Naunyn-schmiedebergs Archives of Pharmacology最新文献

Glioblastoma multiforme (GBM) is a highly malignant central nervous system tumor with a poor prognosis. Developing new therapeutic drugs is crucial. This study evaluates deoxyelephantopin (DET), a major component of *Elephantopus scaber* L., for its potential anti-GBM effects. The effects of DET on GBM cell lines were investigated using the MTT assay and Annexin-V kit to assess cell death and apoptosis. Western blot analysis examined apoptosis and cell cycle-related proteins. ELISA kits measured VEGF and TGF-β levels. In vivo, NOD SCID mice were injected with GL-261 cells and treated with DET to evaluate tumor growth and survival. DET inhibited GBM cell growth in a time- and dose-dependent manner. MTT and Annexin-V assays confirmed cell death and apoptosis. Western blot analysis showed DET downregulated Bcl-2 and increased caspase-3, Bax, and cytochrome c levels. ELISA results indicated that DET suppressed VEGF and TGF-β expression. DET treatment also decreased phosphorylation of AKT and STAT-3, CDK4, cyclin D2, MMP2, and MMP9 levels. In vivo, DET significantly inhibited tumor growth and improved survival rates in mice. DET exhibits significant in vitro and in vivo anticancer effects, making it a promising candidate for further research and potential clinical application against GBM.

Psoriasis is a life-long immune-mediated dermatosis with thickened, reddish, and flaky skin patches. Canagliflozin is a gliflozin antidiabetic with non-classical remarkable antioxidative, anti-inflammatory, anti-proliferative, and immune-modulating effects. The aim of this study is to examine the probable effects of topical canagliflozin on a mouse model of imiquimod-provoked psoriasis-like dermatitis. The study evaluated 20 Swiss white mice, sorted haphazardly into 4 groups of 5 animals each. Every mouse, with the exception of the control group, had imiquimod applied topically to their shaved backs for 7 days. The control group included healthy mice that were not given any treatment. Mice in the other three groups underwent topical treatment with vehicle (induction group), 0.05% clobetasol propionate ointment (clobetasol group), or 4% canagliflozin emulgel (canagliflozin 4% group) on exactly the same day as imiquimod cream was administered. Topical canagliflozin markedly lowered the intensity of imiquimod-provoked psoriasis eruptions, featuring redness, glossy-white scales, and acanthosis, while also correcting histopathological aberrations. Canagliflozin administration to imiquimod-exposed animals resulted in significantly decreased cutaneous concentrations of inflammatory mediators such as IL-8, IL-17, IL-23, and TNF-α, with raised levels of IL-10. Canagliflozin further lowered proliferative factors involving Ki-67 and PCNA, diminished oxidative indicators such as MDA and MPO, and augmented the activity of antioxidant markers, notably SOD and CAT. Canagliflozin might alleviate the imiquimod-induced animal model of psoriasis, probably thanks to its profound anti-inflammatory, antioxidant, antiangiogenic, and antiproliferative activities.

Graphic Abstract

The objective of this study was to evaluate the incidence, clinical features, and risk factors of generic tigecycline-associated hypofibrinogenemia. A single-center retrospective study was conducted in adult patients treated with generic tigecycline. Clinical data were extracted from the electronic medical records. The endpoint was tigecycline-related hypofibrinogenemia, defined as a condition with no abnormality in fibrinogen before tigecycline application, but developing hypofibrinogenemia upon prescription. The risk factors were determined by logistic regression analysis, and the ROC curve was subsequently established. A total of 240 adults prescribed generic tigecycline from May 1st to November 30th 2023 were included. It was shown that hypofibrinogenemia is a frequent side effect of generic tigecycline, with an adverse reaction rate of 42.9% (103/240). However, the incidence of adverse reactions to generic drugs was lower than in previous studies. The cumulative dose of tigecycline (OR:1.002, 95%CI 1.001–1.002, P < 0.001), baseline FIB (OR:0.995, 95%CI 0.992–0.997, P < 0.001), baseline PT (OR:1.247, 95%CI 1.071–1.452, P = 0.004) and baseline ALB (OR:0.931, 95%CI 0.879–0.986, P = 0.025) were identified as independent prognostic factors of tigecycline-related hypofibrinogenemia. We recommend intensive monitoring of coagulation function in patients exhibiting the aforementioned risk factors for generic tigecycline-associated hypofibrinogenemia to ensure patients safety.

Postmenopausal osteoporosis is a common chronic medical illness resulting from an imbalance between bone resorption and bone formation along with microarchitecture degeneration attributed to estrogen deficiency and often accompanied by other medical conditions such as weight gain, depression, and insomnia. Semaglutide (SEM) is a recently introduced GLP-1 receptor agonist (GLP-1RA) for the treatment of obesity and type 2 diabetes mellitus by mitigating insulin resistance. It has been discovered that the beneficial effects of GLP-1 are associated with alterations in lipolysis, adipogenesis, and anti-inflammatory processes. GLP-1 analogs transmit signals directly to adipose tissue. Mesenchymal stem cells (MSCs) are multidisciplinary cells that originate from bone marrow, migrate to injury sites, and promote bone regeneration. MSCs can differentiate into osteoblasts, adipose cells, and cartilage cells. Our aim is to investigate the role of semaglutide on bone formation and the Wnt signaling pathway. Osteoporosis was induced in female rats by ovariectomy, and the ovariectomized rats were treated with alendronate as standard treatment with a dose of 3 mg/kg orally and semaglutide with two doses (150 mcg/kg and 300 mcg/kg) S.C. for 10 successive weeks. Semaglutide ameliorates bone detrimental changes induced by ovariectomy. It improves bone microarchitecture and preserves bone mineral content. Semaglutide ameliorates ovariectomy-induced osteoporosis and increases the expression of β-catenin, leading to increased bone formation and halted receptor activator of nuclear factor kappa-Β ligand (RANKL’s) activation. Semaglutide can be used as a potential prophylactic and therapeutic drug against osteoporosis, possibly by activating Wnt signaling and decreasing bone resorption.

Graphical Abstract

Dichlorvos is an organophosphate pesticide that is commonly used for agricultural and domestic control of pests and insects. Despite its usefulness, it exerts reproductive toxicity and induces male sexual dysfunction. On the other hand, curcumin has been reported to improve sexual dysfunction. However, till date, no study has reported the impact of curcumin on dichlorvos-induced sexual dysfunction. This study investigated the effect and associated mechanism of curcumin on dichlorvos-induced sexual dysfunction. Thirty-two male Wistar rats were randomized into four groups; the control (1 mL of olive oil), curcumin-treated (100 mg/kg), DDVP-treated (98.54 g/m³ of dichlorvos by inhalation), and DDVP + Curcumin-treated. Dichlorvos induced sexual dysfunction as depicted by reduced motivation to mate (8.38 ± 0.18 vs. 4.00 ± 0.33, P < 0.0001), prolonged latencies (46.63 ± 1.30 vs. 98.75 ± 1.32, P < 0.0001) and reduced frequencies of mount (14.88 ± 0.52 vs. 8.63 ± 0.38), intromission (9.38 ± 0.50 vs. 3.75 ± 0.31, P < 0.0001), and ejaculation (7.63 ± 0.38 vs. 1.50 ± 0.19, P < 0.0001). These findings were accompanied by suppression of hypothalamic-pituitary–testicular axis, evidenced by marked reductions in circulating FSH (60.00 ± 1.04 vs. 21.13 ± 0.52, P < 0.0001), LH (46.38 ± 1.38 vs. 19.00 ± 0.46, P < 0.0001), and testosterone (6.01 ± 0.50 vs. 0.74 ± 0.05, P < 0.0001). Nonetheless, the administration of curcumin in dichlorvos-exposed rats significantly attenuated dichlorvos-induced sexual dysfunction by improving the assessed indices of male sexual act. Also, curcumin significantly increased serum levels of FSH (21.13 ± 0.52 vs. 47.25 ± 0.10, P < 0.0001), LH (19.00 ± 0.46 vs. 43.00 ± 1.49), and testosterone (0.74 ± 0.05 vs. 3.98 ± 0.08, P < 0.0001). This study revealed that curcumin attenuated dichlorvos-induced sexual dysfunction by activating the hypothalamic-pituitary–testicular axis and upregulating circulating testosterone.

Background

Rosemary (Rosmarinus officinalis) contains alkaloids, phenolic acids, saponins, tannins, diterpenes, flavonoids, and essential oils and has antioxidant, anti-inflammatory, antibacterial, anticancer, neuroprotective, cardioprotective, and hepatoprotective effects. While rosemary is generally considered safe for consumption and topical application, allergic reactions and dermatitis have been reported in some individuals. This paper provides an in-depth review of the current studies on rosemary toxicity, shedding light on its potential adverse effects and underlying mechanisms.

Methods

Google Scholar, PubMed, Scopus, and Web of Science were used to perform extensive research from the inception of these databases until February 2024.

Results

The toxicological effects explored include affecting several organs such as the liver and kidney by causing atrophic and degenerative changes, increasing blood urea nitrogen (BUN), aspartate aminotransferase (AST), and reducing total serum protein levels. Rosemary may induce reproductive toxicity by decreasing spermatogenesis in the testes, testosterone, sperm density, and motility. It might also trigger genotoxicity and anomalies in fetuses by increasing cytoplasmic membrane shrinkage, the formation of apoptotic bodies, internucleosomal deoxyribonucleic acid (DNA) fragmentation, and DNA ladder formation.

Conclusion

While rosemary is considered safe for food preservation, caution is warranted regarding chronic and high doses due to potential adverse effects on the kidneys, liver, reproductive system, and teratology. Additionally, it underscores the significance of considering drug interactions. The article also highlights the importance of considering toxicological data in realistic exposure situations and discusses the relevance of these findings for human health. Hence, further research is recommended to enhance our understanding of the toxicity profile associated with rosemary.

NLX-112 (i.e., F13640, befiradol) exhibits nanomolar affinity, exceptional selectivity and full agonist efficacy at serotonin 5-HT_1A receptors. NLX-112 shows efficacy in rat, marmoset and macaque models of L-DOPA induced dyskinesia (LID) in Parkinson’s disease and has shown clinical efficacy in a Phase 2a proof-of-concept study for this indication. Here we investigated, in rats, its pharmacodynamic, pharmacokinetic (PK) and brain 5-HT_1A receptor occupancy profiles, and its PK properties in the absence and presence of L-DOPA. Total and free NLX-112 exposure in plasma, CSF and striatal ECF was dose-proportional over the range tested (0.04, 0.16 and 0.63 mg/kg i.p.). NLX-112 exposure increased rapidly (T_max 0.25–0.5h) and exhibited approximately threefold longer half-life in brain than in plasma (1.1 and 3.6h, respectively). At a pharmacologically relevant dose of 0.16 mg/kg i.p., previously shown to elicit anti-LID activity in parkinsonian rats, brain concentration of NLX-112 was 51–63 ng/g from 0.15 to 1h. In microPET imaging experiments, NLX-112 showed dose-dependent reduction of ¹⁸F-F13640 (i.e., ¹⁸F-NLX-112) brain 5-HT_1A receptor labeling in cingulate cortex and striatum, regions associated with motor control and mood, with almost complete inhibition of labeling at the dose of 0.63 mg/kg i.p.. Co-administration of L-DOPA (6 mg/kg s.c., a dose used to elicit LID in parkinsonian rats) together with NLX-112 (0.16 mg/kg i.p.) did not modify PK parameters in rat plasma and brain of either NLX-112 or L-DOPA. Here, we demonstrate that NLX-112’s profile is compatible with ‘druggable’ parameters for CNS indications, and the results provide measures of brain concentrations and 5-HT_1A receptor binding parameters relevant to the anti-dyskinetic activity of the compound.

Modern dietary habits and stressed lifestyle have escalated the tendency to develop functional gastrointestinal disorders (FGIDs) through alteration in the gut-brain-microbiome axis. Clinical practices use symptomatic treatments, neglect root causes, and prolong distress in patients. The past decade has seen the evolution of various interventions to attenuate FGIDs. But clinical translation of such studies is very rare mostly due to lack of awareness. The aim of this review is to meticulously integrate different studies and bridge this knowledge gap. Literature between 2013 and 2023 was retrieved from PubMed, ProQuest, and Web of Science. The data was extracted based on the PRISMA guidelines and using the SYRCLE’s risk of bias and the Cochrane Risk of Bias tools, quality assessment was performed. The review has highlighted molecular insights into the coexistence of FGIDs, stress, and gut dysbiosis. Furthermore, novel interventions focusing on diet, probiotics, herbal formulations, and phytoconstituents were explored which mostly had a multitargeted approach for the management of the diseases. Scientific literature implied positive interactions between the interventions and the gut microbiome by increasing the relative abundance of beneficial bacteria and reducing stress-related hormones. Moreover, the interventions reduced intestinal inflammation and regulated the expression of epithelial tight junction proteins in different in vivo models. This systematic review delves deep into the preclinical interventions to manage coexisting FGIDs, stress, and gut dysbiosis. However, in most of the discussed studies, long-term risks and toxicity profile of the interventions are lacking. So, it is necessary to highlight them for improved clinical outcomes.

In 1887, Hermann Tappeiner (1847–1927) was appointed as professor for medicinal chemistry and pharmacology. He studied the role of intestinal bacteria and contributed to better understanding of digestion. In 1923, Walther Straub (1874–1944) succeeded. He was at the zenith of his scientific career, gained habilitation in Leipzig already in 1900, accepted the direction of the Institute of Pharmacology at Marburg in 1905, of Würzburg in 1906, before he moved to Freiburg in 1907. Straub preferred quantitative studies with various alkaloids, cardiac glycosides, and Senna glycosides on isolated organs. One important legacy is his contribution “Die Digitalisgruppe” in Hefters Handb. Exp. Pharmakol. 1924. Walther Straub was editor of Naunyn–Schmiedeberg’s Archives of Pharmacology and founded the Deutsche Pharmakologische Gesellschaft in 1920. In 1944 when most of the institute was destroyed by air raids, Walther Straub retired and succumbed in Bad Tölz. In 1946, August Wilhelm Forst (1890–1981), a pupil of Straub, was appointed to head the institute ruins. We owe to him the provisional reconstruction of the old building, institution of an Insulin Control Laboratory, and the development of a vibratory cage that allowed the registration of psychomotor activity in rodents. Forst published the first comprehensive review on “Detoxication.” In 1961, Manfred Kiese (1910–1983), a pupil of W. Heubner, came from Tübingen and accompanied the erection of a new building. Kiese made important contributions to the understanding of the biotransformation of foreign compounds and was the first to describe the biological N-oxygenation. His studies on ferrihemoglobin formation resulted in the development of an effective cyanide antidote, 4-dimethylaminophenol. “Methemoglobinemia, a Comprehensive Treatise” is part of his scientific legacy. In 1980, Wolfgang Forth (1932–2009) from Bochum headed the institute and convinced the medical faculty of LMU to rename the building into Walther Straub Institute. His scientific interests were centered on interactions between essential and toxic metals during intestinal absorption. He was co-editor of the German Textbook on Pharmacology and Toxicology founded in 1975, which is presently in its 13th edition. In 2000, Peter Eyer (1942) was commissioned to lead the institute until Thomas Gudermann (1960) was appointed to direct the chair in 2008.

Purpose

Diabetes mellitus (DM) and epilepsy and the psychological and socio-economic implications that are associated with their treatments can be quite perplexing. Metformin is an antihyperglycemic medication that is used to treat type 2 DM. In addition, metformin elicits protective actions against multiple diseases, including neurodegeneration and epilepsy. Recent studies indicate that metformin alters the resident gut microbiota in favor of species producing agmatine, an arginine metabolite which, in addition to beneficially altering metabolic pathways, is a potent neuroprotectant and neuromodulant.

Methods

We first examine the literature for epidemiological and clinical evidences linking DM and epilepsy. Next, basing our analyses on published literature, we propose the possible complementarity of agmatine and metformin in the treatment of DM and epilepsy.

Results

Our analyses of the clinical data suggest a significant association between pathogeneses of epilepsy and DM. Further, both agmatine and metformin appear to be multimodal therapeutic agents and have robust antiepileptogenic and antidiabetic properties. Data from animal and clinical studies largely support the use of metformin/agmatine as a double-edged pharmacotherapeutic agent against DM and epilepsy, particularly in their concurrent pathological occurrences.

Conclusion

The present review explores the evidences and available data on possible uses of metformin/agmatine as pertinent antidiabetic and antiepileptic agents. Our hope is that this will stimulate further research on the therapeutic actions of these multimodal agents, particularly for subject-specific clinical outcomes.