Acta Pharmaceutica最新文献

In the present study the interaction of cannabinoid, PhAR-DBH-Me [(R, Z)-18-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-ylphenyl-acetate] and tramadol in two neuropathy models, as well as their possible toxic effects, was analyzed. The anti-allodynic effect of PhAR-DBH-Me, tramadol, or their combination, were evaluated in neuropathic rats. Furthermore, the effective dose 35 (as the 35 % of the anti allodynic effect) was calculated from the maximum effect of each drug. Moreover, the isobolographic analysis was performed to determine the type of interaction between the drugs. A plasma acute toxicity study was carried out to assess the hepatic, renal, and heart functions after an individual or combined administration of the drugs, as well as histology using the hematoxylin-eosin or Masson-trichome method. PhAR-DBH-Me, tramadol, and their combination produced an antiallodynic effect on spinal nerve ligation (SNL) and cisplatin-induced neuropathic pain in rats. Moreover, PhAR-DBH-Me and tramadol combination showed a synergistic interaction in neuropathic pain rats induced by SNL but not for cisplatin-induced neuropathy. On the other hand, changes in renal and hepatic functions were not observed. Likewise, analysis of liver, kidney and heart histology showed no alterations compared with controls. Results show that the combination of PhAR-DBH-Me and tramadol attenuates the allodynia in SNL rats; the acute toxicology analysis suggests that this combination could be considered safe in administered doses.

In this study Ginkgo biloba leaves (GBL) decoction and commercial capsules were digested using an in vitro model. Thirty-six active compounds were identified and quantified by HPLC-ESI-MS analysis based on the MS/MS patterns (precursor ions and product ions) and retention times, in comparison with reference standards. Most compounds in GBL showed a significant decrease during intestinal digestion, with an exception of vanillic acid and biflavonoids. Bioaccessibility values of chemical compositions varied between decoction and capsules samples. Also, significant reductions of total flavonoids and total phenolic content was observed after in vitro digestion. Both, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazo-line-6-sulfonic acid (ABTS) scavenging capacity decreased after gastric digestion, but increased during intestinal digestion. Nevertheless, different behaviour was observed in reducing antioxidant power (FRAP) assay. Compared to the pH of digestion, the influence of digestive enzymes on the chemical composition and antioxidant activity of GBL was relatively minor. Overall, these results may help provide a valid foundation for further investigations on bioactive compounds and the pharmacodynamics of GBL.

MicroRNA-140-5p (miR-140-5p) plays a pivotal role in human cancers. However, its role and molecular mechanisms in breast carcinoma are not fully explored. Using miR-140-5p transfected breast cancer cell line MDA-MB-231, several in vitro experiments were performed and described in this paper. They consist of the cell proliferation assay, wound healing assay, transwell assay, colony formation assays and qRTPCR. Expression levels of target proteins were determined using Western blotting. In addition, experiments on animal models were performed to study the possible role of miR-140-5p in tumorigenesis of breast carcinoma cells. The induction of experimental breast tumor in mice model was achieved through the incorporation of MDA-MB-231 tumor cells subcutaneously into the middle left side of the mice. The results showed that miR-140-5p up-regulation significantly suppresses proliferation, cellular invasion and migration of breast carcinoma cells. Furthermore, miR-140-5p up-regulation stops breast cancer cells at G0/G1 phase. The results of the animal model indicated that up-regulation of miR-140-5p suppresses its tumorigenic ability. Moreover, we also found that miR-140-5p up-regulation reduces the phosphorylation level of STAT3, p65, and AKT. In addition, miR-140-5p overexpression significantly decreases CDK2 expression while increasing E-cadherin expression level. These data revealed that miR-140-5p suppressed tumor progression of breast carcinoma cells through inhibition of the AKT/STAT3/NF-κB pathway. Taken the present study results together, we can conclude that miR-140-5p may act as a novel target in microRNA-targeting anticancer strategy for the treatment of breast cancer.

¹⁷⁷Lu-EDTMP (Ethylenediamine tetramethylene phosphonic acid) is the most used radioactive agent for pain palliation in bone cancer patients. The present study aims to study the impact of relaxin-2 on the ¹⁷⁷Lu-EDTMP associated cell toxicity and death in osteosarcoma cells. MG63 and Saos-2 cells were cultured with ¹⁷⁷Lu-EDTMP (37 MBq) for 24 h with and without pretreatment of recombinant relaxin 2 (RLXH2) for 12 and 24 h. ¹⁷⁷Lu-EDTMP associated cellular deterioration and death was determined by LDH, MTT, and trypan blue dye assays. ELISA-based kit was used to determine apoptotic DNA fragmentation. Western blotting was used to determine expression levels of apoptotic-related signalling pathway proteins like bcl2, poly(ADP-ribose) polymerase (PARP), and MAPK (mitogen-activated protein kinase). Our results found that RLXH2 counters ¹⁷⁷Lu-EDTMP associated cellular toxicity. Similarly, RLXH2 was able to counter ¹⁷⁷Lu-EDTMP induced cell death in a concentration and time--dependent manner. Furthermore, it was found that RLXH2 treatment prevents apoptosis in ¹⁷⁷Lu-EDTMP challenged cells through activation of the notch-1 pathway in a concentration- and time-dependent manner. We reported that RLXH2 significantly declined cellular toxicity and apoptosis associated with ¹⁷⁷Lu-EDTMP in MG63 and Saos-2 cells through the notch-1 pathway.

Direct oral anticoagulants (DOACs) represent a new generation of drugs that have been increasingly used in the prevention and treatment of thromboembolic states. According to the mechanism of anticoagulant action, DOACs are divided into two groups: direct inhibitors of thrombin (dabigatran) and direct inhibitors of activated factor X (FXa) (rivaroxaban, apixaban, edoxaban, betrixaban). Compared to the vitamin K antagonists, DOACs are superior in terms of onset of action, pharmacokinetic and pharmacodynamics properties and fixed daily dose without the need for routine coagulation monitoring. Despite these advantages, there are clinical conditions in which laboratory measurement of DOACs should be performed. Although DOACs have an impact on screening haemostasis assays (prothrombin time, PT; activated partial thromboplastin time, aPTT; and thrombin time, TT), these tests are not appropriate for quantifying drug levels. Therefore, specific quantitative methods (LC-MS/MS as a gold standard method for all DOACs, coagulometric and chromogenic assays for dabigatran, and chromogenic anti-Xa assays with drug-specific calibrators for inhibitors of FXa) should only be used for determination of DOACs concentration. The aim of this review is to present all aspects of laboratory assessment of DOACs, including pre-analytical, analytical and post-analytical factors in the overall testing process with a special accent on the available specific quantitative methods for measurement of DOACs in circulation.

Allergic asthma is an inflammatory disease of the airways which has a complex etiology. Punicalagin, a major polyphenol present in pomegranates, is reported to possess various biological properties including antioxidant and antiproliferative effects. The current research aimed to evaluate the antiasthmatic effects of punicalagin in an ovalbumin (OVA)-induced experimental model of asthma in female BALB/c mice. Treatment group animals received punicalagin (12.5, 25 or 50 mg kg^-1 body mass) per day for 21 days from day 1 of OVA injection. Dexamethasone (DEX) was administered to a separate group of mice, as the standard drug control. Inflammatory cell infiltration into the broncho-alveolar lavage fluid (BALF) was substantially decreased in punicalagin-treated mice. Punicalagin reduced Th2-derived cytokines and OVA-specific IgE levels. The IL-4/STAT6 and Notch/GATA3 signalling pathways were regulated on punicalagin administration. The data obtained illustrate the potency of punicalagin as an anti-asthmatic drug. Conclusively, the study's observations suggest the potential therapeutic efficiency of punicalagin in allergic asthma.

Fluconazole (FLZ) is the most widely used antifungal agent for treating cutaneous candidiasis. Although oral FLZ has been proved to be effective, the incidence of side effects necessitates the development of an effective formulation that could surpass the pitfalls associated with systemic availability. Accordingly, this research aimed at developing a self-assembled mixed micelles topical delivery system to enhance the topical delivery of the drug. Self-assembled mixed micelles were developed using D-α-tocopheryl polyethylene glycol 1000 succinate and phospholipids and optimized using Box-Behnken design. The optimized formulation with minimized size was then tested in vivo for the antifungal activity against C. albicans in immunocompromised mice. Treatment with the optimized formulation led to decreased peripheral erythema as well as lesions due to fungal infection in comparison to raw FLZ loaded gel. Therefore, the developed formulation was found to be a promising vehicle for the treatment of cutaneous candidiasis.

The COVID-19 pandemic is ongoing and the benefit from vaccines is still insufficient since COVID-19 continues to be dia g-nosed in vaccinated individuals. It is, therefore, necessary to propose specific pharmacological treatments against COVID-19. A new therapeutic target on the human cellular membrane is AXL (anexelekto), proposed as an independent pathway by which interaction with the S protein of SARS-CoV-2 allows the virus to enter the cell, without the participation of ACE2. AXL serves as another gate through which SARS-CoV-2 can enter cells. Therefore, any stage of COVID-19 could be ameliorated by hindering the interaction between AXL and SARS-CoV-2. This study proposes ten compounds (1-10), selected by mole-cu lar docking and using a library of nearly 500,000 compounds, to develop a new drug that will decrease the interaction of AXL with the S protein of SARS-CoV-2. These compounds have a specific potential site of interaction with AXL, between Glu59, His61, Glu70 and Ser74 amino acids. This site is necessary for the interaction of AXL with the S protein. With this, we propose to develop a new adjuvant treatment against COVID-19.

To reveal the mechanism of anti-renal fibrosis effects of an n-butanol extract from Amygdalus mongolica, renal fibrosis was induced with unilateral ureteral obstruction (UUO) and then treated with an n-butanol extract (BUT) from Amygdalus mongolica (Rosaceae). Sixty male Sprague-Dawley rats were randomly divided into the sham-operated, renal fibrosis (RF) model, benazepril hydrochloride-treated model (1.5 mg kg^-1) and BUT-treated (1.75, 1.5 and 1.25 g kg^-1) groups and the respective drugs were administered intragastrically for 21 days. Related biochemical indices in rat serum were determined and histopathological morphology observed. Serum metabolomics was assessed with HPLC-Q-TOF-MS. The BUT reduced levels of blood urea nitrogen, serum creatinine and albumin and lowered the content of malondialdehyde and hydroxyproline in tissues. The activity of superoxide dismutase in tissues was increased and an improvement in the severity of RF was observed. Sixteen possible biomarkers were identified by metabolomic analysis and six key metabolic pathways, including the TCA cycle and tyrosine metabolism, were analyzed. After treatment with the extract, 8, 12 and 9 possible biomarkers could be detected in the high-, medium- and low-dose groups, respectively. Key biomarkers of RF, identified using metabolomics, were most affected by the medium dose. A. mongolica BUT extract displays a protective effect on RF in rats and should be investigated as a candidate drug for the treatment of the disease.