Naunyn-schmiedebergs Archives of Pharmacology最新文献

Trained immunity of monocytes, endothelial, and smooth muscle cells augments the cytokine response to secondary stimuli. Immune training is characterized by stabilization of hypoxia-inducible factor (HIF)-1α, mTOR activation, and aerobic glycolysis. Cardiac fibroblast (CF)-myofibroblast transition upon myocardial ischemia/reperfusion (I/R) features epigenetic and metabolic adaptations reminiscent of trained immunity. We assessed the impact of I/R on characteristics of immune training in human CF and mouse myocardium. I/R was simulated in vitro with transient metabolic inhibition. CF primed with simulated I/R or control buffer were 5 days later re-stimulated with Pam3CSK for 24 h. Mice underwent transient left anterior descending artery occlusion or sham operation with reperfusion for up to 5 days. HIF-regulated metabolic targets and cytokines were assessed by qPCR, immunoblot, and ELISA and glucose consumption, lactate release, and lactate dehydrogenase (LDH) by chromogenic assay. Simulated I/R increased HIF-1α stabilization, mTOR phosphorylation, glucose consumption, lactate production, and transcription of PFKB3 and F2RL3, a HIF-regulated target gene, in human CF. PGK1 and LDH mRNAs were suppressed. Intracellular LDH transiently increased after simulated I/R, and extracellular LDH showed sustained elevation. I/R priming increased abundance of pro-caspase-1, auto-cleaved active caspase-1, and the expression and secretion of interleukin (IL)-1β, but did not augment Pam3CSK-stimulated cytokine transcription or secretion. Myocardial I/R in vivo increased abundance of HIF-1 and the precursor and cleaved forms of caspase-1, caspase-11, and caspase-8, but not of LDH-A or phospho-mTOR. I/R partially reproduces features of immune training in human CF, specifically HIF-1α stabilization, aerobic glycolysis, mTOR phosphorylation, and PFKB3 transcription. I/R does not augment PGK1 or LDH expression or the cytokine response to Pam3CSK. Regulation of PAR4 and inflammasome caspases likely occurs independently of an immune training repertoire.

Graphical Abstract

Ischemia provokes only part of the immune training repertoire in cardiac fibroblasts. Trained immunity in myeloid and non-myeloid cells is triggered by certain infectious and sterile triggers like β-glucan or oxidized LDL, respectively. Key characteristics of immune training are as follows: stabilization of hypoxia-inducible factor (HIF)-1α, mTOR activation, transcriptional induction of lactate dehydrogenase (LDH), phosphoglycerate kinase (PGK)1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), increased glycolysis and lactate production, and enhanced cytokine response to a secondary stimulus such as the toll-like receptor agonist Pam3CSK4. Simulated ischemia/reperfusion (SI/R) reproduces some but not all of these features in human cardiac fibroblasts (CF) as indicated with asterisk (*).

Urinary tract infections (UTIs) are among the most common bacterial infections, posing significant public health challenges due to increasing antimicrobial resistance (AMR). This study aims to assess the prevalence, demographic characteristics, microbial profile, and antimicrobial resistance patterns in Indian patients with UTIs admitted to intensive care unit. A total of 154 patients with positive UTIs were included in this cross-sectional study. The prevalence data including demographics, microbial isolates, and antimicrobial susceptibility patterns were collected. Additionally, risk factors for multidrug resistance uropathogens were assessed using multivariate analyses. The patient cohort had diverse demographic, with a slight male predominance of 52.6% (n = 81). The most common comorbidities were hypertension 59.1% (n = 91) and diabetes mellitus 54.5% (n = 84). The microbial profile was dominated by gram-negative bacteria, particularly Escherichia coli 26.62% (n = 41) and Klebsiella pneumoniae 17.53% (n = 27). The predominant gram-positive and fungal isolate was Enterococcus faecium 7.14% (n = 11) and Candida spp. 18.83% (n = 29), respectively. Substantial resistance was noted against common antimicrobials, with variations across different pathogens. Gram-negative bacteria, particularly Escherichia coli and Klebsiella pneumoniae, exhibited high MDR rates, emphasizing the challenge of antimicrobial resistance. Multivariate logistic regression identified age groups 50–65 and over 65, and prolonged catheterization as significant risk factors for MDR infections. A significantly high resistance rate among pathogens emphasizes the need for judicious antimicrobial use. Our findings emphasize the necessity of ongoing surveillance and tailored interventions based on local pathogen prevalence and antibiogram data to effectively address the threat of AMR threat for better management of UTI management in ICU settings.

As there is lack of research on how drugs are presented in crime literature, we read nearly 25,000 pages of crime literature written between 1890 and 2023 to provide an overview on the pharmacological content in this genre. Correct presentation of pharmacological information decreased over time. Misconceptions about certain substances, especially narcotics and anesthetics appear in many of the analyzed examples. Also, in comparison with crime TV series, books are inferior in providing the reader with additional information and pharmacological plausibility. This especially applies for the newer books which contained less additional information than the older ones. In contrast, some books educate their readers. Newer books show a greater variety of substances also introducing recently developed drugs or new ways of application. On the contrary, older books stick to a small selection of well-known substances during that time, especially metals like arsenic and toxins like strychnine. Gender involvement in poisoning is not realistically presented in the novels. Male victims are overrepresented compared to reality. Also, the etiology is commonly presented incorrectly. Poisoning by accident or for suicidal purposes are rarely presented in the novels, despite their significance in reality. Overall, crime novels educate but also misinform their readers. We discuss the consequences of our findings for the individual reader and public health.

Cisplatin (Cis) is a platinum-based antineoplastic drug used in various types of cancers. This drug can induce nephrotoxicity as a cause of acute kidney injury (AKI) by inducing oxidative stress and inflammation. Empagliflozin (Empa) is a newly developed inhibitor of sodium-glucose cotransporter-2 (SGLT2) approved as an antidiabetic medication for patients with type 2 diabetes mellitus. In addition to its blood glucose-lowering effect, Empa has been shown to exert anti-inflammatory and anti-oxidant properties. The current study aimed to investigate the protective effects of Empa on Cis-induced nephrotoxicity in rats. Male Wistar albino rats were divided into five groups, each of six rats: Sham group (received vehicle for 7 days), Control group (received vehicle for 7 days and Cis injection on day 2), Cis + Empa10 (received 10mg/kg Empa for 7 days and Cis injection on day 2), Cis + Empa30 (received 30mg/kg Empa for 7 days and Cis injection on day 2) and, Empa 30 (received 30mg/kg Empa for 7 days). One day after the last injection in each group, rats were weighed and then sacrificed to analyze the hematological, biochemical, and histological parameters. Cis markedly increased levels of inflammatory parameters such as renal tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and myeloperoxidase (MPO) activity. Notably, malondialdehyde (MDA), blood urea nitrogen (BUN), and creatinine levels were enhanced after Cis administration. Also, the chemotherapeutic agent significantly reduced antioxidant indicators such as renal catalase (CAT), glutathione peroxidase (GpX), and superoxide dismutase (SOD). Furthermore, histopathological examinations also revealed severe renal damage following Cis treatment which was improved by Empa administration. Empa treatment at both doses (10 mg/kg and 30 mg/kg) reversed Cis-induced changes in all the above renal parameters. In conclusion, Empa has protective effects on Cis-induced nephrotoxicity by inhibition of oxidative stress and inflammation.

Ischemia/reperfusion injury (IRI) is a key determining agent in the pathophysiology of clinical organ dysfunction. It is characterized by an aseptic local inflammatory reaction due to a decrease in blood supply, hence deprivation of dependent oxygen and nutrients. In instances of liver transplantation, this injury may have irreversible implications, resulting in eventual organ rejection. The deterioration associated with IRI is affected by the hepatic health status and various factors such as alterations in metabolism, oxidative stress, and pro-inflammatory cytokines. The primary cause of inflammation is the initial immune response of pro-inflammatory cytokines, while Kupffer cells (KFCs) and neutrophil-produced chemokines also play a significant role. Upon reperfusion, the activation of inflammatory responses can elicit further cellular damage and organ dysfunction. This review discusses the interplay between chemokines, pro-inflammatory cytokines, and other inflammatory mediators that contribute to the damage to hepatocytes and liver failure in rats following IR. Furthermore, it delves into the impact of anti-inflammatory therapies in safeguarding against liver failure and hepatocellular damage in rats following IR. This review investigates the correlation between cytokine factors and liver dysfunction via examining databases, such as PubMed, Google Scholar, Science Direct, Egyptian Knowledge Bank (EKB), and Research Gate.

Graphical Abstract

The abstract diagram illustrates the pro-inflammatory cytokines and NF-κB as primary target therapies for cytoprotecting activity versus ischemia/reperfusion injury of the liver.

Inflammation-induced osteoclast proliferation is a crucial contributor to impaired bone metabolism. Kurarinone (KR), a flavonoid extracted from the Radix Sophorae Flavescentis, exhibits notable anti-inflammatory properties. Nevertheless, the precise influence of KR on osteoclast formation remains unclear. This study’s objective was to assess the impact of KR on osteoclast activity in vitro and unravel its underlying mechanism. Initially, a target network for KR-osteoclastogenesis-osteoporosis was constructed using network pharmacology. Subsequently, the intersecting targets were identified through the Venny platform and a PPI network was created using Cytoscape 3.9.1. Key targets within the network were identified employing topological algorithms. GO enrichment and KEGG pathway analysis were then performed on these targets to explore their specific functions and pathways. Additionally, molecular docking of potential core targets of KR was conducted, and the results were validated through cell experiments. A total of 83 target genes overlapped between KR and osteoclastogenesis-osteoporosis targets. Enrichment analysis revealed their role in inflammatory response, protein tyrosine kinase activity, osteoclast differentiation, and MAPK and NF-κB signaling pathways. PPI analysis and molecular docking demonstrate that key targets MAPK14 and MAPK8 exhibit more stable binding with KR compared to other proteins. In vitro experiments demonstrate that KR effectively inhibits osteoclast differentiation and bone resorption without cellular toxicity. It suppresses key osteoclast genes (NFATc1, c-Fos, TRAP, MMP9, Ctsk, Atp6v2), hinders IκB-α degradation, and inhibits ERK and JNK phosphorylation, while not affecting p38 phosphorylation. The results indicate that KR may inhibit osteoclast maturation and bone resorption by blocking NF-κB and MAPK signaling pathways, suggesting its potential as a natural therapeutic agent for osteoporosis.

Latuda^® is a novel antipsychotic drug for schizophrenia and bipolar depression. A bioequivalence trial was performed to investigate the bioequivalence of Latuda^® and its generic drug lurasidone. Two independent trials were carried out, each involving 28 subjects. In the fasting trial, subjects were randomly assigned to two groups (1:1 ratio), receiving either 40 mg of generic lurasidone or Latuda^®. After a 7-day washout period, subjects entered the second period with a crossover administration of 40 mg of generic lurasidone or Latuda^®. The postprandial study design was similar to that of the fasting study. In the fasting study, the pharmacokinetic (PK) parameter values of generic lurasidone and Latuda^® were as follows: the C_max was 28.84 ± 19.34 ng/ml and 28.22 ± 21.19 ng/ml, respectively; the AUC_0-t was 121.39 ± 58.47 h*ng/ml and 118.35 ± 52.24 h*ng/ml, respectively; and the AUC_0-∞ was 129.63 ± 63.26 h*ng/ml and 126.59 ± 57.99 h*ng/ml, respectively. The primary pharmacokinetic parameter, C_max, was assessed for equivalence using reference-scaled average bioequivalence (RSABE), while other parameters (AUC_0-t, AUC_0-∞) were evaluated using average bioequivalence (ABE). The results indicate that both C_max and AUC meet the equivalence criteria. In the postprandial study, the PK values of generic lurasidone and Latuda^® were as follows: the C_max was 74.89 ± 32.06 ng/ml and 83.51 ± 33.52 ng/ml, respectively; the AUC_0-t was 274.77 ± 103.05 h*ng/ml and 289.26 ± 95.25 h*ng/ml, respectively; and the AUC_0-∞ was 302.44 ± 121.60 h*ng/ml and 316.32 ± 109.04 h*ng/ml, respectively. The primary pharmacokinetic parameters (C_max, AUC_0-t, AUC_0-∞) were assessed for equivalence using ABE, and both met the equivalence criteria. In the study, lurasidone and Latuda^® both exhibited acceptable safety and tolerability. The results displayed that lurasidone and Latuda^® were bioequivalent and safe in healthy Chinese participants. Clinical Trial Registry: This trial is registered at chinadrugtrials.org.cn (no.: CTR20191717, date: 2019.08.29).

Estrone (E1) constitutes the primary component in oral conjugated equine estrogens (CEEs) and serves as the principal estrogen precursor in the female circulation in the post-menopause. E1 induces endothelium-dependent vasodilation and activate PI3K/NO/cGMP signaling. To assess whether E1 mitigates vascular dysfunction associated with postmenopause and explore the underlying mechanisms, we examined the vascular effects of E1 in ovariectomized (OVX) rats, a postmenopausal experimental model. Blood pressure was measured using tail-cuff plethysmography, and aortic rings were isolated to assess responses to phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Responses to ACh in rings pre-incubated with superoxide dismutase (SOD), catalase (CAT), or apocynin were also evaluated. Protein expression of SOD, CAT, NOX1, NOX2, and NOX4 was determined by Western blotting. E1 treatment resulted in decreased body weight and retroperitoneal fat, increased uterine weight, and prevented elevated blood pressure in the OVX group. Furthermore, E1 improved endothelium-dependent ACh vasodilation, activated compensatory antioxidant mechanisms – i.e. increased SOD and CAT antioxidant enzymes activity, and decreased NOX4 expression. This, in turn, helped prevent oxidative stress and endothelial dysfunction in OVX rats. Additionally, E1 treatment reversed the increased total LDL cholesterol observed in the OVX group. The findings underscore protective effects of E1 on the cardiovascular system, counteracting OVX-related oxidative stress and endothelial dysfunction in Wistar rats. E1 exhibits promising therapeutic benefits for managing cardiovascular health, particularly in postmenopausal conditions.

Accumulating evidence has demonstrated that M1 microglial polarization and neuroinflammation worsen the development of neuropathic pain. However, the mechanisms underlying microglial activation during neuropathic pain remain incompletely understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), which is a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, plays a crucial role in the regulation of microglial polarization. However, the effect of Mer on microglial polarization during neuropathic pain has not been determined. In this study, western blotting, immunofluorescence analysis, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA) were used to examine the role of Mer in pain hypersensitivity and microglial polarization in rats with chronic constriction injury (CCI) of the sciatic nerve. The results indicated that Mer expression in microglia was prominently increased in the spinal cords of rats subjected to CCI. Furthermore, treatment with recombinant protein S (PS, an activator of Mer) alleviated mechanical allodynia and thermal hyperalgesia, promoted the switch in microglia from the M1 phenotype to the M2 phenotype, and ameliorated neuroinflammation in rats subjected to CCI. However, the use of suppressor of cytokine signalling 3 (SOCS3) siRNA abolished these changes. These results indicated that Mer regulated M1/M2 microglial polarization and neuroinflammation and may be a potential target for treating neuropathic pain.

Diabetes’s effects on wound healing present a major treatment challenge and increase the risk of amputation. When traditional therapies fail, new approaches must be investigated. With their submicron size and improved cellular internalisation, nanoparticles present a viable way to improve diabetic wound healing. They are attractive options because of their innate antibacterial qualities, biocompatibility, and biodegradability. Nanoparticles loaded with organic or inorganic compounds, or embedded in biomimetic matrices such as hydrogels, chitosan, and hyaluronic acid, exhibit excellent anti-inflammatory, antibacterial, and antioxidant properties. Drug delivery systems (DDSs)—more precisely, nanodrug delivery systems (NDDSs)—use the advantages of nanotechnology to get around some of the drawbacks of traditional DDSs. Recent developments show how expertly designed nanocarriers can carry a variety of chemicals, transforming the treatment of diabetic wounds. Biomaterials that deliver customised medications to the wound microenvironment demonstrate potential. Delivery techniques for nanomedicines become more potent than ever, overcoming conventional constraints. Therapeutics for diabetes-induced non-healing wounds are entering a revolutionary era thanks to precisely calibrated nanocarriers that effectively distribute chemicals. This review highlights the therapeutic potential of nanoparticles and outlines the multifunctional nanoparticles of the future that will be used for complete wound healing in diabetics. The investigation of novel nanodrug delivery systems has the potential to revolutionise diabetic wound therapy and provide hope for more efficient and focused therapeutic approaches.