-activate. The aim of the current study was to implement immunoinformatics approaches to infer sequence- and structure-based molecular mimicry between viral and human proteomic datasets. The protein sequences of all the so far known human-infecting viruses were obtained from the VIPR database, and complete human proteome data were retrieved from the NCBI repository. Based on a predefined, stringent threshold of comparative sequence analyses, 24 viral proteins were identified with significant sequence similarity to human proteins. PathDIP identified the enrichment of these homologous proteins in nine metabolic pathways with a p-value < 0.0001. Several viral and human mimic epitopes from these homologous proteins were predicted as strong binders of human HLA alleles, with IC50 < 50 nM. Downstream molecular docking analyses identified that lead virus-human homologous epitopes feasibly interact with HLA and TLR4 types of immune receptors. The vast majority of these top-hit homolog epitopic peptides belong to the herpes simplex and poxvirus families. These lead epitope biological sequences and 3D structural-based molecular mimicry may be promising for interpreting herpes simplex virus and poxvirus infection-mediated autoimmune disorders in humans.
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OBJECTIVES: To identify potential compounds by seeking the knowledge of molecular interactions between human immunodeficiency virus (HIV) glycoprotein (gp) 120 protein and anti-HIV drug (BMS-488043). METHODS: This study is a computational structure-based drug design study, carried out at University of Taif, Saudi Arabia and African Genome Centre (AGC), Mohammed VI Polytechnic University, Benguerir, Morocco from January 2021 to March 2022. Initially, using the docked structure of gp120 with BMS-488043, a structure-based pharmacophore model was created. The generated model was utilized for virtual screening of the ZINC and ChemBridge database in order to identify hit compounds. To further assess the time-dependent stability of the selected complexes, computer simulation was performed. RESULTS: From pharmacophore-based screening, 356 hits were obtained from both the database. The docking studies of the retrieved hit compounds reveal that all the compounds fit into the binding site of gp120. However, based on the significant interactions with the crucial residues and docking scores four compounds were suggested as potential hits. MD simulation of ChemBridge14695864 and ZINC06893293 in complex with gp120 suggested that both compounds significantly stabilized the receptor. CONCLUSION: These findings could aid in the design of effective drugs against HIV by inhibiting the interaction between gp120 and CD4.
Assuntos
HIV-1 , Simulação de Dinâmica Molecular , Humanos , Simulação de Acoplamento Molecular , Ligantes , Farmacóforo , ChumboRESUMO
The current studies were focused on the phytochemical profiling of two local wild Artemisia species, Artemisia scoparia and Artemisia absinthium leaves' essential oils, extracted via the hydro distillation method along with evaluation of their antioxidant as well as antimicrobial effects. The constituents of EOs were identified using a combined gas chromatography-mass spectrometric (GC-MS) technique. A total of 25 compounds in A. scoparia essential oil (EOAS) were identified, and 14 compounds with percentage abundance of >1% were tabulated, the major being tocopherol derivatives (47.55%). A total of nine compounds in Artemisia absinthium essential oil (EOAA) were enlisted (% age > 1%), the majority being oleic acid derivatives (41.45%). Strong antioxidant effects were pronounced by the EOAS in DPPH (IC50 = 285 ± 0.82 µg/mL) and in ABTS (IC50 = 295 ± 0.32 µg/mL) free radical scavenging assays. Both the EOs remained potent in inhibiting the growth of bacterial species; Escherichia coli (55−70%) and Shigella flexneri (60−75%) however remained moderately effective against Bacillus subtilis as well as Staphylococcus aureus. Both EOAS and EOAA strongly inhibited the growth of the tested fungal species, especially Aspergillus species (up to 70%). The oils showed anti-cholinesterase potential by inhibiting both Acetylcholinesterase (AChE; IC50 = 30 ± 0.04 µg/mL (EOAS), 32 ± 0.05 µg/mL (EOAA) and Butyrylcholinesterase (BChE; IC50 = 34 ± 0.07 µg/mL (EOAS), 36 ± 0.03 µg/mL (EOAA). In conclusion, the essential oils of A. scoparia and A. absinthium are promising antioxidant, antimicrobial and anticholinergic agents with a different phytochemical composition herein reported for the first time.