Naunyn-Schmiedeberg's archives of pharmacology最新文献

The greatest challenges that organisms face today are effective responses or detection of life-threatening environmental changes due to an obvious semblance of stress and metabolic fluctuations. These are associated with different pathological conditions among which cancer is most important. Sirtuins (SIRTs; NAD⁺-dependent enzymes) are versatile enzymes with diverse substrate preferences, cellular locations, crucial for cellular processes and pathological conditions. This article describes in detail the distinct roles of SIRT isoforms, unveiling their potential as either cancer promoters or suppressors and also explores how both natural and synthetic compounds influence the SIRT function, indicating promise for therapeutic applications. We also discussed the inhibitors/activators tailored to specific SIRTs, holding potential for diseases lacking effective treatments. It may uncover the lesser-studied SIRT isoforms (e.g., SIRT6, SIRT7) and their unique functions. This article also offers a comprehensive overview of SIRTs, linking them to a spectrum of diseases and highlighting their potential for targeted therapies, combination approaches, disease management, and personalized medicine. We aim to contribute to a transformative era in healthcare and innovative treatments by unraveling the intricate functions of SIRTs.

Oral lichen planus (OLP) is a carcinogenic chronic inflammatory oral disease, which lacks effective treatments. Fraxin is an active ingredient of the traditional Chinese medicine Qin Pi, which has an anti-inflammatory effect, but its effect on OLP is unclear. The aim of this study was to investigate the therapeutic effect of fraxin on OLP and the underlying mechanism. Human immortalized keratinocytes (HaCat) were incubated with fraxin (10, 20, or 40 µM) for 48 h and then treated with 10 µg/mL LPS for 24 h. Cell viability and apoptosis were detected. Next, the interaction between OCT3 and FGF2 was predicted by online database and verified by Co-IP analysis. Fraxin, Ad-OCT3, sh-OCT3, and sh-FGF2 were, respectively, applied to treat LPS-incubated HaCat cells, and cell viability, apoptosis, and secretion of inflammatory factors were detected with MTT, flow cytometry, and ELISA assays. Then, the involvement of OCT3 and FGF2 in the prevention of fraxin on HaCat cells from LPS-induced cell apoptosis and inflammation was investigated through multiple rescue experiments. In addition, OLP models were constructed in VDR^-/- mice and NOD/SCID mice by injecting with human OLP pathological tissue homogenates to verify the therapeutic effect of fraxin on OLP. Fraxin treatment increased cell viability and reduced cell apoptosis and the secretion of IL-6 and TNF-α in a dose-dependent manner. OCT3 was significantly upregulated in oral mucosa tissues of OLP mice. OCT3 silencing inhibited LPS-induced cell apoptosis and secretion of inflammatory factors. Fraxin incubation reduced the expression of OCT3, and OCT3 interacted with FGF2 to upregulate FGF2 protein. FGF2 silencing reduced the expression of p-p65/NF-κB protein and improved LPS-induced cell apoptosis and secretion of inflammatory factors. OCT3 overexpression increased the expression of FGF2 and p-p65/NF-κB proteins, rh-FGF2 aggravated this effect, while FGF2-Neu-Ab reversed this effect. The results of in vivo experiments showed that fraxin alleviated cell apoptosis and inflammation in oral buccal mucosa tissues of OLP mice. Fraxin inhibited cell apoptosis and inflammation by suppressing OCT3-mediated activation of the FGF2/NF-κB pathway, alleviating the progression of OLP.

Eight Novel chalcones were synthesized and their structures were confirmed by different spectral tools. All the prepared compounds were subjected to SRB cytotoxic screening against several cancer cell lines. Compound 5c exerted the most promising effect against MCF7 and HEP2 cells with IC₅₀ values of 9.5 and 12 µg/mL, respectively. Real-time PCR demonstrated the inhibitory effect of compound 5c on the expression level of Antigen kiel 67 (KI-67), Survivin, Interleukin-1beta (IL-1B), Interleukin-6 (IL-6), Cyclooxygenase-2 (COX-2) and Protein kinase B (AKT1) genes. Flow-cytometric analysis of the cell cycle indicated that compound 5c stopped the cell cycle at the G0/G1 and G2/M phases in MCF7 and HEP2 treated cells, respectively. ELISA assay showed that Caspase 8, Caspase 9, P53, BAX, and Glutathione (GSH) were extremely activated and Matrix metalloproteinase 2 (MMP2), Matrix metalloproteinase 9 (MMP9), BCL2, Malondialdehyde (MDA), and IL-6 were deactivated in 5c treated MCF7 and HEP2 cells. Wound healing revealed that chalcone 5c reduced the ability to close the scrape wound and decreased the number of migrating MCF7 and HEP2 cells compared to the untreated cells after 48 h. Theoretical molecular modeling against P53 cancer mutant Y220C and Bcl2 showed binding energies of -22.8 and -24.2 Kcal/mole, respectively, which confirmed our ELISA results.

Our study focused on enhancing the production of anthraquinone derivatives in Oldenlandia umbellata using fungal elicitors. Aspergillus niger, Mucor prayagensis, and Trichoderma viride were used to elicit the anthraquinone derivatives in root cultures. The elicitation process led to an increase in the production of phytochemicals and secondary metabolites, with the highest total protein content observed in A. niger-elicited plants. We performed qualitative and quantitative phytochemical screening of the 80% methanol extract of the plants. Using reverse phase-ultra-fast liquid chromatography, we identified and quantified five anthraquinone compounds: aloe-emodin, rhein, emodin, chrysophanol, and alizarin. The in vitro root samples elicited with A. niger and M. prayagensis exhibited four and three anthraquinone derivatives, respectively, whereas those elicited with T. viride showed only two derivatives. Interestingly, chrysophanol content was the highest in A. niger-elicited root samples. We constructed a system pharmacology framework consisting of 40 nodes and 45 edges with 34 interacting genes. We also identified human proteins that interact with these derivatives, and inferred their roles in cancer-associated pathways. These anthraquinone derivatives interact with various proteins in multiple pathways, including apoptosis, human cytomegalovirus infection, proteoglycans in cancer, MAPK signaling, and hepatitis C, highlighting their potential therapeutic applications in cancer treatment.

This study is aimed at evaluating the effect of empagliflozin in preventing atrial fibrillation after coronary artery bypass grafting (CABG). Eighty-two patients who fulfilled the inclusion criteria were allocated to the empagliflozin group (n = 43) or placebo group (n = 39). In two groups, patients received empagliflozin or placebo tablets 3 days before surgery and on the first three postoperative days (for 6 days) in addition to the standard regimen during hospitalization. During the first 3 days after surgery, types of arrhythmias after cardiac surgery, including supraventricular arrhythmias, especially postoperative atrial fibrillation (POAF), ventricular arrhythmias, and heart blocks, were assessed by electrocardiogram monitoring. C-reactive protein (CRP) levels were evaluated pre-operatively and postoperative on the third day. The incidence of POAF in the treatment group was lower compared to the control group; however, this reduction was statistically non-significant (p = 0.09). The frequency of ventricular tachycardia was reduced significantly in the treatment group versus patients in the control (p = 0.02). Also, a significant reduction in the frequency of premature ventricular contractions (PVCs) was seen in the treatment group in comparison with the control group (p = 0.001). After the intervention, CRP levels were significantly less in the empagliflozin group compared to the control group in the third postoperative day (p = 0.04). The prophylactic use of empagliflozin effectively reduced the incidence of ventricular arrhythmia in patients undergoing CABG surgery.

Breast cancer ranks as the most widespread malignant condition in women, emerging as a primary contributor to mortality. The primary challenges in cancer treatments involve undesirable side effects. Therefore, exploring natural compounds as additional therapy could provide valuable insights. Isoliquiritigenin (ILN), an isoflavonoid featuring a chalcone moiety primarily sourced from Glycyrrhiza species, has garnered increasing interest in breast cancer research. This review aims to provide a comprehensive understanding of ILN's mechanisms of action in breast cancer, drawing from a range of in vitro and in vivo studies. ILN primarily acts by inhibiting angiogenesis, aromatase, inflammation, and cell proliferation, and preventing invasion and metastasis. Mechanistically, it downregulates miR-374a, phosphoinositide-3-kinase-protein kinase B/Akt, maternal embryonic leucine zipper kinase, vascular endothelial growth factor, and estrogen receptor protein levels, and causes enhancement of Wnt inhibitory factor-1, and Unc-51-like kinase 1 expression to treat breast cancer. ILN emerges as a promising natural option, offering therapeutic advantages with minimal side effects. However, it is important to note that current research on ILN is primarily limited to preclinical models, underscoring the need for further investigation to validate its potential efficacy.

Atoguanil™ is a novel complex of atovaquone (ATV) and proguanil (PG) with enhanced ATV bioavailability compared to Malarone®. This pilot study assessed whether the relative bioavailability (F_rel) of ATV, PG, and the primary PG metabolite cycloguanil (CG) following a single oral dose in the fed state of Atoguanil was similar to Malarone despite a 50% lower ATV dose. This open-label, single-dose, randomized 2-period, 2-treatment, balanced crossover study was conducted between 17th November 2021 and 18th March 2022. Eligible participants (aged 18-55 years) were randomized (1:1) in period 1 to Atoguanil (ATV/PG 500/348 mg) or Malarone (ATV/PG hydrochloride 1000/400 mg) administered following a high-fat, high caloric meal. After a 24-day washout period, participants crossed treatment arms. For the doses tested, F_rel was assumed similar if 90%CIs were between 80 and 125% for the geometric mean ratio of the least square mean differences for each exposure parameter. In 15 evaluable participants, F_rel was similar for ATV C_max (93.6% [90%CI 83.6, 104.9]) but not AUC_0-inf (77.8% [67.4, 89.8]), for PG AUC_0-inf (95.6% [92.1, 99.2]) but not C_max (82.4% [75.8, 89.5]), and for both CG C_max (100.8% [95.0, 107.0]) and AUC_0-inf (102.9% [98.4, 107.7]). Nine adverse events occurred; all were of mild severity and not considered treatment related. At the doses tested, ATV F_rel was lower following Atoguanil versus Malarone based on AUC_0-inf, though when adjusted for dose F_rel increased by 156%. Both drugs were well tolerated with no safety concerns. ClinicalTrials.gov: NCT04866602 (April 26th, 2021).

Up to date, digitalis glycosides, also known as "cardiac glycosides", are inhibitors of the Na⁺/K⁺-ATPase. They have a long-standing history as drugs used in patients suffering from heart failure and atrial fibrillation despite their well-known narrow therapeutic range and the intensive discussions on their raison d'être for these indications. This article will review the history and key findings in basic and clinical research as well as potentially overseen pros and cons of these drugs.

There is a substantial body of scientific literature on the use of third-party services (TPS) by academics to assist as "publication consultants" in scholarly publishing. TPS provide a wide range of scholarly services to research teams that lack the equipment, skills, motivation, or time to produce a paper without external assistance. While services such as language editing, statistical support, or graphic design are common and often legitimate, some TPS also provide illegitimate services and send unsolicited e-mails (spam) to academics offering these services. Such illegitimate types of TPS have the potential to threaten the integrity of the peer-reviewed scientific literature. In extreme cases, for-profit agencies known as "paper mills" even offer fake scientific publications or authorship slots for sale. The use of such illegitimate services as well as the failure to acknowledge their use is an ethical violation in academic publishing, while the failure to declare support for a TPS can be considered a form of contract fraud. We discuss some literature on TPS, highlight services currently offered by ten of the largest commercial publishers and expect authors to be transparent about the use of these services in their publications. From an ethical/moral (i.e., non-commercial) point of view, it is the responsibility of editors, journals, and publishers, and it should be in their best interest to ensure that illegitimate TPS are identified and prohibited, while publisher-employed TPS should be properly disclosed in their publications.

A chronic inflammatory condition of the colon called ulcerative colitis (UC) is characterized by mucosal surface irritation that extends from the rectum to the near proximal colon portions. The rationale of this work was to conclude if dulaglutide (Dula) could protect rats from developing colitis caused by exposure to acetic acid (AA). Rats were randomly divided into seven groups (each with eight rats): Normal control, Dula control, AA (received 2 milliliters of 3% v/v AA through the rectum), Sulfasalazine (SLZ); given SLZ (100 mg/kg) orally from day 11 to day 21 then AA intrarectally on day 22 and Dula groups ( pretreated with 50, 100 or 150 μg/kg subcutaneous injection of Dula - once weekly for three weeks and AA on day 22 to induce ulcerative colitis, colon tissues and blood samples were taken on day 23. By generating colonic histological deviations such as inflammatory processes, goblet cell death, glandular hyperplasia, and mucosa ulcers, Dula dropped AA-induced colitis. Additionally, these modifications diminished blood lactate dehydrogenase (LDH), C-reactive protein (CRP), colon weight, and the weight/length ratio of the colon. In addition, Dula decreased the oxidative stress biomarker malondialdehyde (MDA) and increased the antioxidant enzymes (total antioxidant capacity (TAC), reduced glutathione (GSH), and superoxide dismutase (SOD) concentrations). Dula also significantly reduced the expression of transforming growth factor-1 (TGF-β1), phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT) signaling pathway, and the inflammatory cytokines: nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and interferon-γ (IFN-γ) in colonic cellular structures. In addition, Dula enforced the levels of glucagon-like peptide-1 (GLP-1) and trefoil factor-3 (TFF-3) that were crucial to intestinal mucosa regeneration and healing of wounds. By modulating TGF-β1 in conjunction with other inflammatory pathways like PI3K/AKT and NF-κB, regulating the oxidant/antioxidant balance, and improving the integrity of the intestinal barrier, Dula prevented AA-induced colitis in rats.