Pharmaceutical Chemistry Journal最新文献

Signaling pathways guiding the reparative function of endothelial progenitor cells (EPCs) are complex. Conflicts involve the double-face role of NADPH oxidase-4 (NOX-4) and canonical Wnt/ β-catenin pathways in endothelial dysfunction. Resveratrol confers vasoprotection, yet its molecular mechanism is not clearly delineated. The study investigated whether targeting Wnt/β-catenin/NOX-4 signaling pathway could improve EPC repair in dyslipidemia, and whether it is a therapeutic target for resveratrol vasoprotection. Thirty-six Wistar rats were assigned as normal or dyslipidemic and fed on standard-chow or high-fat diet (HFD), respectively. Dyslipidemic rats received an 8-week oral vehicle or resveratrol (10 mg/kg/day). Eight weeks later, body and visceral-fat weights, and lipid profiles were assessed. Aortae were dissected for histopathological examination and immunohistochemical assessment of the EPC marker (CD133/VEGF receptor-2), and b-catenin expression. Aortic NOX-4 mRNAexpression and vascular function were performed. EPC regenerative capacity evidenced by their count and vascular reactivity was reduced by dyslipidemia. Dysregulation of endothelial Wnt/ β-catenin signaling, and NOX-4 expression were noted in conjunction with endothelial atherogenesis and oxidative stress. Resveratrol conferred endothelial protection, anti-atherogenic, and antioxidant action in HFD-fed rats. Improvement of EPC reparative potential played a pivotal role in resveratrol vasoprotection and was mediated by an endothelial Wnt/ β-catenin/NOX-4 signaling crosstalk, constituting a novel therapeutic target for improving EPC repair profile in dyslipidemia.

RAD51 is a core factor for homologous recombination to repair DNA double-strand breaks and overexpressed in breast cancer cells. Truncated peptide BRC4 (1523-1537) was obtained by computer simulation which had the highest binding free energy targeting RAD51. To enhance the binding affinity to the target protein, six nicotinic acid derivatives were modified at the N-terminal of BRC4 (1523-1537) by Fmoc solid-state synthesis to obtain nicotinamide-modified peptides. The interaction of RAD51 (181-200) with BRC4 (1523-1537) and nicotinamide-modified peptides was verified by circular dichroism (CD) spectroscopy and fluorescence spectroscopy. In conclusion, modifying small molecule pharmacophores can improve binding ability. According to spectral results, 2-chloro-5-fluoronicotinic acid modified BRC4 (1523-1537) has the most significant influence on the secondary structure of RAD51 (181-200); binding constant is 1.1×10⁴ L·mol^-1. Cell experiments showed that BRC4 (1523-1537) modified with nicotinic acid N-oxide had the best inhibitory effect on the proliferation of MDA-MB-231 cells.

A method for quantification of antihypertensive drugs (lisinopril, indapamide, metoprolol, valsartan, and amlodipine) in human blood serum was developed using high-performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS). MeOH with added fexofenadine hydrochloride as an internal standard was used for sample preparation. The developed method was validated for the following parameters: selectivity, limit of quantitation, linearity, intra- and inter-run accuracy and precision, sample transfer, matrix effect, extraction effect, and sample stability. The analytical range of the method for all analytes was 1 – 1000 ng/mL, which made it possible to assess the patient adherence to treatment and conduct therapeutic drug monitoring.

To evaluate the efficacy and safety of montelukast sodium tablets combined with budesonide suspension in the treatment of patients with bronchial asthma, ninety patients with bronchial asthma treated in The People’s Hospital of Quanjiao from January 2018 to April 2021 were randomly included in the study and then randomly divided into an observation group and a control group with 45 cases in each group. Patients in both groups were given clinical routine and symptomatic treatment. Patients in the control group were given budesonide suspension treatment on the basis of routine treatment, and patients in the observation group were treated with montelukast sodium tablets on the basis of the control group. The daytime and nighttime cough scores and asthma control scores (ACT scores) of the two groups were recorded before and after treatment. The pulmonary function indexes such as forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEFR), etc., were measured. The daytime cough score and nighttime cough score of the patients in the observation group after treatment were significantly lower than those before treatment and the control group at the same period, and the act score was significantly higher than that before treatment and the control group during the same period (P < 0.05). FEV1, FVC, PEFR and other pulmonary function indexes were significantly better than those before treatment and the control group at the same period (P < 0.05). The total clinical effective rate of the observation group was 93.33%, which was significantly higher than 71.11% of the control group (P < 0.05). There was no significant difference in the incidence of adverse reactions between the other two groups (P > 0.05). Montelukast sodium tablets combined with budesonide suspension can effectively improve cough, asthma symptoms and lung function of patients with bronchial asthma.

[This corrects the article DOI: 10.1177/17585732221124843.].

Filgrastim was pegylated by acylation with a linear 20-kDa pegylating agent (PEG agent) to search for conjugates characterized by biological activity comparable to or exceeding that of commercial drugs. The pegylation kinetics were studied at different pH values taking into account the contribution of the hydrolysis kinetics of the PEG agent. The optimal time for pegylation to a required protein conversion and the method of adding the PEG agent to the reaction mixture (once or fractionally) at a given pH value and ratio between the PEG agent and protein were calculated using a proposed equation based on previously obtained pegylation and hydrolysis rate constants. Various mixtures of pegylated positional isomers were obtained. Their contents in the mixtures depended on the pH value because of the different pK_a values of the amino-acid residues involved in the reaction. The estimated specific biological activity of the obtained monopegylated forms of Filgrastim appeared comparable with that of the product Neulastim.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disorder that affects motor neurons and has limited therapeutic approaches. Dimethyl fumarate (DMF) is a drug approved for the treatment of psoriasis and relapsing-remitting multiple sclerosis (RRMS). Here, we found that DMF improved the neuromuscular strength of Tg-SOD1^G93A mice, a well-established ALS model, without however extending the life expectancy. Also, administration of DMF increased the expression of Nqo1, indicating in vivo activation of the Nrf2 pathway, decreased the motor neuron degeneration, and suppressed the number of vacuolated neurons present in the lumbar spinal cord of Tg-SOD1^G93A mice. Thus, our study supports the further clinical evaluation of DMF for the treatment of ALS.

The pharmacological activity of flavonoids as potential candidates for the development of drugs based on biologically active substances of plant origin is confirmed by research data. The low bioavailability of flavonoids attributed to poor solubility and absorption in the gastrointestinal tract is a limiting factor in their use. Microand nano-milling technologies; complexation with surfactants, cyclodextrins, and chelating agents; and production of solid disperse systems are currently used to improve the physicochemical properties of polyphenolic compounds. Development of solid dispersion systems using hot melt extrusion is the most promising approach from the viewpoint of industrial implementation. The present review is devoted to consideration of current approaches to the use of hot extrusion of polyphenolic compounds to improve their pharmacokinetic and technological properties.

Among a large number of nitrogen-containing heterocyclic compounds, pyrazole is a privileged scaffold with the molecular formula C₃H₃N₂H. It consists of a five-membered ring with 3-carbon atoms and 2-nitrogen atoms which are present in adjacent positions. The nucleus has attracted synthetic interest due to numerous pharmacological activities. This molecule is used as one of the basic moieties for leads in the area of drug discovery and development and thereby plays a vital role in the field of medicinal chemistry. The present review article highlights the SAR studies of potent compounds of pyrazole and its derivatives (2015–2022) reported as anti-inflammatory, anticancer, antidiabetic, anticonvulsant, antimicrobial, antimycobacterial, antineurodegenerative and antioxidant. Furthermore, a patent application published in this period is also discussed. Google, PubMed, Cochrane, Scopus, ResearchGate, Google Scholar, and Science Direct were primarily used for article search, whereas the databases used for the pyrazole patent were Espacenet, Google Patent, and SciFinder. More than one hundred thirty papers were screened after which inclusion and exclusion criteria were applied to make this review article. We hope the current review article can pave the way for the future drug design and development of pyrazole derivatives as a potential drug candidate.

Ulcerative colitis is one of the most common intestinal diseases in the world. Lycium barbarum (Goji Berry) is a type of fruit that is frequently used in alternative medicine, with antioxidant, antimicrobial, anti-aging, and anti-inflammatory effects. Although the effect of Lycium barbarum (LB) on intestinal diseases has been extensively studied, the mechanism of action on apoptosis and autophagic pathways in the ulcerative colitis model has not yet been fully elucidated. In this study, the effect of LB on the apoptosis and autophagy pathways in the ulcerative colitis model was investigated. Wistar albino male rats were used in the study. DSS chemical was used to create an ulcerative colitis model and LB was used to prevent colitis formation. In our study, in the LB+DSS group compared to the DSS group, wherein it was determined that p53 and Beclin 1 protein levels increased, TIGAR protein level decreased, MDA levels decreased, GSH level and catalase activity increased. Also, in the histopathological results, ulcerative colitis did not occur in the LB+DSS group. In general, our findings show that LB prevents the formation of ulcerative colitis, reduces damage, and activates the defense and apoptosis/autophagy mechanisms. When the results of our study are evaluated as a whole, we can say that LB has a promising potential to prevent ulcerative colitis.