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Journal of the American Chemical Society Jun 2024The incorporation of three-dimensional structures into drug molecules has demonstrated significant improvements in clinical success. Late-stage saturation of drug...
The incorporation of three-dimensional structures into drug molecules has demonstrated significant improvements in clinical success. Late-stage saturation of drug molecules provides a direct pathway for this transformation. However, achieving selective and controllable reduction of aromatic rings remains challenging, particularly when multiple aromatic rings coexist. Herein, we present the switchable and chemoselective hydrogenation of benzene and pyridine rings. The utility of the protocol has been comprehensively investigated in diversified substrates with the assistance of a fragment-screening technique. This approach provides convenient access to a diverse array of cyclohexane and piperidine compounds, prevalent in various bioactive molecules and drugs. Furthermore, it discloses promising avenues for applications in the late-stage switchable saturation of drugs, facilitating an increase in the fraction of sp-carbons which holds the potential to enhance the medicinal properties of drugs.
PubMed: 38934861
DOI: 10.1021/jacs.4c05883 -
Virulence Dec 2024The implementation of pretreatment drug-resistance (PDR) surveillance among people living with HIV-1 (PLWH) is a top priority in countries using efavirenz...
The implementation of pretreatment drug-resistance (PDR) surveillance among people living with HIV-1 (PLWH) is a top priority in countries using efavirenz (EFV)/nevirapine (NVP) for first-line ART. In this study, we assessed the prevalence of PDR among PLWH in Shanghai, China during 2017-2021, and to reveal PDR transmission between Shanghai and other regions of China. A total of 5050 PLWH not on ART during 2017-2021 were included. Partial HIV-1 sequences were amplified, sequenced, and analysed for drug-resistance mutations (DRMs). Besides, transmission network of PDR variants was inferred using HIV-TRACE. The overall prevalence of PDR was 4.8% (242/5050; 95% CI, 4.2-5.4). Prevalence of NNRTI-associated PDR was 3.9% (95% CI, 3.4-4.5), higher than those of NRTI-associated (0.8%; 95% CI, 0.5-1.1) and PI-associated PDR (0.9%; 95% CI, 0.6-1.2). High prevalence of PDR (especially high-level resistance) to EFV (132/5050, 2.6%) and NVP (137/5050, 2.7%) were found. CRF01_AE (46.0%) was the predominant HIV-1 genotype with any DRMs, followed by CRF55_01B (21.0%), and CRF07_BC (15.1%). Two NRTI-associated (S68G/N/R and T215A/N/S/Y), five NNRTI-associated (V179D/E/T/L, K103N/R/S/T, E138A/G/K, V106M/I/A and Y181C/I) and two PI-associated mutations (M46I/L/V and Q58E) were the most common observed DRMs in PDR patients in Shanghai. The vast majority of S68G occurred in CRF01_AE (45%). M46I/L/V and Q58E showed a relatively high prevalence in CRF01_AE (4.1%) and CRF07_BC (12.6%). Transmission network analyses demonstrated cross-regional transmission links of PDR variants between Shanghai and other regions of China, which was mainly driven by the potential low-level DRM V179D/E. These results provide crucial information for clinical decision making of first-line ART in PLWH with PDR.
Topics: Humans; China; HIV-1; HIV Infections; Male; Drug Resistance, Viral; Female; Prevalence; Adult; Middle Aged; Anti-HIV Agents; Mutation; Young Adult; Cyclopropanes; Alkynes; Benzoxazines; Adolescent; Genotype; Nevirapine; Aged
PubMed: 38934465
DOI: 10.1080/21505594.2024.2373105 -
Angewandte Chemie (International Ed. in... Jun 2024We show an unexpected aggregation phenomenon of a long oligoyne (Py[16]) with 16 contiguous triple bonds and endcapped with bulky...
We show an unexpected aggregation phenomenon of a long oligoyne (Py[16]) with 16 contiguous triple bonds and endcapped with bulky 3,5-bi(3,5-bis-tert-butylphenyl)pyridine groups. Aggregation of 1D p-conjugated oligoyne chains is rare, given the minimal p-p intermolecular interactions of the weakly polarizable polyyne chain, as well as its flexibility that works against self assembly. In dilute solutions, the reversible aggregation of Py[16] initiates at low temperature in the range of 140-180 K, and is not observed for shorter oligoynes in this series. Cryogenic UV-Vis electronic absorption spectra and vibrational Raman spectra with different laser wavelength lines tuning from in-resonance to off-resonance conditions have been used to extract the vibrational features characterizing the Monomer and aggregate species. Theoretical calculations complement the spectroscopic findings.
PubMed: 38934233
DOI: 10.1002/anie.202404014 -
Frontiers in Endocrinology 2024Tryptophan's (Trp) metabolites are undervalued markers of human health. Their serum concentrations are modified by physical exercise and other factors, among which...
INTRODUCTION
Tryptophan's (Trp) metabolites are undervalued markers of human health. Their serum concentrations are modified by physical exercise and other factors, among which fasting has a well-documented role. Although this mechanism is hardly explored, thus, the study aimed to determine the effect of the 8-day fasting period and the impact of such a procedure on a single bout of an endurance exercise on the concentration of kynurenine pathway (KP) metabolites.
METHODS
10 participants fasted for 8 days, and 10 as a control group participated in the study. The exercise was performed at baseline after an overnight fast and repeated post 8 days.
RESULTS
The 8 days of fasting increased the resting 3-hydroxy-L-kynurenine (3HK), picolinic acid (PA), kynurenic acid (KYNA), and xanthurenic acid (XA) serum concentration. Also elevated phenylalanine (Phe) and tyrosine (Tyr) levels were recorded, suggesting expanded proteolysis of muscle proteins. In turn, physical activity caused a decrease in the concentration of 3-hydroxyanthranilic acid (3HAA) and PA after fasting. The obtained results were not recorded in controls.
CONCLUSION
The results of this study show that the health-promoting effects of fasting are associated with changes in the KYN pathway. The increase in the concentration of PA and XA metabolites following fasting is capable of penetrating the blood-brain barrier, and KYNA, which initiates several beneficial changes, supports this assumption.
Topics: Humans; Male; Fasting; Kynurenine; Exercise; Adult; Young Adult; Rest; Healthy Volunteers; Kynurenic Acid; Tryptophan; Biomarkers; Picolinic Acids
PubMed: 38933822
DOI: 10.3389/fendo.2024.1403491 -
The Pan African Medical Journal 2024tuberculosis (TB) and Human Immunodeficiency Virus (HIV) remain major public health threats globally and worse when they co-exist in susceptible individuals. The study...
INTRODUCTION
tuberculosis (TB) and Human Immunodeficiency Virus (HIV) remain major public health threats globally and worse when they co-exist in susceptible individuals. The study examined TB treatment outcomes and their predictive factors among people living with HIV (PLHIVs).
METHODS
a review of TB/HIV co-infected patients who had TB treatments across comprehensive antiretroviral therapy (ART) sites with ≥500 patients was conducted in seven United States of America President's Emergency Plan for AIDS Relief (PEPFAR)-supported States in Nigeria. Data on patient background, HIV and TB care, and TB treatment outcomes were collected using an Excel abstraction template. The data was analyzed using SPSS and an association was examined using a chi-square test while binary logistic regression was used to determine predictors of TB treatment outcomes (P< 0.05).
RESULTS
two thousand six hundred and fifty-two co-infected patients participated in the study. The mean age of participants was 37 ± 14 years. A majority had TB treatment success (cured = 1059 (39.9%), completed = 1186 (44.7%)). Participants who had pulmonary TB, virally suppressed and commenced isoniazid (INH) before TB diagnosis were more likely to have a favorable TB treatment outcome compared to those who had extrapulmonary TB (AOR = 7.110, 95% CI = 1.506 - 33.565), virally unsuppressed (AOR = 1.677, 95% CI = 1.036 - 2.716) or did not commence INH before TB diagnosis (AOR = 1.486, 95% CI = 1.047 - 2.109).
CONCLUSION
site of infection, immune status, exposure to ART, and INH prophylaxis were found to predict TB treatment outcomes among PLHIVs. Stakeholders should ensure early commencement of ART and INH prophylaxis for PLHIVs.
Topics: Humans; Nigeria; HIV Infections; Adult; Female; Antitubercular Agents; Male; Tuberculosis; Middle Aged; Coinfection; Treatment Outcome; Young Adult; Anti-HIV Agents; Isoniazid; Retrospective Studies; Tuberculosis, Pulmonary
PubMed: 38933432
DOI: 10.11604/pamj.2024.47.149.35719 -
AIDS (London, England) Jul 2024
Topics: Humans; Female; Pregnancy; Pyridones; HIV Infections; Pregnancy Complications, Infectious; Tenofovir; Anti-HIV Agents; Oxazines; Heterocyclic Compounds, 3-Ring; Lamivudine; Piperazines; Treatment Outcome
PubMed: 38932745
DOI: 10.1097/QAD.0000000000003911 -
Molecules (Basel, Switzerland) Jun 2024MnO has attracted much attention as the anode for Li-ion batteries (LIBs) owing to its high specific capacity. However, the low conductivity limited its large...
MnO has attracted much attention as the anode for Li-ion batteries (LIBs) owing to its high specific capacity. However, the low conductivity limited its large application. An effective solution to solve this problem is carbon coating. Biomass carbon materials have aroused much interest for being low-cost and rich in functional groups and hetero atoms. This work designs porous N-containing MnO composites based on the chemical-activated tremella using a self-templated method. The tremella, after activation, could offer more active sites for carbon to coordinate with the Mn ions. And the as-prepared composites could also inherit the special porous nanostructures of the tremella, which is beneficial for Li transfer. Moreover, the pyrrolic/pyridinic N from the tremella can further improve the conductivity and the electrolyte wettability of the composites. Finally, the composites show a high reversible specific capacity of 1000 mAh g with 98% capacity retention after 200 cycles at 100 mA g. They also displayed excellent long-cycle performance with 99% capacity retention (relative to the capacity second cycle) after long 1000 cycles under high current density, which is higher than in most reported transition metal oxide anodes. Above all, this study put forward an efficient and convenient strategy based on the low-cost biomass to construct N-containing porous composite anodes with a fast Li diffusion rate, high electronic conductivity, and outstanding structure stability.
PubMed: 38931003
DOI: 10.3390/molecules29122939 -
Molecules (Basel, Switzerland) Jun 2024In-depth insights into the oligomers of carbon dots (CDs) prepared from small-molecule precursors are important in the study of the carbonization mechanism of CDs and...
In-depth insights into the oligomers of carbon dots (CDs) prepared from small-molecule precursors are important in the study of the carbonization mechanism of CDs and for our knowledge of their complex structure. Herein, citric acid (CA) and ethylenediamine (EDA) were used as small-molecule precursors to prepare CDs in an aqueous solution. The structure of oligomers acquired from CA and EDA in different molar ratios and their formation process were first studied using density functional theory, including the dispersion correction (DFT-D3) method. The results showed that the energy barrier of dimer cyclization was higher than that of its linear polymerization, but the free energy of the cyclized product was much lower than that of its reactant, and IPCA (5-oxo-1,-2,3,5-tetrahydroimidazo [1,2-a]pyridine-7-carboxylic acid) could therefore be obtained under certain conditions. The oligomers obtained from different molar ratios of EDA and CA were molecular clusters formed by short polyamide chains through intermolecular forces; with the exception of when the molar ratio of EDA to CA was 0.5, excessive CA did not undergo an amidation reaction but rather attained molecular clusters directly through intermolecular forces. These oligomers exhibited significant differences in their surface functional groups, which would affect the carbonization process and the surface structure of CDs.
PubMed: 38930988
DOI: 10.3390/molecules29122920 -
Molecules (Basel, Switzerland) Jun 2024Conformations in the solid state are typically fixed during crystallization. Transference of "frozen" C=C conformations in...
Conformations in the solid state are typically fixed during crystallization. Transference of "frozen" C=C conformations in 3,5-bis((E)-2-(pyridin-4-yl)vinyl)methylbenzene (CH-3,5-bpeb) by photodimerization selectively yielded cyclobutane and dicyclobutane isomers, one of which (Isomer 2) exhibited excellent in vitro anti-cancer activity towards T-24, 7402, MGC803, HepG-2, and HeLa cells.
Topics: Cyclobutanes; Humans; Molecular Conformation; Antineoplastic Agents; Stereoisomerism; Cell Line, Tumor; HeLa Cells; Hep G2 Cells; Isomerism
PubMed: 38930974
DOI: 10.3390/molecules29122909 -
Molecules (Basel, Switzerland) Jun 2024Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated...
Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated the protective effects of trametinib, an FDA-approved selective inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), against cisplatin-induced acute kidney injury (AKI) in mice. The experimental design included four groups, control, trametinib, cisplatin, and a combination of cisplatin and trametinib, each consisting of eight mice. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to induce kidney injury, while trametinib was administered via oral gavage at 3 mg/kg daily for three days. Assessments were conducted 72 h after cisplatin administration. Our results demonstrate that trametinib significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities. Additionally, trametinib significantly decreased macrophage infiltration and the expression of pro-inflammatory cytokines in the kidneys. It also lowered lipid peroxidation by-products, restored the reduced glutathione/oxidized glutathione ratio, and downregulated NADPH oxidase 4. Furthermore, trametinib significantly inhibited both apoptosis and necroptosis in the kidneys. In conclusion, our data underscore the potential of trametinib as a therapeutic agent for cisplatin-induced AKI, highlighting its role in reducing inflammation, oxidative stress, and tubular cell death.
Topics: Animals; Cisplatin; Acute Kidney Injury; Pyridones; Oxidative Stress; Mice; Pyrimidinones; Disease Models, Animal; Inflammation; Male; Cell Death; Apoptosis; Kidney Tubules; Lipid Peroxidation; Cytokines; MAP Kinase Signaling System
PubMed: 38930946
DOI: 10.3390/molecules29122881