BMC Pharmacology & Toxicology最新文献

Leukemia, a hematologic malignancy, frequently involves the overexpression of BCL-2 proteins, contributing to cell survival and apoptosis resistance. Although current BCL-2 inhibitors, including Venetoclax, have shown efficacy, they are limited by adverse side effects and restricted bioavailability. This study employs an integrated computational approach to identify natural BCL-2 inhibitors by screening 407,270 natural compounds. Using ligand- and structure-based virtual screening, we identified two promising compounds, CNP0237679 and CNP0420384, demonstrating strong binding affinities, favorable electronic properties, and stability in dynamic aqueous environments. Both compounds exhibited promising toxicity and pharmacokinetic profiles, indicating the possibility of low toxicity and high bioavailability. They are potential candidates for developing selective BCL-2 inhibitors because of these characteristics. The findings represent a positive step in developing new, naturally derived BCL-2 inhibitors and support additional in vitro and in vivo studies to validate their therapeutic efficacy and safety characteristics.

Background: Oxidative stress plays a central role in the degeneration of dopaminergic neurons and is a key factor in the pathogenesis of Parkinson's disease (PD). Therefore, antioxidant therapy represents a promising therapeutic strategy. This process involves numerous enzymes and signaling pathways that contribute to disease progression. In the present study, bacterial melanin (BM), known for its high biological activity and biostimulatory effects, was applied as a potential antioxidant. We examined quantitative and qualitative alterations in total fractions of biomembrane-associated components derived from rat tissue in a rotenone-induced PD model, under both low and high BM concentrations, along with an evaluation of their antioxidant properties.

Methods: PD was induced via intracerebral rotenone injection, and the animals were maintained for 4 weeks. BM was administered twice during the survival period at concentrations of 4.5 mg/ml and 9 mg/ml. To confirm disease progression and evaluate potential therapeutic effects of BM, the Rotarod behavioral test was performed following a 4-week survival period. From the biomembranes of brain, lung, and small intestine tissues, superoxide-generating associates were isolated. Their specific amounts (mg/g) and steady-state concentrations of superoxide (O₂⁻) (M) were determined to assess oxidative stress. Antioxidant activity was quantified using the Coomassie Brilliant Blue (CBB) dye decoloration method.

Results: The results demonstrated that BM exerted a membrane-stabilizing effect, with the 9 mg/ml dose proving more effective than 4.5 mg/ml. BM modulated membrane formation across the brain, lung, and small intestine by inhibiting the release of newly formed membrane-bound structures (NLP-Nox associates) and regulating the steady-state concentration of O₂⁻.Behavioral tests further confirmed the effectiveness of BM, with animal behavior parameters in the high-concentration group closely resembling those of the control group. It was found that different BM concentrations possess different antioxidant activity: specific activity at 4.5 mg/ml concentration amounted to 1.2 U/mg, while at 9 mg/ml it was 2.9 U/mg.

Conclusions: The results demonstrate BM's potential as both an antioxidant and membrane-stabilizing agent for PD treatment. The study revealed a concentration-dependent effect of BM's antioxidant activity in the PD model, with 9 mg/mL showing superior efficacy. Further research and clinical trials are warranted to validate its therapeutic efficacy.

Clinical trial number: Not applicable.

Background: Anaplastic thyroid cancer (ATC) is an extremely aggressive subtype of thyroid cancer associated with poor prognosis. Thus, the necessity to develop innovative treatment approaches is critical. Lenvatinib is the one of the drugs approved for ATC in clinic, however, its efficacy is limited. The present study investigated the combined effect of ultrasound stimulated microbubble cavitation (USMC) and Lenvatinib on tumor growth.

Methods: Undifferentiated thyroid carcinoma C643 cells were subcutaneously inoculated into mice to establish transplanted tumor model and mice were allocated into 4 groups (model group, Lenvatinib group, USMC group, and Lenvatinib + USMC group). Blood perfusion in tumors was estimated with contrast-enhanced ultrasound (CEUS) and the microvascular structures were observed by transmission electron microscopy. H&E and Masson staining was applied. Immunohistochemical staining for CD31, Ki67, Caspase 3 expression, ELISA for VEGFA, NO, and PGF2 levels, western blot for HIF-1α and Akt/PI3K proteins, and immunofluorescence for VEGFA and ICAM-1.

Results: USMC caused mild enlargement and congestion of tumor microvessels. Moreover, upon exposure to USMC, the area under the curve and peak intensity of CEUS (MI = 0.4) showed an increase, indicating that USMC has the potential to augment blood flow within tumors. The combination of USMC and Lenvatinib meaningfully suppressed tumor growth, induced apoptosis, inhibited Ki67 expression and extended the survival of mice bearing C643 tumor. USMC also improved the anti-angiogenesis effect of Lenvatinib, as demonstrated by decreased expression of collagen fiber, CD31, HIF-1α and VEGFA in tumors and inactivation of PI3K/Akt pathway. Increment in ICAM-1, PGF₂ and NO expression was also observed in the combination group.

Conclusions: These results indicated that the combination of Lenvatinib and USMC could serve as a promising and innovative method for ATC therapy, surpassing the effectiveness of Lenvatinib monotherapy.

Background: The prevalence of substandard and falsified (SF) medicines hinders progresses towards sustainable development goals in providing quality health care. It is posed as major public health threat. Cephalosporin are beta-lactam antibiotics used for treating penicillin resistant infections and are widely prescribed. Three tiered level approach is a quality assessment methodology that consists of visual and physical inspection of labelling, packaging, and inserts of the dosage form and then performing rapid screening and finally carrying out full pharmacopoeial tests.

Objectives: It is aimed at assessing the quality of three cephalosporin medicines marketed in Addis Ababa city, Ethiopia.

Methods: Different cephalosporin products for post market quality survey were collected from different health care systems in Addis Ababa, Ethiopia. Purposive sampling was employed for sample collection using the WHO and National Regulatory Authority (NRA) guidelines. A total of 56 samples (13 cefuroxime axetil tablets, 21 cephalexin capsules, and 22 samples of ceftriaxone powder for injections) were collected. All samples had been subjected to visual inspection, then screening test with GPHF-minilab™ protocol, and later confirmatory physicochemical tests per U.S. Pharmacopoeia monograph (USP 44-NF39) methods. Finally, antimicrobial effectiveness tests were carried out.

Results: All samples had passed visual inspections and screening test with GPHF-minilab™. Twenty-four samples were subjected for further confirmatory tests. All samples complied for the dissolution and assay tests with USP 44-NF39 specifications. However, two samples, each from cephalexin capsule and ceftriaxone powder for injection failed to meet the uniformity of dosage units' test. Cephalexin capsule and cefuroxime axetil tablets were found to be more active against S. aureus (with zone of inhibition (Z.O.I.) as 28.7 mm and 32.1 mm, respectively), while ceftriaxone was found to be most effective against P. mirabilis (Z.O.I. as 33.39 mm). For antimicrobial assays, 24 (samples) multiplied by 5 (microorganism types) with total amount of 120 antibiograms were generated. Eighty-five (85) were found to be sensitive, 15 intermediate and 20 resistants.

Conclusion: The tested medicinal products were of good quality. However, there are differences in the antimicrobial activity effectiveness results against tested bacterial strains. It implies that resistance to Cephalosprins' is emerging in the study area.