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Pharmaceuticals (Basel, Switzerland) Apr 2024Facile access to some novel biologically relevant dihydrotriazolopyrimidine carboxylic acid-derived amide analogues using NMI/SOCl, and aromatic and aliphatic primary...
Facile access to some novel biologically relevant dihydrotriazolopyrimidine carboxylic acid-derived amide analogues using NMI/SOCl, and aromatic and aliphatic primary and secondary amines, is reported herein. The role of -methylimidazole (NMI) as the base and sulfuryl chloride (SOCl) as the coupling reagent has been effectively realized in accessing these molecules in good to excellent yields. The feasibility of the developed protocol has also been extended to the gram-scale synthesis of -benzylbenzamide in a 75% yield from benzoic acid and benzyl amine. The newly synthesized compounds were tested via in vitro anti-inflammatory and anti-tubercular activity studies. The compounds and were found to be the most active anti-inflammatory agents, whereas and were found to exhibit promising anti-tubercular potency when compared to other synthesized molecules. The structure-activity relationship (SAR) studies revealed the importance of the presence of electron-donating functionalities in enhancing the anti-inflammatory potential of the newly synthesized molecules. However, the presence of electron-withdrawing substituents was found to be significant for improving their anti-tubercular potency.
PubMed: 38794119
DOI: 10.3390/ph17050548 -
Viruses May 2024The coexistence of HIV infection and latent tuberculosis infection (LTBI) presents a significant public health concern due to the increased risk of tuberculosis (TB)... (Observational Study)
Observational Study
BACKGROUND
The coexistence of HIV infection and latent tuberculosis infection (LTBI) presents a significant public health concern due to the increased risk of tuberculosis (TB) reactivation and progression to active disease. The multicenter observational cohort study, TUBHIVIT, conducted in Italy from 2017 to 2023, aimed to assess the prevalence of LTBI among people living with HIV (PLHIV) and their outcomes following LTBI screening and therapy initiation.
METHODS
We performed a prospective study in five referral centers for HIV care in Italy. PLHIV who consented Tto participate underwent QuantiFERON-TB Gold Plus and clinical, microbiological, and radiological assessments to exclude subclinical tuberculosis, as opportune. PLHIV diagnosed with LTBI who started chemoprophylaxis were followed until the end of therapy.
RESULTS
A total of 1105 PLHIV were screened for LTBI using the QuantiFERON-TB Gold Plus test, revealing a prevalence of 3.4% of positive results (38/1105). Non-Italy-born individuals exhibited a significantly higher likelihood of testing positive. Thirty-one were diagnosed with LTBI, 1 showed active subclinical TB, and 6 were lost to follow-up before discriminating between latent and active TB. Among the PLHIV diagnosed with LTBI, 83.9% (26/31) started chemoprophylaxis. Most individuals received 6-9 months of isoniazid-based therapy. Of the 26 PLHIV commencing chemoprophylaxis, 18 (69.2%) completed the therapy, while 3 discontinued it and 5 were still on treatment at the time of the analysis. Adverse events were observed in two cases, while in one case the patient refused to continue the treatment.
Topics: Humans; Latent Tuberculosis; Italy; Male; Female; Adult; HIV Infections; Prospective Studies; Middle Aged; Mass Screening; Prevalence; Antitubercular Agents; Isoniazid; Coinfection
PubMed: 38793658
DOI: 10.3390/v16050777 -
Viruses Apr 2024Chronic immune activation in tuberculosis (TB) associated with human immunodeficiency virus (HIV) infection (HIV/TB) modifies their clinical course. We prospectively...
Chronic immune activation in tuberculosis (TB) associated with human immunodeficiency virus (HIV) infection (HIV/TB) modifies their clinical course. We prospectively measured osteopontin (OPN), full-length galectin-9 (FL-Gal9), and total-Gal9 (T-Gal9) levels in 32 patients with HIV/TB coinfection treated with anti-tuberculosis and antiretroviral therapies over 6-18 months to determine the amelioration of inflammatory conditions in response to the therapies. We observed a significant time-dependent decrease in FL-Gal9 in both pulmonary TB (PTB, n = 20) and extrapulmonary TB (EPTB, n = 12) patients. The levels of T-Gal9, OPN, and CRP decreased significantly after treatment in only PTB patients. We calculated the inflammatory score (INS) indicating immunologic recovery based on the decline in OPN, FL-Gal9, T-Gal9, and CRP levels. Baseline levels of T-Gal9 and OPN positively correlated with INS in all TB and only PTB patients, respectively, indicating that their levels predict better recovery. In contrast, FL-Gal9 levels at the second visit negatively correlated with INS in EPTB patients. The decrease rate in OPN levels at the second visit also correlated positively with INS in PTB patients. Women showed a higher INS and lower levels of FL-Gal9 than men. The patients with moderate grade severity on chest X-ray had higher CD4 cell numbers than those with limited grade severity. Monitoring these markers will help to predict and assess the response to therapy as well as to devise strategies to reduce the complications caused by chronic immune activation in patients with HIV/TB coinfection.
Topics: Humans; HIV Infections; Female; Male; Coinfection; Adult; Osteopontin; Galectins; Tuberculosis; Middle Aged; Prospective Studies; Biomarkers; Antitubercular Agents; Tuberculosis, Pulmonary; C-Reactive Protein
PubMed: 38793546
DOI: 10.3390/v16050664 -
A New 2-Aminospiropyrazolylammonium Cation with Possible Uses in the Topical Areas of Ionic Liquids.Molecules (Basel, Switzerland) May 2024Based on the fact that 2-aminospiropyrazolinium compounds and structurally related azoniaspiro compounds belong, in a broad sense, to the class of ionic liquids, we have... (Review)
Review
Based on the fact that 2-aminospiropyrazolinium compounds and structurally related azoniaspiro compounds belong, in a broad sense, to the class of ionic liquids, we have reviewed them and studied their practical applications. To search for possible uses of a new 2-aminospiropyrazolinium compounds, it is necessary to undertake a comparison with the related class of azoniaspiro compounds based on available information. The structures of the well-studied class of azoniaspiro compounds and the related but little-studied class of 2-aminospiropyrazolinium have rigid frameworks, limited conformational freedom, and a salt nature. These properties give them the ability to organize the nearby molecular space and enable the structure-forming ability of azoniaspiro compounds in the synthesis of zeolites, as well as the ability to act as phase-transfer catalysts and have selective biological effects. Additionally, these characteristics enable their ability to act as electrolytes and serve as materials for anion exchange membranes in fuel cells and water electrolyzers. Thus, the well-studied properties of azoniaspiro compounds as phase-transfer catalysts, structure-directing agents, electrolytes, and materials for membranes in power sources would encourage the study of the similar properties of 2-aminospiropyrazolinium compounds, which we have studied in relation to in vitro antitubercular, antidiabetic, and antimicrobial activities.
PubMed: 38792187
DOI: 10.3390/molecules29102326 -
International Journal of Molecular... May 2024The interactions with calf thymus DNA (CT-DNA) of three Schiff bases formed by the condensation of hesperetin with benzohydrazide (HHSB or LH), isoniazid (HIN or LH), or...
The interactions with calf thymus DNA (CT-DNA) of three Schiff bases formed by the condensation of hesperetin with benzohydrazide (HHSB or LH), isoniazid (HIN or LH), or thiosemicarbazide (HTSC or LH) and their Cu complexes (CuHHSB, CuHIN, and CuHTSC with the general formula [CuLH(AcO)]) were evaluated in aqueous solution both experimentally and theoretically. UV-Vis studies indicate that the ligands and complexes exhibit hypochromism, which suggests helical ordering in the DNA helix. The intrinsic binding constants () of the Cu compounds with CT-DNA, in the range (2.3-9.2) × 10, from CuHTSC to CuHHSB, were higher than other copper-based potential drugs, suggesting that π-π stacking interaction due to the presence of the aromatic rings favors the binding. Thiazole orange (TO) assays confirmed that ligands and Cu complexes displace TO from the DNA binding site, quenching the fluorescence emission. DFT calculations allow for an assessment of the equilibrium between [Cu(LH)(AcO)] and [Cu(LH)(HO)], the tautomer that binds Cu, amido (am) and not imido (im), and the coordination mode of HTSC (O, N, S), instead of (O, N, NH). The docking studies indicate that the intercalative is preferred over the minor groove binding to CT-DNA with the order [Cu(LH)(AcO)] > [Cu(LH)(AcO)] ≈ TO ≈ LH > [Cu(LH)(AcO)], in line with the experimental constants, obtained from the UV-Vis spectroscopy. Moreover, dockings predict that the binding strength of [Cu(LH)(AcO)] is larger than [Cu(LH)(HO)]. Overall, the results suggest that when different enantiomers, tautomers, and donor sets are possible for a metal complex, a computational approach should be recommended to predict the type and strength of binding to DNA and, in general, to macromolecules.
Topics: DNA; Schiff Bases; Hesperidin; Copper; Coordination Complexes; Animals; Cattle; Ligands; Molecular Docking Simulation; Isoniazid; Semicarbazides
PubMed: 38791321
DOI: 10.3390/ijms25105283 -
International Journal of Molecular... May 2024The main focus of in vitro toxicity assessment methods is to assess the viability of the cells, which is usually based on metabolism changes. Yet, when exposed to toxic...
The main focus of in vitro toxicity assessment methods is to assess the viability of the cells, which is usually based on metabolism changes. Yet, when exposed to toxic substances, the cell triggers multiple signals in response. With this in mind, we have developed a promising cell-based toxicity method that observes various cell responses when exposed to toxic substances (either death, division, or remain viable). Based on the collective cell response, we observed and predicted the dynamics of the cell population to determine the toxicity of the toxicant. The method was tested with two different conformations: In the first conformation, we exposed a monoculture model of blood macrophages to UV light, hydrogen peroxide, nutrient deprivation, tetrabromobisphenol A, fatty acids, and 5-fluorouracil. In the second, we exposed a coculture liver model consisting of hepatocytes, hepatic stellate cells, Kupffer cells, and liver sinusoidal endothelial cells to rifampicin, ibuprofen, and 5-fluorouracil. The method showed good accuracy compared to established toxicity assessment methods. In addition, this approach provided more representative information on the toxic effects of the compounds, as it considers the different cellular responses induced by toxic agents.
Topics: Humans; Fluorouracil; Macrophages; Hepatocytes; Toxicity Tests; Hydrogen Peroxide; Cell Survival; Animals; Coculture Techniques; Ultraviolet Rays; Endothelial Cells; Liver; Ibuprofen; Cells, Cultured; Rifampin; Hepatic Stellate Cells
PubMed: 38791172
DOI: 10.3390/ijms25105133 -
Marine Drugs Apr 2024Influenza A virus (IAV) can cause infection and illness in a wide range of animals, including humans, poultry, and swine, and cause annual epidemics, resulting in...
Influenza A virus (IAV) can cause infection and illness in a wide range of animals, including humans, poultry, and swine, and cause annual epidemics, resulting in thousands of deaths and millions of hospitalizations all over the world. Thus, there is an urgent need to develop novel anti-IAV drugs with high efficiency and low toxicity. In this study, the anti-IAV activity of a marine-derived compound mycophenolic acid methyl ester (MAE) was intensively investigated both in vitro and in vivo. The results showed that MAE inhibited the replication of different influenza A virus strains in vitro with low cytotoxicity. MAE can mainly block some steps of IAV infection post adsorption. MAE may also inhibit viral replication through activating the cellular Akt-mTOR-S6K pathway. Importantly, oral treatment of MAE can significantly ameliorate pneumonia symptoms and reduce pulmonary viral titers, as well as improving the survival rate of mice, and this was superior to the effect of oseltamivir. In summary, the marine compound MAE possesses anti-IAV effects both in vitro and in vivo, which merits further studies for its development into a novel anti-IAV drug in the future.
Topics: Animals; Antiviral Agents; Influenza A virus; Mycophenolic Acid; Mice; Virus Replication; Humans; Orthomyxoviridae Infections; Mice, Inbred BALB C; Dogs; Female; Madin Darby Canine Kidney Cells; A549 Cells; Aquatic Organisms; Influenza, Human
PubMed: 38786581
DOI: 10.3390/md22050190 -
PeerJ 2024Antibiotics are commonly used for controlling microbial growth in diseased organisms. However, antibiotic treatments during early developmental stages can have negative...
BACKGROUND
Antibiotics are commonly used for controlling microbial growth in diseased organisms. However, antibiotic treatments during early developmental stages can have negative impacts on development and physiology that could offset the positive effects of reducing or eliminating pathogens. Similarly, antibiotics can shift the microbial community due to differential effectiveness on resistant and susceptible bacteria. Though antibiotic application does not typically result in mortality of marine invertebrates, little is known about the developmental and transcriptional effects. These sublethal effects could reduce the fitness of the host organism and lead to negative changes after removal of the antibiotics. Here, we quantify the impact of antibiotic treatment on development, gene expression, and the culturable bacterial community of a model cnidarian, .
METHODS
Ampicillin, streptomycin, rifampicin, and neomycin were compared individually at two concentrations, 50 and 200 µg mL, and in combination at 50 µg mL each, to assess their impact on . First, we determined the impact antibiotics have on larval development. Next Amplicon 16S rDNA gene sequencing was used to compare the culturable bacteria that persist after antibiotic treatment to determine how these treatments may differentially select against the native microbiome. Lastly, we determined how acute (3-day) and chronic (8-day) antibiotic treatments impact gene expression of adult anemones.
RESULTS
Under most exposures, the time of larval settlement extended as the concentration of antibiotics increased and had the longest delay of 3 days in the combination treatment. Culturable bacteria persisted through a majority of exposures where we identified 359 amplicon sequence variants (ASVs). The largest proportion of bacteria belonged to Gammaproteobacteria, and the most common ASVs were identified as and . The acute antibiotic exposure resulted in differential expression of genes related to epigenetic mechanisms and neural processes, while constant application resulted in upregulation of chaperones and downregulation of mitochondrial genes when compared to controls. Gene Ontology analyses identified overall depletion of terms related to development and metabolism in both antibiotic treatments.
DISCUSSION
Antibiotics resulted in a significant increase to settlement time of larvae. Culturable bacterial species after antibiotic treatments were taxonomically diverse. Additionally, the transcriptional effects of antibiotics, and after their removal result in significant differences in gene expression that may impact the physiology of the anemone, which may include removal of bacterial signaling on anemone gene expression. Our research suggests that impacts of antibiotics beyond the reduction of bacteria may be important to consider when they are applied to aquatic invertebrates including reef building corals.
Topics: Animals; Anti-Bacterial Agents; Sea Anemones; Larva; Ampicillin; Neomycin; Streptomycin; Rifampin; Gene Expression
PubMed: 38784394
DOI: 10.7717/peerj.17349 -
JPMA. the Journal of the Pakistan... May 2024To compare the efficacy of mycophenolate mofetil with intravenous cyclophosphamideas induction therapy in lupus nephritis. (Observational Study)
Observational Study Comparative Study
OBJECTIVES
To compare the efficacy of mycophenolate mofetil with intravenous cyclophosphamideas induction therapy in lupus nephritis.
METHODS
The observational, prospecrive, cohort study was conducted at the Rheumatology Department of Fatima Memorial Hospital, Lahore, Pakistan, from July 2016 to June 2019, and comprised lupus nephritis patients. For induction therapy, the patients were assigned at the discretion of the treating rheumatologist to mycophenolate mofetil group MMF, and intravenous cyclophosphamide group CYC. The latter group was further divided into NIH subgroup that received the therapy as per the protocol of the National Institutes of Health, and ELNT subgroup which recived the therapy as per the Euro Lupus Nephritis Trial protocol. Maintenance therapy in all groups was mycophenolate mofetil. Tacrolimus was added in case of non-response. The outcome was the achievement of complete renal response at 6, 12 and 24 months. Data was analysed using SPSS 26.
RESULTS
Of the 131 patients, 126(96.2%) were females. The overall mean age was 27±7.7 years. There were 58(44.2%) patients in group MMF and 73(55.7%) in group CYC, which had subgroup NIH 46(63%) and subgrpup ELNT 27(37%). The complete renal response rates at 6, 12, and 24 months were 22 (43.1%), 35 (71.4%), and 40(83.3%) for group MMF; 5(12.5%), 9(22%) and 24 (58.5%) for subgroup NIH, and 6(26.1%), 8(36.4%) and 14(63.6%) for subgroup ELNT. Group MMF outcomes were significantly better than the rest (p<0.05).
CONCLUSIONS
Mycophenolate mofetil induction therapy was more effective than intraveenous cyclophosphamide in terms of achieving remission at 6, 12 and 24 months.
Topics: Humans; Lupus Nephritis; Mycophenolic Acid; Cyclophosphamide; Female; Adult; Pakistan; Male; Immunosuppressive Agents; Tertiary Care Centers; Young Adult; Treatment Outcome; Cohort Studies; Tacrolimus; Induction Chemotherapy; Remission Induction
PubMed: 38783432
DOI: 10.47391/JPMA.8694 -
BMC Public Health May 2024Identifying patients at increased risk of loss to follow-up (LTFU) is key to developing strategies to optimize the clinical management of tuberculosis (TB). The use of...
BACKGROUND
Identifying patients at increased risk of loss to follow-up (LTFU) is key to developing strategies to optimize the clinical management of tuberculosis (TB). The use of national registry data in prediction models may be a useful tool to inform healthcare workers about risk of LTFU. Here we developed a score to predict the risk of LTFU during anti-TB treatment (ATT) in a nationwide cohort of cases using clinical data reported to the Brazilian Notifiable Disease Information System (SINAN).
METHODS
We performed a retrospective study of all TB cases reported to SINAN between 2015 and 2022; excluding children (< 18 years-old), vulnerable groups or drug-resistant TB. For the score, data before treatment initiation were used. We trained and internally validated three different prediction scoring systems, based on Logistic Regression, Random Forest, and Light Gradient Boosting. Before applying our models we splitted our data into training (~ 80% data) and test (~ 20%) sets, and then compared the model metrics using the test data set.
RESULTS
Of the 243,726 cases included, 41,373 experienced LTFU whereas 202,353 were successfully treated. The groups were different with regards to several clinical and sociodemographic characteristics. The directly observed treatment (DOT) was unbalanced between the groups with lower prevalence in those who were LTFU. Three models were developed to predict LTFU using 8 features (prior TB, drug use, age, sex, HIV infection and schooling level) with different score composition approaches. Those prediction scoring systems exhibited an area under the curve (AUC) ranging between 0.71 and 0.72. The Light Gradient Boosting technique resulted in the best prediction performance, weighting specificity and sensitivity. A user-friendly web calculator app was developed ( https://tbprediction.herokuapp.com/ ) to facilitate implementation.
CONCLUSIONS
Our nationwide risk score predicts the risk of LTFU during ATT in Brazilian adults prior to treatment commencement utilizing schooling level, sex, age, prior TB status, and substance use (drug, alcohol, and/or tobacco). This is a potential tool to assist in decision-making strategies to guide resource allocation, DOT indications, and improve TB treatment adherence.
Topics: Humans; Male; Female; Registries; Retrospective Studies; Adult; Brazil; Middle Aged; Lost to Follow-Up; Machine Learning; Tuberculosis; Young Adult; Antitubercular Agents; Adolescent; Algorithms
PubMed: 38783264
DOI: 10.1186/s12889-024-18815-0